Gut Microbes最新文献

{"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":"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":"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":"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":15.3,"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":"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":"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":"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":"Indole-3-acetic acid production is rare among gut bacteria and reflects OFOR-driven amino acid oxidation in acetogens.","authors":"Mary E DeFeo, Yuanyuan Liu, Zhiwei Zhou, Steven K Higginbottom, Dylan Dodd","doi":"10.1080/19490976.2026.2689610","DOIUrl":"10.1080/19490976.2026.2689610","url":null,"abstract":"<p><p>Indole-3-acetic acid (IAA) is a tryptophan-derived gut microbial metabolite with reported anti-inflammatory activities, but the organisms and anaerobic pathways that support robust production remain unclear. Screening 206 human gut bacterial isolates by LC-MS revealed that IAA production is rare: only five strains exceeded the limit of quantitation, and high-capacity production was confined to the acetogens <i>Blautia hydrogenotrophica</i> and <i>Intestinibacter bartlettii</i>. Across growth conditions, IAA was a minor product that rose alongside carbohydrate-sensitive, OFOR-linked catabolism of multiple amino acids, generating abundant branched-chain and aromatic organic acids. In gnotobiotic mice mono-colonized with <i>I. bartlettii</i>, these metabolites were produced <i>in vivo</i> but showed distinct host handling, with branched-chain fatty acids largely extracted between portal and peripheral plasma, whereas aromatic acids and their glycine conjugates appeared in plasma and urine. Genomic analyzes and heterologous enzyme assays identified expanded repertoires of 2-oxoacid:ferredoxin oxidoreductases (OFORs) with activities spanning pyruvate/oxaloacetate, branched-chain, and aromatic 2-oxoacids, including indolepyruvate conversion to indoleacetyl-CoA, a putative intermediate <i>en route</i> to IAA. Finally, position-specific ¹³C tracing showed that CO₂ released during amino acid oxidation is reassimilated into acetate via reductive acetogenesis, indicating that gut acetogens can maintain redox balance without fermenting partner strains. Together, these findings show that high IAA output is restricted to select gut acetogens and linked to a broader OFOR-driven anaerobic metabolism that generates additional metabolites that are absorbed by the host.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2689610"},"PeriodicalIF":15.3,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13290082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148294848","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 microbes mediate the synergistic effects of dietary cholesterol and saturated fat in driving fibrosing MASH.","authors":"Jake B Hermanson, Samar A Tolba, Md Amran Gazi, Evan A Chrisler, Manpreet Kaur, Ashley M Sidebottom, Yongjun Liu, Guillermo Martinez-Boggio, Lauren N Lucas, Daniel Amador-Noguez, Federico E Rey, Vanessa A Leone","doi":"10.1080/19490976.2026.2668121","DOIUrl":"10.1080/19490976.2026.2668121","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of the global population and can progress to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis, increasing the risk of cirrhosis, hepatocellular carcinoma, and mortality. Gut microbes driven by diets high in saturated fat, simple sugar, and cholesterol contribute to disease progression, yet the underlying mechanisms remain undefined. We explored the independent and synergistic effects of dietary saturated fat and cholesterol on MASH development using specific pathogen-free (SPF) and germ-free (GF) mice. We demonstrate that (1) both dietary cholesterol and saturated fat are required to induce fibrosing MASH in SPF mice, whereas GF mice are protected, (2) saturated fat and cholesterol individually alter gut microbial membership, potentially via altered bile acid metabolism, while their combination promotes a distinct composition, including an increase in <i>Parasutterella</i> spp. which correlates with hepatic fibrosis, and (3) diluted cecal contents from SPF, but not GF, mice fed high-fat, high-cholesterol diets are enriched in deoxycholic acid and activate human hepatic stellate cells <i>in vitro</i>, suggesting a mechanistic link between dietary lipid-induced microbiota and liver fibrogenesis. These findings reveal how specific Western dietary components shape the gut microbiota and contribute to hepatic fibrosis via stellate cell activation, offering potential targets for therapeutic interventions against MASLD/MASH.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"18 1","pages":"2668121"},"PeriodicalIF":15.3,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13166192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147868110","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}