Feuerstein Joseph D,Moss Alan C,Farraye Francis A
Mayo Clinic proceedings
Ulcerative colitis (UC) is a chronic inflammatory bowel disease that can involve any aspect of the colon starting with mucosal inflammation in the rectum and extending proximally in a continuous fashion. Typical symptoms on presentation are bloody diarrhea, abdominal pain, fecal urgency, and tenesmus. In some patients, extraintestinal manifestations may predate the onset of gastrointestinal symptoms. A diagnosis of UC is made on the basis of presenting symptoms consistent with UC as well as endoscopic evidence showing continuous and diffuse colonic inflammation that starts in the rectum. Biopsies of the colon documenting chronic inflammation confirm the diagnosis of UC. Most cases are treated with pharmacological therapy to first induce remission and then to maintain a corticosteroid-free remission. There are multiple classes of drugs used to treat the disease. For mild to moderate UC, oral and rectal 5-aminosalycilates are typically used. In moderate to severe colitis, medication classes include thiopurines, biological agents targeting tumor necrosis factor and integrins, and the small-molecule Janus kinase inhibitors. However, in up to 15% of cases, patients in whom medical therapy fails or who have development of dysplasia secondary to their long-standing colitis will require surgical treatment. Finally, to minimize the complications of UC and adverse events from medications, a working collaboration between primary care physicians and gastroenterologists is necessary to make sure that vaccinations are optimized and that patients are screened for colon cancer, skin cancer, bone loss, depression, and other treatable and preventable complications.
Jiaweishaoyao Decoction Alleviates DSS-Induced Ulcerative Colitis via Inhibiting Inflammation.
Qiao Huixia,Huang Yahui,Chen Xiaoyan,Yang Long,Wang Yue,Xu Rongrong
Gastroenterology research and practice
Purpose:Jiaweishaoyao decoction (JWSYD) is a traditional prescription of Chinese medicine that is initially used for the treatment of diarrhea. This study is aimed at investigating the effects of JWSYD on DSS-induced ulcerative colitis (UC). Methods:DSS-induced UC mice and LPS-induced RAW264.7 cells were used as the UC model and . UC was assessed by body weight, disease activity index (DAI), colon length, spleen weight, and histopathological score (HE staining). The levels of TNF-, IL-1, and IL-6 were analyzed by ELISA and qRT-PCR. The levels of NLRP3 inflammasome- and NF-B pathway-associated proteins were measured by western blot. Results:JWSYD alleviated DSS-induced UC in respect to body weight, DAI, colon length, spleen weight, and histopathological score. JWSYD reduced the levels of TNF-, IL-1, and IL-6 in DSS-induced UC mice and the supernatants of LPS-induced RAW264.7 cells. JWSYD suppressed the protein levels of inflammasome-associated proteins, including NLRP3, ASC1, Procaspase-1, Cleaved caspase-1, and Cleaved IL-1 in DSS-induced UC mice and LPS-induced RAW264.7 cells. In addition, JWSYD suppressed the NF-B pathway and . Conclusion:JWSYD alleviated DSS-induced UC via inhibiting the NLRP3 inflammasome and NF-B pathway.
The Abilities of Salidroside on Ameliorating Inflammation, Skewing the Imbalanced Nucleotide Oligomerization Domain-Like Receptor Family Pyrin Domain Containing 3/Autophagy, and Maintaining Intestinal Barrier Are Profitable in Colitis.
Liu Jiuxi,Cai Jiapei,Fan Peng,Zhang Naisheng,Cao Yongguo
Frontiers in pharmacology
Salidroside (Sal), as a major glycoside extracted from L., has exhibited its mighty anti-aging, anti-oxidant, anti-cancer, anti-inflammation, and neuroprotective effects in many diseases. Recently, it has showed its protective effect in colitis mice by activating the SIRT1/FoxOs pathway. Whereas, it is not known whether Sal has other protective mechanisms on dextran sulfate sodium (DSS)-induced colitis in mice. In this study, we investigated the protective effects and mechanisms of Sal on DSS-induced colitis in mice. The results demonstrated Sal was a competent candidate in the treatment of ulcerative colitis (UC). Sal remitted DSS-induced disease activity index (DAI), colon length shortening, and colonic pathological damage. Simultaneously, Sal alleviated excessive inflammation by reversing the IL-1β, TNF-α, and IL-10 protein levels in DSS-treated mice. Western blot analysis revealed that Sal inhibited p65 and p38 activation together with peroxisome proliferator-activated receptor (PPARγ) up-regulation. In addition, Sal skewed the imbalanced activation of nucleotide oligomerization domain-like receptor family pyrin domain containing 3 inflammasome and autophagy contributing to colitis recovery. The damaged intestinal barrier induced by DSS was also alleviated along with plasma lipopolysaccharides (LPS) reduction after Sal treatment. , Sal showed PPARγ-dependent anti-inflammatory effect in LPS-stimulated RAW264.7 cells. In summary, our results demonstrated that Sal might be an effective factor for UC treatment and its pharmacological value deserved further development.
Piperine, a functional food alkaloid, exhibits inhibitory potential against TNBS-induced colitis via the inhibition of IκB-α/NF-κB and induces tight junction protein (claudin-1, occludin, and ZO-1) signaling pathway in experimental mice.
Guo G,Shi F,Zhu J,Shao Y,Gong W,Zhou G,Wu H,She J,Shi W
Human & experimental toxicology
BACKGROUND:Inflammatory bowel disease is a chronic immunoinflammatory disease of the gastrointestinal tract. Piperine, an alkaloid, has been reported to possess antioxidant, anti-inflammatory, antiapoptotic, and antiulcer potential. AIM:To elucidate the plausible mechanisms of action of piperine on experimental trinitrobenzenesufonic acid (TNBS)-induced colitis by assessing various biochemical, molecular, histological, and ultrastructural modifications. METHODS:Colitis was induced in male Sprague-Dawley rats via intrarectal instillation of TNBS. Then, the rats were treated with piperine (10, 20, and 40 mg/kg, p.o.) for 14 days. RESULTS:TNBS induced significant ( 0.05) colonic damage, which was assessed by disease activity index, macroscopic score, and stool consistency. The administration of piperine (20 and 40 mg/kg) significantly inhibited ( 0.05) these damages. Treatments with piperine (20 and 40 mg/kg) notably inhibited ( 0.05) the TNBS-induced elevation of oxido-nitrosative stress (superoxide dismutase, glutathione, malondialdehyde, and nitric oxide), 5-hydroxytryptamine, and hydroxyproline content in the colon. Furthermore, colonic inducible nitric oxide synthase (iNOs), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, interferon-gamma, and cyclooxygenase-2 (COX-2) messenger RNA (mRNA) expressions were upregulated after TNBS instillation and piperine (20 and 40 mg/kg) significantly attenuated ( 0.05) these elevated mRNA expressions. TNBS decreased the expressions of tight junction (TJ) protein (claudin-1, occludin, and zonula occludens-1 (ZO-1)) and increased the expressions of proapoptotic (caspase-1) protein. These expressions were markedly inhibited ( 0.05) by piperine treatment. Histological and ultrastructural studies of transmission electron microscopy suggested that piperine significantly ameliorated ( 0.05) TNBS-induced colonic aberrations. CONCLUSION:Piperine ameliorated the progression of TNBS-induced colitis by modulating the nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha/nuclear factor-kappa B signaling pathway, thus inhibiting the overexpression of proinflammatory cytokines (TNF-α and IL's), COX-2, iNOs, oxido-nitrosative stress, and proapoptotic proteins (caspase-1) that may improve the expression of TJ protein (claudin-1, occludin, and ZO-1).
Targeting Immune Cell Wiring in Ulcerative Colitis.
Neurath Markus F,Chiriac Mircea T
The cytokine TNF is thought to play a major role in the immunopathogenesis of ulcerative colitis, and anti-TNF antibodies are considered as cornerstones of clinical therapy. Two clinical trials published in The New England Journal of Medicine now challenge this paradigm and suggest new avenues for research.
Tricellulin Effect on Paracellular Water Transport.
Ayala-Torres Carlos,Krug Susanne M,Schulzke Jörg D,Rosenthal Rita,Fromm Michael
International journal of molecular sciences
In epithelia, large amounts of water pass by transcellular and paracellular pathways, driven by the osmotic gradient built up by the movement of solutes. The transcellular pathway has been molecularly characterized by the discovery of aquaporin membrane channels. Unlike this, the existence of a paracellular pathway for water through the tight junctions (TJ) was discussed controversially for many years until two molecular components of paracellular water transport, claudin-2 and claudin-15, were identified. A main protein of the tricellular TJ (tTJ), tricellulin, was shown to be downregulated in ulcerative colitis leading to increased permeability to macromolecules. Whether or not tricellulin also regulates water transport is unknown yet. To this end, an epithelial cell line featuring properties of a tight epithelium, Madin-Darby canine kidney cells clone 7 (MDCK C7), was stably transfected with small hairpin RNA (shRNA) targeting tricellulin, a protein of the tTJ essential for the barrier against passage of solutes up to 10 kDa. Water flux was induced by osmotic gradients using mannitol or 4 and 40 kDa-dextran. Water flux in tricellulin knockdown (KD) cells was higher compared to that of vector controls, indicating a direct role of tricellulin in regulating water permeability in a tight epithelial cell line. We conclude that tricellulin increases water permeability at reduced expression.
History of Inflammatory Bowel Diseases.
Actis Giovanni Clemente,Pellicano Rinaldo,Fagoonee Sharmila,Ribaldone Davide Giuseppe
Journal of clinical medicine
Inflammatory bowel diseases (IBD) are characterized by chronic inflammation of the intestinal mucosa and unknown etiology. In this review, we identified three main eras in the IBD history. Between the 19th and the 20th century, the primary task had been the definition of the diagnostic criteria in order to differentiate the new entity from intestinal tuberculosis. In the 20th century, an intense and prolific therapeutic research prevailed, culminating in the introduction of biological drugs in the clinical setting. Since the beginning of the 21st century, traditional definition criteria have been challenged by holistic criteria in an effort to seek a still unattained cure. Centuries of worldwide efforts on IBD etiology and therapy search have culminated in this novel strategy.
Grape Seed Polyphenols Ameliorated Dextran Sulfate Sodium-Induced Colitis via Suppression of Inflammation and Apoptosis.
Wang Yunxia,Wang Yunan,Shen Wanli,Wang Yandi,Cao Yini,Nuerbulati Nuerdida,Chen Wen,Lu Guotao,Xiao Weiming,Qi Rong
BACKGROUND:Ulcerative colitis (UC) is an inflammatory bowel disease. Its onset is typically gradual, usually followed by periods of spontaneous remission and subsequent relapses. Grape seed polyphenols (GSP), a natural product extracted from grape seeds, have strong anti-inflammatory functions. OBJECTIVES:In this study, we investigated whether GSP has an inhibitory effect on UC and its related mechanism or not. METHODS:We induced UC by 2.5% dextran sulfate sodium (DSS) and GSP at different doses (500 and 750 mg/kg body weight per day) was administrated to the mice by gavage. Body weight, diarrhea, and bloody stool were recorded every day to evaluate disease activity index. Hemotoxylin-eosin staining and immunohistochemical staining were used to identify the histological damages and inflammatory infiltration in colon tissues. Real-time polymerase chain reaction was used to evaluate mRNA expression of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α and the expression of phosphorylated-signal transducer and activator of transcription 3 (STAT3) and STAT3 were assessed by western blot. The immunofluorescent assay was used to evaluate the apoptosis of intestinal epithelial cells (IECs). RESULTS:GSP could alleviate the loss of body weight, diarrhea, bloody stool, the mucosal damage, and inflammatory infiltration. GSP could also downregulate the mRNA expression of inflammatory cytokines IL-6, IL-1β, and TNF-α as well as the phosphorylation of STAT3 and ameliorate the apoptosis of IECs. CONCLUSIONS:Our study suggests that GSP has protective effects against DSS-induced UC, which may through suppression of inflammation and apoptosis.
Mucosal Profiling of Pediatric-Onset Colitis and IBD Reveals Common Pathogenics and Therapeutic Pathways.
Huang Bing,Chen Zhanghua,Geng Lanlan,Wang Jun,Liang Huiying,Cao Yujie,Chen Huan,Huang Wanming,Su Meiling,Wang Hanqing,Xu Yanhui,Liu Yukun,Lu Bingtai,Xian Huifang,Li Huiwen,Li Huilin,Ren Lu,Xie Jing,Ye Liping,Wang Hongli,Zhao Junhong,Chen Peiyu,Zhang Li,Zhao Shanmeizi,Zhang Ting,Xu Banglao,Che Di,Si Wenyue,Gu Xiaoqiong,Zeng Liang,Wang Yong,Li Dingyou,Zhan Yifan,Delfouneso David,Lew Andrew M,Cui Jun,Tang Wai Ho,Zhang Yan,Gong Sitang,Bai Fan,Yang Min,Zhang Yuxia
Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn's disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.
Resveratrol Downregulates miR-31 to Promote T Regulatory Cells during Prevention of TNBS-Induced Colitis.
Alrafas Haider Rasheed,Busbee Philip B,Nagarkatti Mitzi,Nagarkatti Prakash S
Molecular nutrition & food research
SCOPE:Colitis, an inflammatory bowel disease, is associated with aberrant regulation of the colonic mucosal immune system. Resveratrol, a natural plant product, has been found to exert anti-inflammatory properties and attenuate the development of murine colitis. In the current study, the role of microRNA (miR) in the ability of resveratrol to suppress colonic inflammation is examined. METHODS AND RESULTS:BALB/C mice with 2,4,6-Trinitrobenzenesulfonic acid solution (TNBS)-induced colitis, when treated with resveratrol, show improved clinical outcomes and reduce induction of inflammatory T cells (Th17 and Th1) while increasing CD4+Foxp3+ regulatory T cells (Tregs) and IL-10-producing CD4+ T cells. miR microarray analysis and polymerase chain reaction (PCR) validation from CD4+ T cells show treatment with resveratrol decreases the expression of several miRs (miR-31, Let7a, miR-132) that targets cytokines and transcription factors involved in anti-inflammatory T cell responses (Foxp3 and TGF-β). Transfection studies with miR-31 confirm that this miR directly regulates the expression of Foxp3. Lastly, analysis of public data from human patients with ulcerative colitis reveals that miR-31 expression is significantly increased when compared to controls. CONCLUSION:Together, the current study demonstrates that resveratrol-mediated attenuation of colitis may be regulated by miR-31 through induction of Tregs and miR-31 may serve as a therapeutic target for human colitis.
Emodin ameliorates ulcerative colitis by the flagellin-TLR5 dependent pathway in mice.
Luo Shuang,Deng Xiangliang,Liu Qi,Pan Zengfeng,Zhao Zhongxiang,Zhou Lian,Luo Xia
Emodin is an anthraquinone compound derived from Rheum officinale Baill. Several reports showed that emodin had efficacy on acute pancreatitis, keratitis, myocarditis, and rheumatoid arthritis. However, the potency of emodin on ulcerative colitis(UC) remains unclear. In this study, we investigated the effect of emodin on dextran sodium sulfate (DSS)-induced ulcerative colitis in mice. Our results showed that emodin significantly alleviated the symptoms of DSS-induced UC in mice, involving prevented the loss of body weight and colon shortening, decreased the disease activity index (DAI), intestinal damages and the count of white blood cells (WBC) in peripheral blood. In addition, emodin treatment decreased the level of anti-flagellin antibody in serum and significantly down-regulated the expression of TLR5 and NF-κB p65 in colon of the UC mice. Further study in vitro showed that emodin down-regulated the expression of TLR5 and MyD88, up-regulated the expression of IκB, inhibited the nuclear translocation of NF-κB p65 and decreased the release of IL-8 in flagellin-stimulated HT-29 cells. These results, for the first time, demonstrated that emodin had the therapeutic potential to ameliorate UC symptoms possibly via regulating the flagellin-TLR5 signaling pathway. Emodin may be a potential candidate ingredient for ulcerative colitis.
Rhubarb Peony Decoction ameliorates ulcerative colitis in mice by regulating gut microbiota to restoring Th17/Treg balance.
Luo Shuang,Wen Ruyan,Wang Qing,Zhao Zhongxiang,Nong Feifei,Fu Yajun,Huang Shaowei,Chen Jinyan,Zhou Lian,Luo Xia
Journal of ethnopharmacology
ETHNOPHARMACOLOGY RELEVANCE:Rhubarb Peony Decoction (RPD) is a formula of traditional Chinese medicine chronicled in Jin Gui Yao Lve, commonly used to treat ulcerative colitis (UC). However, the underlying mechanism of RPD treating UC remains elusive. In our study, we investigated the therapeutic efficacy of RPD and potential mechanism involved in inhibiting dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. METHODS:The colitis was induced by DSS in mice for 5 days and estimated body weight loss, disease activity index (DAI) and colon length. Histological changes were observed by H&E staining. The number and abundance of gut mircrobiota were measured with 16 S rDNA sequencing. GC-MS was used to detect the concentration of short chain fatty acids (SCFAs) in cecum. Flow cytometry analyzed the proportion of Th17 and Treg cells in mesenteric lymph nodes (MLNs). IL-17A and Foxp3 in colon were determined by immunohistochemical analyses. The level of cytokine was determined by Multi-Analyte Flow Assay Kit. RESULTS:Administration of RPD significantly alleviated the pathological changes of UC mice, involving rescued the inflammation-related reduction of colon length, ameliorated body weight loss and damaged tissue. In addition, RPD altered the gut microbiota, involving restored α diversity, increased significantly the abundance of Firmicutes and Actinobacteria, decreased the Proteobacteria and Bacteroidetes. Furthermore, the number of Butyricicoccus pullicaecorum, a butyrate-producing bacterium, were augmented obviously by RPD. Besides, RPD restored the content of SCFA in intestinal tract. Additionally, the proportion of Th17 cells and Treg cells in mesenteric lymph nodes, likewise, the expression of IL-17A and Foxp3 in colon were regulated by RPD, contributing to the restoration of Th17/Treg balance. Moreover, RPD significantly decreased the level of IL-6, TNF-α, IFNγ, IL-10, IL-17A, IL-21, IL-22 in colon, simultaneously increased Treg-related cytokine TGF-β at dose-dependently. CONCLUSIONS:These results demonstrated that RPD had effect on ulcerative colitis, which was related to regulating gut microbiota, especially Butyricicoccus pullicaecorum, and SCFAs to restore the gut Th17/Treg homeostasis.
Activation of adenosine A3 receptor inhibits inflammatory cytokine production in colonic mucosa of patients with ulcerative colitis by down-regulating the nuclear factor-kappa B signaling.
Ren Tian Hua,Lv Min Min,An Xiao Meng,Leung Wai Keung,Seto Wai-Kay
Journal of digestive diseases
OBJECTIVES:The activation of the adenosine A3 receptor (A3AR) can regulate inflammation, but the way that this regulates colonic mucosal inflammation in ulcerative colitis (UC) remains unclear. This study aimed at examining A3AR expression and investigating the effect of A3AR activation on ex vivo cytokine expression and nuclear factor-kappa B (NF-κB) signaling in colonic mucosa. METHODS:Colonic mucosal biopsied tissue from 18 patients with UC and 11 healthy controls was tested for A3AR expression by immunofluorescence, quantitative real-time polymerase chain reaction and Western blot. Following treatment for 24 hours with or without 2-Cl-IB-MECA, an A3AR agonist, TNF-α and IL-1β secreted by the cultured colonic mucosal tissue were quantified by ELISA. The colonic mucosal epithelia were dissected and treated with, or without 2-Cl-IB-MECA for 24 hours. The NF-κB p65 protein and its distribution in the cultured colonic epithelia were examined by immunofluorescence and Western blot. RESULTS:Compared with the controls, down-regulated A3AR expression and up-regulated TNF-α and IL-1β production and NF-κB p65 protein were observed in the UC colonic mucosa. The activation of A3AR by 2-Cl-IB-MECA significantly decreased TNF-α and IL-1β production and attenuated the NF-κB p65 activation in colonic tissues from patients with UC. CONCLUSIONS:A3AR activation inhibited inflammation by mitigating pro-inflammatory cytokine production and the NF-κB signal activation in colonic mucosa of patients with UC. A3AR activation may play a role in the pathogenesis of UC.
Discovery of small-molecule candidates against inflammatory bowel disease.
Bai Renren,Jie Xiaokang,Yao Chuansheng,Xie Yuanyuan
European journal of medicinal chemistry
Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disease in the gastrointestinal tract emerged as a public health challenge worldwide. IBD exhibits a relapsing and remitting course results in negative impacts on both physical and psychological health of IBD patients. Great efforts have been made during the past few years, but relatively limited drugs are currently available for the management of IBD. Clinically, there is a strong demand for new drugs for the treatment of IBD with better efficacy and lower side effects. This review focuses on the drug discovery process of the anti-IBD agents, aiming to introduce the general characteristics of IBD, as well as systematically summarize the recent advances in the discovery of small-molecule candidates and natural products with promising in vivo potential for the treatment of IBD.
Beneficial Effect of Herbal Formulation KM1608 on Inflammatory Bowl Diseases: A Preliminary Experimental Study.
Shin Myoung-Sook,Kim Sang-Back,Lee Jaemin,Choi Han-Seok,Park Jimin,Park Jun Yeon,Lee Sullim,Hwang Gwi Seo,Koo Bon Am,Kang Ki Sung
Molecules (Basel, Switzerland)
DC., Retz and Roscoe have been traditionally used in east Asia to treat chronic diarrhea and abdominal pain. This study aimed to evaluated the anti-inflammatory activity of KM1608, which is composed of three natural herbs in a mouse model of dextran sodium sulfate (DSS)-induced ulcerative colitis. The anti-inflammatory activity and underlying mechanism were assessed in vitro using LPS-treated RAW264.7 cells. The in vivo effect of KM1608 on DSS-induced colitis was examined after oral administration in mice. KM1608 significantly inhibited the inflammatory mediators such as nitric oxide, interleukin (IL)-6, monocyte chemotactic protein 1 (MCP-1) and tumor necrosis factor (TNF)-α in LPS-treated RAW264.7 cells. The inhibitory effect of KM1608 was attributed to the reduction of Akt phosphorylation in the LPS-treated cells. In the mouse model, oral administration of KM1608 significantly improved DSS-induced colitis symptoms, such as disease activity index (DAI), colon length, and colon weight, as well as suppressed the expression of IL-6, TNF-α, and myeloperoxidase (MPO) in the DSS-induced colitis tissues. Taken together, KM1608 improved colitis through the regulation of inflammatory responses, suggesting that KM1608 has potential therapeutic use in the treatment of inflammatory diseases.
Deletion of IL-6 Exacerbates Colitis and Induces Systemic Inflammation in IL-10-Deficient Mice.
Ye Mei,Joosse Maria E,Liu Ling,Sun Yu,Dong Ying,Cai Changchun,Song Zhenmei,Zhang Jennifer,Brant Steven R,Lazarev Mark,Li Xuhang
Journal of Crohn's & colitis
BACKGROUND AND AIMS:Interleukin 6 [IL-6] or its receptor is currently a candidate for targeted biological therapy of inflammatory bowel disease [IBD]. Thus, a comprehensive understanding of the consequences of blocking IL-6 is imperative. We investigated this by evaluating the effects of IL-6 deletion on the spontaneous colitis of IL-10-deficient mice [IL-10-/-]. METHODS:IL-6/IL-10 double-deficient mice [IL-6-/-/IL-10-/-] were generated and analysed for intestinal inflammation, general phenotypes and molecular/biochemical changes in the colonic mucosa compared with wild-type and IL-10-/- mice. RESULTS:Unexpectedly, the IL-6-/-/IL-10-/- mice showed more pronounced gut inflammation and earlier disease onset than IL-10-/- mice, both locally [colon and small bowel] and systemically [splenomegaly, ulcerative dermatitis, leukocytosis, neutrophilia and monocytosis]. IL-6-/-/IL-10-/- mice exhibited elevations of multiple cytokines [IL-1β, IL-4, IL-12, TNFα] and chemokines [MCP-1 and MIG], but not IFN-γ [Th1], IL-17A and IL-17G [Th17], or IL-22 [Th22]. FOXP3 and TGF-β, two key factors for regulatory T [Treg] cell differentiation, were significantly down-regulated in the colonic mucosa, but not in the thymus or mesenteric lymph nodes, of IL-6-/-/IL-10-/- mice. CTLA-4 was diminished while iNOS was up-regulated in the colonic mucosa of IL-6-/-/IL-10-/- mice. CONCLUSION:In IL-10-/- mice, complete IL-6 blockade significantly aggravates gut inflammation, at least in part by suppressing Treg/CTLA-4 and promoting the IL-1β/Th2 pathway. In addition, the double mutant exhibits signs of severe systemic inflammation. Our data define a new function of IL-6 and suggest that caution should be exercised when targeting IL-6 in IBD patients, particularly those with defects in IL-10 signalling.
Protective effects of flavonoid composition rich P. subpeltata Ortega. on indomethacin induced experimental ulcerative colitis in rat models of inflammatory bowel diseases.
Shanmugam Saravanan,Thangaraj Parimelazhagan,Dos Santos Lima Bruno,Trindade Gabriela G G,Narain Narendra,Mara de Oliveira E Silva Ana,Santin José Roberto,Broering Milena Fronza,Serafini Mairim Russo,Quintans-Júnior Lucindo José,Antunes de Souza Araújo Adriano
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Polyphenolics (flavonoid and phenolic) rich plants are the effective source for the treatment of acute and chronic degenerative diseases including inflammatory bowel disease. OBJECTIVE:This study was aimed to examine the effects of polyphenolics rich leaf acetone extract of P. subpeltata against the indomethacin induced ulcerative colitis in rats. MATERIALS AND METHODS:Two consecutive days administration of indomethacin produced chronic inflammation in GIT tissues of rats. Further, the plant extract 200 and 400 mg/kg treatment were continued until 11th day. Then hematological, enzymatic antioxidants, MPO and histological evaluations were analyzed. Moreover, the extracts were treated with RAW267.4 cells for the cytotoxicity, NO and TNF-α analysis. RESULTS:The obtained results revealed, that higher dose of the plant extract dropped neutrophil infiltration followed by inhibiting the MPO enzyme levels and controls the enzymatic antioxidants such as SOD, CAT, GSH and LPO. RAW cells study also proved that the plant extract effectively inhibits NO and TNF-α production. CONCLUSIONS:Thus, these results suggest that P. subpeltata extract may have therapeutic potential for the treatment of IBD although further clinical research is still warranted.
Interleukin-33 delays recovery of mucosal inflammation via downregulation of homeostatic ABCG5/8 in the colon.
Mishima Yoshiyuki,Sonoyama Hiroki,Ishihara Shunji,Oshima Naoki,Moriyama Ichiro,Kawashima Kousaku,Kinoshita Yoshikazu
Laboratory investigation; a journal of technical methods and pathology
Previous studies have suggested that interleukin-33 (IL-33) is involved in the pathogenesis of ulcerative colitis (UC), though the detailed mechanisms are not fully known. We investigated IL-33-mediated colonic homeostasis using a mechanistic method. Il33 mice were more tolerant to dextran sulfate sodium-induced acute colitis than the wild type and also showed delayed recovery from colitis with recombinant IL-33 (rIL-33) administration. Unexpectedly, microarray analysis identified significant downregulation of the Abcg5/8 genes in mouse colons following rIL-33 treatment. ABCG5/8 are known cholesterol transporters in the small intestine and liver, though their colon activities have not been elucidated, thus their role in IL-33-mediated inflammation was investigated. In vitro, toll-like receptor (TLR) stimulation upregulated ABCG5/8 mRNA expression in Caco2 and HCT-15 cells, with subsequent downregulation by rIL-33, while inhibition of ABCG5/8 along with their siRNA increased TLR-stimulated IL-8 production. Together, these results indicated that colonic ABCG5/8 play a regulatory role in TLR-induced inflammation, while histological inflammation in human UC was correlated positively with the level of mucosal IL-33 and inversely with that of colonic ABCG5/8. This is the first report of IL-33-mediated downregulation of colonic ABCG5/8 in a colitis recovery phase, indicating their involvement in UC pathogenesis and potential as a therapeutic target.
Acetylcholinesterase Inhibitor Pyridostigmine Bromide Attenuates Gut Pathology and Bacterial Dysbiosis in a Murine Model of Ulcerative Colitis.
Singh Shashi P,Chand Hitendra S,Banerjee Santanu,Agarwal Hemant,Raizada Veena,Roy Sabita,Sopori Mohan
Digestive diseases and sciences
BACKGROUND:Ulcerative colitis (UC) is a Th2 inflammatory bowel disease characterized by increased IL-5 and IL-13 expression, eosinophilic/neutrophilic infiltration, decreased mucus production, impaired epithelial barrier, and bacterial dysbiosis of the colon. Acetylcholine and nicotine stimulate mucus production and suppress Th2 inflammation through nicotinic receptors in lungs but UC is rarely observed in smokers and the mechanism of the protection is unclear. METHODS:In order to evaluate whether acetylcholine can ameliorate UC-associated pathologies, we employed a mouse model of dextran sodium sulfate (DSS)-induced UC-like conditions, and a group of mice were treated with Pyridostigmine bromide (PB) to increase acetylcholine availability. The effects on colonic tissue morphology, Th2 inflammatory factors, MUC2 mucin, and gut microbiota were analyzed. RESULTS:DSS challenge damaged the murine colonic architecture, reduced the MUC2 mucin and the tight-junction protein ZO-1. The PB treatment significantly attenuated these DSS-induced responses along with the eosinophilic infiltration and the pro-Th2 inflammatory factors. Moreover, PB inhibited the DSS-induced loss of commensal Clostridia and Flavobacteria, and the gain of pathogenic Erysipelotrichia and Fusobacteria. CONCLUSIONS:Together, these data suggest that in colons of a murine model, PB promotes MUC2 synthesis, suppresses Th2 inflammation and attenuates bacterial dysbiosis therefore, PB has a therapeutic potential in UC.
Review article: fungal alterations in inflammatory bowel diseases.
Lam Siu,Zuo Tao,Ho Martin,Chan Francis K L,Chan Paul K S,Ng Siew C
Alimentary pharmacology & therapeutics
BACKGROUND:Emerging data suggest that alterations in gut fungi may be associated with the pathogenesis of inflammatory bowel disease (IBD). In healthy individuals, gut commensal fungi act synergistically with other members of the microbiota to maintain homeostasis but their role in IBD is less clear. AIM:To review the role of gut fungi and their trans-kingdom interactions with bacteria in IBD METHODS: A literature search was conducted on Ovid and Pubmed to select relevant animal and human studies that have reported fungi and IBD. RESULTS:There is an increased total fungal load particularly of Candida and Malassezia species in the faeces and mucosa of Crohn's disease patients, and a lower fungal diversity in the faeces of ulcerative colitis patients. Caspase recruitment domain-containing protein (CARD)-9 polymorphism in Crohn's disease patients favours Malassezia colonisation that worsens gut inflammation. Diet high in carbohydrates increased the total abundance of Candida species, whereas protein-rich diet had the opposite effect. Anti-fungal therapies are mostly used to treat Candida albicans or Histoplasma capsulatum infections in IBD, whereas pilot studies of supplementing fungal probiotics Saccharomycopsis fibuligera, Saccharomyces boulardii and Saccharomyces cerevisiae CNCM I-3856 strain showed therapeutic effects in IBD. CONCLUSIONS:Gut fungi are altered in patients with Crohn's disease and ulcerative colitis. Modulation of the fungal microbiota can be considered as a therapeutic approach for IBD. Future research should focus on understanding how the fungal microbiota interacts with other components of the gut microbiota in association with the pathogenesis and development of IBD.
Anti-inflammatory effects of eriocitrin against the dextran sulfate sodium-induced experimental colitis in murine model.
Guo Gang,Shi Wen,Shi Feiyu,Gong Wenqing,Li Fanni,Zhou Guangju,She Junjun
Journal of biochemical and molecular toxicology
Inflammatory bowel disease (IBD) is a continual ailment condition which engrosses the entire alimentary canal. The IBD can be primarily distinguished into two forms, ulcerative colitis, and Crohn's disease. The major symptoms of IBD include pustules or abscesses, severe abdominal pain, diarrhea, fistula, and stenosis, which may directly affect the patient's quality of life. A variety of mediators can stimulate the circumstances of IBD, some examples include infections by microbes such as bacteria, perturbation of the immune system and the surrounding environment of the intestines. Severe colitis was stimulated in the experimental animals through administering 4% dextran sulfate sodium (DSS) which is mixed in water ad libitum for 6 days. Eriocitrin (30 mg/kg) was then administered to the experimental animals followed by the induction of severe colitis to evaluate the therapeutic prospective of eriocitrin against the colon inflammation stimulated by DSS. In this study, eriocitrin (30 mg/kg) demonstrated significant (P < .05) attenuation activity against the DSS-stimulated severe colitis in experimental animals. Eriocitrin counteracted all of the clinical deleterious effects induced by DSS, such as body-weight loss, colon shortening, histopathological injury, accretion of infiltrated inflammatory cells at the inflamed region and the secretion of inflammatory cytokines. The results clearly showed that eriocitrin effectively attenuated DSS-induced acute colitis in experimental animals.
Mechanisms of Paeonia lactiflora in Treatment of Ulcerative Colitis: A Network Pharmacological Study.
Zhang Yin,Li Xiaoyan,Xu Xianlin,Yang Ningxi
Medical science monitor : international medical journal of experimental and clinical research
BACKGROUND Paeonia lactiflora is the main active ingredient of peony decoction, which is used to treat ulcerative colitis (UC) in traditional Chinese medicine (TCM). Network pharmacology indicates the multiple interactions among genes, proteins, and metabolites associated with diseases and drugs from the network perspective, which shows the multi-component and multi-target attributes of TCM. This study predicted the pharmacological mechanism of Paeonia lactiflora in the treatment of UC by network pharmacological method. MATERIAL AND METHODS Chemical constituents of Paeonia lactiflora were searched from TCMSP data, gene names of target sites were extracted from UniProt database, and disease targets of ulcerative colitis were obtained from the CTD disease database. Use Venny online tools to obtain common targets for drugs and diseases. The DAVID database was used to enrich GO and KEGG for the common target, and the related functions and pathways were obtained. Cytoscape 3.7.1 was used to construct the 'drug-compound-target-disease' network. RESULTS There are 70 common target genes between Paeonia lactiflora and UC. GO analysis showed that the biological functions of the common target genes of Paeonia lactiflora and UC include response to lipopolysaccharide, response to estradiol, response to drug, positive regulation of nitric oxide biosynthetic process, and steroid hormone-mediated signaling pathway. Enrichment of the KEGG signaling pathway mainly involves signaling pathways, including Pathways in cancer, TNF signaling pathway, Tuberculosis, Hepatitis B, and Toxoplasmosis. CONCLUSIONS The network pharmacology intuitively shows the multi-component, multi-target, and multi-channel pharmacological effects of Paeonia lactiflora on UC, and provides a scientific basis for studying the mechanism of the effect of Paeonia lactiflora on UC.
The epidemiology of inflammatory bowel disease: East meets west.
Mak Wing Yan,Zhao Mirabella,Ng Siew Chien,Burisch Johan
Journal of gastroenterology and hepatology
The incidence of inflammatory bowel diseases (IBD) in East has risen over the past decade to become a global disease. The increasing number of studies on the incidence and course of IBD in East has enabled us to explore East versus West differences in the epidemiology of IBD which could enhance our understanding of the heterogeneity of the disease and eventually assist in the discovery of novel therapeutic targets and design of preventive strategies. Comparison of population-based data in East and West reveals that the incidence of IBD has risen rapidly in East while plateauing in West. Furthermore, the clinical presentation and course of IBD differs between East and West with more patients in East presenting with complicated disease. Considering the scarcity of population-based data from East and the lack of studies with long durations of follow-up, it remains to be clarified whether these differences reflect true differences in disease presentation. The effects of genetic and environmental risk factors contributing to IBD also differ between Eastern and Western populations. Considering the differential effects of genetic and environmental risk factors in East and West, future studies should seek to discover novel genetic and environmental risk factors which might specifically apply to eastern populations. In this narrative review, we compare the epidemiology of IBD between eastern and western countries by summarizing evidence from population-based cohort studies in the last ten years. Furthermore, we look at differences in genetic susceptibility and environmental triggers of IBD between East and West.
Identification of potential biomarkers and pathways in ulcerative colitis with combined public mRNA and miRNA expression microarray data analysis.
Yang Lili,Bian Yaoyao,Li Zhengjun,Yan Yan,Li Junyi,Li Wenlin,Zeng Li
Journal of gastrointestinal oncology
Background:Ulcerative colitis (UC) is a chronic, relapsing and non-specific inflammatory disease, involving various genes and pathways in their pathogenesis. Increasing evidences have showed that microRNAs (miRNAs) act as key post-transcriptional regulators of gene expression in UC. This current study aimed to identify key miRNAs, potential target genes, and relevant pathways involved in UC to uncover their underlying molecular mechanisms by using bioinformatics analysis. Methods:The mRNA and miRNA expression profiles were retrieved and downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and miRNAs (DEMIs) were obtained by using the R software package. Results:A total of 79 DEGs and 47 DEMIs were obtained. And a panel of miRNAs and their target mRNAs were identified. It showed that miR-1231 may be a key regulator for DUOX2 and TFF1. CCL11 may be potentially targeted by miR-625. MMP1 may play vital roles in the development of UC by regulating the miR-1228/PPAR signaling pathway. In addition, we validated the most significantly up/down-expressed miRNAs (miR-92b, miR-625) and two of their corresponding target mRNAs (AQP8 and TAGAP, CCL11 and CHI3L1) in colon tissues of UC models preliminarily. The results were consistent with the microarray analysis. Conclusions:These findings may provide new insights into representing key mechanisms associated with the development of UC.
[Anti-inflammatory and immunomodulatory effects of Tripterygium wilfordii processed with licorice on mice model of ulcerative colitis].
Wu Hao,Zhang Cong-En,Yu Xiao-Hong,Ma Guang-Chao,Wang Jia-Bo,Ma Zhi-Jie,Zhao Kui-Jun
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica
The aim of this paper was to investigate the anti-inflammatory effect of Tripterygium wilfordii processed with licorice on DSS-induced ulcerative colitis( UC) mice and its regulation on intestinal immune system. In this study,a DSS-induced animal model of UC mice was established,with mesalazine( Mes) as a positive drug. The pharmacodynamic effects of low( PT1) and high( PT2)doses of T. wilfordii processed with licorice were analyzed by disease activity index( DAI),colon length and colon histopathological score in mice. By detecting the expression levels of TNF-α and IL-6 cytokines in the serum of mice,immunohistochemical CD3+T and Fox P3+Treg staining in the colon of mice,the anti-inflammatory and immunoregulatory effects of T. wilfordii processed with licorice on UC mice were analyzed. The hepatotoxicity of each dose of T. wilfordii processed with licorice was also analyzed by HE staining in liver tissue of mice and ALT and AST levels in serum. The results showed that the colitis symptoms of the mice in the PT1 group and the PT2 group were alleviated,the inflammatory cell infiltration was reduced. And the expression of inflammatory factors was decreased,the difference was statistically significant compared with the model group( P<0. 05). The HE staining and ALT and AST levels in the high dose group and low dose group were not significantly different from those in the normal group. The results showed that T. wilfordii processed with licorice has the anti-inflammatory and immunomodulatory effects on UC mice,and the dose did not show significant hepatotoxicity.
Microbiota and mucosal defense in IBD: an update.
Stange Eduard F,Schroeder Bjoern O
Expert review of gastroenterology & hepatology
: Inflammatory bowel diseases (IBD) are on the rise worldwide. This review covers the current concepts of the etiology of Crohn´s disease and ulcerative colitis by focusing on an unbalanced interaction between the intestinal microbiota and the mucosal barrier. Understanding these issues is of paramount importance for the development of targeted therapies aiming at the disease cause.: Gut microbiota alterations and a dysfunctional intestinal mucosa are associated with IBD. Here we focus on specific defense structures of the mucosal barrier, namely antimicrobial peptides and the mucus layer, which keep the gut microbiota at a distance under healthy conditions and are defective in IBD.: The microbiology of both forms of IBD is different but characterized by a reduced bacterial diversity and richness. Abundance of certain bacterial species is altered, and the compositional changes are related to disease activity. In IBD the mucus layer above the epithelium is contaminated by bacteria and the immune reaction is dominated by the antibacterial response. Human genetics suggest that many of the basic deficiencies in the mucosal response, due to Paneth cell, defensin and mucus defects, are primary. Nutrition may also be important but so far there is no therapy targeting the mucosal barrier.
Fusobacterium nucleatum facilitates ulcerative colitis through activating IL-17F signaling to NF-κB via the upregulation of CARD3 expression.
Chen Yongyu,Chen Yan,Cao Pan,Su Wenhao,Zhan Na,Dong Weiguo
The Journal of pathology
Accumulating evidence links Fusobacterium nucleatum with ulcerative colitis (UC). The mechanism by which F. nucleatum promotes intestinal inflammation in UC remains poorly defined. Here, we first examined the abundance and impact of F. nucleatum on disease activity in UC tissues. Next, we isolated a strain of F. nucleatum from UC tissues and explored whether F. nucleatum aggravates the intestinal inflammatory response in vitro and in vivo. We also examined whether F. nucleatum infection involves the NF-κB or IL-17F signaling pathways. Our data showed that F. nucleatum was enriched in 51.78% of UC tissues and was correlated with the clinical course, clinical activity and refractory behavior of UC (p < 0.05). Furthermore, we demonstrated that F. nucleatum promoted intestinal epithelial damage and the expression of the inflammatory cytokines IL-1β, Il-6, IL-17F and TNF-α. Mechanistically, F. nucleatum targeted caspase activation and recruitment domain 3 (CARD3) through NOD2 to activate the IL-17F/NF-κB pathway in vivo and in vitro. Thus, F. nucleatum orchestrates a molecular network involving CARD3 and IL-17F to control the UC process. Measuring and targeting F. nucleatum and its associated pathways will yield valuable insight into the prevention and treatment of UC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Polysaccharides derived from Morinda citrifolia Linn reduce inflammatory markers during experimental colitis.
Batista Jalles Arruda,Magalhães Diva de Aguiar,Sousa Stefany Guimarães,Ferreira Jayro Dos Santos,Pereira Cynthia Maria Carvalho,Lima José Victor do Nascimento,de Albuquerque Ieda Figueira,Bezerra Nayonara Lanara Sousa Dutra,de Brito Tarcisio Vieira,Monteiro Carlos Eduardo da Silva,Franco Alvaro Xavier,Di Lenardo David,Oliveira Lorena Almeida,Feitosa Judith Pessoa de Andrade,de Paula Regina Célia Monteiro,Barros Francisco Clarck Nogueira,Freitas Ana Lúcia Ponte,de Oliveira Jefferson Soares,Vasconcelos Daniel Fernando Pereira,Soares Pedro Marcos Gomes,Barbosa André Luiz Dos Reis
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:There are many reports of pharmacological activities of extracts and fractions of different vegetable-derived products in the scientific literature and in folk medicine. Ethnopharmacological use of these products by various communities continues to be extensively explored, and they account for more than half of all medications used worldwide. Polysaccharides (PLS) extracted from plants such as Morinda Citrifolia Linn present therapeutic potential in treatment of inflammatory bowel diseases (IBD) such as ulcerative colitis (UC). AIM OF THE STUDY:To evaluate the anti-inflammatory action of Noni-PLS against the intestinal damage in UC induced by acetic acid in mice. MATERIALS AND METHODS:In acetic acid-induced colitis, the mice were treated intraperitoneally (ip) with Noni-PLS (0.1, 0.3, and 3.0 mg/kg) or subcutaneously (sc) with dexamethasone (2.0 mg/kg) 30 min before euthanasia to determine the best dose of Noni-PLS with an anti-inflammatory effect in the course of UC. The colonic tissue samples were collected for macroscopic, wet weight, microscopic and biochemical (myeloperoxidase (MPO), glutathione (GSH), malondialdehyde (MDA), nitrate/nitrite (NO/NO), cytokines, cyclooxygenase (COX-2) and inducible nitric oxide (iNOS)) analyses. RESULTS:Treatment with Noni-PLS reduced the intestinal damage induced by acetic acid as it reduced macroscopic and microscopic scores and the wet weight of the colon. In addition, MPO activity and levels of GSH, MDA, NO/NO, pro-inflammatory cytokines, and COX-2 expression reduced. CONCLUSIONS:This study suggests that Noni-PLS exhibits anti-inflammatory action against intestinal damage by reducing inflammatory cell infiltration, oxidative stress, pro-inflammatory action of cytokines, COX-2 and iNOS expression in the inflamed colon. Noni-PLS shows therapeutic potential against inflammatory disorders like UC.
The Sulfate-Reducing Microbial Communities and Meta-Analysis of Their Occurrence during Diseases of Small-Large Intestine Axis.
Kushkevych Ivan,Leščanová Oľga,Dordević Dani,Jančíková Simona,Hošek Jan,Vítězová Monika,Buňková Leona,Drago Lorenzo
Journal of clinical medicine
Sulfate-reducing bacteria (SRB) are often isolated from animals and people with ulcerative colitis and can be involved in the IBD development in the gut-intestine axis. The background of the research consisted of obtaining mixed cultures of SRB communities from healthy mice and mice with colitis, finding variation in the distribution of their morphology, to determine pH and temperature range tolerance and their possible production of hydrogen sulfide in the small-large intestinal environment. The methods: Microscopic techniques, biochemical, microbiological, and biophysical methods, and statistical processing of the results were used. The results: Variation in the distribution of sulfate-reducing microbial communities were detected. Mixed cultures from mice with ulcerative colitis had 1.39 times higher production of HS in comparison with samples from healthy mice. The species of genus play an important role in diseases of the small-large intestine axis. Meta-analysis was also used for the observation about an SRB occurrence in healthy and not healthy individuals and the same as their metabolic processes. Conclusions: This finding is important for its possible correlation with inflammation of the intestine, where the present of SRB in high concentration plays a major part. It can be a good possible indicator of the occurrence of IBD.
Berberis lycium fruit extract attenuates oxi-inflammatory stress and promotes mucosal healing by mitigating NF-κB/c-Jun/MAPKs signalling and augmenting splenic Treg proliferation in a murine model of dextran sulphate sodium-induced ulcerative colitis.
Sharma Anamika,Tirpude Narendra Vijay,Kulurkar Pankaj Markand,Sharma Rohit,Padwad Yogendra
European journal of nutrition
PURPOSE:There is a growing interest in developing phytomolecule-based therapies for the management of inflammatory disorders owing to rising cost of treatments and unwarranted effects. The present work attempted to assess the efficacy and mechanisms of Berberis lycium Royle fruit extract (BLFE) in mitigating chemical-induced colitis in mice. METHODS:Colitis was induced in Balb/C mice using dextran sulphate sodium (DSS) and protective effects of BLFE were examined. Several oxi-inflammatory parameters, histopathological changes, epithelial barrier integrity and activation of NF-κB/c-Jun/MAPKs in colon tissue were determined. Splenic T cell subpopulations were also gauged to evaluate the systemic effects of BLFE in the modulation of immune responses. RESULTS:BLFE treatment effectively improved animal survival rate, DAI score, colon length and structural damage in DSS-exposed mice. Expression of oxi-inflammatory markers such as MPO, IgE, iNOS, ICAM-1, MCP-1 and RANTES as well as Th1/Th2/Th17 cytokines were decreased in BLFE treated animals. On the other hand, an increased mRNA expression of anti-inflammatory cytokines (IL-4/IL-10), tight junction proteins and IgA levels were also observed during BLFE treatment. BLFE appeared to modulate intestinal epithelial cell proliferation (PCNA) and apoptosis (Bcl2/Bax), thereby suggesting its role in the maintenance of intestinal integrity. Analysis of inflammatory signalling pathways indicated robust activation and expression of NF-κB/c-Jun/MAPKs (JNK and p38) in DSS treated animal which was strongly abrogated by BLFE treatment. BLFE supplementation also enhanced the proliferation of CD3CD4CD25 Treg cells indicating suppression of inflammatory activation. CONCLUSION:These observations provide compelling evidence that BLFE could be considered as a viable natural strategy in the prevention and management of ulcerative colitis.
Dapsone reduced acetic acid-induced inflammatory response in rat colon tissue through inhibition of NF-kB signaling pathway.
Rashidian Amir,Rashki Asma,Abdollahi Alireza,Haddadi Nazgol-Sadat,Chamanara Mohsen,Mumtaz Faiza,Dehpour Ahmad Reza
Immunopharmacology and immunotoxicology
The purpose of this study is to examine the protective effects of Dapsone on inflammation of intestinal tissue through inhibition of NF-kB pathway in acetic acid-induced colitis in rats. Acute colitis was produced by intra-rectal instillation of 2 mL of 4% acetic acid diluted in normal saline. Then, two hours after induction of colitis, DMSO as vehicle, dexamethasone (2 mg/kg) and dapsone (12.5 mg/kg) were given to the animals intraperitoneally (i.p.) and continued for five following days. Evaluation of macroscopic and microscopic damages were done. Myeloid peroxidase enzyme (MPO) activity was measured by a biochemical technique. Moreover, tumor necrosis factor-α (TNF-α) activity was identified by ELISA, and the expression level of pNF-kB protein was evaluated by immunohistochemistry (IHC). Dexamethasone (2 mg/kg) and dapsone (12.5 mg/kg) decreased the macroscopic and microscopic damages compared with acetic acid group ( ˂ .001). Additionally, these agents decreased the activity of MPO ( ˂ .001), TNF-α ( ˂ .001) and the expression level of p-NF-kB ( ˂ .001) in rat colon tissue compared with the acetic acid group. It is proposed that the anti-inflammatory activity of dapsone on acetic acid-induced colitis in rats may involve the inhibition of NF-kB pathway.
Fecal microbiota transplantation results in bacterial strain displacement in patients with inflammatory bowel diseases.
Zou Manli,Jie Zhuye,Cui Bota,Wang Honggang,Feng Qiang,Zou Yuanqiang,Zhang Xiuqing,Yang Huanming,Wang Jian,Zhang Faming,Jia Huijue
FEBS open bio
Fecal microbiota transplantation (FMT), which is thought to have the potential to correct dysbiosis of gut microbiota, has been used to treat inflammatory bowel disease (IBD) for almost a decade. Here, we report an interventional prospective cohort study performed to elucidate the extent of and processes underlying microbiota engraftment in IBD patients after FMT treatment. The cohort included two categories of patients: (a) patients with moderate to severe Crohn's disease (CD) (Harvey-Bradshaw Index ≥ 7, n = 11) and (b) patients with ulcerative colitis (UC) (Montreal classification S2 and S3, n = 4). All patients were treated with a single FMT (via mid-gut, from healthy donors), and follow-up visits were performed at baseline, 3 days, 1 week, and 1 month after FMT (missing time points included). At each follow-up time point, fecal samples and clinical metadata were collected. For comparative analysis, 10 fecal samples from 10 healthy donors were included to represent the diversity level of normal gut microbiota. Additionally, the metagenomic data of 25 fecal samples from five individuals with metabolic syndrome who underwent autologous FMT treatment were downloaded from a previous published paper to represent fluctuations in microbiota induced during FMT. All fecal samples underwent shotgun metagenomic sequencing. We found that 3 days after FMT, 11 out of 15 recipients were in remission (three out of four UC recipients; 8 out of 11 CD recipients). Generally, bacterial colonization was observed to be lower in CD recipients than in UC recipients at both species and strain levels. Furthermore, across species, different strains displayed disease-specific displacement advantages under two-disease status. Finally, most post-FMT species (> 80%) could be properly predicted (area under the curve > 85%) using a random forest classification model, with the gut microbiota composition and clinical parameters of pre-FMT recipients acting as factors that contribute to prediction accuracy.
Colonic mucosa-associated candida assessed by biopsy culture is associated with disease severity in ulcerative colitis: A prospective study.
Shah Jimil,Dutta Usha,Rudramurthy Shivaprakash,Chakrabarti Arunaloke,Sinha Saroj K,Sharma Vishal,Mandavdhare Harshal,Sharma Pankaj,Kalsi Dimple,Popli Priyanka,Radhika Srinivasan,Das Ashim,Kochhar Rakesh
Journal of digestive diseases
OBJECTIVE:To evaluate the relationship of mucosa-associated candida (MAC) and disease severity in patients with ulcerative colitis (UC). METHODS:We prospectively investigated the presence, nature, and quantification of MAC in patients with UC and its relationship with disease severity. Consecutive patients with UC were assessed for clinical, endoscopic, histological features and serum markers of disease severity. All patients underwent mucosal brushing cytology, brushing culture, and biopsy culture for candida growth. MAC was considered present if mucosal biopsy culture grew candida. Candida spp. identification was performed by matrix-assisted laser desorption/ionization. Serum β-D-glucan was measured with a Fungitell assay. Patients with irritable bowel syndrome who had undergone similar investigations were included as controls. RESULTS:Ninety-six patients with UC showed evidence of MAC more often than the controls (n = 20) based on biopsy culture (33.3% vs 5.0%, P = 0.011), brush cytology (30.2% vs 5.0%, P = 0.019), and brush culture (36.5% vs 10.0%, P = 0.021). Patients with UC had higher candida colony counts (≥10 CFU/mL) than controls (34.4% vs 5.0%, P = 0.007). Median β-D-glucan values were higher in patients with UC than in controls (103.26 pg/mL vs 66.51 pg/mL, P = 0.011). The UC group with MAC had a higher median total Mayo score, C-reactive protein, fecal calprotectin, β-D-glucan, and histological activity than those without MAC. CONCLUSIONS:Patients with UC more often show evidence of MAC and a higher candida colony count than controls. The presence of MAC is associated with high disease severity in patients with UC.
The TLR9 Agonist Cobitolimod Induces IL10-Producing Wound Healing Macrophages and Regulatory T Cells in Ulcerative Colitis.
Schmitt Heike,Ulmschneider Julia,Billmeier Ulrike,Vieth Michael,Scarozza Patrizio,Sonnewald Sophia,Reid Stephen,Atreya Imke,Rath Timo,Zundler Sebastian,Langheinrich Melanie,Schüttler Jürgen,Hartmann Arndt,Winkler Thomas,Admyre Charlotte,Knittel Thomas,Dieterich Johansson Christine,Zargari Arezou,Neurath Markus F,Atreya Raja
Journal of Crohn's & colitis
BACKGROUND AND AIMS:The topically applied Toll-like receptor 9 [TLR9] agonist cobitolimod is a first-in-class DNA-based oligonucleotide with demonstrated therapeutic efficacy in clinical trials with ulcerative colitis [UC] patients. We here characterized its anti-inflammatory mechanism in UC. METHODS:Luminal cobitolimod administration was evaluated in an experimental dextran sodium sulfate [DSS]-induced colitis model. Cultured blood and mucosal cells from UC patients were treated with cobitolimod and analysed via microarray, quantitative real-time PCR, ELISA and flow cytometry. Intestinal slides of cobitolimod-treated UC patients were analysed by immunohistochemistry. RESULTS:Cobitolimod administration markedly suppressed experimental colitis activity, and microarray analyses demonstrated mucosal IL10 upregulation and suppression of IL17 signalling pathways. Cobitolimod treatment was associated with significant induction of mucosal IL10+Tr1 and Treg cells and suppression of Th17 cells. TLR9 knockout mice indicated that cobitolimod requires TLR9 signalling for IL10 induction. In UC patients, mucosal TLR9 levels correlated with severity of inflammation. Cobitolimod inhibited IL17A and IL17F, but increased IL10 and FoxP3 expression in cultured intestinal UC T cells. Cobitolimod-mediated suppression of intestinal IL17+T cells was abrogated by IL10 blockade. Furthermore, cobitolimod led to heightened IL10 production by wound healing macrophages. Immunohistochemistry in intestinal biopsies of cobitolimod-treated UC patients indicated increased presence of IL10+mononuclear and regulatory T cells, as well as reduction of IL17+cells. CONCLUSION:Activation of TLR9 via cobitolimod might represent a novel therapeutic approach in UC, as it suppresses Th17 cells and induces anti-inflammatory IL10+macrophages and regulatory T cells, thereby modifying the dysregulated intestinal cytokine balance. PODCAST:This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.
Administration of Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice.
Bian Xiaoyuan,Wu Wenrui,Yang Liya,Lv Longxian,Wang Qing,Li Yating,Ye Jianzhong,Fang Daiqiong,Wu Jingjing,Jiang Xianwan,Shi Ding,Li Lanjuan
Frontiers in microbiology
Inflammatory bowel diseases (IBDs) develop as a result of complex interactions among genes, innate immunity and environmental factors, which are related to the gut microbiota. Multiple clinical and animal data have shown that is associated with a healthy mucosa. However, its precise role in colitis is currently unknown. Our study aimed to determine its protective effects and underlying mechanisms in a dextran sulfate sodium (DSS)-induced colitis mouse model. Twenty-four C57BL/6 male mice were administered Muc or phosphate-buffered saline (PBS) once daily by oral gavage for 14 days. Colitis was induced by drinking 2% DSS from days 0 to 6, followed by 2 days of drinking normal water. Mice were weighed daily and then sacrificed on day 8. We found that improved DSS-induced colitis, which was evidenced by reduced weight loss, colon length shortening and histopathology scores and enhanced barrier function. Serum and tissue levels of inflammatory cytokines and chemokines (TNF-α, IL1α, IL6, IL12A, MIP-1A, G-CSF, and KC) decreased as a result of administration. Analysis of 16S rDNA sequences showed that induced significant gut microbiota alterations. Furthermore, correlation analysis indicated that pro-inflammatory cytokines and other injury factors were negatively associated with , , and , which were prominently abundant in -treated mice. We confirmed that treatment could ameliorate mucosal inflammation either via microbe-host interactions, which protect the gut barrier function and reduce the levels of inflammatory cytokines, or by improving the microbial community. Our findings suggest that may be a potential probiotic agent for ameliorating colitis.