Gut Microbes最新文献

{"title":"Deconfounded, quantitative microbiome profiling identifies robust multiple sclerosis markers and clinical covariate associations.","authors":"Ayla Pauwels, Lindsay Devolder, Gwen Falony, Miguel D'haeseleer, Guy Nagels, Ann Van Remoortel, Muriel Derrien, Marie D'hooghe, Jeroen Raes","doi":"10.1080/19490976.2026.2681876","DOIUrl":"10.1080/19490976.2026.2681876","url":null,"abstract":"<p><p>Despite a wealth of gut microbiota studies in multiple sclerosis (MS), consistent results are lacking. Here, we study confounder effects and use of quantitative microbiome profiling (QMP) in 228 MS patients (103 untreated) and 2860 population controls (Flemish Gut Flora Project (FGFP)). Total bacterial load was lower in relapsing remitting (RR)MS, while strong fecal moisture effects, indicative of longer transit times, in MS vs. FGFP, were driven by primary progressive (PP)MS. Applying cell count and moisture in deconfounded QMP, we identified 21 differentially abundant genera in MS, with a.o. <i>Lachnobacterium</i>, <i>Blautia</i> enriched, and <i>Clostridium</i>, <i>Bacteroides</i> depleted. Deconfounded QMP across 10 published studies (1065 patients, 874 controls) did not confirm commonly detected markers (<i>Akkermansia, Roseburia</i>), yet lowered <i>Bacteroides</i>, and higher <i>Blautia</i> and <i>Methanobrevibacter</i> emerged as robust MS biomarkers. Lowered butyrate producers (<i>Butyricicoccus, Butyricimonas</i>) merit further investigation. Enterotype stratification linked the low cell count <i>Bacteroides 2</i> enterotype to low-efficacy DMTs, and the <i>Prevotella</i> enterotype to lower disease severity. Serum glial fibrillary acidic protein (GFAP), a disease progression biomarker, was identified as a covariate of gut microbial variation and inversely correlated with <i>Faecalibacterium</i> and <i>Roseburia</i> abundance in PPMS. Overall, our study provides robust disease markers and emphasizes the importance of QMP and confounder control.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2681876"},"PeriodicalIF":15.3,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13245062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148162808","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":"Host and <i>Helicobacter pylori</i> HtrA protease variants converge on Wnt/β-catenin signaling to drive stomach adenocarcinoma.","authors":"Bodo Linz, Saiswaroop Rajaratnam, Nicole Tegtmeyer, Aakash Chhetri, Krishnasalini Gunanathan, Subbarao Kanchi, Suneesh Kumar Pachathundikandi, Venketesh Sivaramakrishnan, Steffen Backert","doi":"10.1080/19490976.2026.2704244","DOIUrl":"10.1080/19490976.2026.2704244","url":null,"abstract":"<p><p><i>Helicobacter pylori-</i>associated stomach adenocarcinoma (STAD) represents a highly severe malady, with up to 1 million new cases annually. Here, we examined novel human and bacterial risk determinants as well as related signal transduction events associated with STAD development. <i>H. pylori</i> serine protease HtrA cleaves the junctional protein E-cadherin, which results in the disruption of epithelial cell connections, the release and nuclear accumulation of β-catenin, and the onset of epithelial-mesenchymal transition (EMT), a hallmark of many tumors. In addition, the injection of <i>H. pylori</i> oncoprotein CagA into host epithelial cells targets β-catenin-mediated cell proliferation and other cancer signaling pathways. By analyzing over 2,000 <i>H. pylori</i> genomes, we identified single-nucleotide polymorphism (SNP) variants of HtrA and CagA that are associated with STAD progression. In addition, we investigated the role of the human serine proteases HTRA1, HTRA2, HTRA3, and HTRA4 in STAD progression and linked the genetic and expression data with specific signaling pathways. Elevated HTRA1, HTRA2, and HTRA3 expression in STAD patients correlated with upregulated extracellular matrix (ECM) receptor interactions and signaling that are critical for EMT. Moreover, <i>H. pylori-</i>positive STAD patients exhibited increased epithelial cell signaling, chronic inflammation, transcription factor Wnt/β-catenin signaling, ECM damage and metastasis, and single-cell analyses showed a strong association between HTRA1, the receptor Wnt, β-catenin, and oncogene MYC expression. Analyses of mutations in human HTRA1 and <i>H. pylori</i> HtrA revealed a role in the up- or downregulation of STAD progression. Together, our data show that SNPs in human and <i>H. pylori</i> serine protease HtrA and CagA modulate cancer signaling in complex Wnt-/β-catenin and ECM signaling networks, and that the protein variants can be causative or protective factors. A signaling model is proposed that highlights the complex interplay of human and bacterial factors in critical tumor signaling events, which could serve as predictive STAD biomarkers in patients.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2704244"},"PeriodicalIF":15.3,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13418485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148578353","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":"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":15.3,"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":"Mechanistic pathways linking gut microbial metabolites, microbial structural products, and host-microbe co-metabolites to mitochondrial function.","authors":"Richard E Frye, Daniel A Rossignol","doi":"10.1080/19490976.2026.2694140","DOIUrl":"10.1080/19490976.2026.2694140","url":null,"abstract":"<p><p>Gut-derived microbial metabolites modulate host mitochondrial function. To our knowledge, no prior systematic review has synthesized evidence linking these metabolites to direct mitochondrial endpoints across all major metabolite classes. PubMed, Scopus, and Web of Science were systematically searched through March 2026 for studies examining direct mitochondrial endpoints in relation to ten classes of gut-derived metabolites. Gut-derived microbial metabolites exert diverse effects on mitochondrial function, ranging from bioenergetic enhancement to direct toxicity. After contextual evidence was excluded from the certainty assessment, four metabolite-mitochondrial outcome groupings had moderate certainty: butyrate, propionate, indoxyl sulfate, and lipopolysaccharide. Evidence for p-cresyl sulfate, H₂S, and urolithin A was rated low; evidence for the remaining metabolite classes was low or very low. Butyrate generally enhances mitochondrial biogenesis, ATP generation, and electron transport chain activity across multiple experimental models. Indoxyl sulfate generally impaired mitochondrial function, whereas p-cresyl sulfate produced concentration- and model-dependent effects. PGC-1α emerges as a central regulatory node, integrating microbial metabolic signals to control mitochondrial biogenesis and oxidative metabolism. Many microbial metabolites demonstrate concentration-dependent biphasic effects. These findings support a mechanistic microbiome-mitochondrial framework in which diverse gut-derived molecules converge on a limited set of mitochondrial control nodes: electron transport chain activity, reactive oxygen species handling, biogenesis, and mitophagy. The evidence base is predominantly preclinical; these insights should be considered hypothesis-generating.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2694140"},"PeriodicalIF":15.3,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13456516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684386","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 metabolism of Flutamide attenuates its therapeutic efficacy against prostate cancer.","authors":"Shujing Li, Haiying Ding, Jiaqi Wang, Lingjie Yuan, Ying Zhou, Weiben Xu, Hang Yin, Mengqian Ye, Yuning Sha, Fangyin Li, Yousheng Liu, Zhengqin Zhu, Lulu Song, Xiangyu Jin, Liefeng Ma, Zhajun Zhan, Libin Pan, Luo Fang","doi":"10.1080/19490976.2026.2682803","DOIUrl":"10.1080/19490976.2026.2682803","url":null,"abstract":"<p><p>Endocrine drugs serve as the cornerstone of prostate cancer treatment. Flutamide, a representative first-generation antiandrogen, has been relegated to the treatment of recurrent prostate cancer due to novel drug development and therapeutic resistance. Our study shows the gut microbiota contributes to this resistance. Specifically, gut bacteria metabolize Flutamide into FLU-6 (a nitroreduction product) and FLU-9 (an acetylation product), involving species like <i>Escherichia coli</i>. Gene knockout revealed <i>E. coli nfsA</i> and <i>nfsB</i> as essential for Flutamide nitroreduction, while heterologous expression confirmed acetyltransferases mediate the production of acetylated metabolites. In the antibiotic-treated mouse model, antibiotic intervention significantly reduced microbial metabolites of Flutamide. In addition, FLU-6 was further metabolized by the host into FLU-5. Synthesized FLU-6, FLU-9, and FLU-5 showed no anticancer activity in prostate cancer cell lines. In a xenograft model, oral administration of <i>E. coli</i> diminished Flutamide's efficacy by altering its metabolic profile. Clinical sample analysis revealed substantial interpatient variability, and patients could be categorized into subgroups with high or low metabolic capability. These findings provide new insights into personalized prostate cancer therapy, highlight the role of the gut microbiota in Flutamide response and suggest a strategy for optimizing antiandrogen treatments.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2682803"},"PeriodicalIF":15.3,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13248909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148198588","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":"Why probiotics fail: gut niche tension as the missing variable?","authors":"Nadezhda A Pechnikova, Olga Zoikidou, Anita R Denisova, Theodora Choli-Papadopoulou, Amalia Aggeli, Alexey V Yaremenko","doi":"10.1080/19490976.2026.2728333","DOIUrl":"10.1080/19490976.2026.2728333","url":null,"abstract":"<p><p>Probiotic and live biotherapeutic interventions frequently yield inconsistent clinical benefits despite strong mechanistic rationale and widespread use. We propose that this heterogeneity reflects the ecological state of the gut at the time of dosing, in which an introduced strain must invade an already occupied ecosystem shaped by host physicochemical filters and resident community interactions. We introduce microbial niche tension as a trial-operational state variable capturing the net impedance to engraftment imposed by exclusionary forces (resource competition, antagonism, spatial crowding, and host immune and chemical barriers) and facilitative forces (niche vacancy, cross-feeding, and transient permissive windows). We further define a niche tension index (NTI) as a quantitative framework to estimate engraftment permissiveness across space, time, and host contexts. We synthesize evidence showing that niche tension is structured by gut transit, pH, oxygen gradients, diet, antibiotics, and host factors, including sex and hormonal state. Finally, we outline design rules for precision probiotics, including niche preconditioning, cooperative guild construction, sex-aware stratification, and data-driven prediction tools, to improve reproducibility and clinical efficacy.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2728333"},"PeriodicalIF":15.3,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13568588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148919363","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":"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":15.3,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13154942/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycosylation in gut-brain communication: from the intestinal barrier and microbiota to immune and neural signaling.","authors":"Dan Wang, Dong Zhou, Jianguo Gu, Chao Huang, Wenting Zhang","doi":"10.1080/19490976.2026.2722485","DOIUrl":"10.1080/19490976.2026.2722485","url":null,"abstract":"<p><p>The gut-brain axis is a complex bidirectional communication network linking the gastrointestinal tract and the central nervous system. Its dysregulation is closely associated with a wide range of gastrointestinal, metabolic, and neuropsychiatric disorders. Glycosylation, one of the most prevalent and structurally diverse post-translational modifications of proteins and lipids, is increasingly recognized as a regulator of multiple processes within the gut-brain axis. In this review, we summarize evidence that glycosylation influences several steps of gut-brain communication, including intestinal barrier function, microbial glycan metabolism, immune signaling, enteric and vagal pathways, blood-brain barrier integrity, and neural responses. We distinguish direct mechanistic findings from associative observations and discuss the more limited evidence for brain-to-gut regulation of intestinal glycosylation. In addition, we discuss the potential of glycosylation-targeted nutritional and microbiota-based interventions and highlight emerging opportunities to integrate glycomics with other omics approaches to dissect the complex regulatory networks underlying the gut-brain axis. In conclusion, elucidating how glycosylation shapes signaling along the gut-brain axis may open new avenues for understanding disease pathogenesis and for developing targeted therapeutic strategies.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2722485"},"PeriodicalIF":15.3,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818240","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 virome remodeling after fecal microbiota transplantation is associated with virus-bacteria co-variation and metabolic response in obesity and type 2 diabetes.","authors":"Hui Jiang, Ye Peng, Brian Lam, Keli Yang, Yu Lin, Joyce W Y Mak, Yee Kit Tse, Francis K L Chan, Zhilu Xu, Siew C Ng","doi":"10.1080/19490976.2026.2746820","DOIUrl":"10.1080/19490976.2026.2746820","url":null,"abstract":"<p><p>Fecal microbiota transplantation (FMT) modifies gut bacterial composition and improves metabolic outcomes in subjects with obesity and type 2 diabetes (ObT2), but bacterial changes alone do not fully explain the heterogeneity in clinical response. We performed virus-like particle (VLP)-enriched metagenomic sequencing coupled with bulk-DNA metagenomic sequencing on longitudinal fecal samples from a randomized controlled FMT trial in ObT2. Using random forest classification, post-FMT virome changes showed accuracy comparable to bacteriome changes (84.8% vs 81.4%) in distinguishing LDL responders from non-responders. Donor-derived viral contig engraftment was detected in 64.7% (11/17) of recipients receiving FMT alone and 58.8% (10/17) receiving FMT with lifestyle intervention (LSI), versus 5.6% (1/18) in the sham with LSI group. FMT was associated with increased virome diversity, compositional shifts toward the donor virome, and coordinated virus-bacteria associations, with most responsive viral contigs classified as <i>Caudoviricetes</i>. FMT-responsive viral contigs that were shared between the two FMT groups were predicted to infect <i>Roseburia</i> and <i>Bifidobacterium</i>, while contigs associated with clinical responses were predicted to infect <i>Escherichia</i>, <i>Roseburia</i>, <i>Blautia</i>, and <i>Enterococcus</i>. These findings suggest that the gut virome is a complementary ecological component associated with FMT responses and metabolic outcomes in ObT2.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2746820"},"PeriodicalIF":15.3,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13699845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149244093","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":"The gut microbiota as a regulator of intestinal stem-cell fate: bacterial and fungal control of differentiation and regeneration.","authors":"Yetong Shen, Benjamin James Chadwick, Peng Xue, Yiru Gao, Chen Ding","doi":"10.1080/19490976.2026.2734644","DOIUrl":"10.1080/19490976.2026.2734644","url":null,"abstract":"<p><p>Intestinal stem cells (ISCs) sustain epithelial homeostasis and regeneration in a niche that is shaped by epithelial, stromal, immune, and microbial inputs. This review examines how bacterial and fungal signals influence ISC activity and epithelial repair through microbial metabolites, immune relays, and epithelial sensing. Bacterial metabolites and structural ligands act through Wnt/β-catenin, AHR, IL-22-STAT3, Hippo-YAP, and related pathways, and the effects vary according to the ligand involved, responding cell type, and tissue state. Evidence for fungi is more limited: some fungal products engage repair-associated pathways, whereas improved barrier function or reduced inflammation have been observed without directly measuring ISC fate. Therefore, we distinguish direct changes in stem-cell self-renewal, lineage allocation, or regenerative state from indirect evidence based on epithelial repair. This evidence-based framework evaluates how multi-kingdom microbial signals may shape intestinal renewal and identifies key mechanistic gaps.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2734644"},"PeriodicalIF":15.3,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976715","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}