Variations in Gut Microbiome are Associated with Prognosis of Hypertriglyceridemia-Associated Acute Pancreatitis.
Hu Xiaomin,Gong Liang,Zhou Ruilin,Han Ziying,Ji Li,Zhang Yan,Zhang Shuyang,Wu Dong
Biomolecules
Hypertriglyceridemia-associated acute pancreatitis (HTGAP) is linked with increased severity and morbidity. Intestinal flora plays an important role in the progression of acute pancreatitis (AP). However, pathogenetic association between gut microbiota and HTGAP remains unknown. In this study, we enrolled 30 HTGAP patients and 30 patients with AP that is evoked by other causes. The V3-V4 regions of 16S rRNA sequences of the gut microbiota were analyzed. Clinical characteristics, microbial diversity, taxonomic profile, microbiome composition, microbiological phenotype, and functional pathways were compared between the two groups. Our results showed that the HTGAP group had a higher proportion of severe AP (46.7% vs. 20.0%), organ failure (56.7% vs. 30.0%), and a longer hospital stay (18.0 days vs. 6.5 days). HTGAP group also had poorer microbial diversity, higher abundances of and , but lower abundances of , , and as compared with non-HTGAP group. Correlation analysis revealed that gut bacterial taxonomic and functional changes were linked with local and systemic complications, ICU admission, and mortality. This study revealed that alterations of gut microbiota were associated with disease severity and poor prognosis in HTGAP patients, indicating a potential pathophysiological link between gut microbiota and hypertriglyceridemia related acute pancreatitis.
10.3390/biom11050695
Effects of Ganoderma lucidum polysaccharides on chronic pancreatitis and intestinal microbiota in mice.
Li Koukou,Zhuo Cheng,Teng Chunying,Yu Sumei,Wang Xin,Hu Yang,Ren Guangming,Yu Min,Qu Juanjuan
International journal of biological macromolecules
This study manifested the effects of polysaccharides from Ganoderma lucidum strain S (GLP S) on chronic pancreatitis (CP) therapy and intestinal microbiota modulation in mice induced by diethyldithiocarbamate (DDC). The GLPS was prepared from cultured mycelium and markedly alleviated the pancreatitis in mice through decreasing lipase, AMS, IFN-γ and TNF-α level as well as increasing SOD and total antioxidant activity. Furthermore, high throughput sequencing analysis revealed that GLPS altered the composition and diversity of intestinal microbiota, especially, decreased the relative abundance of phylum Bacteroidetes and increased that of phylum Firmictutes. At the genus level, supplementation of GLPS increased the relative abundance of the beneficial bacteria such as Lactobacillales, Roseburia and Lachnospiraceae. These results disclosed the potential therapy mechanism of GLPS on chronic pancreatitis might be intestinal microbiota dependent.
10.1016/j.ijbiomac.2016.09.029
Association between gut microbiota and acute pancreatitis: a bidirectional Mendelian randomization study.
Journal of gastroenterology and hepatology
BACKGROUND AND AIM:The dysbiosis of gut microbiota has been reported in acute pancreatitis. However, the direction and magnitude between host microbiota and pancreas remains to be established. This study investigated the association between gut microbiota and acute pancreatitis using Mendelian randomization (MR) methods. METHODS:Summary statistics of gut microbiota abundance and acute pancreatitis were extracted from genome-wide association studies (GWAS). The two-sample bidirectional MR design was employed to assess genetic association between the microbiota and pancreatitis, followed by a comprehensive sensitivity analysis to verify the robustness of the results. RESULTS:Seven microbiota taxa have been identified as significantly associated with the development of pancreatitis. Host genetic-driven order Bacteroidales and class Bacteroidia are associated with an increased risk of pancreatitis. The genera Coprococcus and Eubacterium fissicatena group also exhibit a positive effect on the development of pancreatitis, while the genera Prevotella, Ruminiclostridium, and Ruminococcaceae act as protective factors against pancreatitis. In contrast, acute pancreatitis was positively correlated with phylum Proteobacteria and genus Lachnospiraceae and negatively correlated with genus Holdemania. CONCLUSIONS:The bidirectional relationship between gut microbiota and acute pancreatitis suggests a critical role for host-microbiota crosstalk in the development of the disease. Targeted modulation of specific gut microbiota enables the prevention and treatment of acute pancreatitis.
10.1111/jgh.16658
Alterations in microbiome associated with acute pancreatitis.
Current opinion in gastroenterology
PURPOSE OF REVIEW:This review evaluates the current knowledge of gut microbiome alterations in acute pancreatitis, including those that can increase acute pancreatitis risk or worsen disease severity, and the mechanisms of gut microbiome driven injury in acute pancreatitis. RECENT FINDINGS:Recent observational studies in humans showed the association of gut microbiome changes (decreased gut microbiome diversity, alterations in relative abundances of certain species, and association of unique species with functional pathways) with acute pancreatitis risk and severity. Furthermore, in-vivo studies highlighted the role of gut microbiome in the development and severity of acute pancreatitis using FMT models. The gut barrier integrity, immune cell homeostasis, and microbial metabolites appear to play key roles in acute pancreatitis risk and severity. SUMMARY:Large human cohort studies that assess gut microbiome profile, its metabolites and impact on acute pancreatitis risk and severity will be crucial for development of innovative prediction, prevention and treatment strategies.
10.1097/MOG.0000000000001046
The role of gut microbiota in the pathogenesis and treatment of acute pancreatitis: a narrative review.
Lu Wei-Wei,Chen Xi,Ni Jian-Li,Zhu Sheng-Liang,Fei Ai-Hua,Wang Xiao-Su
Annals of palliative medicine
To investigate the role played by gut microbiota in the development and treatment of acute pancreatitis. Gut microbiota is the largest micro-ecosystem in the human body, and is related to various system diseases. Acute pancreatitis is one of the common acute critical diseases in clinical practice, and there are various causative factors for the occurrence of this disease, such as alcohol, infection, obstruction and intestinal microecological factors. The dysbiosis of gut microbiota may play an important role in the pathogenesis of acute pancreatitis and affect prognoses, including gut microbiota structure disorder and bacterial translocation. It can also affect host metabolism and increase the production of toxic metabolites and affect the treatment of acute pancreatitis. Probiotics are live microorganisms that can give health benefits to the host when applied in sufficient quantities, which can effectively stimulate the growth and reproduction of the normal flora of the body, inhibit the overgrowth of pathogenic bacteria, and have a protective effect on the intestinal barrier function. A search of electronic databases (PubMed, EMBASE, Cochrane) has been realized to summarize the information. The paper briefly describes the concept of gut microbiota and acute pancreatitis, examines the role of gut microbiota in the development and treatment of acute pancreatitis, concludes the investigations of the therapeutic effect of probiotics for dysbiosis of gut microbiota in acute pancreatitis in order to provide a valid reference for the development of subsequent clinical strategies.
10.21037/apm-21-429
Trimethylamine N-oxide promotes hyperlipidemia acute pancreatitis via inflammatory response.
Canadian journal of physiology and pharmacology
Trimethylamine N-oxide (TMAO), a metabolite of gut microbiota, is involved in the regulation of lipid metabolism and inflammatory response; however, the role of TMAO in hyperlipidemia acute pancreatitis (HAP) is not clear. In this study, HAP mice were used as an animal model to explore the effects and possible mechanism of TMAO on HAP, which may provide new ideas for the treatment of HAP. Results found that the levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol, nonestesterified fatty acid, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, α-amylase, TMAO, and flavin-containing monooxygenase 3 were significantly increased, the levels of high-density lipoprotein cholesterol and insulin were significantly decreased, and there was an obvious pancreatic injury and inflammatory response in the model group. The choline analogue 3,3-dimethyl-1-butanol (DMB) treatment reversed the changes of serum biochemical parameters, alleviated the pancreatic tissue injury, and reduced the levels of inflammatory cytokines. Further studies of toll-like receptor (TLR)/p-glycoprotein 65 (p65) pathway found that the expressions of TLR2, TLR4, and p-p65/p65 in the model group were significantly increased, which was more obvious after (Migula) Castellani & Chalmers treatment, while activation of the TLR/p65 pathway was inhibited by DMB. The results indicated that TMAO promotes HAP by promoting inflammatory response through TLR/p65 signaling pathway, suggesting that TMAO may be a potential target of HAP.
10.1139/cjpp-2021-0421
Pretreatment with chitosan oligosaccharides attenuate experimental severe acute pancreatitis via inhibiting oxidative stress and modulating intestinal homeostasis.
Acta pharmacologica Sinica
Severe acute pancreatitis (SAP) is a severe acute abdominal disease. Recent evidence shows that intestinal homeostasis is essential for the management of acute pancreatitis. Chitosan oligosaccharides (COS) possess antioxidant activity that are effective in treating various inflammatory diseases. In this study we explored the potential therapeutic effects of COS on SAP and underlying mechanisms. Mice were treated with COS (200 mg·kg·d, po) for 4 weeks, then SAP was induced in the mice by intraperitoneal injection of caerulein. We found that COS administration significantly alleviated the severity of SAP: the serum amylase and lipase levels as well as pancreatic myeloperoxidase activity were significantly reduced. COS administration suppressed the production of proinflammatory cytokines (TNF-α, IL-1β, CXCL2 and MCP1) in the pancreas and ileums. Moreover, COS administration decreased pancreatic inflammatory infiltration and oxidative stress in SAP mice, accompanied by activated Nrf2/HO-1 and inhibited TLR4/NF-κB and MAPK pathways. We further demonstrated that COS administration restored SAP-associated ileal damage and barrier dysfunction. In addition, gut microbiome analyses revealed that the beneficial effect of COS administration was associated with its ability to improve the pancreatitis-associated gut microbiota dysbiosis; in particular, probiotics Akkermansia were markedly increased, while pathogenic bacteria Escherichia-Shigella and Enterococcus were almost eliminated. The study demonstrates that COS administration remarkably attenuates SAP by reducing oxidative stress and restoring intestinal homeostasis, suggesting that COS might be a promising prebiotic agent for the treatment of SAP.
10.1038/s41401-020-00581-5
Intestinal microbiota regulates colonic inflammation in fluorosis mice by TLR/NF-κB pathway through short-chain fatty acids.
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
Intestinal inflammation and microbial dysbiosis are found simultaneously in patients with fluorosis. However, whether the inflammation derived from fluoride exposure only or intestinal microbial disorders has not been clarified. In this study, 100 mg/L NaF exposure for 90 days significantly elevated the expressions of inflammatory factors (TNF-α, IL-1β, IL-6, IFN-γ, TGF-β, and IL-10), and the levels of TLR4, TRAF6, Myd88, IKKβ, and NF-κB P65 in mouse colon, while the above factors were reduced in pseudo germ-free mice with fluorosis, hinting that disordered microbiota might play a more direct role in the development of colonic inflammation than fluoride. Fecal microbiota transplantation (FMT) lowered the levels of inflammatory factors and inactivated the TLR/NF-κB pathway in fluoride-exposed mice. In addition, supplementing short-chain fatty acids (SCFAs) exhibited the identical effects to the model of FMT. In summary, intestinal microbiota may alleviate the colonic inflammatory of mice with fluorosis by regulating TLR/NF-κB pathway through SCFAs.
10.1016/j.fct.2023.113866
Oxymatrine ameliorated experimental colitis via mechanisms involving inflammatory DCs, gut microbiota and TLR/NF-κB pathway.
International immunopharmacology
It is common knowledge that the crosstalk of gut microbiota (GM) and dendritic cells (DCs) are critical for the pathogenesis of inflammatory bowel disease (IBD). As a major bioactive constituent derived from the root of the Sophora flavescens, Oxymatrine (OMT) was used to treat IBD in China. However, it is still unknown whether OMT ameliorates IBD by regulating the crosstalk between DCs and GM. In the present study, after 10 days of OMT (100 mg/kg/day) treated mice with colitis induced by dextran sulfate sodium (DSS), the change rate of body weight, colon weight, colon weight index, colon length, DAI score and colonic pathological damage scores of colitis mice were significantly ameliorate, followed with fewer ulceration and inflammatory cell infiltration, the increased expression of IL-4 and IL-13, and the decreased expression of CCL-2, IL-33 and IFN-γ. The percents of inflammatory DCs (such as TNF-αDCs, iNOSDCs, CXCR5DCs and E-cadherinDCs) were markedly decreased, and the GM composition was regulated. Importantly, it is positive correlated between the efficacy of OMT on colitis, GM and inflammatory DCs. Meanwhile, Western blotting assay showed that OMT suppressed the activation of TLR4, Myd88, IRAK4, IRAK1, TRAF6, TAK1, TAB, MKK3, MKK6, P38, NF-κB in the TLR / NF-κB signaling pathway. In summary, OMT exhibits the protective effect against the DSS-induced experimental colitis, which was achieved by regulating the crosstalk of inflammatory DCs and GM, and inhibiting the TLR / NF-κB signaling pathway.
10.1016/j.intimp.2022.109612
NF-κB in acute pancreatitis: Mechanisms and therapeutic potential.
Jakkampudi Aparna,Jangala Ramaiah,Reddy B Ratnakar,Mitnala Sasikala,Nageshwar Reddy D,Talukdar Rupjyoti
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]
The incidence of acute pancreatitis (AP) is increasing globally and mortality could be high among patients with organ failure and infected necrosis. The predominant factors responsible for the morbidity and mortality of AP are systemic inflammatory response syndrome and multiorgan dysfunction. Even though preclinical studies have shown antisecretory agents (somatostatin), antioxidants (S-adenosyl methionine [SAM], selenium), protease inhibitors, platelet activating factor inhibitor (Lexipafant), and anti-inflammatory immunomodulators (eg. prostaglandin E, indomethacin) to benefit AP in terms of reducing the severity and/or mortality, most of these agents have shown heterogeneous results in clinical studies. Several years of experimental studies have implicated nuclear factor-kappa B (NF-κB) activation as an early and central event in the progression of inflammation in AP. In this manuscript, we review the literature on the role of NF-κB in the pathogenesis of AP, its early intraacinar activation, and how it results in progression of the disease. We also discuss why anti-protease, antisecretory, and anti-inflammatory agents are unlikely to be effective in clinical acute pancreatitis. NF-κB, being a central molecule that links the initial acinar injury to systemic inflammation and perpetuate the inflammation, we propose that more studies be focussed towards targeted inhibition of NF-κB activity. Direct NF-κB inhibition strategies have already been attempted in patients with various cancers. So far, peroxisome proliferator activator receptor gamma (PPAR-γ) ligand, pyrrolidine dithiocarbamate (PDTC), proteasome inhibitor and calpain I inhibitor have been shown to have direct inhibitory effects on NF-κB activation in experimental AP.
10.1016/j.pan.2016.05.001
Negative feedback regulation of NF-κB action by CITED2 in the nucleus.
Lou Xiwen,Sun Shaogang,Chen Wei,Zhou Yi,Huang Yuefeng,Liu Xing,Shan Yufei,Wang Chen
Journal of immunology (Baltimore, Md. : 1950)
NF-κB is a family of important transcription factors that modulate immunity, development, inflammation, and cancer. The biological activity of NF-κB is subjected to various spatial and temporal regulations. Bioinformatics analysis predicts that CITED2 is topologically close to NF-κB in the protein interaction networks. In this study, we show that ectopic expression or knockdown of CITED2 attenuates or potentiates, respectively, the expression of NF-κB-responsive genes. Mechanistically, CITED2 constitutively localizes inside the nucleus and interacts specifically with the coactivator p300. This prevents p65 from binding to p300, impairs p65 acetylation, and attenuates p65 binding to its cognate promoters. Furthermore, LPS induces CITED2 expression via NF-κB in macrophages. CITED2 sensitizes cells to TNF-α-induced apoptosis. Collectively, this study identifies CITED2 as a novel regulator of NF-κB in the nucleus, which reveals a negative feedback mechanism for NF-κB signaling.
10.4049/jimmunol.1001650
Targeted deletion of MyD88 in intestinal epithelial cells results in compromised antibacterial immunity associated with downregulation of polymeric immunoglobulin receptor, mucin-2, and antibacterial peptides.
Mucosal immunology
Intestinal epithelial cells (IECs) form a physical and immunological barrier that separates the vast gut microbiota from host tissues. MyD88-dependent Toll-like receptor signaling is a key mediator of microbial-host cross-talk. We examined the role of epithelial MyD88 expression by generating mice with an IEC-targeted deletion of the Myd88 gene (MyD88(ΔIEC)). Loss of epithelial MyD88 signaling resulted in increased numbers of mucus-associated bacteria; translocation of bacteria, including the opportunistic pathogen Klebsiella pneumoniae, to mesenteric lymph nodes; reduced transmucosal electrical resistance; impaired mucus-associated antimicrobial activity; and downregulated expression of polymeric immunoglobulin receptor (the epithelial IgA transporter), mucin-2 (the major protein of intestinal mucus), and the antimicrobial peptides RegIIIγ and Defa-rs1. We further observed significant differences in the composition of the gut microbiota between MyD88(ΔIEC) mice and wild-type littermates. These physical, immunological, and microbial defects resulted in increased susceptibility of MyD88(ΔIEC) mice to experimental colitis. We conclude that MyD88 signaling in IECs is crucial for maintenance of gut homeostasis.
10.1038/mi.2012.23
Toll-like receptor 2 is critical for induction of Reg3 beta expression and intestinal clearance of Yersinia pseudotuberculosis.
Dessein R,Gironella M,Vignal C,Peyrin-Biroulet L,Sokol H,Secher T,Lacas-Gervais S,Gratadoux J-J,Lafont F,Dagorn J-C,Ryffel B,Akira S,Langella P,Nùñez G,Sirard J-C,Iovanna J,Simonet M,Chamaillard M
Gut
OBJECTIVE:Yersinia pseudotuberculosis causes ileitis and mesenteric lymphadenitis by mainly invading the Peyer's patches that are positioned in the terminal ileum. Whereas toll-like-receptor 2 (TLR2) controls mucosal inflammation by detecting certain microbiota-derived signals, its exact role in protecting Peyer's patches against bacterial invasion has not been defined. DESIGN:Wild-type, Tlr2-, Nod2- and MyD88-deficient animals were challenged by Y pseudotuberculosis via the oral or systemic route. The role of microbiota in conditioning Peyer's patches against Yersinia through TLR2 was assessed by delivering, ad libitum, exogenous TLR2 agonists in drinking water to germ-free and streptomycin-treated animals. Bacterial eradication from Peyer's patches was measured by using a colony-forming unit assay. Expression of cryptdins and the c-type lectin Reg3 beta was quantified by quantitative reverse transcriptase polymerase chain reaction analysis. RESULTS:Our data demonstrated that Tlr2-deficient mice failed to limit Yersinia dissemination from the Peyer's patches and succumbed to sepsis independently of nucleotide-binding and oligomerisation domain 2 (NOD2). Recognition of both microbiota-derived and myeloid differentiation factor 88 (MyD88)-mediated elicitors was found to be critically involved in gut protection against Yersinia-induced lethality, while TLR2 was dispensable to systemic Yersinia infection. Gene expression analyses revealed that optimal epithelial transcript level of the anti-infective Reg3 beta requires TLR2 activation. Consistently, Yersinia infection triggered TLR2-dependent Reg3 beta expression in Peyer's patches. Importantly, oral treatment with exogenous TLR2 agonists in germ-free animals was able to further enhance Yersinia-induced expression of Reg3 beta and to restore intestinal resistance to Yersinia. Lastly, genetic ablation of Reg3 beta resulted in impaired clearance of the bacterial load in Peyer's patches. CONCLUSIONS:TLR2/REG3 beta is thus an essential component in conditioning epithelial defence signalling pathways against bacterial invasion.
10.1136/gut.2008.168443
Determining zebrafish dorsal organizer size by a negative feedback loop between canonical/non-canonical Wnts and Tlr4/NFκB.
Nature communications
In vertebrate embryos, the canonical Wnt ligand primes the formation of dorsal organizers that govern dorsal-ventral patterns by secreting BMP antagonists. In contrast, in Drosophila embryos, Toll-like receptor (Tlr)-mediated NFκB activation initiates dorsal-ventral patterning, wherein Wnt-mediated negative feedback regulation of Tlr/NFκB generates a BMP antagonist-secreting signalling centre to control the dorsal-ventral pattern. Although both Wnt and BMP antagonist are conserved among species, the involvement of Tlr/NFκB and feedback regulation in vertebrate organizer formation remains unclear. By imaging and genetic modification, we reveal that a negative feedback loop between canonical and non-canonical Wnts and Tlr4/NFκB determines the size of zebrafish organizer, and that Tlr/NFκB and Wnts switch initial cue and feedback mediator roles between Drosophila and zebrafish. Here, we show that canonical Wnt signalling stimulates the expression of the non-canonical Wnt5b ligand, activating the Tlr4 receptor to stimulate NFκB-mediated transcription of the Wnt antagonist frzb, restricting Wnt-dependent dorsal organizer formation.
10.1038/s41467-023-42963-3
Interleukin-33 Promotes REG3γ Expression in Intestinal Epithelial Cells and Regulates Gut Microbiota.
Xiao Yi,Huang Xiangsheng,Zhao Ye,Chen Feidi,Sun Mingming,Yang Wenjing,Chen Liang,Yao Suxia,Peniche Alex,Dann Sara M,Sun Jiaren,Golovko George,Fofanov Yuriy,Miao Yinglei,Liu Zhanju,Chen Daiwen,Cong Yingzi
Cellular and molecular gastroenterology and hepatology
BACKGROUND & AIMS:Regenerating islet-derived protein (REG3γ), an antimicrobial peptide, typically expressed by intestinal epithelial cells (IEC), plays crucial roles in intestinal homeostasis and controlling gut microbiota. However, the mechanisms that regulate IEC expression of REG3γ are still largely unclear. In this study, we investigated whether and how interleukin (IL) 33, an alarmin produced by IEC in response to injury, regulates REG3γ expression in IEC, thus contributing to intestinal homeostasis. METHODS:IEC were isolated from wild-type and IL33 mice to determine expression of REG3γ and other antimicrobial peptides by quantitative real-time polymerase chain reaction and Western blot. IEC cell lines were used for mechanistic studies. 16S rRNA pyrosequencing analysis was used for measuring gut microbiota. Citrobacter rodentium was used for enteric infections. RESULTS:The expression of REG3γ, but not β-defensins, in IECs of IL33 mice was significantly lower than wild-type mice. IL33 treatment induced IEC expression of REG3γ in both mice and human cell lines. Mechanistically, IL33 activated STAT3, mTOR, and ERK1/2 in IEC. Inhibition of these pathways abrogated IL33-induction of REG3γ. IL33 mice demonstrated higher bacteria loads and altered microbiota composition. IL33 did not directly inhibit bacterial growth, but promoted wild-type, not REG3γKO, IECs to kill bacteria in vitro. Consistently, C rodentium infection induced IEC IL33 expression, and IL33 mice demonstrated an impaired bacterial clearance with C rodentium infection. CONCLUSIONS:Our study demonstrated that IL33, which is produced by IEC in response to injury and inflammatory stimulation, in turn promotes IEC expression of REG3γ, and controls the gut microbiota of the host.
10.1016/j.jcmgh.2019.02.006
Melatonin controls microbiota in colitis by goblet cell differentiation and antimicrobial peptide production through Toll-like receptor 4 signalling.
Kim Seung Won,Kim Soochan,Son Mijeong,Cheon Jae Hee,Park Young Sook
Scientific reports
Microbial dysbiosis has long been postulated to be associated with the pathogenesis of inflammatory bowel disease (IBD). Although evidence supporting the anti-colitic effects of melatonin have been accumulating, it is not clear how melatonin affects the microbiota. Herein, we investigated the effects of melatonin on the microbiome in colitis and identified involvement of Toll-like receptor (TLR) 4 signalling in the effects. Melatonin improved dextran sulfate sodium (DSS)-induced colitis and reverted microbial dysbiosis in wild-type (WT) mice but not in TLR4 knockout (KO) mice. Induction of goblet cells was observed with melatonin administration, which was accompanied by suppression of Il1b and Il17a and induction of melatonin receptor and Reg3β, an antimicrobial peptide (AMP) against Gram-negative bacteria. In vitro, melatonin treatment of HT-29 intestinal epithelial cells promotes mucin and wound healing and inhibits growth of Escherichia coli. Herein, we showed that melatonin significantly increases goblet cells, Reg3β, and the ratio of Firmicutes to Bacteriodetes by suppressing Gram-negative bacteria through TLR4 signalling. Our study suggests that sensing of bacteria through TLR4 and regulation of bacteria through altered goblet cells and AMPs is involved in the anti-colitic effects of melatonin. Melatonin may have use in therapeutics for IBD.
10.1038/s41598-020-59314-7
Decoding Toll-like receptors: Recent insights and perspectives in innate immunity.
Immunity
Toll-like receptors (TLRs) are an evolutionarily conserved family in the innate immune system and are the first line of host defense against microbial pathogens by recognizing pathogen-associated molecular patterns (PAMPs). TLRs, categorized into cell surface and endosomal subfamilies, recognize diverse PAMPs, and structural elucidation of TLRs and PAMP complexes has revealed their intricate mechanisms. TLRs activate common and specific signaling pathways to shape immune responses. Recent studies have shown the importance of post-transcriptional regulation in TLR-mediated inflammatory responses. Despite their protective functions, aberrant responses of TLRs contribute to inflammatory and autoimmune disorders. Understanding the delicate balance between TLR activation and regulatory mechanisms is crucial for deciphering their dual role in immune defense and disease pathogenesis. This review provides an overview of recent insights into the history of TLR discovery, elucidation of TLR ligands and signaling pathways, and their relevance to various diseases.
10.1016/j.immuni.2024.03.004
Small-Molecule Modulators of Toll-like Receptors.
Wang Yibo,Zhang Shuting,Li Hongyuan,Wang Hongshuang,Zhang Tianshu,Hutchinson Mark R,Yin Hang,Wang Xiaohui
Accounts of chemical research
Toll-like receptors (TLRs) are the "gatekeepers" of the immune system in humans and other animals to protect the host from invading bacteria, viruses, and other microorganisms. Since TLR4 was discovered as the receptor for endotoxin in the late 1990s, significant progress has been made in exploiting an understanding of the function of TLRs. The TLR-signaling pathway is crucial for the induction and progression of various diseases. Dysregulation of TLR signaling contributes to numerous pathological conditions, including chronic inflammation, sepsis, cancers, asthma, neuropathic pain, drug addiction, and autoimmune diseases. Therefore, manipulation of TLR signaling is promising to halt their activity in inflammatory diseases, to enhance their signaling to fight cancers, to modulate their role in autoimmune diseases, and to suppress them to treat drug addiction. TLR agonists have demonstrated great potential as antimicrobial agents and vaccine adjuvants, whereas TLR antagonists are being developed as reagents and drugs to dampen immune responses. Because of their pivotal potential therapeutic applications, fruitful small-molecule compounds and peptide fragments have been discovered, and many of them have advanced to various stages of clinical trials (though only two have been approved by the Food and Drug Administration (FDA): MPLA as a TLR4 agonist and imiquimod as a TLR7 agonist).In this Account, we focus on the progress in developing TLR signaling pathway modulators (mainly focused on the Yin and Wang laboratories) over the past decade and highlight the accomplishments and currently existing challenges in the development of TLR modulators. First, we briefly describe the members of the human TLR family along with their natural modulators. Second, we illustrate our endeavors to discover TLR-targeted agents using comprehensive approaches. Specifically, a discussion of identification and characterization of new chemical entities, determination of modes of action, and further applications is presented. For instance, the TLR3 antagonist was first discovered through screening, and the inhibitory activity was confirmed in murine cells. Considering the glycosylation on TLR3, a new direction for TLR3 modulator design was pointed out to target asparagine glycosylation. We have particularly focused on the discovery of TLR4 antagonists and have assessed their great potential in the clinical treatment of drug addiction and alcohol use disorders. In addition, we discuss multiple other popular and robust techniques for modulator discovery. Not only small organic modulators but also stapled peptides and peptidomimetics will attract more and more attention in the future. Finally, current challenges, opportunities, and future perspectives for TLR-targeted agents are also discussed.
10.1021/acs.accounts.9b00631
The non-canonical NF-κB pathway in immunity and inflammation.
Sun Shao-Cong
Nature reviews. Immunology
The nuclear factor-κB (NF-κB) family of transcription factors is activated by canonical and non-canonical signalling pathways, which differ in both signalling components and biological functions. Recent studies have revealed important roles for the non-canonical NF-κB pathway in regulating different aspects of immune functions. Defects in non-canonical NF-κB signalling are associated with severe immune deficiencies, whereas dysregulated activation of this pathway contributes to the pathogenesis of various autoimmune and inflammatory diseases. Here we review the signalling mechanisms and the biological function of the non-canonical NF-κB pathway. We also discuss recent progress in elucidating the molecular mechanisms regulating non-canonical NF-κB pathway activation, which may provide new opportunities for therapeutic strategies.
10.1038/nri.2017.52
NF-κB: blending metabolism, immunity, and inflammation.
Trends in immunology
The procurement and management of nutrients and ability to fight infections are fundamental requirements for survival. These defense responses are bioenergetically costly, requiring the immune system to balance protection against pathogens with the need to maintain metabolic homeostasis. NF-κB transcription factors are central regulators of immunity and inflammation. Over the last two decades, these factors have emerged as a pivotal node coordinating the immune and metabolic systems in physiology and the etiopathogenesis of major threats to human health, including cancer, autoimmunity, chronic inflammation, and others. In this review, we discuss recent advances in understanding how NF-κB-dependent metabolic programs control inflammation, metabolism, and immunity and how improved knowledge of them may lead to better diagnostics and therapeutics for widespread human diseases.
10.1016/j.it.2022.07.004
NF-κB dynamics determine the stimulus specificity of epigenomic reprogramming in macrophages.
Science (New York, N.Y.)
The epigenome of macrophages can be reprogrammed by extracellular cues, but the extent to which different stimuli achieve this is unclear. Nuclear factor κB (NF-κB) is a transcription factor that is activated by all pathogen-associated stimuli and can reprogram the epigenome by activating latent enhancers. However, we show that NF-κB does so only in response to a subset of stimuli. This stimulus specificity depends on the temporal dynamics of NF-κB activity, in particular whether it is oscillatory or non-oscillatory. Non-oscillatory NF-κB opens chromatin by sustained disruption of nucleosomal histone-DNA interactions, enabling activation of latent enhancers that modulate expression of immune response genes. Thus, temporal dynamics can determine a transcription factor's capacity to reprogram the epigenome in a stimulus-specific manner.
10.1126/science.abc0269
Post-translational modification-centric base editor screens to assess phosphorylation site functionality in high throughput.
Nature methods
Signaling pathways that drive gene expression are typically depicted as having a dozen or so landmark phosphorylation and transcriptional events. In reality, thousands of dynamic post-translational modifications (PTMs) orchestrate nearly every cellular function, and we lack technologies to find causal links between these vast biochemical pathways and genetic circuits at scale. Here we describe the high-throughput, functional assessment of phosphorylation sites through the development of PTM-centric base editing coupled to phenotypic screens, directed by temporally resolved phosphoproteomics. Using T cell activation as a model, we observe hundreds of unstudied phosphorylation sites that modulate NFAT transcriptional activity. We identify the phosphorylation-mediated nuclear localization of PHLPP1, which promotes NFAT but inhibits NFκB activity. We also find that specific phosphosite mutants can alter gene expression in subtle yet distinct patterns, demonstrating the potential for fine-tuning transcriptional responses. Overall, base editor screening of PTM sites provides a powerful platform to dissect PTM function within signaling pathways.
10.1038/s41592-024-02256-z
CLK2 mediates IκBα-independent early termination of NF-κB activation by inducing cytoplasmic redistribution and degradation.
Nature communications
Activation of the NF-κB pathway is strictly regulated to prevent excessive inflammatory and immune responses. In a well-known negative feedback model, IκBα-dependent NF-κB termination is a delayed response pattern in the later stage of activation, and the mechanisms mediating the rapid termination of active NF-κB remain unclear. Here, we showed IκBα-independent rapid termination of nuclear NF-κB mediated by CLK2, which negatively regulated active NF-κB by phosphorylating the RelA/p65 subunit of NF-κB at Ser180 in the nucleus to limit its transcriptional activation through degradation and nuclear export. Depletion of CLK2 increased the production of inflammatory cytokines, reduced viral replication and increased the survival of the mice. Mechanistically, CLK2 phosphorylated RelA/p65 at Ser180 in the nucleus, leading to ubiquitin‒proteasome-mediated degradation and cytoplasmic redistribution. Importantly, a CLK2 inhibitor promoted cytokine production, reduced viral replication, and accelerated murine psoriasis. This study revealed an IκBα-independent mechanism of early-stage termination of NF-κB in which phosphorylated Ser180 RelA/p65 turned off posttranslational modifications associated with transcriptional activation, ultimately resulting in the degradation and nuclear export of RelA/p65 to inhibit excessive inflammatory activation. Our findings showed that the phosphorylation of RelA/p65 at Ser180 in the nucleus inhibits early-stage NF-κB activation, thereby mediating the negative regulation of NF-κB.
10.1038/s41467-024-48288-z
NF-κB and Extrinsic Cell Death Pathways - Entwined Do-or-Die Decisions for T cells.
Blanchett Sam,Boal-Carvalho Ines,Layzell Scott,Seddon Benedict
Trends in immunology
NF-κB signaling is required at multiple stages of T cell development and function. The NF-κB pathway integrates signals from many receptors and involves diverse adapters and kinases. Recent advances demonstrate that kinases controlling NF-κB activation, such as the IKK complex, serve dual independent functions because they also control cell death checkpoints. Survival functions previously attributed to NF-κB are in fact mediated by these upstream kinases by novel mechanisms. This new understanding has led to a refined view of how NF-κB and cell death signaling are interlinked and how they regulate cell fate. We discuss how NF-κB activation and control of cell death signaling by common upstream triggers cooperate to regulate different aspects of T cell development and function.
10.1016/j.it.2020.10.013
Liquid phase separation of NEMO induced by polyubiquitin chains activates NF-κB.
Molecular cell
The NF-κB essential modulator (NEMO) is a regulatory subunit of the IκB kinase (IKK) complex that phosphorylates the NF-κB inhibitors IκBs. NEMO mediates IKK activation by binding to polyubiquitin chains (polyUb). Here, we show that Lys63(K63)-linked or linear polyUb binding to NEMO robustly induced the formation of liquid-like droplets in which IKK was activated. This liquid phase separation of NEMO was driven by multivalent interactions between NEMO and polyUb. Both the NEMO ubiquitin-binding (NUB) domain and the zinc-finger (ZF) domain of NEMO mediated binding to polyUb and contributed to NEMO phase separation and IKK activation in cells. Moreover, NEMO mutations associated with human immunodeficiency impaired its phase separation. These results demonstrate that polyUb activates IKK and NF-κB signaling by promoting the phase separation of NEMO.
10.1016/j.molcel.2022.03.037
Molecular mechanism of IKK catalytic dimer docking to NF-κB substrates.
Nature communications
The inhibitor of κB (IκB) kinase (IKK) is a central regulator of NF-κB signaling. All IKK complexes contain hetero- or homodimers of the catalytic IKKβ and/or IKKα subunits. Here, we identify a YDDΦxΦ motif, which is conserved in substrates of canonical (IκBα, IκBβ) and alternative (p100) NF-κB pathways, and which mediates docking to catalytic IKK dimers. We demonstrate a quantitative correlation between docking affinity and IKK activity related to IκBα phosphorylation/degradation. Furthermore, we show that phosphorylation of the motif's conserved tyrosine, an event previously reported to promote IκBα accumulation and inhibition of NF-κB gene expression, suppresses the docking interaction. Results from integrated structural analyzes indicate that the motif binds to a groove at the IKK dimer interface. Consistently, suppression of IKK dimerization also abolishes IκBα substrate binding. Finally, we show that an optimized bivalent motif peptide inhibits NF-κB signaling. This work unveils a function for IKKα/β dimerization in substrate motif recognition.
10.1038/s41467-024-52076-0
Gut Microbiota-Derived Diaminopimelic Acid Promotes the NOD1/RIP2 Signaling Pathway and Plays a Key Role in the Progression of Severe Acute Pancreatitis.
Frontiers in cellular and infection microbiology
Impaired intestinal barrier function and gut microbiota dysbiosis are believed to be related to exacerbation of acute pancreatitis (AP). As a bacterial cell wall peptidoglycan component, diaminopimelic acid (DAP) is a specific ligand of NOD1 that regulates the NOD1/RIP2/NF-kB signaling pathway. Here, we investigated the role of DAP in the crosstalk between the gut microbiota and pancreas during the occurrence of AP. Upregulation of NOD1/RIP2/NF-kB and elevated serum DAP levels were found in severe AP (SAP) model rats. The accumulation of DAP in SAP patients corroborated its ability to serve as an indicator of disease severity. Subsequently, SAP rats were treated with oral administration of the traditional Chinese medicine Qingyi Keli (QYKL) as well as neomycin, which can widely eliminate DAP-containing bacteria. Both QYKL and neomycin intervention ameliorated intestinal and pancreatic damage and systemic inflammation in SAP rats. Through 16S rDNA sequencing, we found that QYKL could rehabilitate the gut microbiota structure and selectively inhibit the overgrowth of enteric bacteria, such as Helicobacter and Lactobacillus, in SAP rats without affecting some protective strains, including Romboutsia and Allobaculum. Interestingly, we demonstrated that the decrease in serum DAP was accompanied by suppression of the NOD1/RIP2/NF-kB signaling pathway in both the intestine and pancreas of the two intervention groups. Taken together, these results suggested that the gut microbiota-DAP-NOD1/RIP2 signaling pathway might play a critical role in the progression of AP and that SAP could be alleviated intervention in the signaling pathway. Our work provides new potential early warning indicators of SAP and targets for intervention.
10.3389/fcimb.2022.838340
Resveratrol pre-treatment alleviated caerulein-induced acute pancreatitis in high-fat diet-feeding mice via suppressing the NF-κB proinflammatory signaling and improving the gut microbiota.
BMC complementary medicine and therapies
BACKGROUND:hyperlipidemia acute pancreatitis (HTG-AP) is a major hidden danger affecting human health, however, whether there is a protective effect of resveratrol on HTG-AP is unclear. Therefore our study was aimed to investigate the preventive effect and the underlying mechanism of resveratrol in the HTG-AP mice model. METHODS:This research was divided into two parts. In the first part, mice were adaptively fed with normal chow or HFD for 6 weeks. From the second week, resveratrol-treated mice were in intragastric administration with resveratrol (45 mg/kg/d) for 4 weeks. In the second part, the procedures were the same as the first part. After the last intragastric administration with resveratrol, all mice were intraperitoneal injections of cerulean. RESULTS:We found resveratrol effectively inhibited pancreatic pathological injury in the HFD, AP, and HTG-AP mice. Resveratrol reduced the LPS, IL-6, TNF-α, and MCP-1 expressions in the HFD mice. Resveratrol also reduced TNF-α, MDA, and MCP-1 expressions and increased SOD and T-AOC expressions in the AP and HTG-AP mice. Furthermore, resveratrol suppressed the NF-κB pro-inflammatory signaling pathway in pancreatic tissues in the AP and HTG-AP mice. Moreover, resveratrol improved the gut microbiota in the HFD mice. CONCLUSION:The resveratrol pre-treatment could attenuate pancreas injury, inflammation, and oxidative stress in the HTG-AP mice, via restraining the NF-κB signaling pathway and regulating gut microbiota. Therefore, Our study proved that the resveratrol pre-treatment had a preventive effect on HTG-AP.
10.1186/s12906-022-03664-4
American Gastroenterological Association Clinical Practice Update: Management of Pancreatic Necrosis.
Baron Todd H,DiMaio Christopher J,Wang Andrew Y,Morgan Katherine A
Gastroenterology
DESCRIPTION:The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update is to review the available evidence and expert recommendations regarding the clinical care of patients with pancreatic necrosis and to offer concise best practice advice for the optimal management of patients with this highly morbid condition. METHODS:This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology. This review is framed around the 15 best practice advice points agreed upon by the authors, which reflect landmark and recent published articles in this field. This expert review also reflects the experiences of the authors, who are advanced endoscopists or hepatopancreatobiliary surgeons with extensive experience in managing and teaching others to care for patients with pancreatic necrosis. BEST PRACTICE ADVICE 1: Pancreatic necrosis is associated with substantial morbidity and mortality and optimal management requires a multidisciplinary approach, including gastroenterologists, surgeons, interventional radiologists, and specialists in critical care medicine, infectious disease, and nutrition. In situations where clinical expertise may be limited, consideration should be given to transferring patients with significant pancreatic necrosis to an appropriate tertiary-care center. BEST PRACTICE ADVICE 2: Antimicrobial therapy is best indicated for culture-proven infection in pancreatic necrosis or when infection is strongly suspected (ie, gas in the collection, bacteremia, sepsis, or clinical deterioration). Routine use of prophylactic antibiotics to prevent infection of sterile necrosis is not recommended. BEST PRACTICE ADVICE 3: When infected necrosis is suspected, broad-spectrum intravenous antibiotics with ability to penetrate pancreatic necrosis should be favored (eg, carbapenems, quinolones, and metronidazole). Routine use of antifungal agents is not recommended. Computed tomography-guided fine-needle aspiration for Gram stain and cultures is unnecessary in the majority of cases. BEST PRACTICE ADVICE 4: In patients with pancreatic necrosis, enteral feeding should be initiated early to decrease the risk of infected necrosis. A trial of oral nutrition is recommended immediately in patients in whom there is absence of nausea and vomiting and no signs of severe ileus or gastrointestinal luminal obstruction. When oral nutrition is not feasible, enteral nutrition by either nasogastric/duodenal or nasojejunal tube should be initiated as soon as possible. Total parenteral nutrition should be considered only in cases where oral or enteral feeds are not feasible or tolerated. BEST PRACTICE ADVICE 5: Drainage and/or debridement of pancreatic necrosis is indicated in patients with infected necrosis. Drainage and/or debridement may be required in patients with sterile pancreatic necrosis and persistent unwellness marked by abdominal pain, nausea, vomiting, and nutritional failure or with associated complications, including gastrointestinal luminal obstruction; biliary obstruction; recurrent acute pancreatitis; fistulas; or persistent systemic inflammatory response syndrome. BEST PRACTICE ADVICE 6: Pancreatic debridement should be avoided in the early, acute period (first 2 weeks), as it has been associated with increased morbidity and mortality. Debridement should be optimally delayed for 4 weeks and performed earlier only when there is an organized collection and a strong indication. BEST PRACTICE ADVICE 7: Percutaneous drainage and transmural endoscopic drainage are both appropriate first-line, nonsurgical approaches in managing patients with walled-off pancreatic necrosis (WON). Endoscopic therapy through transmural drainage of WON may be preferred, as it avoids the risk of forming a pancreatocutaneous fistula. BEST PRACTICE ADVICE 8: Percutaneous drainage of pancreatic necrosis should be considered in patients with infected or symptomatic necrotic collections in the early, acute period (<2 weeks), and in those with WON who are too ill to undergo endoscopic or surgical intervention. Percutaneous drainage should be strongly considered as an adjunct to endoscopic drainage for WON with deep extension into the paracolic gutters and pelvis or for salvage therapy after endoscopic or surgical debridement with residual necrosis burden. BEST PRACTICE ADVICE 9: Self-expanding metal stents in the form of lumen-apposing metal stents appear to be superior to plastic stents for endoscopic transmural drainage of necrosis. BEST PRACTICE ADVICE 10: The use of direct endoscopic necrosectomy should be reserved for those patients with limited necrosis who do not adequately respond to endoscopic transmural drainage using large-bore, self-expanding metal stents/lumen-apposing metal stents alone or plastic stents combined with irrigation. Direct endoscopic necrosectomy is a therapeutic option in patients with large amounts of infected necrosis, but should be performed at referral centers with the necessary endoscopic expertise and interventional radiology and surgical backup. BEST PRACTICE ADVICE 11: Minimally invasive operative approaches to the debridement of acute necrotizing pancreatitis are preferred to open surgical necrosectomy when possible, given lower morbidity. BEST PRACTICE ADVICE 12: Multiple minimally invasive surgical techniques are feasible and effective, including videoscopic-assisted retroperitoneal debridement, laparoscopic transgastric debridement, and open transgastric debridement. Selection of approach is best determined by pattern of disease, physiology of the patient, experience and expertise of the multidisciplinary team, and available resources. BEST PRACTICE ADVICE 13: Open operative debridement maintains a role in the modern management of acute necrotizing pancreatitis in cases not amenable to less invasive endoscopic and/or surgical procedures. BEST PRACTICE ADVICE 14: For patients with disconnected left pancreatic remnant after acute necrotizing mid-body necrosis, definitive surgical management with distal pancreatectomy should be undertaken in patients with reasonable operative candidacy. Insufficient evidence exists to support the management of the disconnected left pancreatic remnant with long-term transenteric endoscopic stenting. BEST PRACTICE ADVICE 15: A step-up approach consisting of percutaneous drainage or endoscopic transmural drainage using either plastic stents and irrigation or self-expanding metal stents/lumen-apposing metal stents alone, followed by direct endoscopic necrosectomy, and then surgical debridement is reasonable, although approaches may vary based on the available clinical expertise.
10.1053/j.gastro.2019.07.064
Acute pancreatitis.
Boxhoorn Lotte,Voermans Rogier P,Bouwense Stefan A,Bruno Marco J,Verdonk Robert C,Boermeester Marja A,van Santvoort Hjalmar C,Besselink Marc G
Lancet (London, England)
Acute pancreatitis is an unpredictable and potentially lethal disease. The prognosis mainly depends on the development of organ failure and secondary infection of pancreatic or peripancreatic necrosis. In the past 10 years, treatment of acute pancreatitis has moved towards a multidisciplinary, tailored, and minimally invasive approach. Despite improvements in treatment and critical care, severe acute pancreatitis is still associated with high mortality rates. In this Seminar, we outline the latest evidence on diagnostic and therapeutic strategies for acute pancreatitis.
10.1016/S0140-6736(20)31310-6
A procalcitonin-based algorithm to guide antibiotic use in patients with acute pancreatitis (PROCAP): a single-centre, patient-blinded, randomised controlled trial.
The lancet. Gastroenterology & hepatology
BACKGROUND:Differentiating inflammation from bacterial infection in patients with acute pancreatitis can be difficult. Procalcitonin can distinguish infection from inflammation, and algorithms based on procalcitonin measurement can differentiate bacterial sepsis from a systemic inflammatory response. We aimed to test the hypothesis that a procalcitonin-based algorithm to guide initiation, continuation, and discontinuation of antibiotics could lead to reduced antibiotic use without an adverse effect on outcome in acute pancreatitis. METHODS:PROCAP was a single-centre, patient-blinded, randomised controlled trial done at the Manchester Royal Infirmary (Manchester, UK). Eligible participants were aged 18 years or older and had a clinical diagnosis of acute pancreatitis. Participants were randomly assigned (1:1) to procalcitonin-guided care or usual care using web-based randomisation software. The randomisation sequence was stratified by disease severity and admission pathway, using variable block sizes of 4, 6, or 8. Patients, but not clinicians, were masked to group assignment. In the procalcitonin-guided care group, procalcitonin testing was conducted on days 0, 4, 7, and weekly thereafter. Guidance was to stop or not start antibiotics following a test value of less than 1·0 ng/mL and to start or continue antibiotics following a test value of 1·0 ng/mL or more. In the intervention group, any empirical clinical decision to use antibiotics was preceded by measurement of procalcitonin. Otherwise, both groups received standard care. The primary outcome was use of antibiotics during the index admission to hospital. All analyses were done in the intention-to-treat population. This study was registered with the International Standard Randomised Controlled Trial registry, ISRCTN 50584992. FINDINGS:Between July 29, 2018, and Nov 13, 2020, 369 patients were screened, of whom 260 were enrolled and randomly assigned to a treatment group (132 to procalcitonin-guided care and 128 to usual care). 59 (45%) of patients in the procalcitonin-guided care group were prescribed antibiotics compared with 79 (63%) in the usual care group (adjusted risk difference -15·6% [95% CI -27·0 to -4·2]; p=0·0071). The odds ratio for the treatment effect was 0·49 (95% CI 0·29 to 0·83; p=0·0077). There was no significant difference between groups in terms of the number of clinical infections or hospital-acquired infections per patient. Four (3%) patients in the procalcitonin-guided care group and three (2%) patients in the usual care group died; all deaths were related to underlying severe pancreatitis. There was no difference in adverse events between the groups. INTERPRETATION:Our findings suggest that procalcitonin-guided care can reduce antibiotic use without increasing infection or harm in patients with acute pancreatitis. Procalcitonin-based algorithms to guide antibiotic use should be considered in the care of this group of patients and be incorporated into future guidelines on the management of acute pancreatitis. FUNDING:None.
10.1016/S2468-1253(22)00212-6
Diagnosis and Management of Acute Pancreatitis.
Gastroenterology
Acute pancreatitis (AP) is increasing in incidence across the world, and in all age groups. Major changes in management have occurred in the last decade. Avoiding total parenteral nutrition and prophylactic antibiotics, avoiding overly aggressive fluid resuscitation, initiating early feeding, avoiding endoscopic retrograde cholangiopancreatography in the absence of concomitant cholangitis, same-admission cholecystectomy, and minimally invasive approaches to infected necrosis should now be standard of care. Increasing recognition of the risk of recurrence of AP, and progression to chronic pancreatitis, along with the unexpectedly high risk of diabetes and exocrine insufficiency after AP is the subject of large ongoing studies. In this review, we provide an update on important changes in management for this increasingly common disease.
10.1053/j.gastro.2024.02.052
Gut microbiota aggravates neutrophil extracellular traps-induced pancreatic injury in hypertriglyceridemic pancreatitis.
Nature communications
Hypertriglyceridemic pancreatitis (HTGP) is featured by higher incidence of complications and poor clinical outcomes. Gut microbiota dysbiosis is associated with pancreatic injury in HTGP and the mechanism remains unclear. Here, we observe lower diversity of gut microbiota and absence of beneficial bacteria in HTGP patients. In a fecal microbiota transplantation mouse model, the colonization of gut microbiota from HTGP patients recruits neutrophils and increases neutrophil extracellular traps (NETs) formation that exacerbates pancreatic injury and systemic inflammation. We find that decreased abundance of Bacteroides uniformis in gut microbiota impairs taurine production and increases IL-17 release in colon that triggers NETs formation. Moreover, Bacteroides uniformis or taurine inhibits the activation of NF-κB and IL-17 signaling pathways in neutrophils which harness NETs and alleviate pancreatic injury. Our findings establish roles of endogenous Bacteroides uniformis-derived metabolic and inflammatory products on suppressing NETs release, which provides potential insights of ameliorating HTGP through gut microbiota modulation.
10.1038/s41467-023-41950-y
Long-term follow-up study of necrotising pancreatitis: interventions, complications and quality of life.
Gut
OBJECTIVE:To describe the long-term consequences of necrotising pancreatitis, including complications, the need for interventions and the quality of life. DESIGN:Long-term follow-up of a prospective multicentre cohort of 373 necrotising pancreatitis patients (2005-2008) was performed. Patients were prospectively evaluated and received questionnaires. Readmissions (ie, for recurrent or chronic pancreatitis), interventions, pancreatic insufficiency and quality of life were compared between initial treatment groups: conservative, endoscopic/percutaneous drainage alone and necrosectomy. Associations of patient and disease characteristics during index admission with outcomes during follow-up were assessed. RESULTS:During a median follow-up of 13.5 years (range 12-15.5 years), 97/373 patients (26%) were readmitted for recurrent pancreatitis. Endoscopic or percutaneous drainage was performed in 47/373 patients (13%), of whom 21/47 patients (45%) were initially treated conservatively. Pancreatic necrosectomy or pancreatic surgery was performed in 31/373 patients (8%), without differences between treatment groups. Endocrine insufficiency (126/373 patients; 34%) and exocrine insufficiency (90/373 patients; 38%), developed less often following conservative treatment (p<0.001 and p=0.016, respectively). Quality of life scores did not differ between groups. Pancreatic gland necrosis >50% during initial admission was associated with percutaneous/endoscopic drainage (OR 4.3 (95% CI 1.5 to 12.2)), pancreatic surgery (OR 3.2 (95% CI 1.1 to 9.5) and development of endocrine insufficiency (OR13.1 (95% CI 5.3 to 32.0) and exocrine insufficiency (OR6.1 (95% CI 2.4 to 15.5) during follow-up. CONCLUSION:Acute necrotising pancreatitis carries a substantial disease burden during long-term follow-up in terms of recurrent disease, the necessity for interventions and development of pancreatic insufficiency, even when treated conservatively during the index admission. Extensive (>50%) pancreatic parenchymal necrosis seems to be an important predictor of interventions and complications during follow-up.
10.1136/gutjnl-2023-329735
Extracorporeal Shock-Wave Lithotripsy and Endoscopy for the Treatment of Pain in Chronic Pancreatitis : A Sham-Controlled, Randomized Trial.
Annals of internal medicine
BACKGROUND:No randomized controlled trials have substantiated endoscopic decompression of the pancreatic duct in patients with painful chronic pancreatitis. OBJECTIVE:To investigate the pain-relieving effect of pancreatic duct decompression in patients with chronic pancreatitis and intraductal stones. DESIGN:24-week, parallel-group, randomized controlled trial (ClinicalTrials.gov: NCT03966781). SETTING:Asian Institute of Gastroenterology in India from February 2021 to July 2022. PARTICIPANTS:106 patients with chronic pancreatitis. INTERVENTION:Combined extracorporeal shock-wave lithotripsy (ESWL) and endoscopic retrograde pancreatography (ERP) compared with sham procedures. MEASUREMENTS:The primary end point was pain relief on a 0- to 10-point visual analog scale (VAS) at 12 weeks. Secondary outcomes were assessed after 12 and 24 weeks and included 30% pain relief, opioid use, pain-free days, questionaries, and complications to interventions. RESULTS:52 patients in the ESWL/ERP group and 54 in the sham group were included. At 12 weeks, the ESWL/ERP group showed better pain relief compared with the sham group (mean difference in change, -0.7 [95% CI, -1.3 to 0] on the VAS; = 0.039). The difference between groups was not sustained at the 24-week follow-up, and no differences were seen for 30% pain relief at 12- or 24-week follow-up. The number of pain-free days was increased (median difference, 16.2 days [CI, 3.9 to 28.5 days]), and the number of days using opioids was reduced (median difference, -5.4 days [CI, -9.9 to -0.9 days]) in the ESWL/ERP group compared with the sham group at 12-week follow-up. Safety outcomes were similar between groups. LIMITATION:Single-center study and limited duration of follow-up. CONCLUSION:In patients with chronic pancreatitis and intraductal stones, ESWL with ERP provided modest short-term pain relief. PRIMARY FUNDING SOURCE:Asian Institute of Gastroenterology and Aalborg University Hospital.
10.7326/M24-0210
Western-type diet influences mortality from necrotising pancreatitis and demonstrates a central role for butyrate.
van den Berg Fons F,van Dalen Demi,Hyoju Sanjiv K,van Santvoort Hjalmar C,Besselink Marc G,Wiersinga Willem Joost,Zaborina Olga,Boermeester Marja A,Alverdy John
Gut
OBJECTIVE:The gut microbiota are the main source of infections in necrotising pancreatitis. We investigated the effect of disruption of the intestinal microbiota by a Western-type diet on mortality and bacterial dissemination in necrotising pancreatitis and its reversal by butyrate supplementation. DESIGN:C57BL/6 mice were fed either standard chow or a Western-type diet for 4 weeks and were then subjected to taurocholate-induced necrotising pancreatitis. Blood and pancreas were collected for bacteriology and immune analysis. The cecum microbiota composition of mice was analysed using 16S rRNA gene amplicon sequencing and cecal content metabolites were analysed by targeted (ie, butyrate) and untargeted metabolomics. Prevention of necrotising pancreatitis in this model was compared between faecal microbiota transplantation (FMT) from healthy mice, antibiotic decontamination against Gram-negative bacteria and oral or systemic butyrate administration. Additionally, the faecal microbiota of patients with pancreatitis and healthy subjects were analysed. RESULTS:Mortality, systemic inflammation and bacterial dissemination were increased in mice fed Western diet and their gut microbiota were characterised by a loss of diversity, a bloom of and an altered metabolic profile with butyrate depletion. While antibiotic decontamination decreased mortality, Gram-positive dissemination was increased. Both oral and systemic butyrate supplementation decreased mortality, bacterial dissemination, and reversed the microbiota alterations. Paradoxically, mortality and bacterial dissemination were increased with FMT administration. Finally, patients with acute pancreatitis demonstrated an increase in Proteobacteria and a decrease of butyrate producers compared with healthy subjects. CONCLUSION:Butyrate depletion and its repletion appear to play a central role in disease progression towards necrotising pancreatitis.
10.1136/gutjnl-2019-320430
Nonfasting Mild-to-Moderate Hypertriglyceridemia and Risk of Acute Pancreatitis.
JAMA internal medicine
IMPORTANCE:Severe hypertriglyceridemia is associated with increased risk of acute pancreatitis. However, the threshold above which triglycerides are associated with acute pancreatitis is unclear. OBJECTIVE:To test the hypothesis that nonfasting mild-to-moderate hypertriglyceridemia (177-885 mg/dL; 2-10 mmol/L) is also associated with acute pancreatitis. DESIGN, SETTING, AND PARTICIPANTS:This prospective cohort study examines individuals from the Copenhagen General Population Study in 2003 to 2015 and the Copenhagen City Heart Study initiated in 1976 to 1978 with follow-up examinations in 1981 to1983, 1991 to 1994, and in 2001 to 2003. Median follow-up was 6.7 years (interquartile range, 4.0-9.4 years); and includes 116 550 individuals with a triglyceride measurement from the Copenhagen General Population Study (n = 98 649) and the Copenhagen City Heart Study (n = 17 901). All individuals were followed until the occurrence of an event, death, emigration, or end of follow-up (November 2014), whichever came first. EXPOSURES:Plasma levels of nonfasting triglycerides. MAIN OUTCOMES AND MEASURES:Hazard ratios (HRs) for acute pancreatitis (n = 434) and myocardial infarction (n = 3942). RESULTS:Overall, 116 550 individuals were included in this study (median [interquartile range] age, 57 [47-66] years). Compared with individuals with plasma triglyceride levels less than 89 mg/dL (<1 mmol/L), the multivariable adjusted HRs for acute pancreatitis were 1.6 (95% CI, 1.0-2.6; 4.3 events/10 000 person-years) for individuals with triglyceride levels of 89 mg/dL to 176 mg/dL (1.00 mmol/L-1.99 mmol/L), 2.3 (95% CI, 1.3-4.0; 5.5 events/10 000 person-years) for 177 mg/dL to 265 mg/dL (2.00 mmol/L-2.99 mmol/L), 2.9 (95% CI, 1.4-5.9; 6.3 events/10 000 person-years) for 366 mg/dL to 353 mg/dL (3.00 mmol/L-3.99 mmol/L), 3.9 (95% CI, 1.5-10.0; 7.5 events/10 000 person-years) for 354 mg/dL-442 mg/dL (4.00 mmol/L-4.99 mmol/L), and 8.7 (95% CI, 3.7-20.0; 12 events/10 000 person-years) for individuals with triglyceride levels greater than or equal to 443 mg/dL (≥5.00 mmol/L) (trend, P = 6 × 10-8). Corresponding HRs for myocardial infarction were 1.6 (95% CI, 1.4-1.9; 41 events/10 000 person-years), 2.2 (95% CI, 1.9-2.7; 57 events/10 000 person-years), 3.2 (95% CI, 2.6-4.1; 72 events/10 000 person-years), 2.8 (95% CI, 2.0-3.9; 68 events/10 000 person-years), and 3.4 (95% CI, 2.4-4.7; 78 events/10 000 person-years) (trend, P = 6 × 10-31), respectively. The multivariable adjusted HR for acute pancreatitis was 1.17 (95% CI, 1.10-1.24) per 89 mg/dL (1 mmol/L) higher triglycerides. When stratified by sex, age, education, smoking, hypertension, statin use, study cohort, diabetes, body mass index (calculated as weight in kilograms divided by height in meters squared), alcohol intake, and gallstone disease, these results were similar with no statistical evidence of interaction. CONCLUSIONS AND RELEVANCE:Nonfasting mild-to-moderate hypertriglyceridemia from 177 mg/dL (2 mmol/L) and above is associated with high risk of acute pancreatitis, with HR estimates higher than for myocardial infarction.
10.1001/jamainternmed.2016.6875
Malondialdehyde-Acetaldehyde Extracellular Matrix Protein Adducts Attenuate Unfolded Protein Response During Alcohol and Smoking-Induced Pancreatitis.
Gastroenterology
BACKGROUND & AIMS:Epidemiological studies have established alcohol and smoking as independent risk factors for recurrent acute pancreatitis and chronic pancreatitis. However, the molecular players responsible for the progressive loss of pancreatic parenchyma and fibroinflammatory response are poorly characterized. METHODS:Tandem mass tag-based proteomic and bioinformatics analyses were performed on the pancreata of mice exposed to alcohol, cigarette smoke, or a combination of alcohol and cigarette smoke. Biochemical, immunohistochemistry, and transcriptome analyses were performed on the pancreatic tissues and primary acinar cells treated with cerulein in combination with ethanol (50 mmol/L) and cigarette smoke extract (40 μg/mL) for the mechanistic studies. RESULTS:A unique alteration in the pancreatic proteome was observed in mice exposed chronically to the combination of alcohol and cigarette smoke (56.5%) compared with cigarette smoke (21%) or alcohol (17%) alone. The formation of toxic metabolites (P < .001) and attenuated unfolded protein response (P < .04) were the significantly altered pathways on combined exposure. The extracellular matrix (ECM) proteins showed stable malondialdehyde-acetaldehyde (MAA) adducts in the pancreata of the combination group and chronic pancreatitis patients with a history of smoking and alcohol consumption. Interestingly, MAA-ECM adducts significantly suppressed expression of X-box-binding protein-1, leading to acinar cell death in the presence of alcohol and smoking. The stable MAA-ECM adducts persist even after alcohol and smoking cessation, and significantly delay pancreatic regeneration by abrogating the expression of cyclin-dependent kinases (CDK7 and CDK5) and regeneration markers. CONCLUSIONS:The combined alcohol and smoking generate stable MAA-ECM adducts that increase endoplasmic reticulum stress and acinar cell death due to attenuated unfolded protein response and suppress expression of cell cycle regulators. Targeting aldehyde adducts might provide a novel therapeutic strategy for the management of recurrent acute pancreatitis and chronic pancreatitis.
10.1053/j.gastro.2022.06.071
The Combination of Alcohol and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in Pancreatic Acinar Cells.
Lugea Aurelia,Gerloff Andreas,Su Hsin-Yuan,Xu Zhihong,Go Ariel,Hu Cheng,French Samuel W,Wilson Jeremy S,Apte Minoti V,Waldron Richard T,Pandol Stephen J
Gastroenterology
BACKGROUND & AIMS:Smoking, an independent risk factor for pancreatitis, accelerates the development of alcoholic pancreatitis. Alcohol feeding of mice induces up-regulation of spliced X-box binding protein 1 (XBP1s), which regulates the endoplasmic reticulum (ER) unfolded protein response and promotes cell survival upon ER stress. We examined whether smoking affects the adaptive mechanisms induced by alcohol and accelerates disorders of the ER in pancreatic acinar cells. METHODS:We studied the combined effects of ethanol (EtOH) and cigarette smoke extract (CSE) on ER stress and cell death responses in mouse and human primary acini and the acinar cell line AR42J. Cells were incubated with EtOH (50 mmol/L), CSE (20-40 μg/mL), or both (CSE+EtOH), and analyzed by immunoblotting, quantitative reverse-transcription polymerase chain reaction, and cell death assays. Some cells were incubated with MKC-3946, an inhibitor of endoplasmic reticulum to nucleus signaling 1 (ERN1, also called IRE1) that blocks XBP1s formation. Male Sprague-Dawley rats were fed isocaloric amounts of an EtOH-containing (Lieber-DeCarli) or control diet for 11 weeks and exposed to cigarette smoke or room air in an exposure chamber for 2 hours each day. During the last 3 weeks, a subset of rats received intravenous injections of lipopolysaccharide (LPS, 3 mg/kg per week) to induce pancreatitis or saline (control). Pancreatic tissues were collected and analyzed by histology and immunostaining techniques. RESULTS:In AR42J and primary acini, CSE+EtOH induced cell death (necrosis and apoptosis), but neither agent alone had this effect. Cell death was associated with a significant decrease in expression of XBP1s. CSE+EtOH, but neither agent alone, slightly decreased adenosine triphosphate levels in AR42J cells, but induced oxidative stress and sustained activation (phosphorylation) of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also called PERK) and increased protein levels of DNA damage inducible transcript 3 (DDIT3, also called CHOP). CHOP regulates transcription to promote apoptosis. Incubation of AR42J or primary mouse or human acinar cells with MKC-3946 reduced expression of XBP1s, increased levels of CHOP, and induced cell death. In rats fed an EtOH diet, exposure to cigarette smoke increased ER stress in acinar cells and sensitized the pancreas to LPS-induced pathology. CONCLUSIONS:Cigarette smoke promotes cell death and features of pancreatitis in EtOH-sensitized acinar cells by suppressing the adaptive unfolded protein response signaling pathway. It also activates ER stress pathways that promote acinar cell death.
10.1053/j.gastro.2017.08.036
Mitochondrial Dysfunction, Through Impaired Autophagy, Leads to Endoplasmic Reticulum Stress, Deregulated Lipid Metabolism, and Pancreatitis in Animal Models.
Gastroenterology
BACKGROUND & AIMS:Little is known about the signaling pathways that initiate and promote acute pancreatitis (AP). The pathogenesis of AP has been associated with abnormal increases in cytosolic Ca, mitochondrial dysfunction, impaired autophagy, and endoplasmic reticulum (ER) stress. We analyzed the mechanisms of these dysfunctions and their relationships, and how these contribute to development of AP in mice and rats. METHODS:Pancreatitis was induced in C57BL/6J mice (control) and mice deficient in peptidylprolyl isomerase D (cyclophilin D, encoded by Ppid) by administration of L-arginine (also in rats), caerulein, bile acid, or an AP-inducing diet. Parameters of pancreatitis, mitochondrial function, autophagy, ER stress, and lipid metabolism were measured in pancreatic tissue, acinar cells, and isolated mitochondria. Some mice with AP were given trehalose to enhance autophagic efficiency. Human pancreatitis tissues were analyzed by immunofluorescence. RESULTS:Mitochondrial dysfunction in pancreas of mice with AP was induced by either mitochondrial Ca overload or through a Ca overload-independent pathway that involved reduced activity of ATP synthase (80% inhibition in pancreatic mitochondria isolated from rats or mice given L-arginine). Both pathways were mediated by cyclophilin D and led to mitochondrial depolarization and fragmentation. Mitochondrial dysfunction caused pancreatic ER stress, impaired autophagy, and deregulation of lipid metabolism. These pathologic responses were abrogated in cyclophilin D-knockout mice. Administration of trehalose largely prevented trypsinogen activation, necrosis, and other parameters of pancreatic injury in mice with L-arginine AP. Tissues from patients with pancreatitis had markers of mitochondrial damage and impaired autophagy, compared with normal pancreas. CONCLUSIONS:In different animal models, we find a central role for mitochondrial dysfunction, and for impaired autophagy as its principal downstream effector, in development of AP. In particular, the pathway involving enhanced interaction of cyclophilin D with ATP synthase mediates L-arginine-induced pancreatitis, a model of severe AP the pathogenesis of which has remained unknown. Strategies to restore mitochondrial and/or autophagic function might be developed for treatment of AP.
10.1053/j.gastro.2017.10.012
Clinical practice guideline: management of acute pancreatitis.
Greenberg Joshua A,Hsu Jonathan,Bawazeer Mohammad,Marshall John,Friedrich Jan O,Nathens Avery,Coburn Natalie,May Gary R,Pearsall Emily,McLeod Robin S
Canadian journal of surgery. Journal canadien de chirurgie
ABSTRACT:There has been an increase in the incidence of acute pancreatitis reported worldwide. Despite improvements in access to care, imaging and interventional techniques, acute pancreatitis continues to be associated with significant morbidity and mortality. Despite the availability of clinical practice guidelines for the management of acute pancreatitis, recent studies auditing the clinical management of the condition have shown important areas of noncompliance with evidence-based recommendations. This underscores the importance of creating understandable and implementable recommendations for the diagnosis and management of acute pancreatitis. The purpose of the present guideline is to provide evidence-based recommendations for the management of both mild and severe acute pancreatitis as well as the management of complications of acute pancreatitis and of gall stone-induced pancreatitis.
10.1503/cjs.015015
Acute Pancreatitis: A Review.
Mederos Michael A,Reber Howard A,Girgis Mark D
JAMA
Importance:In the United States, acute pancreatitis is one of the leading causes of hospital admission from gastrointestinal diseases, with approximately 300 000 emergency department visits each year. Outcomes from acute pancreatitis are influenced by risk stratification, fluid and nutritional management, and follow-up care and risk-reduction strategies, which are the subject of this review. Observations:MEDLINE was searched via PubMed as was the Cochrane databases for English-language studies published between January 2009 and August 2020 for current recommendations for predictive scoring tools, fluid management and nutrition, and follow-up and risk-reduction strategies for acute pancreatitis. Several scoring systems, such as the Bedside Index of Severity in Acute Pancreatitis (BISAP) and the Acute Physiology and Chronic Health Evaluation (APACHE) II tools, have good predictive capabilities for disease severity (mild, moderately severe, and severe per the revised Atlanta classification) and mortality, but no one tool works well for all forms of acute pancreatitis. Early and aggressive fluid resuscitation and early enteral nutrition are associated with lower rates of mortality and infectious complications, yet the optimal type and rate of fluid resuscitation have yet to be determined. The underlying etiology of acute pancreatitis should be sought in all patients, and risk-reduction strategies, such as cholecystectomy and alcohol cessation counseling, should be used during and after hospitalization for acute pancreatitis. Conclusions and Relevance:Acute pancreatitis is a complex disease that varies in severity and course. Prompt diagnosis and stratification of severity influence proper management. Scoring systems are useful adjuncts but should not supersede clinical judgment. Fluid management and nutrition are very important aspects of care for acute pancreatitis.
10.1001/jama.2020.20317
Gut microbiota predicts severity and reveals novel metabolic signatures in acute pancreatitis.
Gut
OBJECTIVE:Early disease prediction is challenging in acute pancreatitis (AP). Here, we prospectively investigate whether the microbiome predicts severity of AP (Pancreatitis-Microbiome As Predictor of Severity; P-MAPS) early at hospital admission. DESIGN:Buccal and rectal microbial swabs were collected from 424 patients with AP within 72 hours of hospital admission in 15 European centres. All samples were sequenced by full-length 16S rRNA and metagenomic sequencing using Oxford Nanopore Technologies. Primary endpoint was the association of the orointestinal microbiome with the revised Atlanta classification (RAC). Secondary endpoints were mortality, length of hospital stay and severity (organ failure >48 hours and/or occurrence of pancreatic collections requiring intervention) as post hoc analysis. Multivariate analysis was conducted from normalised microbial and corresponding clinical data to build classifiers for predicting severity. For functional profiling, gene set enrichment analysis (GSEA) was performed and normalised enrichment scores calculated. RESULTS:After data processing, 411 buccal and 391 rectal samples were analysed. The intestinal microbiome significantly differed for the RAC (Bray-Curtis, p value=0.009), mortality (Bray-Curtis, p value 0.006), length of hospital stay (Bray-Curtis, p=0.009) and severity (Bray-Curtis, p value=0.008). A classifier for severity with 16 different species and systemic inflammatory response syndrome achieved an area under the receiving operating characteristic (AUROC) of 85%, a positive predictive value of 67% and a negative predictive value of 94% outperforming established severity scores. GSEA revealed functional pathway units suggesting elevated short-chain fatty acid (SCFA) production in severe AP. CONCLUSIONS:The orointestinal microbiome predicts clinical hallmark features of AP, and SCFAs may be used for future diagnostic and therapeutic concepts. TRIAL REGISTRATION NUMBER:NCT04777812.
10.1136/gutjnl-2023-330987
Impact of characteristics of organ failure and infected necrosis on mortality in necrotising pancreatitis.
Schepers Nicolien J,Bakker Olaf J,Besselink Marc G,Ahmed Ali Usama,Bollen Thomas L,Gooszen Hein G,van Santvoort Hjalmar C,Bruno Marco J,
Gut
OBJECTIVE:In patients with pancreatitis, early persisting organ failure is believed to be the most important cause of mortality. This study investigates the relation between the timing (onset and duration) of organ failure and mortality and its association with infected pancreatic necrosis in patients with necrotising pancreatitis. DESIGN:We performed a post hoc analysis of a prospective database of 639 patients with necrotising pancreatitis from 21 hospitals. We evaluated the onset, duration and type of organ failure (ie, respiratory, cardiovascular and renal failure) and its association with mortality and infected pancreatic necrosis. RESULTS:In total, 240 of 639 (38%) patients with necrotising pancreatitis developed organ failure. Persistent organ failure (ie, any type or combination) started in the first week in 51% of patients with 42% mortality, in 13% during the second week with 46% mortality and in 36% after the second week with 29% mortality. Mortality in patients with persistent multiple organ failure lasting <1 week, 1-2 weeks, 2-3 weeks or longer than 3 weeks was 43%, 38%, 46% and 52%, respectively (p=0.68). Mortality was higher in patients with organ failure alone than in patients with organ failure and infected pancreatic necrosis (44% vs 29%, p=0.04). However, when excluding patients with very early mortality (within 10 days of admission), patients with organ failure with or without infected pancreatic necrosis had similar mortality rates (28% vs 34%, p=0.33). CONCLUSION:In patients with necrotising pancreatitis, early persistent organ failure is not associated with increased mortality when compared with persistent organ failure which develops further on during the disease course. Furthermore, no association was found between the duration of organ failure and mortality.
10.1136/gutjnl-2017-314657
An Endoscopic Transluminal Approach, Compared With Minimally Invasive Surgery, Reduces Complications and Costs for Patients With Necrotizing Pancreatitis.
Bang Ji Young,Arnoletti Juan Pablo,Holt Bronte A,Sutton Bryce,Hasan Muhammad K,Navaneethan Udayakumar,Feranec Nicholas,Wilcox C Mel,Tharian Benjamin,Hawes Robert H,Varadarajulu Shyam
Gastroenterology
BACKGROUND & AIMS:Infected necrotizing pancreatitis is a highly morbid disease with poor outcomes. Intervention strategies have progressed from open necrosectomy to minimally invasive approaches. We compared outcomes of minimally invasive surgery vs endoscopic approaches for patients with infected necrotizing pancreatitis. METHODS:We performed a single-center, randomized trial of 66 patients with confirmed or suspected infected necrotizing pancreatitis who required intervention from May 12, 2014, through March 24, 2017. Patients were randomly assigned to groups that received minimally invasive surgery (laparoscopic or video-assisted retroperitoneal debridement, depending on location of collection, n = 32) or an endoscopic step-up approach (transluminal drainage with or without necrosectomy, n = 34). The primary endpoint was a composite of major complications (new-onset multiple organ failure, new-onset systemic dysfunction, enteral or pancreatic-cutaneous fistula, bleeding and perforation of a visceral organ) or death during 6 months of follow-up. RESULTS:The primary endpoint occurred in 11.8% of patients who received the endoscopic procedure and 40.6% of patients who received the minimally invasive surgery (risk ratio 0.29; 95% confidence interval 0.11-0.80; P = .007). Although there was no significant difference in mortality (endoscopy 8.8% vs surgery 6.3%; P = .999), none of the patients assigned to the endoscopic approach developed enteral or pancreatic-cutaneous fistulae compared with 28.1% of the patients who underwent surgery (P = .001). The mean number of major complications per patient was significantly higher in the surgery group (0.69 ± 1.03) compared with the endoscopy group (0.15 ± 0.44) (P = .007). The physical health scores for quality of life at 3 months was better with the endoscopic approach (P = .039) and mean total cost was lower ($75,830) compared with $117,492 for surgery (P = .039). CONCLUSIONS:In a randomized trial of 66 patients, an endoscopic transluminal approach for infected necrotizing pancreatitis, compared with minimally invasive surgery, significantly reduced major complications, lowered costs, and increased quality of life. Clinicaltrials.gov no: NCT02084537.
10.1053/j.gastro.2018.11.031
Acute pancreatitis at the beginning of the 21st century: the state of the art.
Tonsi Alfredo F,Bacchion Matilde,Crippa Stefano,Malleo Giuseppe,Bassi Claudio
World journal of gastroenterology
Acute pancreatitis is an acute inflammatory disease of the pancreas which can lead to a systemic inflammatory response syndrome with significant morbidity and mortality in 20% of patients. Gallstones and alcohol consumption are the most frequent causes of pancreatitis in adults. The treatment of mild acute pancreatitis is conservative and supportive; however severe episodes characterized by necrosis of the pancreatic tissue may require surgical intervention. Advanced understanding of the pathology, and increased interest in assessment of disease severity are the cornerstones of future management strategies of this complex and heterogeneous disease in the 21st century.
10.3748/wjg.15.2945
Acute pancreatitis: recent advances through randomised trials.
van Dijk Sven M,Hallensleben Nora D L,van Santvoort Hjalmar C,Fockens Paul,van Goor Harry,Bruno Marco J,Besselink Marc G,
Gut
Acute pancreatitis is one of the most common GI conditions requiring acute hospitalisation and has a rising incidence. In recent years, important insights on the management of acute pancreatitis have been obtained through numerous randomised controlled trials. Based on this evidence, the treatment of acute pancreatitis has gradually developed towards a tailored, multidisciplinary effort, with distinctive roles for gastroenterologists, radiologists and surgeons. This review summarises how to diagnose, classify and manage patients with acute pancreatitis, emphasising the evidence obtained through randomised controlled trials.
10.1136/gutjnl-2016-313595
Chanzyme TRPM7 Mediates the Ca Influx Essential for Lipopolysaccharide-Induced Toll-Like Receptor 4 Endocytosis and Macrophage Activation.
Schappe Michael S,Szteyn Kalina,Stremska Marta E,Mendu Suresh K,Downs Taylor K,Seegren Philip V,Mahoney Michelle A,Dixit Sumeet,Krupa Julia K,Stipes Eric J,Rogers Jason S,Adamson Samantha E,Leitinger Norbert,Desai Bimal N
Immunity
Toll-like receptors (TLRs) sense pathogen-associated molecular patterns to activate the production of inflammatory mediators. TLR4 recognizes lipopolysaccharide (LPS) and drives the secretion of inflammatory cytokines, often contributing to sepsis. We report that transient receptor potential melastatin-like 7 (TRPM7), a non-selective but Ca-conducting ion channel, mediates the cytosolic Ca elevations essential for LPS-induced macrophage activation. LPS triggered TRPM7-dependent Ca elevations essential for TLR4 endocytosis and the subsequent activation of the transcription factor IRF3. In a parallel pathway, the Ca signaling initiated by TRPM7 was also essential for the nuclear translocation of NFκB. Consequently, TRPM7-deficient macrophages exhibited major deficits in the LPS-induced transcriptional programs in that they failed to produce IL-1β and other key pro-inflammatory cytokines. In accord with these defects, mice with myeloid-specific deletion of Trpm7 are protected from LPS-induced peritonitis. Our study highlights the importance of Ca signaling in macrophage activation and identifies the ion channel TRPM7 as a central component of TLR4 signaling.
10.1016/j.immuni.2017.11.026
Management of acute pancreatitis in the first 72 hours.
Current opinion in gastroenterology
PURPOSE OF REVIEW:Acute pancreatitis is a common condition that affects patients with varying degrees of severity and may lead to significant morbidity and mortality. The present article will review the current paradigm in acute pancreatitis management within the first 72 h of diagnosis. RECENT FINDINGS:Patients presenting with acute pancreatitis should be evaluated clinically for signs and symptoms of organ failure in order to appropriately triage. Initial management should focus on fluid resuscitation, with some data to support Ringer's lactate over physiological saline. Routine use of prophylactic antibiotics in acute pancreatitis is not recommended, nor is urgent endoscopic retrograde cholangiopancreatography in the absence of concomitant acute cholangitis. Early oral feeding should be encouraged, not avoided, and use of parenteral nutrition is discouraged. Cholecystectomy during the same admission of biliary pancreatitis should be performed in order to prevent future acute pancreatitis episodes. Patients with acute pancreatitis secondary to alcohol should receive alcohol counseling. Finally, there is ongoing interest in the development of prognostic laboratory tests in acute pancreatitis and pharmacological therapies to reduce the inflammation that occurs in acute pancreatitis. SUMMARY:Acute pancreatitis is a common and heterogeneous condition with the potential for significant morbidity. Best practices in acute pancreatitis management focus on triage, hydration and enteral feeding.
10.1097/MOG.0000000000000456
Intercrypt sentinel macrophages tune antibacterial NF-κB responses in gut epithelial cells via TNF.
The Journal of experimental medicine
Intestinal epithelial cell (IEC) NF-κB signaling regulates the balance between mucosal homeostasis and inflammation. It is not fully understood which signals tune this balance and how bacterial exposure elicits the process. Pure LPS induces epithelial NF-κB activation in vivo. However, we found that in mice, IECs do not respond directly to LPS. Instead, tissue-resident lamina propria intercrypt macrophages sense LPS via TLR4 and rapidly secrete TNF to elicit epithelial NF-κB signaling in their immediate neighborhood. This response pattern is relevant also during oral enteropathogen infection. The macrophage-TNF-IEC axis avoids responses to luminal microbiota LPS but enables crypt- or tissue-scale epithelial NF-κB responses in proportion to the microbial threat. Thereby, intercrypt macrophages fulfill important sentinel functions as first responders to Gram-negative microbes breaching the epithelial barrier. The tunability of this crypt response allows the induction of defense mechanisms at an appropriate scale according to the localization and intensity of microbial triggers.
10.1084/jem.20210862
Galactooligosaccharides and Limosilactobacillus reuteri synergistically alleviate gut inflammation and barrier dysfunction by enriching Bacteroides acidifaciens for pentadecanoic acid biosynthesis.
Nature communications
Ulcerative colitis (UC) is a debilitating inflammatory bowel disease characterized by intestinal inflammation, barrier dysfunction, and dysbiosis, with limited treatment options available. This study systematically investigates the therapeutic potential of a synbiotic composed of galactooligosaccharides (GOS) and Limosilactobacillus reuteri in a murine model of colitis, revealing that GOS and L. reuteri synergistically protect against intestinal inflammation and barrier dysfunction by promoting the synthesis of pentadecanoic acid, an odd-chain fatty acid, from Bacteroides acidifaciens. Notably, the synbiotic, B. acidifaciens, and pentadecanoic acid are each capable of suppressing intestinal inflammation and enhancing tight junction by inhibiting NF-κB activation. Furthermore, similar reduction in B. acidifaciens and pentadecanoic acid levels are also observed in the feces from both human UC patients and lipopolysaccharide-induced intestinal inflammation in pigs. Our findings elucidate the protective mechanism of the synbiotic and highlight its therapeutic potential, along with B. acidifaciens and pentadecanoic acid, for UC and other intestinal inflammatory disorders.
10.1038/s41467-024-53144-1
New insights into acute pancreatitis.
Lee Peter J,Papachristou Georgios I
Nature reviews. Gastroenterology & hepatology
The incidence of acute pancreatitis continues to increase worldwide, and it is one of the most common gastrointestinal causes for hospital admission in the USA. In the past decade, substantial advancements have been made in our understanding of the pathophysiological mechanisms of acute pancreatitis. Studies have elucidated mechanisms of calcium-mediated acinar cell injury and death and the importance of store-operated calcium entry channels and mitochondrial permeability transition pores. The cytoprotective role of the unfolded protein response and autophagy in preventing sustained endoplasmic reticulum stress, apoptosis and necrosis has also been characterized, as has the central role of unsaturated fatty acids in causing pancreatic organ failure. Characterization of these pathways has led to the identification of potential molecular targets for future therapeutic trials. At the patient level, two classification systems have been developed to classify the severity of acute pancreatitis into prognostically meaningful groups, and several landmark clinical trials have informed management strategies in areas of nutritional support and interventions for infected pancreatic necrosis that have resulted in important changes to acute pancreatitis management paradigms. In this Review, we provide a summary of recent advances in acute pancreatitis with a special emphasis on pathophysiological mechanisms and clinical management of the disorder.
10.1038/s41575-019-0158-2
Activation of nuclear factor-κB in acinar cells increases the severity of pancreatitis in mice.
Gastroenterology
BACKGROUND & AIMS:Nuclear factor-κB (NF-κB) is activated during early stages of pancreatitis. This transcription factor regulates genes that control many cell activities, including inflammation and survival. There is evidence that activation of NF-κB protects against pancreatitis, and, in other cases, that it promotes this disease. We compared the effects of NF-κB in different mouse models of pancreatitis to understand these complications. METHODS:To model constitutive activation of NF-κB, we expressed a transgene that encodes its p65 subunit or the inhibitor of κB kinase (IKK)2 in pancreatic acinar cells of mice. We analyzed effects on pancreatic tissues and levels of NF-κB target genes in these mice and compared them with mice that did not express transgenic p65 or IKK2 (controls). RESULTS:Transgenic expression of p65 led to compensatory expression of the inhibitory subunit IKB-α and, therefore, no clear phenotype. However, p65 transgenic mice given injections of cerulein, to induce acute pancreatitis, had higher levels of NF-κB activity in acinar cells, greater levels of inflammation, and more severe outcomes than control mice. In contrast, constitutive expression of IKK2 directly increased the activity of NF-κB in acinar cells and induced pancreatitis. Prolonged activity of IKK2 (3 months) resulted in activation of stellate cells, loss of acinar cells, and fibrosis, which are characteristics of chronic pancreatitis. Co-expression of IKK2 and p65 greatly increased the expression of inflammatory mediators and the severity of pancreatitis, compared with control mice. CONCLUSIONS:The level of NF-κB activation correlates with the severity of acute pancreatitis in mice. Longer periods of activation (3 months) lead to chronic pancreatitis. These findings indicate that strategies to inactivate NF-κB might be used to treat patients with acute or chronic pancreatitis.
10.1053/j.gastro.2012.09.059
Cathepsin B-Mediated Activation of Trypsinogen in Endocytosing Macrophages Increases Severity of Pancreatitis in Mice.
Gastroenterology
BACKGROUND & AIMS:Acute pancreatitis is characterized by premature intracellular activation of digestive proteases within pancreatic acini and a consecutive systemic inflammatory response. We investigated how these processes interact during severe pancreatitis in mice. METHODS:Pancreatitis was induced in C57Bl/6 wild-type (control), cathepsin B (CTSB)-knockout, and cathepsin L-knockout mice by partial pancreatic duct ligation with supramaximal caerulein injection, or by repetitive supramaximal caerulein injections alone. Immune cells that infiltrated the pancreas were characterized by immunofluorescence detection of Ly6g, CD206, and CD68. Macrophages were isolated from bone marrow and incubated with bovine trypsinogen or isolated acinar cells; the macrophages were then transferred into pancreatitis control or cathepsin-knockout mice. Activities of proteases and nuclear factor (NF)-κB were determined using fluorogenic substrates and trypsin activity was blocked by nafamostat. Cytokine levels were measured using a cytometric bead array. We performed immunohistochemical analyses to detect trypsinogen, CD206, and CD68 in human chronic pancreatitis (n = 13) and acute necrotizing pancreatitis (n = 15) specimens. RESULTS:Macrophages were the predominant immune cell population that migrated into the pancreas during induction of pancreatitis in control mice. CD68-positive macrophages were found to phagocytose acinar cell components, including zymogen-containing vesicles, in pancreata from mice with pancreatitis, as well as human necrotic pancreatic tissues. Trypsinogen became activated in macrophages cultured with purified trypsinogen or co-cultured with pancreatic acini and in pancreata of mice with pancreatitis; trypsinogen activation required macrophage endocytosis and expression and activity of CTSB, and was sensitive to pH. Activation of trypsinogen in macrophages resulted in translocation of NF-kB and production of inflammatory cytokines; mice without trypsinogen activation (CTSB-knockout mice) in macrophages developed less severe pancreatitis compared with control mice. Transfer of macrophage from control mice to CTSB-knockout mice increased the severity of pancreatitis. Inhibition of trypsin activity in macrophages prevented translocation of NF-κB and production of inflammatory cytokines. CONCLUSIONS:Studying pancreatitis in mice, we found activation of digestive proteases to occur not only in acinar cells but also in macrophages that infiltrate pancreatic tissue. Activation of the proteases in macrophage occurs during endocytosis of zymogen-containing vesicles, and depends on pH and CTSB. This process involves macrophage activation via NF-κB-translocation, and contributes to systemic inflammation and severity of pancreatitis.
10.1053/j.gastro.2017.10.018
Acute pancreatitis: A narrative review.
JPMA. The Journal of the Pakistan Medical Association
Acute pancreatitis is a common cause of acute abdominal pain and can range from mild oedema to severe necrosis of the pancreas. It has a significant impact on morbidity, mortality and financial burden. The global prevalence of pancreatitis is substantial, with the highest rates observed in central and eastern Europe. Diagnosing acute pancreatitis involves considering clinical symptoms, elevated serum amylase and/or lipase levels, and characteristic imaging findings. The causes of acute pancreatitis include obstructive disorders, such as gallstones and biliary sludge, alcohol consumption, smoking, drug-induced pancreatitis, metabolic disorders, trauma, medical procedures, infections, vascular diseases and autoimmune pancreatitis. Appropriate management of acute pancreatitis involves determining the severity of the condition, providing supportive care, addressing the underlying cause, and preventing complications. Advances in classifying the severity of acute pancreatitis and implementing goal-directed therapy have contributed to a decrease in mortality rates. Understanding its prevalence, aetiology and management principles is crucial for clinicians to appropriately diagnose and manage patients with acute pancreatitis.
10.47391/JPMA.9280
Study on acute recent stage pancreatitis.
Feng Ye-Chen,Wang Min,Zhu Feng,Qin Ren-Yi
World journal of gastroenterology
Acute pancreatitis (AP) is an inflammatory disease of the pancreas which involves the pancreas and surrounding tissue, and systemic inflammation with a characteristic systemic increase of vascular permeability and increased risk of multiple organ dysfunction. Currently, the pathogenesis of AP is fuzzy, and the diagnosis and treatment need to be standardized. Nevertheless, increased knowledge of AP may achieve more thorough understanding of the pathogenesis. The use of further advanced diagnostic tools and superior treatment, potentially will help clinicians to manage AP at an appropriate stage. However, in view of the multi factorial disease and the complex clinical manifestations, the management of patients with AP is also remaining areas for improvement.
10.3748/wjg.v20.i43.16138
Global Incidence of Acute Pancreatitis Is Increasing Over Time: A Systematic Review and Meta-Analysis.
Gastroenterology
BACKGROUND & AIMS:Acute pancreatitis is a common disease with significant associated morbidity and mortality. We performed a systematic review and meta-analysis of population-based studies to explore the changing temporal trends of acute pancreatitis incidence globally. METHODS:We performed a systematic literature search to identify population-based studies reporting the annual incidence of acute pancreatitis. Abstracts were assessed independently to identify applicable articles for full-text review and data extraction. Joinpoint temporal trend analyses were performed to calculate the average annual percent change (AAPC) with 95% confidence intervals (CIs). The AAPCs were pooled in a meta-analysis to capture the overall and regional trends in acute pancreatitis incidence over time. Temporal data were summarized in a static map and an interactive, web-based map. RESULTS:Forty-four studies reported the temporal incidence of acute pancreatitis (online interactive map: https://kaplan-acute-pancreatitis-ucalgary.hub.arcgis.com/). The incidence of acute pancreatitis has increased from 1961 to 2016 (AAPC, 3.07%; 95% CI, 2.30% to 3.84%; n = 34). Increasing incidence was observed in North America (AAPC, 3.67%; 95% CI, 2.76% to 4.57%; n = 4) and Europe (AAPC, 2.77%; 95% CI, 1.91% to 3.63%; n = 23). The incidence of acute pancreatitis was stable in Asia (AAPC, -0.28%; 95% CI, -5.03% to 4.47%; n = 4). CONCLUSIONS:This meta-analysis provides a comprehensive overview of the global incidence of acute pancreatitis over the last 56 years and demonstrates a steadily rising incidence over time in most countries of the Western world. More studies are needed to better define the changing incidence of acute pancreatitis in Asia, Africa, and Latin America.
10.1053/j.gastro.2021.09.043
Organ Failure Due to Systemic Injury in Acute Pancreatitis.
Gastroenterology
Acute pancreatitis may be associated with both local and systemic complications. Systemic injury manifests in the form of organ failure, which is seen in approximately 20% of all cases of acute pancreatitis and defines "severe acute pancreatitis." Organ failure typically develops early in the course of acute pancreatitis, but also may develop later due to infected pancreatic necrosis-induced sepsis. Organ failure is the most important determinant of outcome in acute pancreatitis. We review here the current understanding of the risk factors, pathophysiology, timing, impact on outcome, and therapy of organ failure in acute pancreatitis. As we discuss the pathophysiology of severe systemic injury, the distinctions between markers and mediators of severity are highlighted based on evidence supporting their causality in organ failure. Emphasis is placed on clinically relevant end points of organ failure and the mechanisms underlying the pathophysiological perturbations, which offer insight into potential therapeutic targets to treat.
10.1053/j.gastro.2018.12.041
Acute pancreatitis.
Lankisch Paul Georg,Apte Minoti,Banks Peter A
Lancet (London, England)
Acute pancreatitis, an inflammatory disorder of the pancreas, is the leading cause of admission to hospital for gastrointestinal disorders in the USA and many other countries. Gallstones and alcohol misuse are long-established risk factors, but several new causes have emerged that, together with new aspects of pathophysiology, improve understanding of the disorder. As incidence (and admission rates) of acute pancreatitis increase, so does the demand for effective management. We review how to manage patients with acute pancreatitis, paying attention to diagnosis, differential diagnosis, complications, prognostic factors, treatment, and prevention of second attacks, and the possible transition from acute to chronic pancreatitis.
10.1016/S0140-6736(14)60649-8
Acute Pancreatitis.
Gardner Timothy B
Annals of internal medicine
Acute pancreatitis is one of the most common reasons for gastroenterology-related hospitalization in the United States. With significant morbidity and subsequent mortality related to both the acute presentation and subsequent sequelae, prompt diagnosis and appropriate management are critical, especially in the first 24 hours of illness. It is also important to accurately recognize complications, such as pancreatic fluid collections and vascular events, and identify a definitive cause so that a strategy to prevent future attacks can be implemented.
10.7326/AITC202102160