Gut Microbes最新文献

{"title":"The functional and catalytic landscape of urease reveals a conserved target against <i>Helicobacter pylori</i>.","authors":"Qiang Song, Huimin Wu, Zhengcai Ma, Ting Huang, Xinhu Zhu, Zhipeng Zhang, Guicheng Wu, Rakia Manzoor, Shiyu Liu, Ye Wang, Xuegang Li, Wenjin Zhang, Xiaoli Ye, Hang Ma","doi":"10.1080/19490976.2026.2653575","DOIUrl":"10.1080/19490976.2026.2653575","url":null,"abstract":"<p><p>Nearly half of the global population is infected with <i>Helicobacter pylori</i>. Antibiotic use has led to substantial antimicrobial resistance and unintended gut microbiota depletion, creating an urgent need for alternative therapeutic strategies. Here, we demonstrate that urease, a key enzyme that enables <i>H. pylori</i> survival by hydrolysing urea to neutralize stomach acid, is a conserved antibacterial target with low risk of resistance development. Using comprehensive deep mutational scanning coupled with phage-based functional screening, we systematically evaluated how mutations in core residues affect urease expression, enzymatic activity, bacterial colonization, and virulence, uncovering the catalytic nature of <i>H. pylori</i> urease. We found exceptional evolutionary conservation within the urease catalytic pocket, and potential mutation sites that affect urease activity are not close to the core of this pocket. Analysis of existing urease inhibitors revealed that their binding sites are not typically in these potential mutation sites, which indicates that the potential for resistance development is low. In addition, we show that targeting urease alone is effective in eradicating <i>H. pylori</i> and synergistically boosts the efficacy of antibiotics. Notably, the incorporation of urease inhibitors into antibiotic-based therapeutic regimens effectively preserves gut microbiota diversity and microbial genomic stability, thereby lowering the risk of antibiotic resistance. Collectively, our study elucidate the inherent resistance-resistant property of urease and establish the clinical value of combining urease inhibitors with antibiotics to reduce antibiotic resistance.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2653575"},"PeriodicalIF":11.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13051613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147616211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactic acid bacteria and endogenous ethanol mediate proton pump inhibitor-associated MASLD: a multicohort cross-sectional mediation analysis.","authors":"Mark Davids, Hilde Herrema, Albert K Groen, Henrike Galenkamp, Aeilko Zwinderman, Joonatan Palmu, Aki Havulinna, Teemu Niiranen, Rob Knight, Yaïr Acherman, Rutger Franken, Joanne Verheij, Michael Dukas, Jasmohan Bajaj, Cristina Llorente, Bernd Schnabl, Max Nieuwdorp, Abraham Meijnikman","doi":"10.1080/19490976.2026.2664712","DOIUrl":"https://doi.org/10.1080/19490976.2026.2664712","url":null,"abstract":"<p><strong>Background & aims: </strong>Proton pump inhibitor (PPI) use has been associated with metabolic dysfunction associated with steatotic liver disease (MASLD) in multiple studies. While the association is confounded by various risk factors, such as BMI and age, a potential mediating factor of the microbiome has been suggested. In this study, we aimed to identify bacterial clades with the highest mediating potential and evaluate the serially mediated path through microbially derived endogenous ethanol.</p><p><strong>Methods: </strong>Microbiome mediation analysis of PPI use and MASLD was conducted in two cohorts. In a bariatric surgery cohort (<i>n</i> = 122), liver biopsy-proven steatosis grade and postprandial ethanol concentrations were used as outcomes. In the HELIUS cohort (<i>n</i> = 2440), a general population cohort study, mediation was performed using the Fatty Liver Index (FLI) score. The strongest associations were validated in the FINRISK cohort (<i>n</i> = 7066).</p><p><strong>Results: </strong>Several bacterial taxa, which are predominantly found in the small intestine, showed a potential role in mediating the effects of PPIs on MASLD, postprandial ethanol levels, and FLI score. The Lactobacillales order showed the strongest mediating potential across the outcomes tested in both discovery cohorts. A notable serial mediation pathway was identified, linking PPI use to MASLD via Lactobacillales abundance and postprandial plasma ethanol concentrations. The mediating role of Lactobacillales in the association between PPI use and FLI scores was confirmed in the final study cohort.</p><p><strong>Conclusions: </strong>Data from multiple cross-sectional cohort studies support a mediating potential of the microbiome in the association between PPI use and hepatic steatosis, independent of alcohol consumption. The effect of PPIs on MASLD appears to be mediated mainly by increased lactic acid bacteria abundance, and is potentially, in part, serially mediated by endogenous ethanol production.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2664712"},"PeriodicalIF":11.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bile salt hydrolase activity as a rational target for MASLD therapy.","authors":"Elizabeth V Jones, Yongtao Wang, Wenchao Wei, James C Reed, Snehal N Chaudhari, Darrick K Li, Jerome Boursier, Sonja Lang, Münevver Demir, Anna Mae Diehl, Andrew S Allegretti, Bernd Schnabl, Raymond T Chung, A Sloan Devlin","doi":"10.1080/19490976.2025.2608437","DOIUrl":"10.1080/19490976.2025.2608437","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease in the United States, yet therapeutic options remain limited. Emerging evidence implicates the gut‒liver axis and intestinal permeability in disease pathogenesis. Previous studies in animal models and human cell culture indicated that bile salt hydrolases (BSHs), which are gut bacterial enzymes that deconjugate host-derived bile acids, damage intestinal barrier integrity and cause liver damage through the generation of unconjugated bile acids (UBAs). However, the relevance of these findings to MASLD patients is unknown. Here, we demonstrate that BSH activity is elevated in fecal samples from MASLD patients with advanced liver fibrosis and correlates with reduced fecal bile acid levels, which is consistent with a proposed model of increased intestinal permeability during MASLD progression. Through anaerobic culturing and activity-guided screening, we identify diverse BSH-active bacteria from patient fecal samples, suggesting broad microbial contributions to bile acid deconjugation in MASLD patients. Importantly, small-molecule BSH inhibitors suppressed BSH activity in both fecal communities and monocultures from MASLD patients without affecting bacterial viability. These findings indicate that BSH activity is a microbial function associated with MASLD progression and suggest that BSH inhibitors could be developed as a microbiome-targeted strategy for MASLD treatment.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2608437"},"PeriodicalIF":11.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12773562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intestinal epithelial TLR4 knock out induces sex-specific effects on gut barrier and microbiome in an activity-based anorexia model.","authors":"Colin Salaün, Marion Huré, Charlène Guérin, Christine Bôle-Feysot, Audrey Valentin, Fatima Léon, Sarah Lenoir, Jean-Luc do-Rego, Jean-Claude do-Rego, Ludovic Langlois, David Ribet, Najate Achamrah, Moïse Coëffier","doi":"10.1080/19490976.2026.2637316","DOIUrl":"10.1080/19490976.2026.2637316","url":null,"abstract":"<p><p>The role of the microbiota‒gut‒brain axis in the pathophysiology of anorexia nervosa has emerged in recent decades. Increased expression of Toll-like receptor 4 (TLR4) has been reported in the intestinal epithelial cells (IEC) of activity-based anorexia (ABA) mice. The inducible TLR4 knockout in IEC (TLR4^IEC^-/-) was subsequently associated with behavioral and energy balance changes in ABA mice. Our study aimed to assess the intestinal response to TLR4^IEC^-/- in both male and female ABA mice by focusing on three components: inflammation, the gut barrier, and the gut microbiota composition. After 12 d of undernutrition with free wheel access, the colonic expression of 43 markers was measured by RT-qPCR. The gut microbiota composition was analyzed by Illumina sequencing of the 16S rRNA gene. First, TLR4^IEC^-/- was associated with more marked alterations in male control mice compared to females. Indeed, a reduction in the mRNA expression of eight inflammatory factors, seven tight junction proteins and fecal calprotectin levels was observed in males. Control TLR4^IEC^-/- females showed increased expression of four inflammatory markers and one target involved in the gut barrier. The levels of the <i>Bacillota</i> phylum and the <i>Deltaproteobacteria</i> class and their subdivisions, up to the <i>Desulfovibrio</i> genus, increased in the control TLR4^IEC^-/- males compared to wt. In females, only an increase in the <i>Alcaligenaceae</i> genus, which ranks from the <i>Betaproteobacteria</i> phylum, was observed. Interestingly, in both males and females, these alterations were not observed in response to ABA model in TLR4^IEC^-/- mice. Similarly, ABA increased <i>Tjp1</i> expression and <i>Lactobacillus</i> abundance, both of which were decreased by TLR4^IEC^-/-. Our study shows for the first time the impact of inducible TLR4^IEC^-/- on the intestinal response. TLR4^IEC^-/- induced sex-specific colonic alterations and changes in the gut microbiota, which disappeared after the ABA model. Further studies are warranted to decipher the underlying mechanisms.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2637316"},"PeriodicalIF":11.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12959196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Invasion of gut-derived escherichia coli extracellular vesicles exacerbates myocardial ischemia/reperfusion injury.","authors":"Junzhuo Wang, Ke Hu, He Lu, Ke Chen, Jian Zhang, Shaojun Wu, Lina Kang, Jun Xie, Biao Xu","doi":"10.1080/19490976.2026.2635818","DOIUrl":"10.1080/19490976.2026.2635818","url":null,"abstract":"<p><p>Recent studies have highlighted the close relationship between gut microbiota and the cardiovascular system; however, the precise mechanisms and modes of their interaction remain incompletely understood. Among the various factors involved, bacterial extracellular vesicles (EVs) are often overlooked, despite their potential roles in multiple pathological processes. To investigate the role of bacterial EVs in shaping the inflammatory microenvironment following myocardial ischemia-reperfusion injury, we colonized the intestines of Rosa26.tdTomato reporter mice with <i>Escherichia coli</i> (<i>E. coli</i>) expressing Cre recombinase. Using FACS-beads and immunofluorescence techniques, we found that myocardial ischemia-reperfusion injury in mice significantly enhanced the invasion of gut-derived bacterial EVs. Meanwhile, in patients with ST-segment elevation myocardial infarction, we also confirmed the invasion of bacterial EVs via the FACS-bead method, and there was a significant correlation between extracellular vesicles in peripheral blood and LPS, suggesting that these EVs can be key carriers for LPS translocation. In this pathological process, invading <i>E. coli</i> EVs exacerbate the mobilization and infiltration of systemic and local inflammatory cells, thereby aggravating myocardial damage and impairing cardiac function. Notably, glucagon-like peptide-2 can effectively alleviate inflammatory responses and myocardial injury by inhibiting the translocation of E. coli-derived EVs. In conclusion, our study is the first to confirm the impact of gut-derived EVs on myocardial ischemia-reperfusion injury, revealing that <i>E. coli</i> EVs can amplify inflammatory responses. These findings provide new insights into the gut-heart axis and offer a theoretical basis for the therapeutic potential of glucagon-like peptide-2 in cardiovascular diseases.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2635818"},"PeriodicalIF":11.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12959223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bacterial constipation: Mucin-degrading intestinal commensal bacteria cause constipation.","authors":"Tomonari Hamaguchi, Noriaki Gibo, Misuzu Ohara, Mikako Ito, Tomoyuki Ogura, Jun-Ichi Takeda, Hiroshi Nishiwaki, Fei Zhao, Ryo Kinoshita-Daitoku, Masashi Hattori, Koji Nonogaki, Tetsuya Maeda, Kenichi Kashihara, Yoshio Tsuboi, Masaaki Hirayama, Mitsuhiro Fujishiro, Hiroki Kawashima, Kinji Ohno","doi":"10.1080/19490976.2025.2596809","DOIUrl":"10.1080/19490976.2025.2596809","url":null,"abstract":"<p><p>The contribution of gut microbes to constipation remains mechanistically underexplored, despite constipation being one of the most prevalent gastrointestinal disorders. Here, we identify cooperative induction of constipation by two mucin-degrading gut commensals: <i>Akkermansia muciniphila</i> and <i>Bacteroides thetaiotaomicron</i>. In constipated patients with Parkinson's disease (PD) and chronic idiopathic constipation (CIC), we observed that <i>A. muciniphila</i> and <i>B. thetaiotaomicron</i> were increased. Gnotobiotic mice colonized with either bacterium exhibited no constipation, whereas mice co-colonized with both bacteria developed constipation. Fecal mucins but not gastric mucins carry terminal sulfates. As fecal transcriptome of gnotobiotic mice suggested a sulfatase-dependent mechanism, we generated an anaerobic sulfatase-maturating enzyme (anSME)-deficient <i>B. thetaiotaomicron</i> strain that cannot catabolize the terminal sulfates of mucins. In the absence of anSME, constipation was ameliorated in co-colonized gnotobiotic mice. The synergic effect of the two bacteria is in accordance with our observation that <i>A. muciniphila</i> alone and constipation are not correlated in humans. As a bunch of intestinal bacteria other than <i>B. thetaiotaomicron</i> also catabolize mucin sulfates, they may substitute for <i>B. thetaiotaomicron</i> in patients with constipation. We propose bacterial constipation, in which cooperative degradation of colonic mucins by sulfatases and glycosylases by two commensal bacteria reduces lubrication and induces fecal dehydration, leading to the development of constipation. Targeting microbial sulfatase activity may be a promising therapeutic approach for patients with bacterial constipation.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2596809"},"PeriodicalIF":11.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12928629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146219478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<b>Gut bacterial</b> <i><b>O</b></i><b>-demethylation modulates systemic exposure to oral etoposide</b>.","authors":"Ashutosh Tripathi, Toe Ein Kyawt, Jongoh Shin, Kyoung-Jae Won, Abigail T Armstrong, Giokdjen Ilktach, Peter Sullivan, Holly A Weilbaker, Yeonju Ko, Seongsoo Lee, Wooin Lee, Bruce R Cooper, Byung-Kwan Cho, Jimmy Orjala, Hyunwoo Lee, Hyunyoung Jeong","doi":"10.1080/19490976.2026.2628358","DOIUrl":"10.1080/19490976.2026.2628358","url":null,"abstract":"<p><p>Gut microbial <i>O</i>-demethylation has been reported for plant-derived dietary compounds containing <i>O</i>-methylated aromatic(s). However, the significance of gut microbial <i>O</i>-demethylation in drug metabolism and disposition remains unexplored. This study examined 64 clinically used oral drugs containing one or more methoxylated aromatics for gut microbial <i>O</i>-demethylation using high-resolution mass spectrometry (HRMS). For 35 of the tested drugs, including the anticancer agent etoposide, we detected metabolites corresponding to <i>O</i>-demethylation (i.e., a mass difference of -14 and its multiples) when individual drugs were incubated with mouse cecal contents. We confirmed that the <i>O</i>-demethylated metabolite (M1) of the model drug etoposide is etoposide catechol using HRMS and proton nuclear magnetic resonance spectroscopy. By testing an in-house collection of 56 gut bacteria individually, we identified seven previously unknown gut bacterial species that exhibit etoposide <i>O</i>-demethylating activity. Etoposide anticancer therapy has been associated with an increased risk of acute myeloid leukemia. We demonstrated that M1 is more genotoxic to myeloid cells when it is orally administered to mice, whereas M1 is less cytotoxic against MCF-7 and HeLa cancer cells than the parent etoposide, suggesting that the gut microbiota may contribute to the secondary genotoxicity of etoposide via <i>O</i>-demethylation. Comparative pharmacokinetic analysis of orally administered etoposide in control and antibiotic-treated mice showed that systemic exposure to etoposide increased 1.9-fold, while M1 exposure decreased 3.7-fold in antibiotic-treated mice, suggesting that gut microbial <i>O</i>-demethylation is a significant determinant of etoposide metabolism and disposition. Collectively, our study reveals the prevalence of gut bacteria with <i>O</i>-demethylation activity, illustrates the contribution of gut microbial <i>O</i>-demethylation to altering drug efficacy and toxicity with the model drug etoposide, and provides a knowledge basis for in-depth characterization of other drugs identified as being susceptible to gut microbial <i>O</i>-demethylation.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2628358"},"PeriodicalIF":11.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12915777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146194518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intra-species competition combats vancomycin-resistant enterococci.","authors":"Nadav Ben-Assa, Rawi Naddaf, Shaqed Carasso, Omri Dagan, Aviv Sason, Tal Gefen, Naama Geva-Zatorsky","doi":"10.1080/19490976.2026.2647529","DOIUrl":"10.1080/19490976.2026.2647529","url":null,"abstract":"<p><p>Vancomycin-resistant <i>Enterococcus</i> (VRE) is a leading cause of multidrug-resistant infections in hospitalized patients, yet no reproducible microbiota therapies exist to selectively displace it. Here we harness intra-species competition within <i>Enterococcus</i> to suppress VRE colonization. Through <i>in vitro</i> screening and mouse colonization models, we identified a single antibiotic-susceptible strain, <i>E. faecalis</i> X98, that significantly reduced VRE burden both <i>in vitro</i> and in mouse experiments, whereas multi-strain consortia failed due to competitive interference among consortium members. In parallel, we subjected the vancomycin-sensitive strain <i>E. faecalis</i> OG1RF to phage selection, which produced a prophage-integrated derivative with convergent glycosyltransferase mutations that secreted a VRE-killing factor, conferring enhanced antagonism even without exogenous phage. These findings reveal ecological and evolutionary principles for selecting strains as targeted microbial therapeutics. Exploiting intra-species antagonism and phage-driven evolution provides a practical framework for developing microbiota-based interventions that minimize collateral damage to the microbiome while addressing antibiotic-resistant pathogens.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2647529"},"PeriodicalIF":11.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13011632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Helicobacter pylori</i> induces the production of interleukin-37 to promote broad immunosuppression and enhance colonization.","authors":"Rishi Pathirana, Nagaja Capitani, Christopher McCrory, Chiara Della Bella, Isabella Stuart, William Gilmore, Natalie J Bitto, Michelle D Tate, Ella L Johnston, Lauren Zavan, Steven Batinovic, John Pedersen, Sam Norden, Hassan Chaudhry, Richard L Ferrero, Tony M Korman, David Greening, Neil O'Brien-Simpson, Andrew M Ellisdon, James C Whisstock, Steve Petrovski, Renea A Taylor, Mario M D'Elios, Claudia A Nold-Petry, Marcel F Nold, Maria Kaparakis-Liaskos","doi":"10.1080/19490976.2026.2618860","DOIUrl":"10.1080/19490976.2026.2618860","url":null,"abstract":"<p><p><i>Helicobacter pylori</i> infects approximately half of the world's population, resulting in lifelong gastric infections. To promote lifelong colonization, <i>H.</i> <i>pylori</i> modulates host immunity via unknown mechanisms. Here we show that <i>H.</i> <i>pylori</i> can harness the pan-immunosuppressive cytokine interleukin-37 (IL-37) to facilitate pathogenesis, enhance colonization and prevent the development of innate, cellular and humoral immunity. We show that <i>H.</i> <i>pylori</i> increased the production of IL-37 in human gastric biopsies, and IL-37 secretion by gastric epithelial cells and human gastric mucosoids. We found that <i>H.</i> <i>pylori</i> induced IL-37 secretion by epithelial cells via activation of host pathogen recognition receptors TLR2, TLR4 and NOD1, in addition to the <i>H.</i> <i>pylori</i>-encoded cag pathogenicity island, revealing that <i>H.</i> <i>pylori</i> utilises multiple mechanisms to induce IL-37 production during infection. Once produced, IL-37 attenuated TLR2, TLR4 and NOD1-mediated activation and TLR-mediated IL-8 responses to <i>H.</i> <i>pylori</i> infection. Using transgenic mice expressing human IL-37, we found that IL-37 promoted immunosuppression by significantly increasing <i>H.</i> <i>pylori</i> colonization, limiting gastric inflammation, and reducing <i>H.</i> <i>pylori</i>-specific antibody responses. Furthermore, we identified the multiple mechanisms whereby IL-37 functions to impair the development of adaptive immunity. IL-37 abolished human T and B cell responses by impairing their activation, migration, and preventing immune synapse formation. Moreover, IL-37 inhibited proliferation of gastric-derived <i>H.</i> <i>pylori</i>-specific T cells isolated from <i>H.</i> <i>pylori</i>-infected patients, revealing a mechanism whereby IL-37 functions to prevent pathogen-specific cellular immune responses. Collectively, our findings reveal that <i>H.</i> <i>pylori</i> induces production of the pan-immunosuppressive cytokine IL-37 to enhance colonization, modulate gastritis and suppress innate, cellular and humoral immunity to ultimately promote pathogenesis in the host. These findings advance our understanding of <i>H.</i> <i>pylori</i>-mediated disease and identify gastric IL-37 as a therapeutic target to combat <i>H.</i> <i>pylori</i> infection and associated diseases.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2618860"},"PeriodicalIF":11.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12915765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146194474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbial ammonia as a mediator of PFOS neurotoxicity and its remediation by the flavonoid Icaritin.","authors":"Yang Yi, Wenfang Zhang, Yu Wei, Wang Ran, Dongjing Liu, Weikun Deng, Songyuan Duan, Jiyong Yao, Lianhang Wang, Yuandong Zhang, Jianmei Gao, Qihai Gong","doi":"10.1080/19490976.2026.2620125","DOIUrl":"10.1080/19490976.2026.2620125","url":null,"abstract":"<p><p>Perfluorooctane sulfonate (PFOS), a persistent environmental pollutant, is associated with cognitive dysfunction through mechanisms involving neuroinflammation, oxidative stress, and metabolic disruption. Icaritin, a bioactive flavonoid with antioxidant and anti-inflammatory properties, exhibits therapeutic potential, though its efficacy against PFOS-induced cognitive impairment remains unexplored. Herein, a mouse model of PFOS-induced cognitive dysfunction was established and treated with oral ICT. Integrated 16S rRNA sequencing and untargeted metabolomics revealed that ICT restored gut microbial homeostasis by enriching beneficial genera (e.g. <i>Akkermansia</i>, <i>Lactobacillus</i>) and reducing ammonia-producing bacteria (e.g. <i>Proteus</i>, <i>Helicobacter</i>, <i>Escherichia</i>), thereby improving gut barrier integrity. Metabolomic profiling identified significant perturbations in ammonia-related pathways, particularly arginine and proline metabolism, underscoring ammonia dysmetabolism as a pivotal mediator of PFOS neurotoxicity. These modifications attenuated systemic and cerebral ammonia accumulation, mitigated neuroinflammation and oxidative stress, and ultimately improved cognitive function. Our findings elucidate ammonia dysmetabolism as a central mechanism in PFOS-induced cognitive decline and highlight the microbiota-gut-brain axis as a promising therapeutic target. This study provides a mechanistic foundation for targeting microbial and metabolic pathways in environmental neurotoxicity.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2620125"},"PeriodicalIF":11.0,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12885405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146105374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}