ThermoTRP channels and cold sensing: what are they really up to?
Pflugers Archiv : European journal of physiology
Cooling is sensed by peripheral thermoreceptors, the main transduction mechanism of which is probably a cold- and menthol-activated ion channel, transient receptor potential (melastatin)-8 (TRPM8). Stronger cooling also activates another TRP channel, TRP (ankyrin-like)-1, (TRPA1), which has been suggested to underlie cold nociception. This review examines the roles of these two channels and other mechanisms in thermal transduction. TRPM8 is activated directly by gentle cooling and depolarises sensory neurones; its threshold temperature (normally approximately 26-31 degrees C in native neurones) is very flexible and it can adapt to long-term variations in baseline temperature to sensitively detect small temperature changes. This modulation is enabled by TRPM8's low intrinsic thermal sensitivity: it is sensitised to varying degrees by its cellular context. TRPM8 is not the only thermosensitive element in cold receptors and interacts with other ionic currents to shape cold receptor activity. Cold can also cause pain: the transduction mechanism is uncertain, possibly involving TRPM8 in some neurones, but another candidate is TRPA1 which is activated in expression systems by strong cooling. However, native neurones that appear to express TRPA1 respond very slowly to cold, and TRPA1 alone cannot account readily for cold nociceptor activity or cold pain in humans. Other, as yet unknown, mechanisms of cold nociception are likely.
The molecular and cellular basis of cold sensation.
McKemy David D
ACS chemical neuroscience
Of somatosensory modalities, cold is one of the more ambiguous percepts, evoking the pleasant sensation of cooling, the stinging bite of cold pain, and welcome relief from chronic pain. Moreover, unlike the precipitous thermal thresholds for heat activation of thermosensitive afferent neurons, thresholds for cold fibers are across a range of cool to cold temperatures that spans over 30 °C. Until recently, how cold produces this myriad of biological effects has been poorly studied, yet new advances in our understanding of cold mechanisms may portend a better understanding of sensory perception as well as provide novel therapeutic approaches. Chief among these was the identification of a number of ion channels that either serve as the initial detectors of cold as a stimulus in the peripheral nervous system, or are part of rather sophisticated differential expression patterns of channels that conduct electrical signals, thereby endowing select neurons with properties that are amenable to electrical signaling in the cold. This review highlights the current understanding of the channels involved in cold transduction as well as presents a hypothetical model to account for the broad range of cold thermal thresholds and distinct functions of cold fibers in perception, pain, and analgesia.
How cold is it? TRPM8 and TRPA1 in the molecular logic of cold sensation.
McKemy David D
Recognition of temperature is a critical element of sensory perception and allows us to evaluate both our external and internal environments. In vertebrates, the somatosensory system can discriminate discrete changes in ambient temperature, which activate nerve endings of primary afferent fibers. These thermosensitive nerves can be further segregated into those that detect either innocuous or noxious (painful) temperatures; the latter neurons being nociceptors. We now know that thermosensitive afferents express ion channels of the transient receptor potential (TRP) family that respond at distinct temperature thresholds, thus establishing the molecular basis for thermosensation. Much is known of those channels mediating the perception of noxious heat; however, those proposed to be involved in cool to noxious cold sensation, TRPM8 and TRPA1, have only recently been described. The former channel is a receptor for menthol, and links the sensations provided by this and other cooling compounds to temperature perception. While TRPM8 almost certainly performs a critical role in cold signaling, its part in nociception is still at issue. The latter channel, TRPA1, is activated by the pungent ingredients in mustard and cinnamon, but has also been postulated to mediate our perception of noxious cold temperatures. However, a number of conflicting reports have suggested that the role of this channel in cold sensation needs to be confirmed. Thus, the molecular logic for the perception of cold-evoked pain remains enigmatic. This review is intended to summarize our current understanding of these cold thermoreceptors, as well as address the current controversy regarding TRPA1 and cold signaling.
Involvement of thermosensitive TRP channels in energy metabolism.
Uchida Kunitoshi,Dezaki Katsuya,Yoneshiro Takeshi,Watanabe Tatsuo,Yamazaki Jun,Saito Masayuki,Yada Toshihiko,Tominaga Makoto,Iwasaki Yusaku
The journal of physiological sciences : JPS
To date, 11 thermosensitive transient receptor potential (thermo-TRP) channels have been identified. Recent studies have characterized the mechanism of thermosensing by thermo-TRPs and the physiological role of thermo-TRPs in energy metabolism. In this review, we highlight the role of various thermo-TRPs in energy metabolism and hormone secretion. In the pancreas, TRPM2 and other TRPs regulate insulin secretion. TRPV2 expressed in brown adipocytes contributes to differentiation and/or thermogenesis. Sensory nerves that express TRPV1 promote increased energy expenditure by activating sympathetic nerves and adrenaline secretion. Here, we first show that capsaicin-induced adrenaline secretion is completely impaired in TRPV1 knockout mice. The thermogenic effects of TRPV1 agonists are attributable to brown adipose tissue (BAT) activation in mice and humans. Moreover, TRPA1- and TRPM8-expressing sensory nerves also contribute to potentiation of BAT thermogenesis and energy expenditure in mice. Together, thermo-TRPs are promising targets for combating obesity and metabolic disorders.
Transient receptor potential ion channels as participants in thermosensation and thermoregulation.
Caterina Michael J
American journal of physiology. Regulatory, integrative and comparative physiology
Living organisms must evaluate changes in environmental and internal temperatures to mount appropriate physiological and behavioral responses conducive to survival. Classical physiology has provided a wealth of information regarding the specialization of thermosensory functions among subclasses of peripheral sensory neurons and intrinsically thermosensitive neurons within the hypothalamus. However, until recently, the molecular mechanisms by which these cells carry out thermometry have remained poorly understood. The demonstration that certain ion channels of the transient receptor potential (TRP) family can be activated by increases or decreases in ambient temperature, along with the recognition of their heterogeneous expression patterns and heterogeneous temperature sensitivities, has led investigators to evaluate these proteins as candidate endogenous thermosensors. Much of this work has involved one specific channel, TRP vanilloid 1 (TRPV1), which is both a receptor for capsaicin and related pungent vanilloid compounds and a "heat receptor," capable of directly depolarizing neurons in response to temperatures >42 degrees C. Evidence for a contribution of TRPV1 to peripheral thermosensation has come from pharmacological, physiological, and genetic approaches. In contrast, although capsaicin-sensitive mechanisms clearly influence core body temperature regulation, the specific contribution of TRPV1 to this process remains a matter of debate. Besides TRPV1, at least six additional thermally sensitive TRP channels have been identified in mammals, and many of these also appear to participate in thermosensation. Moreover, the identification of invertebrate TRP channels, whose genetic ablation alters thermally driven behaviors, makes it clear that thermosensation represents an evolutionarily conserved role of this ion channel family.
Pharmacokinetics of a multicomponent herbal preparation in healthy Chinese and African volunteers.
Alolga Raphael N,Fan Yong,Zhang Gang,Li Jin,Zhao Yi-Jing,Lelu Kakila Jimmy,Chen Yan,Li Ping,Qi Lian-Wen
K-601 is an herbal formulation for influenza consisting of Lonicera japonica, Isatis indigotica, Rheum palmatum, Phellodendron chinense, and Scutellaria baicalensis. In this work, we characterized the chemical constituents in K-601, identified the absorbed compounds and determined their pharmacokinetics in 6 Chinese and African volunteers by liquid chromatography with time-of-flight mass spectrometry. Similarity evaluation for chromatographic fingerprint of nine different batches showed values above 0.983. Totally, 50 components were identified in K-601. Then, 15 major prototype compounds and 17 metabolites were identified in human plasma. Major metabolic pathways included glucuronidation, sulfation, methylation, demethylation, and reduction. The pharmacokinetics of the most abundant prototype compounds, berberine, jatrorrhizine, palmatine and magnoflorine were determined. Significant pharmacokinetic differences were observed between the African and Chinese subjects. The AUCs of the African is about 4-10 fold higher than that of the Chinese for the three benzylisoquinoline alkaloids. Magnoflorine, an aporphine alkaloid, was absorbed better in the Chinese than in the African. The biotransformation of K-601 by human intestinal microflora was also investigated. The major reactions included hydroxylation, methylation, demethylation, acetylation and reduction. Glucuronidation and sulfation were not observed with fecal flora. These results may be important and useful in linking data from pharmacological assays and clinical effects.
[Pathomechanism and treatment of gut microbiota dysbiosis in chronic kidney disease and interventional effects of Chinese herbal medicine].
Han Wen-Bei,Liu Ying-Lu,Wan Yi-Gang,Sun Wei,Tu Yue,Yang Jing-Jing,Wu Wei,He Wei-Ming,Yao Jian
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
The gut microbiota dysbiosis is one of the risk factors in the progression from the advanced chronic kidney disease（CKD）to uremia, characterized by the reduction of probiotics and the increase of opportunistic pathogens including urease-related microbes, endotoxin-related microbes and toxin-related microbes, which can produce uremic toxins. According to the core point of "the gut-kidney axis" theory and "the chronic kidney disease-colonic axis" concept, the gut microbiota dysbiosis aggravates renal damage by accumulating uremic toxins and inducing the systemic micro-inflammation. The preliminary clinical trials and animal experiments show that the probiotics biologicals from Lactobacillus acidophilus or Bifidobacterium, and the prebiotics including inulin and galactooligosaccharides, as well as lubiprostone and activated carbon adsorbents can be used for improving dysfunction of CKD patients with the gut microbiota dysbiosis via reducing uremic toxins and inhibiting the systemic micro-inflammation. But not only that, it is reported that, to some extent, a number of the single Chinese herbal medicine（CHM）, the CHM prescriptions and the CHM extracts（emodin, etc.）with oral or enema administration can also regulate the gut microbiota dysbiosis, protect the intestinal epithelial barrier, reduce uremic toxins accumulation and delay CKD progression. Thereinto, Dahuang Gancao Decoction（the concentrated granule TJ-84）, a classical CHM prescription of rhubarb, can ameliorate uremic toxins accumulation in the animal models with renal failure probably through targeting the gut-kidney axis triggered from gut microbiota, but not targeting the kidney. Based on these results, the interventional studies targeting the gut microbiota-related pathological factors such as tight junction proteins, helper T cells and regulatory T cells in the intestinal tract of the advanced CKD patients will become one of the key development directions in the future.
Investigation and manipulation of metabolically active methanogen community composition during rumen development in black goats.
Wang Zuo,Elekwachi Chijioke O,Jiao Jinzhen,Wang Min,Tang Shaoxun,Zhou Chuanshe,Tan Zhiliang,Forster Robert J
This study was performed to investigate the initial colonization of metabolically active methanogens and subsequent changes in four fractions: the rumen solid-phase (RS), liquid-phase (RL), protozoa-associated (RP), and epithelium-associated (RE) from 1 to 60 d after birth, and manipulate methanogen community by early weaning on 40 d and supplementing rhubarb from 40 to 60 d in black goats. The RNA-based real-time quantitative PCR and 16S rRNA amplicon sequencing were employed to indicate the metabolically active methanogens. Results showed that active methanogens colonized in RL and RE on 1 d after birth. RP and RE contained the highest and lowest density of methanogens, respectively. Methanobrevibacter, Candidatus Methanomethylophilus, and Methanosphaera were the top three genera. The methanogen communities before weaning differed from those post weaning and the structure of the methanogen community in RE was distinct from those in the other three fractions. The discrepancies in the distribution of methanogens across four fractions, and various fluctuations in abundances among four fractions according to age were observed. The addition of rhubarb significantly (P < 0.05) reduced the abundances of Methanimicrococcus spp. in four fractions on 50 d, but did not change the methanogen community composition on 60 d.
Optimization of GC/TOF MS analysis conditions for assessing host-gut microbiota metabolic interactions: Chinese rhubarb alters fecal aromatic amino acids and phenol metabolism.
Yin Shan,Guo Pan,Hai Dafu,Xu Li,Shu Jiale,Zhang Wenjin,Khan Muhammad Idrees,Kurland Irwin J,Qiu Yunping,Liu Yumin
Analytica chimica acta
In this paper, an optimized method based on gas chromatography/time-of-flight mass spectrometry (GC-TOFMS) platform has been developed for the analysis of gut microbial-host related co-metabolites in fecal samples. The optimization was performed with proportion of chloroform (C), methanol (M) and water (W) for the extraction of specific metabolic pathways of interest. Loading Bi-plots from the PLS regression model revealed that high concentration of chloroform emphasized the extraction of short chain fatty acids and TCA intermediates, while the higher concentration of methanol emphasized indole and phenyl derivatives. Low level of organic solution emphasized some TCA intermediates but not for indole and phenyl species. The highest sum of the peak area and the distribution of metabolites corresponded to the extraction of methanol/chloroform/water of 225:75:300 (v/v/v), which was then selected for method validation and utilized in our application. Excellent linearity was obtained with 62 reference standards representing different classes of gut microbial-host related co-metabolites, with correlation coefficients (r) higher than 0.99. Limit of detections (LODs) and limit of qualifications (LOQs) for these standards were below 0.9 nmol and 1.6 nmol, respectively. The reproducibility and repeatability of the majority of tested metabolites in fecal samples were observed with RSDs lower than 15%. Chinese rhubarb-treated rats had elevated indole and phenyl species, and decreased levels of polyamine such as putrescine, and several amino acids. Our optimized method has revealed host-microbe relationships of potential importance for intestinal microbial metabolite receptors such as pregnane X receptor (PXR) and aryl hydrocarbon receptor (AHR) activity, and for enzymes such as ornithine decarboxylase (ODC).
Rhubarb Supplementation Promotes Intestinal Mucosal Innate Immune Homeostasis through Modulating Intestinal Epithelial Microbiota in Goat Kids.
Jiao Jinzhen,Wu Jian,Wang Min,Zhou Chuanshe,Zhong Rongzhen,Tan Zhiliang
Journal of agricultural and food chemistry
The abuse and misuse of antibiotics in livestock production pose a potential health risk globally. Rhubarb can serve as a potential alternative to antibiotics, and several studies have looked into its anticancer, antitumor, and anti-inflammatory properties. The aim of this study was to test the effects of rhubarb supplementation to the diet of young ruminants on innate immune function and epithelial microbiota in the small intestine. Goat kids were fed with a control diet supplemented with or without rhubarb (1.25% DM) and were slaughtered at days 50 and 60 of age. Results showed that the supplementation of rhubarb increased ileal villus height (P = 0.036), increased jejujal and ileal anti-inflammatory IL-10 production (P < 0.05), increased jejunal and ileal Claudin-1 expression at both mRNA and protein levels (P < 0.05), and decreased ileal pro-inflammatory IL-1β production (P < 0.05). These changes in innate immune function were accompanied by shifts in ileal epithelial bacterial ecosystem in favor of Blautia, Clostridium, Lactobacillus, and Pseudomonas, and with a decline in the relative abundance of Staphylococcus (P < 0.001) when rhubarb was supplemented. Additionally, age also affected (P < 0.05) crypt depth, cytokine production, Claudin-1 expression and relative abundances of specific genera in epithelial bacteria. Collectively, the supplementation of rhubarb could enhance host mucosal innate immune homeostasis by modulating intestinal epithelial microbiota during the early stages of animal development.
Effects of rhubarb on intestinal flora and toll-like receptors of intestinal mucosa in rats with severe acute pancreatitis.
Yao Ping,Cui Min,Li Yan,Deng Yiyun,Wu Hao
OBJECTIVE:The aim of this study was to examine the effects of rhubarb on intestinal flora and toll-like receptors (TLRs) of intestinal mucosa in rats with severe acute pancreatitis (SAP). METHODS:Healthy male Sprague-Dawley rats were randomly allocated into sham-operated surgical model of SAP without or with postoperative rhubarb treatment groups (7 in each group). Rats in with rhubarb group received 10% rhubarb decoction (1 mL/200 g) through tube feeding at every 8 hours during postoperative 24 hours. Serum amylase, amount of intestinal flora, and TLR2/TLR4 messenger RNA expression in intestinal mucosa were tested among 3 groups at postoperative 24 hours. RESULTS:TLR2 and TLR4 messenger RNA expression levels in intestinal mucosa in SAP without rhubarb group were significantly higher than those in sham-operated or SAP with rhubarb groups (P < 0.05). The amount of intestinal lactobacilli and bifidobacteria in SAP without rhubarb group were significantly fewer than in those sham-operated group (P < 0.05) but not significantly different from those in SAP with rhubarb group (P > 0.05). The amount of intestinal Escherichia coli was relatively higher in SAP group than in sham-operated group (P > 0.05) but lesser in rhubarb treatment group (P > 0.05). CONCLUSIONS:Rhubarb might maintain the intestinal mucosal barrier through regulating intestinal flora and inhibiting intestinal inflammatory response in rats with SAP.
Metabolism and mutual biotransformations of anthraquinones and anthrones in rhubarb by human intestinal flora using UPLC-Q-TOF/MS.
Huang Zhenghai,Xu Yang,Wang Qing,Gao Xiaoyan
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
Anthraquinones and anthrones are the main active components of rhubarb. To investigate the metabolism and possible mutual biotransformations pathways of anthraquinones and anthrones by human intestinal flora, 9 representative constituents (aloe-emodin, rhein, emodin, chrysophanol, physcion, sennosides A, B, C and D) were studied. An ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) with mass spectrometry (MS) technology was employed to separate and identify their metabolites. As a result, a total of 64 metabolites were identified or characterized from 9 components. Among them, 12 of them were identified by compared with the reference substances, 52 of them were tentatively identified. The results indicated that reduction, hydrolysis, acetylation, oxidation, demethylation, methylation, hydroxylation, dehydroxylation and the bond cleavage of CO and CC were likely to be the metabolic pathways involved in the generation of these metabolites. Moreover, mutual biotransformations existed among the nine representative constituents in rhubarb by human intestinal flora. This study will provide evidences that intestinal flora may play an important role in mediating the bioactivities in vivo of anthraquinones and anthrones in rhubarb.
Reactive metabolite activation by CYP2C19-mediated rhein hepatotoxicity.
He Li-Na,Yang Ai-Hong,Cui Tian-Yi,Zhai Yi-Ran,Zhang Fang-Liang,Chen Jun-Xiu,Jin Chun-Huan,Fan Yao-Wen,Wu Zi-Jun,Wang Li-Li,He Xin
Xenobiotica; the fate of foreign compounds in biological systems
1. Rhein, an active ingredient in the root of rhubarb, is used for its beneficial effects in a variety of clinical applications including the treatment of osteoarthritis and diabetic nephropathy. However, its hepatotoxicity has been reported in recent years. Rhein belongs to the conjugate structure which could be activated to reactive metabolites (RMs) inducing side-effects. This study is to explore the relationship between RMs and hepatotoxicity. 2. Based on the early detection of RMs, we have established a series of key technologies to research rhein hepatotoxicity mechanism: IC50 shift experiments and reduced glutathione (GSH) trapping experiment are adopted to identify RMs. The model of low activity of CYP450 enzymes (CYPs) in primary rat hepatocyte is constructed to analyze the relationship between the primary metabolic enzyme and hepatotoxicity of rhein better. 3. The IC50 shift value for CYP2C19 is 1.989, it suggests that CYP2C19 could activate rhein to RM. The structure of RM is epoxide intermediate. Besides, it is found that CYP2C19 is a primary metabolic enzyme for rhein. In the cytotoxicity assay, it is reported that rhein could cause mitochondrial dysfunction. Furthermore, mitochondrial membrane potential (Δψm) and AST levels could be restored by adding inhibitor of CYP2C19 together with rhein, which further shows that CYP2C19 could mediate the hepatotoxicity of rhein. 4. We put forward the possible mechanism that reactive metabolite activation by CYP2C19 mediated rhein hepatotoxicity, it provides important information on predicting in vivo drug-induced liver injury (DILI).
Chemical Reactivity of Aloe-Emodin and Its Hydroxylation Metabolites to Thiols.
Wang Xu,Xin Xin,Sun Ying,Zou Lizhu,Li Hui,Zhao Yufei,Li Ruihong,Peng Ying,Zheng Jiang
Chemical research in toxicology
Aloe-emodin (AE), an anthraquinone derivative, is a bioactive ingredient isolated from rhubarb which is used to treat inflammatory illnesses in China and many other countries in Asia. AE has shown a wide range of pharmacological effects. Recent studies showed that exposure to AE could cause DNA damage and cytotoxicity. The goals of the present study are aimed at (1) exploration of oxidative metabolism pathways of AE, (2) identification of P450 enzymes which respond the hydroxylation of AE, and (3) determination of electrophilicity of AE and its oxidative metabolites. Two hydroxylation metabolites (M1 and M2) and four GSH conjugates (M3-M6) were found in incubations consisting of AE, rat or human liver microsomes, and NADPH supplemented with GSH. Conjugates M3 and M4 came from AE itself, and M5 and M6 originated from M1 and M2 individually. M1 and M2 (5-hydroxy aloe-emodin) and M3-M6 were also detected in rat primary hepatocytes after exposure to AE. Additionally, biliary M3, M4, and M6 were detected in rats given AE. Urinary M1, M2, and M7 (a NAC conjugate) were observed in animals administered AE. Recombinant P450 enzyme incubations illustrated that hydroxylation of AE was primarily catalyzed by P450 1A2, 3A4, and 3A5. The metabolism investigation will help us to better understand the biochemical mechanisms of cytotoxicity induced by AE.
Inhibition of Mitochondrial Complex Function-The Hepatotoxicity Mechanism of Emodin Based on Quantitative Proteomic Analyses.
Lin Longfei,Liu Yuling,Fu Sai,Qu Changhai,Li Hui,Ni Jian
Emodin is the main component of traditional Chinese medicines including rhubarb, , and . It has confirmed hepatotoxicity and may be the main causative agent of liver damage associated with the above-mentioned traditional Chinese medicines. However, current research does not explain the mechanism of emodin in hepatotoxicity. In this study, L02 cells were used as a model to study the mechanism of emodin-induced hepatocyte apoptosis using quantitative proteomics, and the results were verified by Western blot. A total of 662 differentially expressed proteins were discovered and analyzed using Gene Ontology (GO) and pathway enrichment analysis. The results show that the oxidative phosphorylation pathway is highly represented. Abnormalities in this pathway result in impaired mitochondrial function and represent mitochondrial damage. This result is consistent with mitochondria membrane potential measurements. Analysis of differentially expressed proteins revealed that emodin mainly affects oxidative phosphorylation pathways by inhibiting the function of the mitochondrial respiratory chain complexes; the mitochondrial respiratory chain complex activity assay result also confirmed that emodin could inhibit the activity of all mitochondrial complexes. This results in an increase in caspase-3, a decrease in mitochondrial membrane potential (MMP,) an increase in reactive oxygen species (ROS), and disorders in ATP synthesis, etc., eventually leading to mitochondrial damage and hepatocyte apoptosis in vitro.
[Current research situation of nephrotoxicity of Chinese herbal medicine].
Feng Xue,Fang Sai-Nan,Gao Yu-Xin,Liu Jian-Ping,Chen Wei
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
To provide the basis for the future research on the nephrotoxicity of Chinese herbal medicine through systematic and comprehensive summary of all the Chinese herbal medicines which may lead to nephrotoxicity. Foreign resources included PubMed and Cochrane library， and domestic research resources was China Food and Drug Administration(CDFA) Adverse Drug Reaction Monitoring Center database. The databases were searched from establishment to January 1， 2017. There was no limitation on research type. 28 English studies were found， including 97 Chinese herbs or prescriptions with the risk of nephrotoxicity. The following six Chinese herbal medicines with the risk of nephrotoxicity had a large number of studies： aristolochic acid(5 studies)， Tripterygium wilfordii(4 studies)， Erycibe obtusifolia(2 studies)， Rheum palmatum(2 studies)， Ephedra sinica(2 studies)， and Atractylodes lances(2 studies). The remaining 91 Chinese medicines were reported with risk of nephrotoxicity in only 1 study respectively. CDFA reported 16 Chinese herbal medicines with the risk of nephrotoxicity， including Ganmaoqing Pian(capsule)， Zhenju Jiangya Pian， T. wilfordii preparation， Vc-Yinqiao Pian， Chuanhuning injection， Shuanghuanglian injection， Qingkailing injection， Lianbizhi injection， herbal decoction containing Aristolochiae Radix， Guanxin Suhe Wan， Shugan Liqi Wan， Ershiwuwei Songshi Wan， herbal decoction containing Aristolochia Fangchi， herbal granules containing root of Kaempfer Dutchmanspipe， Ganmaotong(tablets)， and Longdan Xiegan Wan. Currently， in addition to aristolochic acids， the most reported Chinese herbal medicine with the risk of nephrotoxicity is T. wilfordii preparation.
Gender Differences in the Hepatotoxicity and Toxicokinetics of Emodin: The Potential Mechanisms Mediated by UGT2B7 and MRP2.
Wu Lili,Han Weichao,Chen Yulian,Zhang Tao,Liu Junjin,Zhong Shilong,Liu Han,Han Congcong,Zhang Zhongyi,Liu Shuwen,Tang Lan
Emodin is a main anthraquinone compound which exists in Chinese traditional medicines including Polygonum multiflorum and Rhubarb. It is documented to have obvious liver and kidney toxicity. This study aims to (a) estimate gender differences of the hepatotoxicity and toxicokinetics in rats after oral administration of emodin (60 and 150 mg/kg/d) for a consecutive 28 days and (b) clarify relative mechanisms caused by glucuronidation and disposition. Hepatotoxicity was significantly higher in female rats than that in male rats, as evidenced by histopathological and biochemical tests. Similarly, the toxicokinetic profiles of emodin have time and gender differences, which could cause time and gender differences in hepatotoxicity. The metabolic and transcriptomics data of 55 human liver and 36 human kidney samples demonstrated that UDP-glucuronosyltransferase 2B7 (UGT2B7) was the predominant enzyme for emodin glucuronidation. A genome-wide association study (GWAS) identified that rs11726899 located within ∼50 kb of the transcript of UGT2B could significantly affect emodin metabolism. Knockdown of UGT2B7 in HepG2 cells significantly decreased emodin glucuronidation and increased cytotoxicity of emodin. The gene expression and protein levels of UGT2B7 were decreased, but those of the multidrug-resistant-protein 2 (MRP2) were increased in HepG2 cells after being treated with 50 μM emodin for 48 h. Long-term use of emodin could decrease the intrinsic clearance (CL, decreased by 18.5%-35.4%) values of zidovidue (UGT2B7 substrate) glucuronide in both male and female liver microsomes from rats administrated with emodin for 28 days, thus causing the accumulation of emodin. However, higher self-induced MRP2 expression and lower hepatotoxicity were observed in emodin-treated male rats compared to that in female rats. Therefore, gender differences in the hepatotoxicity and toxicokinetics of emodin are potentially mediated by the coupling of UGT2B7 and MRP2 in vivo.
Emodin: A Review of its Pharmacology, Toxicity and Pharmacokinetics.
Dong Xiaoxv,Fu Jing,Yin Xingbin,Cao Sali,Li Xuechun,Lin Longfei, ,Ni Jian
Phytotherapy research : PTR
Emodin is a natural anthraquinone derivative that occurs in many widely used Chinese medicinal herbs, such as Rheum palmatum, Polygonum cuspidatum and Polygonum multiflorum. Emodin has been used as a traditional Chinese medicine for over 2000 years and is still present in various herbal preparations. Emerging evidence indicates that emodin possesses a wide spectrum of pharmacological properties, including anticancer, hepatoprotective, antiinflammatory, antioxidant and antimicrobial activities. However, emodin could also lead to hepatotoxicity, kidney toxicity and reproductive toxicity, particularly in high doses and with long-term use. Pharmacokinetic studies have demonstrated that emodin has poor oral bioavailability in rats because of its extensive glucuronidation. This review aims to comprehensively summarize the pharmacology, toxicity and pharmacokinetics of emodin reported to date with an emphasis on its biological properties and mechanisms of action. Copyright © 2016 John Wiley & Sons, Ltd.
Toxicity of anthraquinones: differential effects of rumex seed extracts on rat organ weights and biochemical and haematological parameters.
Islam Rabigul,Mamat Yultuz,Ismayil Ilyar,Yan Ming,Kadir Mahsutjan,Abdugheny Abdujilil,Rapkat Haximjan,Niyaz Mardan,Ali Yusupjan,Abay Sirapil
Phytotherapy research : PTR
The genus Rumex and related species such as Rheum and Polygonum are widely used as medicinal herbs and foods. They contain anthraquinones (AQ) such as emodin and chrysophanol as active ingredients, and there is concern about the toxicity of these compounds. This study evaluated the chronic effects of Rumex patientia seed aqueous and ethanolic extracts, in male and female rats separately, on organ weights and over 30 haematological, biochemical and histological parameters, immediately after 14-week administration and after a further period of 15 days without drug treatment. Adverse changes were associated with long-term AQ administration, and these focussed on the liver, lung and kidney, but after 15-day convalescence, most had reverted to normal. In general, male rats appeared to be more susceptible than female rats at similar doses. The water extract produced no irreversible changes, which may reflect the lower dose of the AQ constituents or the presence of different ancillary compounds, and supports the traditional method of extracting Rumex seeds with water. In conclusion, ethanolic extracts of R. patientia caused irreversible pathological changes at very high doses (4000mg/kg), but lower doses and aqueous extracts produced either non-significant or reversible changes. Long-term administration of high doses of AQ extracts over a long period of time should be avoided until further assurances can be given, and given other existing reports of reproductive toxicity, should be avoided altogether during pregnancy.
Evaluation of Rheum Turkestanicum in Hexachlorobutadien-Induced Renal Toxicity.
Boroushaki Mohammad Taher,Fanoudi Sahar,Rajabian Arezoo,Boroumand Samaneh,Aghaee Azita,Hosseini Azar
Hexachlorobutadien is nephrotoxic agent in rodents. The mechanism of toxicity includes generation of free radicals, depletion of thiol groups and production of toxic metabolites. Antioxidant compounds may reduce HCBD-nephrotoxicity. In this research we investigated the effect of Rheum turkeatanicum extract against HCBD-toxicity. The animals were divided to 4 groups which were including control (saline, 1 mL/kg), HCBD (100 mg/kg) and treatment groups which received extract at doses 100 and 200 mg/kg. The extract were administered as intraperitoneally (i.p.) 1 h before HCBD injection (i.p.). The animals were anesthetized by ether, 24 h after HCBD administration. The results showed elevation of serum creatinine, serum urea, urinary protein, urinary glucose, malondialdehyde levels in kidney and reduction of thiol in kidney by HCBD. The histopathological studies showed that there was apoptosis and necrosis in HCBD treated groups. Administration of R.turkestanicum reduced HCBD toxicity. The extract reduced hitopathological changes in kidney. It may be concluded that the nephroprotective effect of extract may be due to different mechanisms such as antioxidant activity or by decreasing the toxic metabolites of HCBD or inhibition of enzymes which are involved in the bioactivation of HCBD such as glutathione-S-transferase (GST) or cysteine-S-conjugate β-lyase.
Pharmacological properties of Janisch.
Ghorbani Ahmad,Amiri Mohammad Sadegh,Hosseini Azar
Medicinal herbs have been increasingly used worldwide for diseases prevention and treatment. Janisch. is a perennial shrub of the Polygonaceae family. Genus includes more than 60 species growing around the world which are used in foods and traditional medicines. is believed to be able to improve different kinds of disorders including diabetes, hypertension, jaundice and cancer. In recent years, this medicinal plant has been a subject of many experimental studies to document its health-beneficial properties. These studies have revealed antidiabetic, anticancer, nephroprotective, cardioprotective, and hepatoprotective properties of The presence of flavonoids (e.g. epicatechin and quercetin) and anthraquinones (e.g. chrysophanol, physcion, and emodin) in justifies its health-beneficial effects. Nevertheless, possible therapeutic applications and safety of this plant still need to be elucidated in further clinical studies.
Metabolic Activation of Rhein: Insights into the Potential Toxicity Induced by Rhein-Containing Herbs.
Yuan Yuan,Zheng Jiyue,Wang Meiyu,Li Yuan,Ruan Jianqing,Zhang Hongjian
Journal of agricultural and food chemistry
Rhein is a major component of the many medicinal herbs such as rhubarb. Despite wide use, intoxication cases associated with rhein-containing herbs are often reported. The present work aimed to investigate if rhein was subject to metabolic activation leading to toxicity. Upon incubations with different species of liver microsomes, three monoglucuronides were identified, corresponding to two hydroxyl glucuronides and one acyl glucuronide via the carboxyl group, respectively. Further study revealed that rhein acyl glucuronide was chemically reactive, and showed cytotoxicity toward hepatocarcinoma cells. In addition, significant species differences in glucuronidation of rhein were observed between laboratory animals and humans. Reaction phenotyping experiments demonstrated that rhein acyl glucuronide was catalyzed predominantly by uridine 5'-diphospho-glucuronosyltransferase 1A1, 1A9, and 2B7. Taken together, the present study confirmed that rhein could be metabolically activated via the formation of acyl glucuronide, especially in human.
Network pharmacology oriented study reveals inflammatory state-dependent dietary supplement hepatotoxicity responses in normal and diseased rats.
Tu Can,Niu Ming,Li Chunyu,Liu Zhenjie,He Qin,Li Ruisheng,Zhang Yaming,Xiao Xiaohe,Wang Jiabo
Food & function
Rhubarb, a well-used herbal and dietary supplement, has been widely used as a laxative in many countries. The dietary supplement rhubarb may reveal differential hepatotoxicity responses in normal and diseased subjects; however, its underlying mechanism is unclear. By using a network pharmacology approach, we found that the components contained in rhubarb had associations with a liver disease-related protein network that could be enriched into two subnetworks: a pro-inflammatory protein network associated with liver inflammation and an anti-inflammatory protein network related to liver fibrosis. In addition, macrophages were found to have an association with these subnetworks. Herein, the differential toxicity responses of rhubarb in normal and diseased rats were illustrated by in vivo pharmacology experiments. Rhubarb induced liver injury in normal rats with dose-dependent increases in the pro-inflammatory response; in contrast, it failed to induce hepatotoxic effects in a liver fibrosis rat model and was accompanied by an increase in anti-inflammatory protein expression. Further study showed elevation of high mobility group box-1 (HMGB1) in the sera and liver tissues and remarkable pro-inflammatory activation of Kupffer cells in liver tissue; these phenomena were associated with the hepatotoxic effect of rhubarb and could be blocked by inhibiting either HMGB1 or Kupffer cells through glycyrrhizin or GdCl3, respectively. Interestingly, we also observed attenuated pro-inflammatory activation of Kupffer cells in a liver fibrosis rat model together with a non-hepatotoxic response to rhubarb. These results suggest that the divergent immune states in normal and diseased subjects may contribute to the differential toxicity responses to rhubarb.
Pharmacokinetic alterations of rhubarb anthraquinones in experimental colitis induced by dextran sulfate sodium in the rat.
Wu Wen-Jin,Yan Ru,Li Ting,Li Ya-Ping,Zhou Rui-Na,Wang Yi-Tao
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Rhubarb (Rhei Rhizoma et Radix) is used for the treatment of digestive diseases in traditional medicinal practice in China. Recent studies also support its beneficial activities in alleviating ulcerative colitis (UC). AIM OF THE STUDY:This study aimed to characterize the oral pharmacokinetics of rhubarb anthraquinones, the main bioactive components of this herb, in the experimental chronic colitis rat model induced by dextran sulfate sodium (DSS) and to identify the factors causing the pharmacokinetic alterations. MATERIALS AND METHODS:Rats received drinking water (normal group) or 5% DSS for the first 7 days and 3% DSS for additional 14 days (UC group). On day 21 both groups received an oral dose of the rhubarb extract (equivalent to 5.0g crude drug/kg body weight). Plasma anthraquinone aglycones levels were determined directly by an LC-MS/MS method and the total of each anthraquinone (aglycone+conjugates) was quantified after β-glucuronidases hydrolysis. RESULTS:Rhubarb anthraquinones predominantly existed as conjugates in plasma samples from both groups and only free aloe-emodin, rhein and emodin were detected. Compared to the normal rats, both C and AUC of the three free anthraquinones were increased, while the systemic exposure (AUC) of the total (aglycone+conjugates) of most anthraquinones decreased by UC accompanied by the disappearance of multiple-peak phenomenon in the plasma concentration-time profiles. Gut bacteria from UC rats exhibited a decreased activity in hydrolyzing anthraquinone glycosides to form respective aglycone and there were significant decreases in microbial β-glucosidases and β-glucuronidases activities. Moreover, the intestinal microsomes from UC rats catalyzed glucuronidation of free anthraquinones with higher activities, while the activities of hepatic microsomes were comparable to normal rats. CONCLUSIONS:The decreases of β-glucuronidases activity in DSS-induced chronic rat colitis should mainly account for the decreases in systemic exposure and abrogation of enterohepatic recirculation of most rhubarb anthraquinones after oral intake.
[Understanding differences between Rheum palmatum and R. franzenbachii from perspective of chemistry, efficacy and toxicity].
Yan Xiao-Jin,Feng Tian-Shi,Wang Yu-Gang,Yuan Zhi-Yi,Lei Fan,Xiao Xin-Yue,Xing Dong-Ming,Du Li-Jun
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
Rheum franzenbachii (called Tudahuang in local) has some similarities with R. palmatum (rhubarb) collected by "China Pharmacopoeia" and is often used as a substitute of rhubarb. Can Tudahuang simply replace rhubarb in the application or whether is there difference between Tudahuang and rhubarb, and what is the difference it is important to verify the difference and understand its proper application in the field of clinical practice. In this paper, we discussed the differences of the two herbs from the views of chemistry, efficacy and toxicity based on the author's previous research work as well as literatures, by using the major role of the rhubarb "diarrhea" as the basic point. The analysis result showed that the role of diarrhea Tudahuang was much weaker than that of rhubarb. The reason lies in the difference between the contents of combined anthraquinones component. While acute toxicity in mice of Tudahuang is stronger than that of rhubarb. Thus, Tudahuang should not simply replace rhubarb in practice.
[Study on dosage-toxicity/efficacy relationship of prepared rhubarb on basis of symptom-based prescription theory].
Wang Yan-Hui,Zhao Hai-Ping,Wang Jia-Bo,Zhao Yan-Ling,Xiao Xiao-He
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
OBJECTIVE:To investigate the dosage-efficacy/toxicity relationship of prepared rhubarb, in order to explore the bidirectional effects in hepatoprotection and hepatotoxicity of prepared rhubarb and the objective authenticity for attenuating toxicity by processing. METHOD:Normal and pathological animals were adopted simultaneous to investigate the effect of total extracts from prepared rhubarb within a high dose range (2.0, 5.4, 14.7, 40.0 g x kg(-1) x d(-1)) on normal state, biochemical index and histopathology of experimental animals. The factor analytic approach was used to analyze the dosage-efficacy/toxicity relationship of prepared rhubarb. RESULT:The factor analytic approach was used to extract two common factors from the nine biochemical indexes. The firs common factor was mainly dominated by HA, LN and TGF-β1, and could be explained as fibrotic factors. The second common factor was mainly dominated by ALT, AST and ALP, and could be explained as cellular factor. The results of the factor analysis suggested that prepared rhubarb showed significant bidirectional effects in hepatoprotection and hepatotoxicity, which could protect liver in CC14 injured chronic hepatic injury, but had a certain hepatotoxic effect to normal animals. The pathological examination showed consistent results with the factor analysis. Under comparable dosages, prepared rhubarb showed a stronger liver protecting effect than crude rhubarb, with a lower toxicity. CONCLUSION:Although prepared rhubarb has a certain hepatotoxic effect to normal animals, it has also a significant therapeutic effect to animals with liver injury. The results proved the symptom-based prescription theory and the scientificity of the symptom-based medication. The symptom-based prescription theory is important to correctly realize the dosage-efficacy/toxicity relationship of traditional Chinese medicines and guide the symptom-based medication.
[Mechanism of nephrotoxicity of rhubarb in rats].
Deng Nuo,Yi Yan,Liang Ai-Hua,Li Chun-Ying,Zhao Yong,Pan Chen,Zhang Yu-Shi,Wang Lian-Mei,Han Jia-Yin,Liu Su-Yan,Tian Jing-Zhuo,Li Gui-Qin,Liu Jing
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
The aim of this study was to investigate the renal toxicity of rhubarb and its mechanism. The SD rats were randomly divided into three groups: normal group and two rhubarb extract groups (16, 2 g·kg⁻¹). According to the dose conversion method between human and animal, rhubarb 16 g·kg⁻¹ and 2 g·kg⁻¹ were equivalent to 10 times and 1.25 times of human clinical dose respectively. Rhubarb extract was administered by a gastric gavage to rats once daily for 30 days. Serum urea nitrogen （BUN）, creatinine （CRE） and urine KIM-1, NGAL and renal morphology were analyzed. The expressions of OAT1, OAT3 and clusterin mRNA in kidney were measured. The results showed that the low dose of rhubarb had no obvious renal toxicity. The high dose group showed mild and moderate renal injury and a down-regulation of clusterin mRNA expression in the kidney tissue. The renal toxicity in male animals was heavier than that in female animals. There was no significant change in blood BUN and CRE in the high dose group. But urine NGAL level of the high dose group increased by 51.53% compared with normal group, of which male animals increased more significantly (<0.05, compared with the normal group). The expressions of renal OAT1 and OAT3 mRNA in the low dose group were obviously higher than that in the normal group. The results indicated that the high dose of rhubarb could cause the renal toxicity. The dosage should be controlled reasonably in the clinical use. OAT1 and OAT3 mRNA related to anionic transport in kidney tissue played a compensatory protective role in rhubarb-induced renal injury. But the compensatory effect is relatively weak at the high dose level. In addition, routine renal function indicators BUN and CRE had limitation for monitoring the kidney toxicity of rhubarb. It is suggested that urine NGAL detection might be helpful for monitoring the renal toxicity of rhubarb.
[Dose-toxicity-effect relationship between licorice combined with rhubarb in purgation].
Chen Yan-Yan,Cao Yu-Jie,Tang Yu-Ping,Chen Jia-Qian,Yue Shi-Jun,Li Jia-Jia,Zhang Sai,Zhou Gui-Sheng,Duan Jin-Ao
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
The dose-toxicity-effect relationship between licorice combined with rhubarb in purgation was studied. A total of 108 ICR mice were divided into control group,model group,positive group,low,medium and high-dose rhubarb groups,and low,medium and high-dose rhubarb-liquorice decoction group. After 6 days of continuous administration of loperamide hydrochloride,the constipation model of mice was replicated,and each group was given lactulose,different doses of rhubarb and rhubarb-liquorice decoction for 14 days. After administration,the defecation characteristics,blood biochemistry,liver,kidney and colon pathological changes in each group were compared. Based on the objective weight given by factor analysis,the dose-toxicity-effect relationship was comprehensively analyzed by multi-index scoring method. Two common factors were extracted by factor analysis,representing effect and toxicity respectively. The results showed that rhubarb could exert a diarrhea effect at the dosage of 1/2,2 and 8 times of the high limit set forth in the Chinese Pharmacopoeia,increase the defecation volume and the intestinal tract propulsion rate,reduce the time of anal and the oral transmission,and increase the water content of feces. The combination with licorice could alleviate its diarrhea effect,especially at the dosage of 1/2 times of the high limit set forth in the Chinese Pharmacopoeia. However,rhubarb showed obvious hepatic and colon toxicities at the dosage of 2 and 8 times of the high limit set forth in the Chinese Pharmacopoeia,and the combination with licorice could significantly reduce its toxicity. It shows that licorice has a " mediating" effect on rhubarb by alleviating the purgation property and reducing the toxicity.
Naturally occurring compounds in differentiation based therapy of cancer.
Mijatović Sanja,Bramanti Alessia,Nicoletti Ferdinando,Fagone Paolo,Kaluđerović Goran N,Maksimović-Ivanić Danijela
Differentiation of cancer cells entails the reversion of phenotype from malignant to the original. The conversion to cell type characteristic for another tissue is named transdifferentiation. Differentiation/transdifferentiation of malignant cells in high grade tumor mass could serve as a nonaggressive approach that potentially limits tumor progression and augments chemosensitivity. While this therapeutic strategy is already being used for treatment of hematological cancers, its feasibility for solid malignancies is still debated. We will presently discuss the natural compounds that show these properties, with focus on anthraquinones from Aloe vera, Senna, Rheum sp. and hop derived prenylflavonoids.
Separation of three polar compounds from Rheum tanguticum by high-speed countercurrent chromatography with an ethyl acetate/glacial acetic acid/water system.
Chen Tao,Wang Ping,Wang Nana,Sun Chongyang,Yang Xue,Li Hongmei,Zhou Guoying,Li Yulin
Journal of separation science
The separation of polar compounds by high-speed countercurrent chromatography is still regarded as a challenge. In this study, an efficient strategy for the separation of three polar compounds from Rheum tanguticum has been successfully conducted by using high-speed countercurrent chromatography. X-5 macroporous resin chromatography was used for the fast enrichment of the target compounds. Then, the target fraction was directly introduced into high-speed countercurrent chromatography for separation using ethyl acetate/glacial acetic acid/water (100:1:100, v/v/v) as the solvent system. Consequently, three polar compounds including gallic acid, catechin, and gallic acid 4-O-β-d-(6'-O-galloyl) glucoside were obtained with purities higher than 98%. The results showed glacial acetic acid could be such an appropriate regulator for the ethyl acetate/water system. This study provides a reference for the separation of polar compounds from natural products by high-speed countercurrent chromatography.
iTRAQ-based quantitative proteomics reveals the neuroprotection of rhubarb in experimental intracerebral hemorrhage.
Liu Tao,Zhou Jing,Cui Hanjin,Li Pengfei,Luo Jiekun,Li Teng,He Feng,Wang Yang,Tang Tao
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Rhubarb is a traditional Chinese medicine(TCM), that possesses neuroprotective, anti-inflammatory, antibacterial, antioxidative, purgative and anticancer properties, and has been used to treat intracerebral hemorrhage (ICH) and many other diseases. AIMS OF THE STUDY:This study aimed to investigate the changes of brain protein in ICH rats treated with rhubarb and to explore the multi-target mechanism of rhubarb in the treatment of ICH via bioinformatics analysis of differentially expressed proteins (DEPs). MATERIALS AND METHODS:Rats were subjected to collagenase-induced ICH and then treated orally with 3 or 12 g/kg rhubarb daily for 2 days following ICH. After sacrifice, total protein of brain tissue was extracted, and isobaric tag for relative and absolute quantification (iTRAQ)-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was employed to quantitatively identify of the DEPs in two treatment groups compared with the vehicle group. The DEPs were analyzed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and STRING databases. Bioinformatics Analysis Tool for Molecular mechanism of TCM (BATMAN-TCM) was used to predict the target of rhubarb and western blotting was used for verification. RESULTS:In total, 1356 proteins were identified with a 1% false discovery rate (FDR). Among them, 55 DEPs were significantly altered in the sham, vehicle, low dose rhubarb group (LDR, 3 g/kg), and high dose rhubarb group (HDR, 12 g/kg). Enrichment analysis of GO annotations indicated that rhubarb mainly regulated expression of some neuron projection proteins involved in the response to drug and nervous system development. The dopaminergic synapse pathway was found to be the most significant DEP in the combined analysis of the KEGG and BATMAN-TCM databases. Based on the results of the STRING analysis, oxidative stress (OS), calcium binding protein regulation, vascularization, and energy metabolism were important in the rhubarb therapeutic process. CONCLUSION:Rhubarb achieves its effects mainly through the dopaminergic synapse pathway in ICH treatment. The ICH-treating mechanisms of rhubarb may also involve anti-OS, calcium binding protein regulation, angiogenic regulation, and energy metabolism improvement. This study adds new evidence to clinical applications of rhubarb for ICH.
Full-Spectral Multiplexing of Bioluminescence Resonance Energy Transfer in Three TRPV Channels.
Ruigrok Hermanus Johannes,Shahid Guillaume,Goudeau Bertrand,Poulletier de Gannes Florence,Poque-Haro Emmanuelle,Hurtier Annabelle,Lagroye Isabelle,Vacher Pierre,Arbault Stéphane,Sojic Neso,Veyret Bernard,Percherancier Yann
Multiplexed bioluminescence resonance energy transfer (BRET) assays were developed to monitor the activation of several functional transient receptor potential (TRP) channels in live cells and in real time. We probed both TRPV1 intramolecular rearrangements and its interaction with Calmodulin (CaM) under activation by chemical agonists and temperature. Our BRET study also confirmed that: (1) capsaicin and heat promoted distinct transitions, independently coupled to channel gating, and that (2) TRPV1 and Ca-bound CaM but not Ca-free CaM were preassociated in resting live cells, while capsaicin activation induced both the formation of more TRPV1/CaM complexes and conformational changes. The BRET assay, based on the interaction with Calmodulin, was successfully extended to TRPV3 and TRPV4 channels. We therefore developed a full-spectral three-color BRET assay for analyzing the specific activation of each of the three TRPV channels in a single sample. Such key improvement in BRET measurement paves the way for the simultaneous monitoring of independent biological pathways in live cells.
Voltage- and temperature-dependent activation of TRPV3 channels is potentiated by receptor-mediated PI(4,5)P2 hydrolysis.
Doerner Julia F,Hatt Hanns,Ramsey I Scott
The Journal of general physiology
TRPV3 is a thermosensitive channel that is robustly expressed in skin keratinocytes and activated by innocuous thermal heating, membrane depolarization, and chemical agonists such as 2-aminoethyoxy diphenylborinate, carvacrol, and camphor. TRPV3 modulates sensory thermotransduction, hair growth, and susceptibility to dermatitis in rodents, but the molecular mechanisms responsible for controlling TRPV3 channel activity in keratinocytes remain elusive. We show here that receptor-mediated breakdown of the membrane lipid phosphatidylinositol (4,5) bisphosphate (PI(4,5)P(2)) regulates the activity of both native TRPV3 channels in primary human skin keratinocytes and expressed TRPV3 in a HEK-293-derived cell line stably expressing muscarinic M(1)-type acetylcholine receptors. Stimulation of PI(4,5)P(2) hydrolysis or pharmacological inhibition of PI 4 kinase to block PI(4,5)P(2) synthesis potentiates TRPV3 currents by causing a negative shift in the voltage dependence of channel opening, increasing the proportion of voltage-independent current and causing thermal activation to occur at cooler temperatures. The activity of single TRPV3 channels in excised patches is potentiated by PI(4,5)P(2) depletion and selectively decreased by PI(4,5)P(2) compared with related phosphatidylinositol phosphates. Neutralizing mutations of basic residues in the TRP domain abrogate the effect of PI(4,5)P(2) on channel function, suggesting that PI(4,5)P(2) directly interacts with a specific protein motif to reduce TRPV3 channel open probability. PI(4,5)P(2)-dependent modulation of TRPV3 activity represents an attractive mechanism for acute regulation of keratinocyte signaling cascades that control cell proliferation and the release of autocrine and paracrine factors.
Ambient temperature affects the temperature threshold for TRPM8 activation through interaction of phosphatidylinositol 4,5-bisphosphate.
Fujita Fumitaka,Uchida Kunitoshi,Takaishi Masayuki,Sokabe Takaaki,Tominaga Makoto
The Journal of neuroscience : the official journal of the Society for Neuroscience
Cold sensation is an important and fundamental sense for animals and it is known to be affected by ambient temperature. Transient Receptor Potential Melastatin 8 (TRPM8), a nonselective cation channel expressed in a subset of peripheral afferent fibers, acts as a cold sensor, having an activation threshold of ∼28°C. Although the cold temperature threshold of TRPM8 is affected by menthol or pH, ambient temperature has not been reported to affect it. Because the cold temperature threshold was thought to be unchanged by alterations in ambient temperature, the relativity of temperature sensing in different ambient temperatures could not be understood at the level of molecular function of thermosensitive TRP channels. Here, we show that ambient temperature changed the temperature threshold for activation of human and rat TRPM8 in a heterologous expression system and cold responses in mouse DRG neurons. Moreover, reducing the level of cellular phosphatidylinositol 4,5-bisphosphate (PIP2) attenuated changes in the cold temperature threshold after alterations in ambient temperature. A single amino acid mutation at position 1008 in the C terminus of TRPM8 (arginine to glutamine) also attenuated changes in the cold temperature threshold induced by ambient temperature. These findings suggest that ambient temperature does affect the temperature threshold for TRPM8 activation through interaction of PIP2.
Thermal imaging of receptor-activated heat production in single cells.
Zohar O,Ikeda M,Shinagawa H,Inoue H,Nakamura H,Elbaum D,Alkon D L,Yoshioka T
Changes in enthalpy (i.e., heat content) occur during the diverse intracellular chemical and biophysical interactions that take place in the life cycle of biological cells. Such changes have previously been measured for cell suspensions or cell-free biochemical extracts by using microcalorimetry, thermocouples, or pyroelectric films, all of which afford minimal spatial or temporal resolution. Here we present a novel thermal imaging method that combines both diffraction-limited spatial (approximately 300 nm) and sampling-rate-limited time resolution, using the temperature-dependent phosphorescence intensity of the rare earth chelate Eu-TTA (europium (III) thenoyltrifluoro-acetonate). With this thermosensitive dye, we imaged intracellular heat waves evoked in Chinese hamster ovary cells after activation of the metabotropic m1-muscarinic receptor. Fast application of acetylcholine onto the cells evoked a biphasic heat wave that was blocked by atropine, and after a brief delay was followed by a calcium wave. Atropine applied by itself produced a monophasic heat wave in the cells, suggesting that its interactions with the receptor activate some intracellular metabolic pathways. The thermal imaging technique introduced here should provide new insights into cellular functions by resolving the location, kinetics, and quantity of intracellular heat production.
Commensal bacteria make GPCR ligands that mimic human signalling molecules.
Cohen Louis J,Esterhazy Daria,Kim Seong-Hwan,Lemetre Christophe,Aguilar Rhiannon R,Gordon Emma A,Pickard Amanda J,Cross Justin R,Emiliano Ana B,Han Sun M,Chu John,Vila-Farres Xavier,Kaplitt Jeremy,Rogoz Aneta,Calle Paula Y,Hunter Craig,Bitok J Kipchirchir,Brady Sean F
Commensal bacteria are believed to have important roles in human health. The mechanisms by which they affect mammalian physiology remain poorly understood, but bacterial metabolites are likely to be key components of host interactions. Here we use bioinformatics and synthetic biology to mine the human microbiota for N-acyl amides that interact with G-protein-coupled receptors (GPCRs). We found that N-acyl amide synthase genes are enriched in gastrointestinal bacteria and the lipids that they encode interact with GPCRs that regulate gastrointestinal tract physiology. Mouse and cell-based models demonstrate that commensal GPR119 agonists regulate metabolic hormones and glucose homeostasis as efficiently as human ligands, although future studies are needed to define their potential physiological role in humans. Our results suggest that chemical mimicry of eukaryotic signalling molecules may be common among commensal bacteria and that manipulation of microbiota genes encoding metabolites that elicit host cellular responses represents a possible small-molecule therapeutic modality (microbiome-biosynthetic gene therapy).
Plant-Derived Exosomal MicroRNAs Shape the Gut Microbiota.
Teng Yun,Ren Yi,Sayed Mohammed,Hu Xin,Lei Chao,Kumar Anil,Hutchins Elizabeth,Mu Jingyao,Deng Zhongbin,Luo Chao,Sundaram Kumaran,Sriwastva Mukesh K,Zhang Lifeng,Hsieh Michael,Reiman Rebecca,Haribabu Bodduluri,Yan Jun,Jala Venkatakrishna Rao,Miller Donald M,Van Keuren-Jensen Kendall,Merchant Michael L,McClain Craig J,Park Juw Won,Egilmez Nejat K,Zhang Huang-Ge
Cell host & microbe
The gut microbiota can be altered by dietary interventions to prevent and treat various diseases. However, the mechanisms by which food products modulate commensals remain largely unknown. We demonstrate that plant-derived exosome-like nanoparticles (ELNs) are taken up by the gut microbiota and contain RNAs that alter microbiome composition and host physiology. Ginger ELNs (GELNs) are preferentially taken up by Lactobacillaceae in a GELN lipid-dependent manner and contain microRNAs that target various genes in Lactobacillus rhamnosus (LGG). Among these, GELN mdo-miR7267-3p-mediated targeting of the LGG monooxygenase ycnE yields increased indole-3-carboxaldehyde (I3A). GELN-RNAs or I3A, a ligand for aryl hydrocarbon receptor, are sufficient to induce production of IL-22, which is linked to barrier function improvement. These functions of GELN-RNAs can ameliorate mouse colitis via IL-22-dependent mechanisms. These findings reveal how plant products and their effects on the microbiome may be used to target specific host processes to alleviate disease.
Inflammatory networks underlying colorectal cancer.
Lasry Audrey,Zinger Adar,Ben-Neriah Yinon
Inflammation is emerging as one of the hallmarks of cancer, yet its role in most tumors remains unclear. Whereas a minority of solid tumors are associated with overt inflammation, long-term treatment with non-steroidal anti-inflammatory drugs is remarkably effective in reducing cancer rate and death. This indicates that inflammation might have many as-yet-unrecognized facets, among which an indolent course might be far more prevalent than previously appreciated. In this Review, we explore the various inflammatory processes underlying the development and progression of colorectal cancer and discuss anti-inflammatory means for its prevention and treatment.
Gut microbiota modulation of chemotherapy efficacy and toxicity.
Alexander James L,Wilson Ian D,Teare Julian,Marchesi Julian R,Nicholson Jeremy K,Kinross James M
Nature reviews. Gastroenterology & hepatology
Evidence is growing that the gut microbiota modulates the host response to chemotherapeutic drugs, with three main clinical outcomes: facilitation of drug efficacy; abrogation and compromise of anticancer effects; and mediation of toxicity. The implication is that gut microbiota are critical to the development of personalized cancer treatment strategies and, therefore, a greater insight into prokaryotic co-metabolism of chemotherapeutic drugs is now required. This thinking is based on evidence from human, animal and in vitro studies that gut bacteria are intimately linked to the pharmacological effects of chemotherapies (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) and novel targeted immunotherapies such as anti-PD-L1 and anti-CLTA-4 therapies. The gut microbiota modulate these agents through key mechanisms, structured as the 'TIMER' mechanistic framework: Translocation, Immunomodulation, Metabolism, Enzymatic degradation, and Reduced diversity and ecological variation. The gut microbiota can now, therefore, be targeted to improve efficacy and reduce the toxicity of current chemotherapy agents. In this Review, we outline the implications of pharmacomicrobiomics in cancer therapeutics and define how the microbiota might be modified in clinical practice to improve efficacy and reduce the toxic burden of these compounds.
Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.
Routy Bertrand,Le Chatelier Emmanuelle,Derosa Lisa,Duong Connie P M,Alou Maryam Tidjani,Daillère Romain,Fluckiger Aurélie,Messaoudene Meriem,Rauber Conrad,Roberti Maria P,Fidelle Marine,Flament Caroline,Poirier-Colame Vichnou,Opolon Paule,Klein Christophe,Iribarren Kristina,Mondragón Laura,Jacquelot Nicolas,Qu Bo,Ferrere Gladys,Clémenson Céline,Mezquita Laura,Masip Jordi Remon,Naltet Charles,Brosseau Solenn,Kaderbhai Coureche,Richard Corentin,Rizvi Hira,Levenez Florence,Galleron Nathalie,Quinquis Benoit,Pons Nicolas,Ryffel Bernhard,Minard-Colin Véronique,Gonin Patrick,Soria Jean-Charles,Deutsch Eric,Loriot Yohann,Ghiringhelli François,Zalcman Gérard,Goldwasser François,Escudier Bernard,Hellmann Matthew D,Eggermont Alexander,Raoult Didier,Albiges Laurence,Kroemer Guido,Zitvogel Laurence
Science (New York, N.Y.)
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Oral supplementation with after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9CXCR3CD4 T lymphocytes into mouse tumor beds.
International Cancer Microbiome Consortium consensus statement on the role of the human microbiome in carcinogenesis.
Scott Alasdair J,Alexander James L,Merrifield Claire A,Cunningham David,Jobin Christian,Brown Robert,Alverdy John,O'Keefe Stephen J,Gaskins H Rex,Teare Julian,Yu Jun,Hughes David J,Verstraelen Hans,Burton Jeremy,O'Toole Paul W,Rosenberg Daniel W,Marchesi Julian R,Kinross James M
OBJECTIVE:In this consensus statement, an international panel of experts deliver their opinions on key questions regarding the contribution of the human microbiome to carcinogenesis. DESIGN:International experts in oncology and/or microbiome research were approached by personal communication to form a panel. A structured, iterative, methodology based around a 1-day roundtable discussion was employed to derive expert consensus on key questions in microbiome-oncology research. RESULTS:Some 18 experts convened for the roundtable discussion and five key questions were identified regarding: (1) the relevance of dysbiosis/an altered gut microbiome to carcinogenesis; (2) potential mechanisms of microbiota-induced carcinogenesis; (3) conceptual frameworks describing how the human microbiome may drive carcinogenesis; (4) causation versus association; and (5) future directions for research in the field.The panel considered that, despite mechanistic and supporting evidence from animal and human studies, there is currently no direct evidence that the human commensal microbiome is a key determinant in the aetiopathogenesis of cancer. The panel cited the lack of large longitudinal, cohort studies as a principal deciding factor and agreed that this should be a future research priority. However, while acknowledging gaps in the evidence, expert opinion was that the microbiome, alongside environmental factors and an epigenetically/genetically vulnerable host, represents one apex of a tripartite, multidirectional interactome that drives carcinogenesis. CONCLUSION:Data from longitudinal cohort studies are needed to confirm the role of the human microbiome as a key driver in the aetiopathogenesis of cancer.
Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE-Mediated Suppression of Antitumor Immunity.
Loo Tze Mun,Kamachi Fumitaka,Watanabe Yoshihiro,Yoshimoto Shin,Kanda Hiroaki,Arai Yuriko,Nakajima-Takagi Yaeko,Iwama Atsushi,Koga Tomoaki,Sugimoto Yukihiko,Ozawa Takayuki,Nakamura Masaru,Kumagai Miho,Watashi Koichi,Taketo Makoto M,Aoki Tomohiro,Narumiya Shuh,Oshima Masanobu,Arita Makoto,Hara Eiji,Ohtani Naoko
Obesity increases the risk of cancers, including hepatocellular carcinomas (HCC). However, the precise molecular mechanisms through which obesity promotes HCC development are still unclear. Recent studies have shown that gut microbiota may influence liver diseases by transferring its metabolites and components. Here, we show that the hepatic translocation of obesity-induced lipoteichoic acid (LTA), a Gram-positive gut microbial component, promotes HCC development by creating a tumor-promoting microenvironment. LTA enhances the senescence-associated secretory phenotype (SASP) of hepatic stellate cells (HSC) collaboratively with an obesity-induced gut microbial metabolite, deoxycholic acid, to upregulate the expression of SASP factors and COX2 through Toll-like receptor 2. Interestingly, COX2-mediated prostaglandin E (PGE) production suppresses the antitumor immunity through a PTGER4 receptor, thereby contributing to HCC progression. Moreover, COX2 overexpression and excess PGE production were detected in HSCs in human HCCs with noncirrhotic, nonalcoholic steatohepatitis (NASH), indicating that a similar mechanism could function in humans. We showed the importance of the gut-liver axis in obesity-associated HCC. The gut microbiota-driven COX2 pathway produced the lipid mediator PGE in senescent HSCs in the tumor microenvironment, which plays a pivotal role in suppressing antitumor immunity, suggesting that PGE and its receptor may be novel therapeutic targets for noncirrhotic NASH-associated HCC. .
Roles for Interleukin 17 and Adaptive Immunity in Pathogenesis of Colorectal Cancer.
Hurtado Christopher G,Wan Fengyi,Housseau Franck,Sears Cynthia L
Sporadic colorectal cancer is one of the most common and lethal cancers worldwide. The locations and functions of immune cells in the colorectal tumor microenvironment are complex and heterogeneous. T-helper (Th)1 cell-mediated responses against established colorectal tumors are associated with better outcomes of patients (time of relapse-free or overall survival), whereas Th17 cell-mediated responses and production of interleukin 17A (IL17A) have been associated with worse outcomes of patients. Tumors that develop in mouse models of colorectal cancer are rarely invasive and differ in many ways from human colorectal tumors. However, these mice have been used to study the mechanisms by which Th17 cells and IL17A promote colorectal tumor initiation and growth, which appear to involve their direct effects on colon epithelial cells. Specific members of the colonic microbiota may promote IL17A production and IL17A-producing cell functions in the colonic mucosa to promote carcinogenesis. Increasing our understanding of the interactions between the colonic microbiota and the mucosal immune response, the roles of Th17 cells and IL17 in these interactions, and how these processes are altered during colon carcinogenesis, could lead to new strategies for preventing or treating colorectal cancer.
A randomised trial of the effect of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota.
Watson Henry,Mitra Suparna,Croden Fiona C,Taylor Morag,Wood Henry M,Perry Sarah L,Spencer Jade A,Quirke Phil,Toogood Giles J,Lawton Clare L,Dye Louise,Loadman Paul M,Hull Mark A
OBJECTIVE:Omega-3 polyunsaturated fatty acids (PUFAs) have anticolorectal cancer (CRC) activity. The intestinal microbiota has been implicated in colorectal carcinogenesis. Dietary omega-3 PUFAs alter the mouse intestinal microbiome compatible with antineoplastic activity. Therefore, we investigated the effect of omega-3 PUFA supplements on the faecal microbiome in middle-aged, healthy volunteers (n=22). DESIGN:A randomised, open-label, cross-over trial of 8 weeks' treatment with 4 g mixed eicosapentaenoic acid/docosahexaenoic acid in two formulations (soft-gel capsules and Smartfish drinks), separated by a 12-week 'washout' period. Faecal samples were collected at five time-points for microbiome analysis by 16S ribosomal RNA PCR and Illumina MiSeq sequencing. Red blood cell (RBC) fatty acid analysis was performed by liquid chromatography tandem mass spectrometry. RESULTS:Both omega-3 PUFA formulations induced similar changes in RBC fatty acid content, except that drinks were associated with a larger, and more prolonged, decrease in omega-6 PUFA arachidonic acid than the capsule intervention (p=0.02). There were no significant changes in α or β diversity, or phyla composition, associated with omega-3 PUFA supplementation. However, a reversible increased abundance of several genera, including , and was observed with one or both omega-3 PUFA interventions. Microbiome changes did not correlate with RBC omega-3 PUFA incorporation or development of omega-3 PUFA-induced diarrhoea. There were no treatment order effects. CONCLUSION:Omega-3 PUFA supplementation induces a reversible increase in several short-chain fatty acid-producing bacteria, independently of the method of administration. There is no simple relationship between the intestinal microbiome and systemic omega-3 PUFA exposure. TRIAL REGISTRATION NUMBER:ISRCTN18662143.
Gavage of Fecal Samples From Patients With Colorectal Cancer Promotes Intestinal Carcinogenesis in Germ-Free and Conventional Mice.
Wong Sunny H,Zhao Liuyang,Zhang Xiang,Nakatsu Geicho,Han Juqiang,Xu Weiqi,Xiao Xue,Kwong Thomas N Y,Tsoi Ho,Wu William K K,Zeng Benhua,Chan Francis K L,Sung Joseph J Y,Wei Hong,Yu Jun
BACKGROUND & AIMS:Altered gut microbiota is implicated in development of colorectal cancer (CRC). Some intestinal bacteria have been reported to potentiate intestinal carcinogenesis by producing genotoxins, altering the immune response and intestinal microenvironment, and activating oncogenic signaling pathways. We investigated whether stool from patients with CRC could directly induce colorectal carcinogenesis in mice. METHODS:We obtained stored stool samples from participants in a metagenome study performed in Hong Kong. Conventional (male C57BL/6) mice were given azoxymethane to induce colon neoplasia after receiving a course of antibiotics in drinking water. Mice were gavaged twice weekly with stool from 5 patients with CRC or 5 healthy individuals (controls) for 5 weeks. Germ-free C57BL/6 mice were gavaged once with stool from 5 patients with CRC or 5 controls. We collected intestinal tissues from mice and performed histology, immunohistochemistry, expression microarray, quantitative polymerase chain reaction, immunoblot, and flow cytometry analyses. We performed 16S ribosomal RNA gene sequencing analysis of feces from mice. RESULTS:Significantly higher proportions of conventional mice fed with stool from individuals with CRC than control stool developed high-grade dysplasia (P < .05) and macroscopic polyps (P < .01). We observed a higher proportion of proliferating (Ki-67-positive) cells in colons of germ-free mice fed with stool from patients with CRC vs those fed with stool from controls (P < .05). Feces from germ-free and conventional mice fed with stool from patients with CRC vs controls contained different microbial compositions, with lower richness in mice fed with stool from patients with CRC. Intestines collected from conventional and germ-free mice fed with stool from patients with CRC had increased expression of cytokines that modulate inflammation, including C-X-C motif chemokine receptor 1, C-X-C motif chemokine receptor 2, interleukin 17A (IL17A), IL22, and IL23A. Intestines from conventional and germ-free mice fed with stool from patients with CRC contained higher proportions of T-helper 1 (Th1) cells (2.25% vs 0.44%) and Th17 cells (2.08% vs 0.31%) (P < .05 for each) than mice fed with stool from controls. Real-time polymerase chain reaction arrays revealed up-regulation of genes involved in cell proliferation, stemness, apoptosis, angiogenesis, invasiveness, and metastasis in mice fed with stool from patients with CRC. CONCLUSIONS:We fed stool samples from patients with CRC and heathy individuals to germ-free mice and conventional mice with azoxymethane. We found stool from patients with CRC to increase the numbers of polyps, levels of intestinal dysplasia and proliferation, markers of inflammation, and proportions of Th1 and Th17 cells in colon, compared with stool from individuals without CRC. This study provides evidence that the fecal microbiota from patients with CRC can promote tumorigenesis in germ-free mice and mice given a carcinogen.
Gut microbiota modulate T cell trafficking into human colorectal cancer.
Cremonesi Eleonora,Governa Valeria,Garzon Jesus Francisco Glaus,Mele Valentina,Amicarella Francesca,Muraro Manuele Giuseppe,Trella Emanuele,Galati-Fournier Virginie,Oertli Daniel,Däster Silvio Raffael,Droeser Raoul A,Weixler Benjamin,Bolli Martin,Rosso Raffaele,Nitsche Ulrich,Khanna Nina,Egli Adrian,Keck Simone,Slotta-Huspenina Julia,Terracciano Luigi M,Zajac Paul,Spagnoli Giulio Cesare,Eppenberger-Castori Serenella,Janssen Klaus-Peter,Borsig Lubor,Iezzi Giandomenica
OBJECTIVE:Tumour-infiltrating lymphocytes (TILs) favour survival in human colorectal cancer (CRC). Chemotactic factors underlying their recruitment remain undefined. We investigated chemokines attracting T cells into human CRCs, their cellular sources and microenvironmental triggers. DESIGN:Expression of genes encoding immune cell markers, chemokines and bacterial 16S ribosomal RNA (16SrRNA) was assessed by quantitative reverse transcription-PCR in fresh CRC samples and corresponding tumour-free tissues. Chemokine receptor expression on TILs was evaluated by flow cytometry on cell suspensions from digested tissues. Chemokine production by CRC cells was evaluated in vitro and in vivo, on generation of intraperitoneal or intracecal tumour xenografts in immune-deficient mice. T cell trafficking was assessed on adoptive transfer of human TILs into tumour-bearing mice. Gut flora composition was analysed by 16SrRNA sequencing. RESULTS:CRC infiltration by distinct T cell subsets was associated with defined chemokine gene signatures, including CCL5, CXCL9 and CXCL10 for cytotoxic T lymphocytes and T-helper (Th)1 cells; CCL17, CCL22 and CXCL12 for Th1 and regulatory T cells; CXCL13 for follicular Th cells; and CCL20 and CCL17 for interleukin (IL)-17-producing Th cells. These chemokines were expressed by tumour cells on exposure to gut bacteria in vitro and in vivo. Their expression was significantly higher in intracecal than in intraperitoneal xenografts and was dramatically reduced by antibiotic treatment of tumour-bearing mice. In clinical samples, abundance of defined bacteria correlated with high chemokine expression, enhanced T cell infiltration and improved survival. CONCLUSIONS:Gut microbiota stimulate chemokine production by CRC cells, thus favouring recruitment of beneficial T cells into tumour tissues.
Microbiota: a key orchestrator of cancer therapy.
Roy Soumen,Trinchieri Giorgio
Nature reviews. Cancer
The microbiota is composed of commensal bacteria and other microorganisms that live on the epithelial barriers of the host. The commensal microbiota is important for the health and survival of the organism. Microbiota influences physiological functions from the maintenance of barrier homeostasis locally to the regulation of metabolism, haematopoiesis, inflammation, immunity and other functions systemically. The microbiota is also involved in the initiation, progression and dissemination of cancer both at epithelial barriers and in sterile tissues. Recently, it has become evident that microbiota, and particularly the gut microbiota, modulates the response to cancer therapy and susceptibility to toxic side effects. In this Review, we discuss the evidence for the ability of the microbiota to modulate chemotherapy, radiotherapy and immunotherapy with a focus on the microbial species involved, their mechanism of action and the possibility of targeting the microbiota to improve anticancer efficacy while preventing toxicity.
SYK-CARD9 Signaling Axis Promotes Gut Fungi-Mediated Inflammasome Activation to Restrict Colitis and Colon Cancer.
Malik Ankit,Sharma Deepika,Malireddi R K Subbarao,Guy Clifford S,Chang Ti-Cheng,Olsen Scott R,Neale Geoffrey,Vogel Peter,Kanneganti Thirumala-Devi
Fungi represent a significant proportion of the gut microbiota. Aberrant immune responses to fungi are frequently observed in inflammatory bowel diseases (IBD) and colorectal cancer (CRC), and mutations in the fungal-sensing pathways are associated with the pathogenesis of IBD. Fungal recognition receptors trigger downstream signaling via the common adaptor protein CARD9 and the kinase SYK. Here we found that commensal gut fungi promoted inflammasome activation during AOM-DSS-induced colitis. Myeloid cell-specific deletion of Card9 or Syk reduced inflammasome activation and interleukin (IL)-18 maturation and increased susceptibility to colitis and CRC. IL-18 promoted epithelial barrier restitution and interferon-γ production by intestinal CD8 T cells. Supplementation of IL-18 or transfer of wild-type myeloid cells reduced tumor burden in AOM-DSS-treated Card9 and SykLysM mice, whereas treatment with anti-fungal agents exacerbated colitis and CRC. CARD9 deletion changes the gut microbial landscape, suggesting that SYK-CARD9 signaling maintains a microbial ecology that promotes inflammasome activation and thereby restrains colitis and colon tumorigenesis.
Gut dysbiosis: a potential link between increased cancer risk in ageing and inflammaging.
Biragyn Arya,Ferrucci Luigi
The Lancet. Oncology
Cancer incidence substantially increases with ageing in both men and women, although the reason for this increase is unknown. In this Series paper, we propose that age-associated changes in gut commensal microbes, otherwise known as the microbiota, facilitate cancer development and growth by compromising immune fitness. Ageing is associated with a reduction in the beneficial commensal microbes, which control the expansion of pathogenic commensals and maintain the integrity of the intestinal barrier through the production of mucus and lipid metabolites, such as short-chain fatty acids. Expansion of gut dysbiosis and leakage of microbial products contributes to the chronic proinflammatory state (inflammaging), which negatively affects the immune system and impairs the removal of mutant and senescent cells, thereby enabling tumour outgrowth. Studies in animal models and the importance of commensals in cancer immunotherapy suggest that this status can be reversible. Thus, interventions that alter the composition of the gut microbiota might reduce inflammaging and rejuvenate immune functions to provide anticancer benefits in frail elderly people.
Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer.
Association studies have linked microbiome alterations with many human diseases. However, they have not always reported consistent results, thereby necessitating cross-study comparisons. Here, a meta-analysis of eight geographically and technically diverse fecal shotgun metagenomic studies of colorectal cancer (CRC, n = 768), which was controlled for several confounders, identified a core set of 29 species significantly enriched in CRC metagenomes (false discovery rate (FDR) < 1 × 10). CRC signatures derived from single studies maintained their accuracy in other studies. By training on multiple studies, we improved detection accuracy and disease specificity for CRC. Functional analysis of CRC metagenomes revealed enriched protein and mucin catabolism genes and depleted carbohydrate degradation genes. Moreover, we inferred elevated production of secondary bile acids from CRC metagenomes, suggesting a metabolic link between cancer-associated gut microbes and a fat- and meat-rich diet. Through extensive validations, this meta-analysis firmly establishes globally generalizable, predictive taxonomic and functional microbiome CRC signatures as a basis for future diagnostics.
Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy.
Yu TaChung,Guo Fangfang,Yu Yanan,Sun Tiantian,Ma Dan,Han Jixuan,Qian Yun,Kryczek Ilona,Sun Danfeng,Nagarsheth Nisha,Chen Yingxuan,Chen Haoyan,Hong Jie,Zou Weiping,Fang Jing-Yuan
Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium (F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, our bioinformatic and functional studies demonstrated that F. nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F. nucleatum orchestrates a molecular network of the Toll-like receptor, microRNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F. nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes.
The microbiome and innate immunity.
Thaiss Christoph A,Zmora Niv,Levy Maayan,Elinav Eran
The intestinal microbiome is a signalling hub that integrates environmental inputs, such as diet, with genetic and immune signals to affect the host's metabolism, immunity and response to infection. The haematopoietic and non-haematopoietic cells of the innate immune system are located strategically at the host-microbiome interface. These cells have the ability to sense microorganisms or their metabolic products and to translate the signals into host physiological responses and the regulation of microbial ecology. Aberrations in the communication between the innate immune system and the gut microbiota might contribute to complex diseases.
Gut microbiota in colorectal cancer: mechanisms of action and clinical applications.
Wong Sunny H,Yu Jun
Nature reviews. Gastroenterology & hepatology
Colorectal cancer (CRC) accounts for about 10% of all new cancer cases globally. Located at close proximity to the colorectal epithelium, the gut microbiota comprises a large population of microorganisms that interact with host cells to regulate many physiological processes, such as energy harvest, metabolism and immune response. Sequencing studies have revealed microbial compositional and ecological changes in patients with CRC, whereas functional studies in animal models have pinpointed the roles of several bacteria in colorectal carcinogenesis, including Fusobacterium nucleatum and certain strains of Escherichia coli and Bacteroides fragilis. These findings give new opportunities to take advantage of our knowledge on the gut microbiota for clinical applications, such as gut microbiota analysis as screening, prognostic or predictive biomarkers, or modulating microorganisms to prevent cancer, augment therapies and reduce adverse effects of treatment. This Review aims to provide an overview and discussion of the gut microbiota in colorectal neoplasia, including relevant mechanisms in microbiota-related carcinogenesis, the potential of utilizing the microbiota as CRC biomarkers, and the prospect for modulating the microbiota for CRC prevention or treatment. These scientific findings will pave the way to clinically translate the use of gut microbiota for CRC in the near future.
The Adaptor Protein CARD9 Protects against Colon Cancer by Restricting Mycobiota-Mediated Expansion of Myeloid-Derived Suppressor Cells.
Wang Tingting,Fan Chaogang,Yao Anran,Xu Xingwei,Zheng Guoxing,You Yun,Jiang Changying,Zhao Xueqiang,Hou Yayi,Hung Mien-Chie,Lin Xin
The adaptor protein CARD9 links detection of fungi by surface receptors to the activation of the NF-κB pathway. Mice deficient in CARD9 exhibit dysbiosis and are more susceptible to colitis. Here we examined the impact of Card9 deficiency in the development of colitis-associated colon cancer (CAC). Treatment of Card9 mice with AOM-DSS resulted in increased tumor loads as compared to WT mice and in the accumulation of myeloid-derived suppressor cells (MDSCs) in tumor tissue. The impaired fungicidal functions of Card9 macrophages led to increased fungal loads and variation in the overall composition of the intestinal mycobiota, with a notable increase in C. tropicalis. Bone marrow cells incubated with C. tropicalis exhibited MDSC features and suppressive functions. Fluconazole treatment suppressed CAC in Card9 mice and was associated with decreased MDSC accumulation. The frequency of MDSCs in tumor tissues of colon cancer patients correlated positively with fungal burden, pointing to the relevance of this regulatory axis in human disease.
Trapping of Lipopolysaccharide to Promote Immunotherapy against Colorectal Cancer and Attenuate Liver Metastasis.
Song Wantong,Tiruthani Karthik,Wang Ying,Shen Limei,Hu Mengying,Dorosheva Oleksandra,Qiu Kunyu,Kinghorn Karina A,Liu Rihe,Huang Leaf
Advanced materials (Deerfield Beach, Fla.)
The development and progression of colorectal cancer (CRC) is closely related to gut microbiome. Here, the impact of lipopolysaccharide (LPS), one of the most prevalent products in the gut microbiome, on CRC immunotherapy is investigated. It is found that LPS is abundant in orthotopic CRC tissue and is associated with low responses to anti-PD-L1 mAb therapy, and clearance of Gram-negative bacteria from the gut using polymyxin B (PmB) or blockade of Toll-like receptor 4 using TAK-242 will both relieve the immunosuppressive microenvironment and boost T-cell infiltration into the CRC tumor. Further, an engineered LPS-targeting fusion protein is designed and its coding sequence is loaded into a lipid-protamine-DNA (LPD) nanoparticle system for selective expression of LPS trap protein and blocking LPS inside the tumor, and this nanotrapping system significantly relieves the immunosuppressive microenvironment and boosts anti-PD-L1 mAb therapy against CRC tumors. This LPS trap system even attenuates CRC liver metastasis when applied, suggesting the importance of blocking LPS in the gut-liver axis. The strategy applied here may provide a useful new way for treating CRC as well as other epithelial cancers that interact with mucosa microbiome.
Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System.
Postler Thomas Siegmund,Ghosh Sankar
The human gastrointestinal tract is populated by a diverse, highly mutualistic microbial flora, which is known as the microbiome. Disruptions to the microbiome have been shown to be associated with severe pathologies of the host, including metabolic disease, cancer, and inflammatory bowel disease. Mood and behavior are also susceptible to alterations in the gut microbiota. A particularly striking example of the symbiotic effects of the microbiome is the immune system, whose cells depend critically on a diverse array of microbial metabolites for normal development and behavior. This includes metabolites that are produced by bacteria from dietary components, metabolites that are produced by the host and biochemically modified by gut bacteria, and metabolites that are synthesized de novo by gut microbes. In this review, we highlight the role of the intestinal microbiome in human metabolic and inflammatory diseases and focus in particular on the molecular mechanisms that govern the gut-immune axis.
Meta-analysis of gut microbiome studies identifies disease-specific and shared responses.
Duvallet Claire,Gibbons Sean M,Gurry Thomas,Irizarry Rafael A,Alm Eric J
Hundreds of clinical studies have demonstrated associations between the human microbiome and disease, yet fundamental questions remain on how we can generalize this knowledge. Results from individual studies can be inconsistent, and comparing published data is further complicated by a lack of standard processing and analysis methods. Here we introduce the MicrobiomeHD database, which includes 28 published case-control gut microbiome studies spanning ten diseases. We perform a cross-disease meta-analysis of these studies using standardized methods. We find consistent patterns characterizing disease-associated microbiome changes. Some diseases are associated with over 50 genera, while most show only 10-15 genus-level changes. Some diseases are marked by the presence of potentially pathogenic microbes, whereas others are characterized by a depletion of health-associated bacteria. Furthermore, we show that about half of genera associated with individual studies are bacteria that respond to more than one disease. Thus, many associations found in case-control studies are likely not disease-specific but rather part of a non-specific, shared response to health and disease.
Gut microbiota injury in allogeneic haematopoietic stem cell transplantation.
Shono Yusuke,van den Brink Marcel R M
Nature reviews. Cancer
Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered to be the strongest curative immunotherapy for various malignancies (primarily, but not limited to, haematologic malignancies). However, application of allo-HSCT is limited owing to its life-threatening major complications, such as graft-versus-host disease (GVHD), relapse and infections. Recent advances in large-scale DNA sequencing technology have facilitated rapid identification of the microorganisms that make up the microbiota and evaluation of their interactions with host immunity in various diseases, including cancer. This has resulted in renewed interest regarding the role of the intestinal flora in patients with haematopoietic malignancies who have received an allo-HSCT and in whether the microbiota affects clinical outcomes, including GVHD, relapse, infections and transplant-related mortality. In this Review, we discuss the potential role of intestinal microbiota in these major complications after allo-HSCT, summarize clinical trials evaluating the microbiota in patients who have received allo-HSCT and discuss how further studies of the microbiota could inform the development of strategies that improve outcomes of allo-HSCT.
Human gut microbiome: hopes, threats and promises.
Cani Patrice D
The microbiome has received increasing attention over the last 15 years. Although gut microbes have been explored for several decades, investigations of the role of microorganisms that reside in the human gut has attracted much attention beyond classical infectious diseases. For example, numerous studies have reported changes in the gut microbiota during not only obesity, diabetes, and liver diseases but also cancer and even neurodegenerative diseases. The human gut microbiota is viewed as a potential source of novel therapeutics. Between 2013 and 2017, the number of publications focusing on the gut microbiota was, remarkably, 12 900, which represents four-fifths of the total number of publications over the last 40 years that investigated this topic. This review discusses recent evidence of the impact of the gut microbiota on metabolic disorders and focus on selected key mechanisms. This review also aims to provide a critical analysis of the current knowledge in this field, identify putative key issues or problems and discuss misinterpretations. The abundance of metagenomic data generated on comparing diseased and healthy subjects can lead to the erroneous claim that a bacterium is causally linked with the protection or the onset of a disease. In fact, environmental factors such as dietary habits, drug treatments, intestinal motility and stool frequency and consistency are all factors that influence the composition of the microbiota and should be considered. The cases of the bacteria and will be discussed as key examples.
Leveraging sequence-based faecal microbial community survey data to identify a composite biomarker for colorectal cancer.
Shah Manasi S,DeSantis Todd Z,Weinmaier Thomas,McMurdie Paul J,Cope Julia L,Altrichter Adam,Yamal Jose-Miguel,Hollister Emily B
OBJECTIVE:Colorectal cancer (CRC) is the second leading cause of cancer-associated mortality in the USA. The faecal microbiome may provide non-invasive biomarkers of CRC and indicate transition in the adenoma-carcinoma sequence. Re-analysing raw sequence and metadata from several studies uniformly, we sought to identify a composite and generalisable microbial marker for CRC. DESIGN:Raw 16S rRNA gene sequence data sets from nine studies were processed with two pipelines, (1) QIIME closed reference (QIIME-CR) or (2) a strain-specific method herein termed SS-UP (Strain Select, UPARSE bioinformatics pipeline). A total of 509 samples (79 colorectal adenoma, 195 CRC and 235 controls) were analysed. Differential abundance, meta-analysis random effects regression and machine learning analyses were carried out to determine the consistency and diagnostic capabilities of potential microbial biomarkers. RESULTS:Definitive taxa, including ATCC 33270, and yet-to-be-cultured members of Proteobacteria, were frequently and significantly increased in stools from patients with CRC compared with controls across studies and had high discriminatory capacity in diagnostic classification. Microbiome-based CRC versus control classification produced an area under receiver operator characteristic (AUROC) curve of 76.6% in QIIME-CR and 80.3% in SS-UP. Combining clinical and microbiome markers gave a diagnostic AUROC of 83.3% for QIIME-CR and 91.3% for SS-UP. CONCLUSIONS:Despite technological differences across studies and methods, key microbial markers emerged as important in classifying CRC cases and such could be used in a universal diagnostic for the disease. The choice of bioinformatics pipeline influenced accuracy of classification. Strain-resolved microbial markers might prove crucial in providing a microbial diagnostic for CRC.
The Intestinal Microbiota in Colorectal Cancer.
Tilg Herbert,Adolph Timon E,Gerner Romana R,Moschen Alexander R
Experimental evidence from the past years highlights a key role for the intestinal microbiota in inflammatory and malignant gastrointestinal diseases. Diet exhibits a strong impact on microbial composition and provides risk for developing colorectal carcinoma (CRC). Large metagenomic studies in human CRC associated microbiome signatures with the colorectal adenoma-carcinoma sequence, suggesting a fundamental role of the intestinal microbiota in the evolution of gastrointestinal malignancy. Basic science established a critical function for the intestinal microbiota in promoting tumorigenesis. Further studies are needed to decipher the mechanisms of tumor promotion and microbial co-evolution in CRC, which may be exploited therapeutically in the future.
Gut Microbiota Promotes Tumor Growth in Mice by Modulating Immune Response.
Sethi Vrishketan,Kurtom Saba,Tarique Mohammad,Lavania Shweta,Malchiodi Zoe,Hellmund Leonor,Zhang Li,Sharma Umakant,Giri Bhuwan,Garg Bharti,Ferrantella Anthony,Vickers Selwyn M,Banerjee Sulagna,Dawra Rajinder,Roy Sabita,Ramakrishnan Sundaram,Saluja Ashok,Dudeja Vikas
We studied the effects of gut microbiome depletion by oral antibiotics on tumor growth in subcutaneous and liver metastases models of pancreatic cancer, colon cancer, and melanoma. Gut microbiome depletion significantly reduced tumor burden in all the models tested. However, depletion of gut microbiome did not reduce tumor growth in Rag1-knockout mice, which lack mature T and B cells. Flow cytometry analyses demonstrated that gut microbiome depletion led to significant increase in interferon gamma-producing T cells with corresponding decrease in interleukin 17A and interleukin 10-producing T cells. Our results suggest that gut microbiome modulation could emerge as a novel immunotherapeutic strategy.
Molecular Basis of Gut Microbiome-Associated Colorectal Cancer: A Synthetic Perspective.
Healy Alan R,Herzon Seth B
Journal of the American Chemical Society
A significant challenge toward studies of the human microbiota involves establishing causal links between bacterial metabolites and human health and disease states. Certain strains of commensal Escherichia coli harbor the 54-kb clb gene cluster which codes for small molecules named precolibactins and colibactins. Several studies suggest colibactins are genotoxins and support a role for clb metabolites in colorectal cancer formation. Significant advances toward elucidating the structures and biosynthesis of the precolibactins and colibactins have been made using genetic approaches, but their full structures remain unknown. In this Perspective we describe recent synthetic efforts that have leveraged biosynthetic advances and shed light on the mechanism of action of clb metabolites. These studies indicate that deletion of the colibactin peptidase ClbP, a modification introduced to promote accumulation of precolibactins, leads to the production of non-genotoxic pyridone-based isolates derived from the diversion of linear biosynthetic intermediates toward alternative cyclization pathways. Furthermore, these studies suggest the active genotoxins (colibactins) are unsaturated imines that are potent DNA damaging agents, thereby confirming an earlier mechanism of action hypothesis. Although these imines have very recently been detected in bacterial extracts, they have to date confounded isolation. As the power of "meta-omics" approaches to natural products discovery further advance, we anticipate that chemical synthetic and biosynthetic studies will become increasingly interdependent.
Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells.
Ma Chi,Han Miaojun,Heinrich Bernd,Fu Qiong,Zhang Qianfei,Sandhu Milan,Agdashian David,Terabe Masaki,Berzofsky Jay A,Fako Valerie,Ritz Thomas,Longerich Thomas,Theriot Casey M,McCulloch John A,Roy Soumen,Yuan Wuxing,Thovarai Vishal,Sen Shurjo K,Ruchirawat Mathuros,Korangy Firouzeh,Wang Xin Wei,Trinchieri Giorgio,Greten Tim F
Science (New York, N.Y.)
Primary liver tumors and liver metastasis currently represent the leading cause of cancer-related death. Commensal bacteria are important regulators of antitumor immunity, and although the liver is exposed to gut bacteria, their role in antitumor surveillance of liver tumors is poorly understood. We found that altering commensal gut bacteria in mice induced a liver-selective antitumor effect, with an increase of hepatic CXCR6 natural killer T (NKT) cells and heightened interferon-γ production upon antigen stimulation. In vivo functional studies showed that NKT cells mediated liver-selective tumor inhibition. NKT cell accumulation was regulated by CXCL16 expression of liver sinusoidal endothelial cells, which was controlled by gut microbiome-mediated primary-to-secondary bile acid conversion. Our study suggests a link between gut bacteria-controlled bile acid metabolism and liver antitumor immunosurveillance.
The microbiome in cancer immunotherapy: Diagnostic tools and therapeutic strategies.
Zitvogel Laurence,Ma Yuting,Raoult Didier,Kroemer Guido,Gajewski Thomas F
Science (New York, N.Y.)
The fine line between human health and disease can be driven by the interplay between host and microbial factors. This "metagenome" regulates cancer initiation, progression, and response to therapies. Besides the capacity of distinct microbial species to modulate the pharmacodynamics of chemotherapeutic drugs, symbiosis between epithelial barriers and their microbial ecosystems has a major impact on the local and distant immune system, markedly influencing clinical outcome in cancer patients. Efficacy of cancer immunotherapy with immune checkpoint antibodies can be diminished with administration of antibiotics, and superior efficacy is observed with the presence of specific gut microbes. Future strategies of precision medicine will likely rely on novel diagnostic and therapeutic tools with which to identify and correct defects in the microbiome that compromise therapeutic efficacy.
The gut microbiota and gastrointestinal surgery.
Guyton Kristina,Alverdy John C
Nature reviews. Gastroenterology & hepatology
Surgery involving the gastrointestinal tract continues to prove challenging because of the persistence of unpredictable complications such as anastomotic leakage and life-threatening infections. Removal of diseased intestinal segments results in substantial catabolic stress and might require complex reconstructive surgery to maintain the functional continuity of the intestinal tract. As gastrointestinal surgery necessarily involves a breach of an epithelial barrier colonized by microorganisms, preoperative intestinal antisepsis is used to reduce infection-related complications. The current approach to intestinal antisepsis varies widely across institutions and countries with little understanding of its mechanism of action, effect on the gut microbiota and overall efficacy. Many of the current approaches to intestinal antisepsis before gastrointestinal surgery run counter to emerging concepts of intestinal microbiota contributing to immune function and recovery from injury. Here, we review evidence outlining the role of gut microbiota in recovery from gastrointestinal surgery, particularly in the development of infections and anastomotic leak. To make surgery safer and further reduce complications, a molecular, genetic and functional understanding of the response of the gastrointestinal tract to alterations in its microbiota is needed. Methods can then be developed to preserve the health-promoting functions of the microbiota while at the same time suppressing their harmful effects.
The microbiome, cancer, and cancer therapy.
Helmink Beth A,Khan M A Wadud,Hermann Amanda,Gopalakrishnan Vancheswaran,Wargo Jennifer A
With the advent of next-generation sequencing, we have an unprecedented ability to study tumor and host genomes as well as those of the vast array of microorganisms that exist within living organisms. Evidence now suggests that these microbes may confer susceptibility to certain cancers and may also influence response to therapeutics. A prime example of this is seen with immunotherapy, for which gut microbes have been implicated in influencing therapeutic responses in preclinical models and patient cohorts. However, these microbes may influence responses to other forms of therapy as well and may also affect treatment-associated toxicity. Based on these influences, there is growing interest in targeting these microbes in the treatment of cancer and other diseases. Yet complexities exist, and a deeper understanding of host-microbiome interactions is critical to realization of the full potential of such approaches. These concepts and the means through which such findings may be translated into the clinic will be discussed herein.
The gut microbiome and liver cancer: mechanisms and clinical translation.
Yu Le-Xing,Schwabe Robert F
Nature reviews. Gastroenterology & hepatology
Hepatocellular carcinoma (HCC) is the third leading cause of worldwide cancer mortality. HCC almost exclusively develops in patients with chronic liver disease, driven by a vicious cycle of liver injury, inflammation and regeneration that typically spans decades. Increasing evidence points towards a key role of the bacterial microbiome in promoting the progression of liver disease and the development of HCC. Here, we will review mechanisms by which the gut microbiota promotes hepatocarcinogenesis, focusing on the leaky gut, bacterial dysbiosis, microbe-associated molecular patterns and bacterial metabolites as key pathways that drive cancer-promoting liver inflammation, fibrosis and genotoxicity. On the basis of accumulating evidence from preclinical studies, we propose the intestinal-microbiota-liver axis as a promising target for the simultaneous prevention of chronic liver disease progression and HCC development in patients with advanced liver disease. We will review in detail therapeutic modalities and discuss clinical settings in which targeting the gut-microbiota-liver axis for the prevention of disease progression and HCC development seems promising.
A microbiota-centric view of diseases of the upper gastrointestinal tract.
Nardone Gerardo,Compare Debora,Rocco Alba
The lancet. Gastroenterology & hepatology
The distinctive anatomy and physiology of the upper gastrointestinal tract and the difficulty of obtaining samples led to the theory that it was bacteria free. However, multiomics studies are indicating otherwise. Although influenced by both oral and gastric bacteria, the resident microbial ecosystem in the oesophagus is dominated by Streptococcus. A shift from Gram-positive to Gram-negative bacteria occurs in oesophagitis and Barrett's oesophagus, and this shift might be involved in the pathogenesis of oesophageal adenocarcinoma. The gastric microenvironment is populated by microbial communities mainly of the Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria phyla and species of the Lactobacillus, Streptococcus, and Propionibacterium genera. The composition of gastric microbiota is highly dynamic, and is influenced by acid suppression, gastric inflammation, and Helicobacter pylori. Duodenal microbes are also implicated in the onset and outcome of coeliac disease. Bacteria of the genera Bacteroides, Clostridium, and Staphylococcus dominate the duodenal flora in active coeliac disease whereas lactobacilli and bifidobacteria decrease. Although knowledge of the composition of the microbiota of the upper gastrointestinal tract has advanced substantially, this information is far from being translated to the clinical setting. In this Review, we assess the data related to the potential contribution of microbes to the susceptibility for and pathogenesis of upper gastrointestinal diseases.
Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis.
Jia Wei,Xie Guoxiang,Jia Weiping
Nature reviews. Gastroenterology & hepatology
Emerging evidence points to a strong association between the gut microbiota and the risk, development and progression of gastrointestinal cancers such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Bile acids, produced in the liver, are metabolized by enzymes derived from intestinal bacteria and are critically important for maintaining a healthy gut microbiota, balanced lipid and carbohydrate metabolism, insulin sensitivity and innate immunity. Given the complexity of bile acid signalling and the direct biochemical interactions between the gut microbiota and the host, a systems biology perspective is required to understand the liver-bile acid-microbiota axis and its role in gastrointestinal carcinogenesis to reverse the microbiota-mediated alterations in bile acid metabolism that occur in disease states. An examination of recent research progress in this area is urgently needed. In this Review, we discuss the mechanistic links between bile acids and gastrointestinal carcinogenesis in CRC and HCC, which involve two major bile acid-sensing receptors, farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5). We also highlight the strategies and cutting-edge technologies to target gut-microbiota-dependent alterations in bile acid metabolism in the context of cancer therapy.
Adiposity and gastrointestinal cancers: epidemiology, mechanisms and future directions.
Murphy Neil,Jenab Mazda,Gunter Marc J
Nature reviews. Gastroenterology & hepatology
Excess adiposity is a risk factor for several cancers of the gastrointestinal system, specifically oesophageal adenocarcinoma and colorectal, small intestine, pancreatic, liver, gallbladder and stomach cancers. With the increasing prevalence of obesity in nearly all regions of the world, this relationship could represent a growing source of cancers of the digestive system. Experimental and molecular epidemiological studies indicate important roles for alterations in insulin signalling, adipose tissue-derived inflammation and sex hormone pathways in mediating the association between adiposity and gastrointestinal cancer. The intestinal microbiome, gut hormones and non alcoholic fatty liver disease (NAFLD) also have possible roles. However, important gaps remain in our knowledge. For instance, our understanding of how adiposity throughout the life course is related to the risk of gastrointestinal cancer development and of how obesity influences gastrointestinal cancer prognosis and survival is limited. Nonetheless, the increasing use of state-of-the-art analytical methods (such as omics technologies, Mendelian randomization and MRI) in large-scale epidemiological studies offers exciting opportunities to advance our understanding of the complex relationship between adiposity and gastrointestinal cancers. Here, we examine the epidemiology of associations between obesity and gastrointestinal cancer, explore potential mechanisms underlying these relationships and highlight important unanswered research questions.
Gut microbiota-mediated inflammation in obesity: a link with gastrointestinal cancer.
Cani Patrice D,Jordan Benedicte F
Nature reviews. Gastroenterology & hepatology
Overweight and obesity are associated with increased risk of developing metabolic disorders such as diabetes and cardiovascular diseases. However, besides these metabolic diseases, excess body weight is also associated with different cancers, including gastrointestinal cancers, such as liver, pancreatic and colon cancers. Inflammation is a common feature of both obesity and cancer; however, the origin of this inflammation has been largely debated. Over the past decade, growing evidence has shown that the composition of the gut microbiota and its activity might be associated not only with the onset of inflammation but also with metabolic disorders and cancer. Here, we review the links between the gut microbiota, gut barrier function and the onset of low-grade inflammation in the development of gastrointestinal cancer. We also describe the mechanisms by which specific microorganism-associated molecular patterns crosstalk with the immune system and how the metabolic activity of bacteria induces specific signalling pathways beyond the gut that eventually trigger carcinogenesis.
Energy balance and gastrointestinal cancer: risk, interventions, outcomes and mechanisms.
Ulrich Cornelia M,Himbert Caroline,Holowatyj Andreana N,Hursting Stephen D
Nature reviews. Gastroenterology & hepatology
Obesity increases the risk of multiple gastrointestinal cancers and worsens disease outcomes. Conversely, strong inverse associations have emerged between physical activity and colon cancer and possibly other gastrointestinal malignancies. The effect of weight loss interventions - such as modifications of diet and/or physical activity or bariatric surgery - remains unclear in patients who are obese and have gastrointestinal cancer, although large clinical trials are underway. Human intervention studies have already shed light on potential mechanisms underlying the energy balance-cancer relationship, with preclinical models supporting emerging pathway effects. Central to interventions that reduce obesity or increase physical activity are pluripotent cancer-preventive effects (including reduced systemic and adipose tissue inflammation and angiogenesis, altered adipokine levels and improved insulin resistance) that directly interface with the hallmarks of cancer. Other mechanisms, such as DNA repair, oxidative stress and telomere length, immune function, effects on cancer stem cells and the microbiome, could also contribute to energy balance effects on gastrointestinal cancers. Although some mechanisms are well understood (for instance, systemic effects on inflammation and insulin signalling), other areas remain unclear. The current state of knowledge supports the need to better integrate mechanistic approaches with preclinical and human studies to develop effective, personalized diet and exercise interventions to reduce the burden of obesity on gastrointestinal cancer.
An obesity-associated gut microbiome reprograms the intestinal epigenome and leads to altered colonic gene expression.
Qin Yufeng,Roberts John D,Grimm Sara A,Lih Fred B,Deterding Leesa J,Li Ruifang,Chrysovergis Kaliopi,Wade Paul A
BACKGROUND:The gut microbiome, a key constituent of the colonic environment, has been implicated as an important modulator of human health. The eukaryotic epigenome is postulated to respond to environmental stimuli through alterations in chromatin features and, ultimately, gene expression. How the host mediates epigenomic responses to gut microbiota is an emerging area of interest. Here, we profile the gut microbiome and chromatin characteristics in colon epithelium from mice fed either an obesogenic or control diet, followed by an analysis of the resultant changes in gene expression. RESULTS:The obesogenic diet shapes the microbiome prior to the development of obesity, leading to altered bacterial metabolite production which predisposes the host to obesity. This microbiota-diet interaction leads to changes in histone modification at active enhancers that are enriched for binding sites for signal responsive transcription factors. These alterations of histone methylation and acetylation are associated with signaling pathways integral to the development of colon cancer. The transplantation of obesogenic diet-conditioned microbiota into germ free mice, combined with an obesogenic diet, recapitulates the features of the long-term diet regimen. The diet/microbiome-dependent changes are reflected in both the composition of the recipient animals' microbiome as well as in the set of transcription factor motifs identified at diet-influenced enhancers. CONCLUSIONS:These findings suggest that the gut microbiome, under specific dietary exposures, stimulates a reprogramming of the enhancer landscape in the colon, with downstream effects on transcription factors. These chromatin changes may be associated with those seen during colon cancer development.
Genetic Factors and the Intestinal Microbiome Guide Development of Microbe-Based Therapies for Inflammatory Bowel Diseases.
Cohen Louis J,Cho Judy H,Gevers Dirk,Chu Hiutung
The intestinal microbiota is a dynamic community of bacteria, fungi, and viruses that mediates mucosal homeostasis and physiology. Imbalances in the microbiome and aberrant immune responses to gut bacteria can disrupt homeostasis and are associated with inflammatory bowel diseases (IBDs) in humans and colitis in mice. We review genetic variants associated with IBD and their effects on the intestinal microbiome, the immune response, and disease pathogenesis. The intestinal microbiome, which includes microbial antigens, adjuvants, and metabolic products, affects the development and function of the intestinal mucosa, influencing inflammatory responses in the gut. Therefore, strategies to manipulate the microbiome might be used in treatment of IBD. We review microbe-based therapies for IBD and the potential to engineer patients' intestinal microbiota. We discuss how studies of patients with IBD and mouse models have advanced our understanding of the interactions between genetic factors and the gut microbiome, and challenges to the development of microbe-based therapies for IBD.
The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy.
Gopalakrishnan Vancheswaran,Helmink Beth A,Spencer Christine N,Reuben Alexandre,Wargo Jennifer A
The microbiome is receiving significant attention given its influence on a host of human diseases including cancer. Its role in response to cancer treatment is becoming increasingly apparent, with evidence suggesting that modulating the gut microbiome may affect responses to numerous forms of cancer therapy. A working knowledge of the microbiome is vital as we move forward in this age of precision medicine, and an understanding of the microbiome's influence on immune responses and cancer is key. It is also important to understand factors influencing the gut microbiome and strategies to manipulate the microbiome to augment therapeutic responses.
Gut Reactions: Breaking Down Xenobiotic-Microbiome Interactions.
Clarke Gerard,Sandhu Kiran V,Griffin Brendan T,Dinan Timothy G,Cryan John F,Hyland Niall P
The microbiome plays a key role in health and disease, and there has been considerable interest in therapeutic targeting of the microbiome as well as mining this rich resource in drug discovery efforts. However, a growing body of evidence suggests that the gut microbiota can itself influence the actions of a range of xenobiotics, in both beneficial and potentially harmful ways. Traditionally, clinical studies evaluating the pharmacokinetics of new drugs have mostly ignored the important direct and indirect effects of the gut microbiome on drug metabolism and efficacy. Despite some important observations from xenobiotic metabolism in general, there is only an incomplete understanding of the scope of influence of the microbiome specifically on drug metabolism and absorption, and how this might influence systemic concentrations of parent compounds and toxic metabolites. The significance of both microbial metabolism of xenobiotics and the impact of the gut microbiome on host hepatic enzyme systems is nonetheless gaining traction and presents a further challenge in drug discovery efforts, with implications for improving treatment outcomes or counteracting adverse drug reactions. Microbial factors must now be considered when determining drug pharmacokinetics and the impact that an evolving and dynamic microbiome could have in this regard. In this review, we aim to integrate the contribution of the gut microbiome in health and disease to xenobiotic metabolism focusing on therapeutic interventions, pharmacological drug action, and chemical biotransformations that collectively will have implications for the future practice of precision medicine.
The gut-liver axis and the intersection with the microbiome.
Tripathi Anupriya,Debelius Justine,Brenner David A,Karin Michael,Loomba Rohit,Schnabl Bernd,Knight Rob
Nature reviews. Gastroenterology & hepatology
In the past decade, an exciting realization has been that diverse liver diseases - ranging from nonalcoholic steatohepatitis, alcoholic steatohepatitis and cirrhosis to hepatocellular carcinoma - fall along a spectrum. Work on the biology of the gut-liver axis has assisted in understanding the basic biology of both alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD). Of immense importance is the advancement in understanding the role of the microbiome, driven by high-throughput DNA sequencing and improved computational techniques that enable the complexity of the microbiome to be interrogated, together with improved experimental designs. Here, we review gut-liver communications in liver disease, exploring the molecular, genetic and microbiome relationships and discussing prospects for exploiting the microbiome to determine liver disease stage and to predict the effects of pharmaceutical, dietary and other interventions at a population and individual level. Although much work remains to be done in understanding the relationship between the microbiome and liver disease, rapid progress towards clinical applications is being made, especially in study designs that complement human intervention studies with mechanistic work in mice that have been humanized in multiple respects, including the genetic, immunological and microbiome characteristics of individual patients. These 'avatar mice' could be especially useful for guiding new microbiome-based or microbiome-informed therapies.
Cross-Domain and Viral Interactions in the Microbiome.
Rowan-Nash Aislinn D,Korry Benjamin J,Mylonakis Eleftherios,Belenky Peter
Microbiology and molecular biology reviews : MMBR
The importance of the microbiome to human health is increasingly recognized and has become a major focus of recent research. However, much of the work has focused on a few aspects, particularly the bacterial component of the microbiome, most frequently in the gastrointestinal tract. Yet humans and other animals can be colonized by a wide array of organisms spanning all domains of life, including bacteria and archaea, unicellular eukaryotes such as fungi, multicellular eukaryotes such as helminths, and viruses. As they share the same host niches, they can compete with, synergize with, and antagonize each other, with potential impacts on their host. Here, we discuss these major groups making up the human microbiome, with a focus on how they interact with each other and their multicellular host.
Temporal development of the gut microbiome in early childhood from the TEDDY study.
The development of the microbiome from infancy to childhood is dependent on a range of factors, with microbial-immune crosstalk during this time thought to be involved in the pathobiology of later life diseases such as persistent islet autoimmunity and type 1 diabetes. However, to our knowledge, no studies have performed extensive characterization of the microbiome in early life in a large, multi-centre population. Here we analyse longitudinal stool samples from 903 children between 3 and 46 months of age by 16S rRNA gene sequencing (n = 12,005) and metagenomic sequencing (n = 10,867), as part of the The Environmental Determinants of Diabetes in the Young (TEDDY) study. We show that the developing gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3-14), a transitional phase (months 15-30), and a stable phase (months 31-46). Receipt of breast milk, either exclusive or partial, was the most significant factor associated with the microbiome structure. Breastfeeding was associated with higher levels of Bifidobacterium species (B. breve and B. bifidum), and the cessation of breast milk resulted in faster maturation of the gut microbiome, as marked by the phylum Firmicutes. Birth mode was also significantly associated with the microbiome during the developmental phase, driven by higher levels of Bacteroides species (particularly B. fragilis) in infants delivered vaginally. Bacteroides was also associated with increased gut diversity and faster maturation, regardless of the birth mode. Environmental factors including geographical location and household exposures (such as siblings and furry pets) also represented important covariates. A nested case-control analysis revealed subtle associations between microbial taxonomy and the development of islet autoimmunity or type 1 diabetes. These data determine the structural and functional assembly of the microbiome in early life and provide a foundation for targeted mechanistic investigation into the consequences of microbial-immune crosstalk for long-term health.
Regional Diversity of the Gastrointestinal Microbiome.
Martinez-Guryn Kristina,Leone Vanessa,Chang Eugene B
Cell host & microbe
The role of gut microbes in health and disease has often been surmised from stool, which is easily sampled and rich in microbial diversity, density, and abundance. Microbial analyses of stool have been accepted as measures to determine the relationship of gut microbiomes with host health and disease, based on the belief that it represents all microbial populations throughout the gut. However, functional heterogeneity of each gastrointestinal tract (GIT) segment gives rise to regional differences in gut microbial populations. Herein, we summarize the literature regarding the microbial landscape along the rostral to caudal, i.e., horizontal mouth to anus, axis of the GIT. We aim to identify gaps in the literature, particularly regarding small intestinal microbiota abundance and diversity, highlight the importance of regional microbiota on host health and disease, as well as discuss opportunities to advance this line of research.
Human Gut Microbiome: Function Matters.
Heintz-Buschart Anna,Wilmes Paul
Trends in microbiology
The human gut microbiome represents a complex ecosystem contributing essential functions to its host. Recent large-scale metagenomic studies have provided insights into its structure and functional potential. However, the functional repertoire which is actually contributed to human physiology remains largely unexplored. Here, by leveraging recent omics datasets, we challenge current assumptions regarding key attributes of the functional gut microbiome, in particular with respect to its variability. We further argue that the closing of existing gaps in functional knowledge should be addressed by a most-wanted gene list, the development and application of molecular and cellular high-throughput measurements, the development and sensible use of experimental models, as well as the direct study of observable molecular effects in the human host.
Impacts of the Human Gut Microbiome on Therapeutics.
Vázquez-Baeza Yoshiki,Callewaert Chris,Debelius Justine,Hyde Embriette,Marotz Clarisse,Morton James T,Swafford Austin,Vrbanac Alison,Dorrestein Pieter C,Knight Rob
Annual review of pharmacology and toxicology
The human microbiome contains a vast source of genetic and biochemical variation, and its impacts on therapeutic responses are just beginning to be understood. This expanded understanding is especially important because the human microbiome differs far more among different people than does the human genome, and it is also dramatically easier to change. Here, we describe some of the major factors driving differences in the human microbiome among individuals and populations. We then describe some of the many ways in which gut microbes modify the action of specific chemotherapeutic agents, including nonsteroidal anti-inflammatory drugs and cardiac glycosides, and outline the potential of fecal microbiota transplant as a therapeutic. Intriguingly, microbes also alter how hosts respond to therapeutic agents through various pathways acting at distal sites. Finally, we discuss some of the computational and practical issues surrounding use of the microbiome to stratify individuals for drug response, and we envision a future where the microbiome will be modified to increase everyone's potential to benefit from therapy.
[Microbial regulation of tumor development and responses to tumor therapy].
Zeitschrift fur Gastroenterologie
Viruses and bacteria play central roles in gastrointestinal tumor development. This includes well-characterized contributions of Helicobacter pylori to gastric carcinoma and MALT lymphoma and of Hepatitis B and C virus infections to hepatocellular cancer. However, recent studies have demonstrated a much broader role of the microbiota in the regulation of cancer development. As such, it was shown that barrier defects and alterations in microbial community structure contribute to colorectal and hepatocellular cancer. Moreover, intriguing studies have highlighted the microbiota as a central regulator of the efficacy of systemic anti-tumor therapies. Here, we provide an overview of recent observations on the role of the microbiota in tumor development and the regulation of therapeutic anti-tumor responses and discuss the implications of these findings for clinical diagnostics and treatment.
Integrating tumor genomics into studies of the microbiome in colorectal cancer.
Burns Michael B,Blekhman Ran
Although the gut microbiome has been linked to colorectal cancer (CRC) development, associations of microbial taxa with CRC status are often inconsistent across studies. We have recently shown that tumor genomics, a factor that is rarely incorporated in analyses of the CRC microbiome, has a strong effect on the composition of the microbiota. Here, we discuss these results in the wider context of studies characterizing interaction between host genetics and the microbiome, and describe the implications of our findings for understanding the role of the microbiome in CRC.
[Progress in research of human microbiota for upper gastrointestinal tumors and precancerous lesions].
Shao D T,Wei W W
Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi
With the widely application of the metagenomics, the relationship between microbiota and disease has become a hot research topic. Understanding the potential association between upper gastrointestinal cancer or precancerous lesions and microbiota may play an important role in the early detection, clinical diagnosis and treatment, and prognostic evaluation of upper gastrointestinal cancer. Therefore, a literature retrieval was conducted by using PubMed, Embase and wanfang databases to summarize the latest research progress in the microbiota of upper gastrointestinal cancer, including oral, esophageal, gastric cancer and precancerous lesions. Lower microbial diversity or richness in esophageal cancer and precancerous lesions and specific prognostic biomarkers for esophageal cancer were found. Lactobacillus richness showed an increase trend during the process from gastritis to gastric cancer. This paper summarizes the progress in the research of potential biological etiology of upper gastrointestinal cancer from the perspective of metagenomics in order to provide evidence on the, prevention and control of upper gastrointestinal cancer.
On the Search to Elucidate the Role of Microbiota in the Genesis of Cancer: The Cases of Gastrointestinal and Cervical Cancer.
Avilés-Jiménez Francisco,Yu Guoqin,Torres-Poveda Kirvis,Madrid-Marina Vicente,Torres Javier
Archives of medical research
The microbiota that inhabits the human body plays an important role in health and disease, by their fundamental role in food digestion, training of the immune system or protection against pathogen colonization. However, when the equilibrium with its host is altered, some diseases like cancer might be promoted. In this review we describe the information collected in recent studies between the microbiota and its association with cancer. We conducted the review of the relation of microbiome and cancer etiology focusing on the gastrointestinal and cervical cancer. The MEDLINE database was used for the search. The gastrointestinal tract harbours a diverse and site specific microbiota, and several studies have demonstrated that perturbation of these microbial communities might be associated with different types of cancer. In particular, alteration of the colorectal, gastric and oesophageal microbiota have been reported associated with cancer development. Likewise, cervical microbiome studies suggest that some members of the cervical microbiota are possible modifiers of the cytokine profile of the cervical microenvironment during the development of cervical lesions and cervical cancer. Larger prospective studies are needed to examine whether microbiome dysbiosis could cause cancer, and to evaluate the utility of microbiome profiles as biomarkers for prevention and early diagnosis. This is an important area of research if we consider that microbiota may be a modifiable factor by the use of pre- and probiotics, in order to prevent cancer evolution or even to potentiate cancer treatment.
The gastrointestinal microbiota and its role in oncogenesis.
Lam S Y,Yu J,Wong S H,Peppelenbosch M P,Fuhler G M
Best practice & research. Clinical gastroenterology
Advances in research techniques have made it possible to map the microbial communities in the gastrointestinal (GI) tract, where the majority of bacteria in the human body reside. Disturbances in these communities are referred to as dysbiosis and have been associated with GI cancers. Although dysbiosis is observed in several GI malignancies, the specific role of these changes has not been understood to the extent of Helicobacter pylori (HP) in gastric cancer (GC). This review will address the bacterial communities along the GI tract, from the oral cavity to the anal canal, particularly focusing on bacterial dysbiosis and carcinogenesis. Just as non-HP bacteria in the stomach may interact with HP in gastric carcinogenesis, the same may hold true for other GI tract malignancies, where an interplay between microbes in carcinogenesis seems conceivable, especially in colorectal cancer (CRC). In the last part of this review we will discuss the potential mechanisms of bacterial dysbiosis in GI carcinogenesis.
Maintenance use of non-steroidal anti-inflammatory drugs and risk of gastrointestinal cancer in a nationwide population-based cohort study in Sweden.
Brusselaers Nele,Lagergren Jesper
OBJECTIVES:Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are potential candidates for chemoprevention of gastrointestinal cancer. We aimed to assess the association between contemporary NSAID use (≥180 days) and gastrointestinal cancer. DESIGN:Nationwide Swedish population-based cohort study (2005-2012). SETTING:Sweden PARTICIPANTS: All adults exposed to maintenance NSAIDs use (aspirin, n=783 870; unselective NSAIDs, n=566 209, selective cyclo-oxygenase (COX)-2 inhibitors, n=17 948) compared with the Swedish background population of the same age, sex and calendar period. OUTCOME MEASURES:The risk of different gastrointestinal cancer types expressed as standardised incidence ratios (SIR) and 95% CIs, taking into account concurrent proton pump inhibitors (PPIs) and statins usage. RESULTS:The SIR for gastrointestinal cancer for aspirin use was 1.02 (95% CI 1.00 to 1.04), with clearly reduced risk for long-term users (SIR=0.31, 95% CI 0.30 to 0.33 for 5.5-7.7 years), but an increased risk for short-term users (SIR=2.77, 95% CI 2.69 to 2.85), and stronger protective effect for low-dose aspirin (SIR=0.86, 95% CI 0.85 to 0.88). Users of non-selective NSAIDs showed an overall decreased risk of gastrointestinal cancer (SIR=0.79, 95% CI 0.77 to 0.82), in particular for cancer of the stomach, colorectum and oesophagus, and the SIRs were further decreased among long-term users. Users of selective COX-2 inhibitors showed a SIR=0.89 (95% CI 0.73 to 1.09) for gastrointestinal cancers. Both aspirin and unselective NSAIDs users who also were using PPIs, had higher risks for all gastrointestinal cancer types; and lower risk if using statins. CONCLUSION:Long-term use of (low-dose) aspirin and non-selective NSAIDs was associated with a decreased risk of all gastrointestinal cancer types.
Inflammasomes in the gastrointestinal tract: infection, cancer and gut microbiota homeostasis.
Man Si Ming
Nature reviews. Gastroenterology & hepatology
Inflammasome signalling is an emerging pillar of innate immunity and has a central role in the regulation of gastrointestinal health and disease. Activation of the inflammasome complex mediates both the release of the pro-inflammatory cytokines IL-1β and IL-18 and the execution of a form of inflammatory cell death known as pyroptosis. In most cases, these mediators of inflammation provide protection against bacterial, viral and protozoal infections. However, unchecked inflammasome activities perpetuate chronic inflammation, which underpins the molecular and pathophysiological basis of gastritis, IBD, upper and lower gastrointestinal cancer, nonalcoholic fatty liver disease and obesity. Studies have also highlighted an inflammasome signature in the maintenance of gut microbiota and gut-brain homeostasis. Harnessing the immunomodulatory properties of the inflammasome could transform clinical practice in the treatment of acute and chronic gastrointestinal and extragastrointestinal diseases. This Review presents an overview of inflammasome biology in gastrointestinal health and disease and describes the value of experimental and pharmacological intervention in the treatment of inflammasome-associated clinical manifestations.
The Role of the Microbiome in Gastrointestinal Cancer.
Wroblewski Lydia E,Peek Richard M,Coburn Lori A
Gastroenterology clinics of North America
Humans are host to complex microbial communities previously termed normal flora and largely overlooked. However, resident microbes contribute to both health and disease. Investigators are beginning to define microbes that contribute to the development of gastrointestinal malignancies and the mechanisms by which this occurs. Resident microbes can induce inflammation, leading to cell proliferation and altered stem cell dynamics, which can lead to alterations in DNA integrity and immune regulation and promote carcinogenesis. Studies in human patients and rodent models of cancer have identified alterations in the microbiota of the stomach, esophagus, and colon that increase the risk for malignancy.
Gut Microbiome and Gastrointestinal Cancer: Les liaisons Dangereuses.
Tözün Nurdan,Vardareli Eser
Journal of clinical gastroenterology
Gastrointestinal (GI) cancers are the leading cause of mortality worldwide. These cancers are the end result of a complex interplay between gene and environment. Bacteria, parasites, and viruses have been implicated in some cancers. Recent data have put at focus the gut microbiome as the key player firing tumorigenesis. Experimental and human studies have provided evidence on the role of microbiota in cancer development. Although subject to changes in different settings such as antibiotic treatment, diet or lifestyle, our microbiome is quite stable and is capable of increasing susceptibility to cancer or decrease and halt its progression. The crucial event in carcinogenesis triggered by microbiome seems to be chronic inflammation influencing the genomic stability of host cells and activating immune mechanisms. Infection-related cancers represent 5.5% of the global cancer burden. Chronic inflammation predisposes to cancer in various GI organs, including hepatocellular carcinoma caused by hepatitis B or hepatitis C virus-related chronic hepatitis, gastric cancer (GC) caused by Helicobacter pylori-associated chronic gastritis, colorectal cancer caused by inflammatory bowel disease, bile duct cancer by primary sclerosing cholangitis, and esophageal cancer caused by Barrett esophagus. Apart from its impact in GI cancer development microbiota can also play an important role in the progression of cancer, response to chemotherapy or cancer prevention. In this review we will discuss the role of microbiome in GI cancers in the light of the current literature and the possible therapeutic options targeting microbiota in the near future.
Progress in characterizing the linkage between Fusobacterium nucleatum and gastrointestinal cancer.
Liu Yang,Baba Yoshifumi,Ishimoto Takatsugu,Iwatsuki Masaaki,Hiyoshi Yukiharu,Miyamoto Yuji,Yoshida Naoya,Wu Rong,Baba Hideo
Journal of gastroenterology
Microbiome research is a rapidly advancing field in human cancers. Fusobacterium nucleatum is an oral bacterium, indigenous to the human oral cavity, that plays a role in periodontal disease. Recent studies have found that F. nucleatum can promote gastrointestinal tumor progression and affect the prognosis of the disease. In addition, F. nucleatum may contribute to the chemo-resistance of gastrointestinal cancers. This review summarizes recent progress in the pathogenesis of F. nucleatum and its impact on gastrointestinal cancer.
The Expression of Toll-like Receptors in Normal Human and Murine Gastrointestinal Organs and the Effect of Microbiome and Cancer.
Huhta Heikki,Helminen Olli,Kauppila Joonas H,Salo Tuula,Porvari Katja,Saarnio Juha,Lehenkari Petri P,Karttunen Tuomo J
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society
Toll-like receptors (TLRs) are innate immune receptors expressed in all parts of the alimentary tract. However, analyses comparing expression in different segments and data on germ-free animals are lacking. Alimentary tract cancers show increased TLR expression. According to the field effect concept, carcinogenetic factors induce subtle cancer predisposing alterations in the whole organ. We studied TLR1 to TLR9 expression in all segments of the alimentary tract from cancer patients' tumor-adjacent normal mucosa, healthy organ donors, and conventional and germ-free mice by using immunohistochemistry and quantitative PCR. All TLRs were expressed in all segments of the alimentary tract. Expression was most intensive in the small intestine in humans and conventional mice, but germ-free mice showed less expression in the small intestine. TLR expression levels were similar in cancer patients and organ donors. We provide systematic baseline data on the TLR expression in the alimentary tract. Normal epithelium adjacent to tumor seems to have similar TLR expression compared with healthy tissues suggesting absence of any field effect in TLR expression. Accordingly, specimens from cancer patients' normal tumor-adjacent tissue can be used as control tissues in immunohistochemical TLR studies in gastrointestinal cancer.
DNA Mismatch Repair Deficiency and Immune Checkpoint Inhibitors in Gastrointestinal Cancers.
Ruiz-Bañobre Juan,Goel Ajay
In the recent few years, significant efforts have been undertaken for the development of different immunotherapeutic approaches against cancer. In this context, immune checkpoint inhibitors (ICIs), a novel class of immunotherapeutic drugs with the potential to unleash the immune system, have emerged as authentic game-changers for managing patients with various cancers, including gastrointestinal malignancies. Although the majority of gastrointestinal cancers are generally considered poorly immunogenic, basic research findings and data from clinical trials have proven that subset(s) of patients with various digestive tract cancers are highly responsive to ICI-based therapy. In this context, a better understanding on the role of various DNA repair pathway alterations, especially the evidence supporting the significant importance of DNA mismatch repair deficiencies and the efficacy of the anti-programmed cell death 1 drugs, have led to US Food and Drug Administration approval of 2 anti-programmed cell death 1 antibodies (pembrolizumab and nivolumab) for the treatment of patients with microsatellite instability. This review aims to provide a comprehensive and up-to-date summary for the role of DNA mismatch repair deficiency in cancer, and its importance in the development of ICI therapy. In addition, we provide insights into the spectrum of various genetic alterations underlying ICI resistance, together with the important influence that the tumor microenvironment plays in mediating the therapeutic response to this new class of drugs. Finally, we provide a comprehensive yet succinct glimpse into the most exciting preclinical discoveries and ongoing clinical trials in the field, highlighting bench-to-beside translational impact of this exciting area of research.