American journal of physiology. Gastrointestinal and liver physiology最新文献

{"title":"Roux-en-Y gastric bypass alters microbial circadian rhythms with links to metabolic improvement.","authors":"Daphne Moutsoglou, Mohammad Jarrah, Jessica Jaques, Leeann Aguilar, Shailesh K Shahi, Ashutosh K Mangalam, Mohamad Mokadem","doi":"10.1152/ajpgi.00440.2025","DOIUrl":"10.1152/ajpgi.00440.2025","url":null,"abstract":"<p><p>The circadian clock and gut microbiome are integral regulators of metabolic homeostasis, with disruptions in either system contributing to obesity pathogenesis. Roux-en-Y gastric bypass (RYGB) effectively treats severe obesity, yet the mechanisms underlying its benefits remain incompletely characterized. We investigated the impact of RYGB on cecal gut microbial composition and function using 16S rRNA sequencing in relation to host circadian gene expression and metabolic parameters in diet-induced obese mice. Diet-induced obese mice underwent RYGB or sham surgery and were compared with lean controls across multiple circadian Zeitgeber time (ZT) points (ZT3, ZT9, ZT15, and ZT21). Principal component analysis at the amplicon sequence variant level revealed significant differences in all ZT points (ZT3, ZT9, ZT15, and ZT21) in the lean and sham-operated mice; however, only a significant difference between ZT9 and ZT21 was observed in RYGB mice. Microbial gene counts and microbial pathways were also different between RYGB and sham-operated mice, with several correlating with hepatic <i>Clock</i> and <i>Bmal1</i> gene expression. Notably, specific taxa showed differential associations with glucose homeostasis, independent of surgical intervention. These findings demonstrate that RYGB alters the gut microbiome and host circadian rhythms, suggesting an association between microbial remodeling, circadian gene expression, and metabolic improvement following bariatric surgery.<b>NEW & NOTEWORTHY</b> We find that Roux-en-Y gastric bypass alters circadian patterns, including taxonomy, microbial metabolic gene counts, and microbial metabolic pathways that align with circadian gene expression, <i>Clock</i>, Liver <i>Period1</i>, and <i>Bmal1</i>. These findings in Roux-en-Y gastric bypass mice differ from those in sham-operated mice (also on a high-fat diet), which may contribute to the metabolic benefits of the surgery.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G155-G164"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epithelial fucosylation regulates intestinal stem cell differentiation.","authors":"Haiqin Wu, Chunlong Mu, Xuan Li, Le Shen, Ziyu Liu, Kaifan Yu, Weiyun Zhu","doi":"10.1152/ajpgi.00460.2025","DOIUrl":"10.1152/ajpgi.00460.2025","url":null,"abstract":"<p><p>The potential role of human milk oligosaccharides (HMOs) in regulating intestinal epithelial cell proliferation and differentiation in mammals has attracted considerable attention. Fucosylated HMO can provide fucosylated glycans to the intestine of newborns, an outcome similar to genetic overexpression of fucosyltransferase. However, how HMOs, such as 2'-fucosyllactose (2'-FL), may impact small intestinal fucosylation to regulate intestinal stem cell (ISC)-mediated intestinal epithelial development remains unknown. In the present study, we employed a model of small intestinal fucosylation inhibition in pups by orally administering a fucosylation inhibitor, 2 F-peracetyl-fucose (2 F-Fuc) from <i>postnatal day 4</i> (PN4) to <i>postnatal day 21</i> (PN21). Inhibition of jejunal fucosylation of pups during the breastfeeding stage significantly promoted ISC differentiation toward the secretory lineage by inhibiting Notch signaling pathways. Furthermore, fucosylation inhibition caused ISC differentiation deregulation in the jejunum that persisted until <i>PN day 42</i>, even though 2 F-Fuc was no longer administered after weaning at PN21. Supplementation of 1,2-fucosylated oligosaccharide by 2'-FL after weaning ameliorated the long-term effects of fucosylation inhibition in rats on ISC differentiation and changes in mucus-degrading microbiota. These results demonstrate that intestinal fucosylation in pups plays an important role in maintaining the balance between ISC proliferation and differentiation. Our study offers new insights into the interactions between intestinal fucosylation and ISC function. It also establishes a research foundation for using 2'-FL as a donor for α1,2-fucosylated glycans, enabling targeted modifications in intestinal fucosylation to enhance gut health, particularly small intestine health.<b>NEW & NOTEWORTHY</b> Inhibition of jejunal fucosylation of pups during the breastfeeding stage significantly promoted ISC differentiation toward the secretory lineage, and this effect persisted until <i>PN day 42</i> via inhibiting Notch signaling pathways. In addition, supplementation with 2'-FL after weaning ameliorated the long-term effects of fucosylation inhibition in rats on ISC differentiation and the dysregulation of mucus-degrading microbiota.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G229-G243"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MYO5B deficiency is associated with altered MUC13 localization and DMBT1 accumulation in intestinal epithelial cells.","authors":"Rachel Stubler, Charulekha Packirisamy, Jenna G Cagle, Piper McKee, Ana Pettijohn, Elena Kolobova, Sarah A Dooley, Rachel Edens, Lauren Giordano, Robin Muise-Helmericks, Kristen A Engevik, Melinda A Engevik, Amy C Engevik","doi":"10.1152/ajpgi.00131.2026","DOIUrl":"10.1152/ajpgi.00131.2026","url":null,"abstract":"<p><p>Myosin 5b (MYO5B) is a motor protein that plays an essential role in trafficking proteins to the apical membrane. Recent studies have demonstrated that MYO5B traffics ion transporters, like NHE3, DRA, and SGLT1, water channels, like AQP7, and efflux transporters, like P-glycoprotein. However, the role of MYO5B in trafficking glycoproteins involved in mucosal defense remains unclear. Here, we investigate whether MYO5B is required for the apical localization of mucin 13 (MUC13) and deleted in malignant brain tumors 1 (DMBT1), two glycoproteins critical for epithelial protection and wound healing. To address the requirement of MYO5B in glycoprotein trafficking, we immunostained the small intestine and colon of neonatal germline and adult inducible intestine-specific MYO5B knockout (KO) mice and examined MUC13 and DMBT1 localization. Organoids derived from germline and inducible KO mice were analyzed to confirm findings in an epithelial-only system. In addition, staining was performed on human organoids expressing MYO5B-tail green fluorescent protein (GFP). MYO5B loss in vivo resulted in the intracellular accumulation of MUC13 and DMBT1, reducing their colocalization with the apical marker γ-actin in both models. MUC13 colocalized with the lysosomal marker lysosomal-associated membrane protein 1 (LAMP1) in adult mice after MYO5B loss, indicating that a portion of cytoplasmic MUC13 undergoes lysosomal degradation. Mislocalization of MUC13 was observed in vitro in intestinal MYO5B-deficient organoids. MYO5B-tail GFP was associated with MUC13 in human intestinal organoids. MYO5B is required for the apical delivery of MUC13 and DMBT1 in the intestinal epithelium. Disrupting this pathway may contribute to mucosal dysfunction in MYO5B-related diseases, highlighting potential therapeutic targets for restoring epithelial barrier integrity.<b>NEW & NOTEWORTHY</b> This work identifies MYO5B as an important regulator of the apical localization of the mucosal defense glycoprotein MUC13. Our findings suggest a link between epithelial trafficking machinery and glycocalyx organization, demonstrating that MYO5B deficiency is associated with altered localization of these proteins and increased lysosomal accumulation of MUC13. These observations provide additional insight into epithelial dysfunction in MYO5B-associated enteropathies and may have broader relevance to inflammatory bowel disease.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G183-G192"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intestinal permeability responses to maximal and submaximal exercise in individuals with normal-weight obesity: an exploratory study.","authors":"Bryant H Keirns, Ashley Keller, Alexis R Quirk, Daniel Lawson, Harrison Smith, Sam R Emerson","doi":"10.1152/ajpgi.00124.2026","DOIUrl":"10.1152/ajpgi.00124.2026","url":null,"abstract":"<p><p>Intestinal permeability may contribute to low-grade inflammation and cardiovascular disease (CVD). Despite health benefits, aerobic exercise acutely increases intestinal permeability in healthy populations. Whether at-risk groups display exaggerated intestinal permeability and inflammatory responses to exercise versus healthy individuals is unknown. Individuals with a normal body mass index (BMI) and high body fat percent (normal-weight obesity; NWO) are at increased CVD risk. Inflammation is one suggested mechanism promoting risk in NWO; yet drivers remain unclear. Here, we explored gut permeability and inflammatory biomarkers in NWO (33 ± 7 yr; 55% males) pre/post maximal and submaximal exercise (cycle ergometer) vs. normal-weight lean (NWL; normal BMI, low body fat; 33 ± 7 yr; 50% males) and obese BMI, high body fat (OB; 39 ± 10; 30% males) participants (<i>N</i> = 31; <i>n</i> = 10-11/group). Each participant completed a peak oxygen consumption ([Formula: see text]) test (T1) and 45 min at 65% [Formula: see text] (T2). Full sample and within-group changes postexercise were assessed (paired <i>t</i> tests) and absolute change scores across groups compared (one-way ANOVAs). Following T1, sCD14 increased in the full sample, NWL, and OB (<i>P</i>s ≤ 0.05). T1 fatty-acid binding protein 2 (FABP2) increased in NWO (<i>P</i> < 0.05). At T2, FABP2 increased in the full sample and OB (<i>P</i>s ≤ 0.05). T2 also increased IL-6 in all participants, NWL, NWO (<i>P</i>s ≤ 0.05), and nearly OB (<i>P</i> = 0.06). The absolute changes across groups were similar for all biomarkers at T1 and T2. Body fat percent was moderately correlated with T1 ΔsCD14 in the full sample (<i>r</i> = 0.36; <i>P</i> < 0.05). Overall, NWO's gut barrier response to exercise was largely similar to other groups, with some preliminary exceptions. The influence of relative adiposity on exercise-induced intestinal permeability warrants further examination.<b>NEW & NOTEWORTHY</b> This work is the first to characterize the gastrointestinal response to exercise in NWO and traditional obesity. In addition, we are the first, to our knowledge, to identify a relationship between adiposity and exercise-induced intestinal permeability.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G208-G215"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-oxygen gas-permeable culture improves viability and supports quantitative antifibrotic pharmacology in precision-cut liver slices.","authors":"Yusaku Komoike, Hideyuki Hiyoshi, Teruyoshi Yamashita, Shinsuke Araki","doi":"10.1152/ajpgi.00144.2026","DOIUrl":"10.1152/ajpgi.00144.2026","url":null,"abstract":"<p><p>Liver fibrosis remains a major unmet medical need, and quantitative evaluation of antifibrotic candidates requires ex vivo models that preserve tissue function while supporting higher-throughput pharmacological testing. Precision-cut liver slices (PCLSs) maintain native multicellular architecture but are limited by suboptimal oxygenation and insufficient throughput, particularly in fibrotic tissue. Therefore, we aimed to establish a high-oxygen culture system using commercially available gas-permeable plates to enable quantitative antifibrotic testing in rat PCLSs. Normal and choline-deficient high-fat diet-induced fibrotic PCLSs were cultured under 20% or 80% O₂ in gas-permeable (G-Rex; NOK, InnoCell) or conventional nongas-permeable formats. High-oxygen gas-permeable conditions improved viability, assessed by cumulative lactate dehydrogenase release, and enhanced hepatic function, including albumin secretion and glycogen preservation. Under optimized conditions, transforming growth factor-β1 and platelet-derived growth factor-BB markedly induced <i>Col1a1</i> and <i>Acta2</i> expression and increased collagen type I production. Fibrotic PCLSs maintained activated stellate cell features and sustained collagen secretion for 96 h. This platform enabled quantitative pharmacological profiling: the activin receptor-like kinase 5 (ALK5) inhibitor SB-525334 consistently suppressed fibrogenic gene expression and collagen production, whereas the multikinase inhibitor nintedanib showed weaker inhibition. Miniaturization to gas-permeable 96-well plates preserved functional and pharmacological performance, increasing experimental yield per liver. Overall, this accessible, high-oxygen PCLS system overcomes oxygenation limitations and enables reliable, medium-throughput antifibrotic testing in a physiologically intact ex vivo fibrosis model.<b>NEW & NOTEWORTHY</b> Precision-cut liver slices preserve native hepatic architecture but are difficult to maintain and miniaturize for quantitative drug testing, particularly in fibrotic tissue. High-oxygen culture using readily available gas-permeable plates improves viability and hepatocyte function while sustaining fibrogenic readouts, enabling concentration-response antifibrotic testing in 96-well formats. This medium-throughput workflow increases data yield per liver and provides a practical, consistent platform for antifibrotic evaluation.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G216-G228"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148443882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physical, chemical, and structural properties of human gastric organoid-derived mucus.","authors":"Katrina N Lyon, Barkan Sidar, Jasper Gattiker, Cameron Dudiak, Chloe Vermulm, Grace Jordan, Thomas A Sebrell, Maeve T Morris, Lawrence Tabone, Nova Szoka, Salim Abunnaja, Brian A Boone, Jonathan T Busada, Alexis Burcham, Luke Domanico, Richard F Helm, Wentian Liao, Bret Davis, Jennifer Brown, Scott G McCalla, James N Wilking, Rama Bansil, Diane Bimczok","doi":"10.1152/ajpgi.00001.2026","DOIUrl":"10.1152/ajpgi.00001.2026","url":null,"abstract":"<p><p>The gastric mucus layer protects the epithelium from gastric acid and ingested pathogens. However, studies of human gastric mucus have been limited due to poor accessibility of native human mucus and the abundance of contaminants in these samples. Here, we explored the potential of human gastric organoids as models for mucus production. Immunofluorescence staining confirmed that the organoids produced mucus containing MUC5AC and MUC6. The luminal mucus had viscoelastic properties similar to those of native human gastric mucus, as determined by particle tracking microrheology. To collect organoid-produced gastric mucus, termed bioengineered gastric mucus (BGM), organoids were cultured as monolayers at the air-liquid interface (ALI), and apically secreted mucus was harvested and analyzed by MUC5AC ELISA, proteomics, cryo-field emission scanning electron microscopy (CryoFE-SE), and rheometry. BGM contained high-molecular weight molecules also found in native gastric mucus. Proteomic analysis confirmed that BGM contained MUC5AC, MUC6, MUC1, and other stomach-specific molecules such as pepsin C, trefoil factor 2, and gastrokine. CryoFE-SE showed that both BGM and native mucus had a porous structure and a characteristic honeycomb scaffold. However, the viscosity of the BGM was generally lower than that of native human gastric mucus, and BGM failed to exhibit gelation at low pH. Collectively, these findings demonstrate the potential as well as some limitations of BGM as an accessible model system for human gastric mucus.<b>NEW & NOTEWORTHY</b> We demonstrate the structural and functional similarities of organoid-derived gastric mucus and native mucus collected from human patients. The bioengineered gastric mucus mimics its native counterpart in its proteomic profile and physical architecture. This work highlights the translational potential of organoid-derived mucus for functional investigations of the human gastric mucus layer.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G244-G261"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13600236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated circulating bile acids driven erythrocyte osmotic resistance marks hepatobiliary disease.","authors":"Beng San Yeoh, Sadhana K Sah, Piu Saha, Bina Joe, Andrew T Gewirtz, Thomas Sodeman, Lavanya Reddivari, Matam Vijay-Kumar","doi":"10.1152/ajpgi.00096.2026","DOIUrl":"10.1152/ajpgi.00096.2026","url":null,"abstract":"<p><p>Cholemia [i.e., elevated circulating bile acids (BA)] is an early feature of hepatobiliary disorders. However, cholemia often goes undetected because BA are not measured in routine health screenings. We hypothesized that the membrane-disrupting properties of BA might impact red blood cell (RBC) osmotic resistance (OR), potentially providing a means to detect cholemia. To test this, RBC OR was examined in multiple mouse models of cholemia, germ-free animals, and patients with cholestatic liver disease. RBC from cholemic mice exhibited markedly elevated OR against hypotonic sodium chloride, potassium chloride, and ammonium chloride solutions. Elevated OR was observed in an array of mouse models of cholemia, including mice with spontaneous portosystemic shunts, deficiencies in aryl hydrocarbon receptor, multidrug resistance protein 2, and farnesoid X receptor. The degree of OR correlated with serum BA levels. RBC OR increased upon ex vivo treatment with cholemic plasma or unconjugated BA. Conversely, the absence of gut microbiota in germ-free animals was associated with reduced BA levels and decreased RBC OR. Colonizing gut microbiota into germ-free animals via cohousing increased their RBC OR. RBC from patients with cholestatic liver disease also displayed increased OR, indicating potential human relevance. The elevated cholesterol-to-phospholipid ratio in the membranes of RBC from both cholemic mice and humans suggests increased membrane rigidity. Consistent with this, treatment with dimethyl sulfoxide to enhance membrane permeability reduced RBC OR. Taken together, these findings provide <i>proof</i>-<i>of</i>-<i>concept</i> that increased RBC OR is associated with cholemia and may serve as a basis for a whole blood approach to its detection.<b>NEW & NOTEWORTHY</b> Elevated circulating bile acids are associated with increased red blood cell (RBC) resistance to osmotic hemolysis in mice and humans. This phenotype reflects bile acid-driven remodeling of RBC membranes and provides a basis for a whole blood assay to assess cholemia using small blood volumes.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G262-G276"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13431454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbiota dysbiosis and mucosal hyperinnervation contribute to intestinal hyperalgesia in a mouse model of postinfectious irritable bowel syndrome.","authors":"Li-Yu Lin, Yu-Hsuan Lin, Chia-Hung Tu, Ming-Shiang Wu, Wei-Ting Kuo, Chin-Hung Sun, Ling-Wei Hsin, Linda Chia-Hui Yu","doi":"10.1152/ajpgi.00007.2026","DOIUrl":"10.1152/ajpgi.00007.2026","url":null,"abstract":"<p><p>Postinfectious irritable bowel syndrome (PI-IBS) is defined by persistent gastrointestinal symptoms that follow recovery from an episode of infectious enteritis, which worsen after experiencing psychological stress. Mucosal neurite outgrowth stimulated by neurotrophins and serotonin/5-hydroxytryptamine receptor subtype 7 (5-HT₇) activation is linked to visceral hypersensitivity. Rifaximin (RFX) is a poorly absorbed antibiotic that improves IBS symptoms; however, the exact mechanisms remain unclear. The aims are to evaluate changes in microbiota and neuroplasticity in PI-IBS mice after RFX treatment and the analgesic effects of combined treatment with a novel 5-HT₇ antagonist, CYY1005 (CYY). A mouse model with dual triggers of <i>Giardia</i> postinfection and water avoidance stress exhibited intestinal hyperalgesia, as measured by visceromotor responses (VMRs). Higher Shannon diversity and increased relative abundances of <i>Lachnospiraceae, Dehalobacteriaceae,</i> and <i>Ruminococcus gnavus</i> were observed in the microbiota of PI-IBS mice, which were restored to baseline after RFX treatment. Reduced VMRs were associated with attenuated mucosal neurite outgrowth and brain-derived neurotrophic factor (BDNF) expression after RFX treatment. BDNF/high affinity tropomyosin receptor kinase B activation induced mTOR-dependent nerve fiber elongation and upregulated tryptophan hydroxylase 2 and 5-HT₇ expression via Rac1/ROCK pathway in SH-SY5Y neuron cultures. Combined treatment with RFX and CYY reduced VMRs to levels comparable with those of the control groups. Finally, bacteria-free colonic mouse supernatants induced neurite elongation in SH-SY5Y cells, which was inhibited by neutralizing anti-BDNF antibodies. In conclusion, microbiota restoration by RFX treatment attenuated BDNF-induced neurite outgrowth and alleviated visceral hypersensitivity in mice. Analgesic combinations of RFX and a 5-HT₇ receptor antagonist reduced intestinal nociception to baseline levels.<b>NEW & NOTEWORTHY</b> A mouse model of postinfectious IBS was developed using dual triggers of <i>Giardia</i> postinfection and water avoidance stress to mimic diverse risk factors. Rifaximin treatment reduced intestinal hyperalgesia and was associated with decreased mucosal neurite outgrowth and brain-derived neurotrophic factor (BDNF) expression. BDNF activation induced nerve fiber elongation and upregulated 5-HT₇ expression via separate signaling pathways. Analgesic combinations of RFX and a 5-HT₇ receptor antagonist reduced intestinal nociception to baseline.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G165-G182"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reevaluating the role of TRPV6 deficiency in human and mouse pancreatitis.","authors":"Gergő Berke, Máté Sándor, Sumiyya Raheem, Nataly C Morales Granda, Zsófia Gabriella Pesei, Réka Hegede, Alexandra Demcsák, Balázs Csaba Németh, Heiko Witt, Andrea Szentesi, Péter Hegyi, Tibor Rohacs, Eszter Hegyi, Miklós Sahin-Tóth","doi":"10.1152/ajpgi.00070.2026","DOIUrl":"10.1152/ajpgi.00070.2026","url":null,"abstract":"<p><p>Functionally defective genetic variants of the calcium channel transient receptor potential vanilloid type 6 (TRPV6) have been shown to markedly increase the risk for chronic pancreatitis in humans. Genetic inactivation of <i>Trpv6</i> in mice worsened the severity of pancreatitis induced by secretagogue hyperstimulation. The aims of the present study were to reexamine the role of loss-of-function <i>TRPV6</i> gene variants in an adult Hungarian cohort with nonalcoholic chronic pancreatitis and to characterize cerulein-induced pancreatitis in a novel <i>Trpv6</i>-deleted mouse strain. We found that 2.1% of chronic pancreatitis patients carried defective <i>TRPV6</i> variants, whereas no such variants were identified in control subjects. Homozygous deletion of <i>Trpv6</i> in C57BL/6N mice (<i>Trpv6-KO</i>) caused no spontaneous pancreatitis but slightly increased the severity of cerulein-induced acute pancreatitis and delayed recovery after an acute episode in a subset of mice. Cerulein-induced intrapancreatic trypsin and chymotrypsin activity was unchanged in <i>Trpv6-KO</i> mice relative to C57BL/6N controls. Crossing homozygous <i>Trpv6-KO</i> mice with heterozygous <i>Spink1-KO</i> mice did not result in spontaneous pancreatitis. Our results confirmed the association of defective <i>TRPV6</i> variants with human chronic pancreatitis in a nonalcoholic cohort. Furthermore, we found that TRPV6 played a relatively minor role in cerulein-induced murine pancreatitis, highlighting the need for better animal models for studying human <i>TRPV6</i> variants.<b>NEW & NOTEWORTHY</b> Prior studies indicated that defective variants of transient receptor potential vanilloid type 6 (<i>TRPV6</i>) encoding a constitutive calcium channel increased the risk of chronic pancreatitis in humans, and genetic inactivation of <i>Trpv6</i> aggravated the severity of experimental pancreatitis in mice. We reexamined these findings by conducting a genetic case-control study and characterizing novel <i>Trpv6</i>-deleted mice. We confirmed the association of defective <i>TRPV6</i> variants with human chronic pancreatitis but found that <i>Trpv6</i> deficiency had limited impact on secretagogue-induced pancreatitis in mice.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G193-G207"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13541285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma metabolomics identifies trimethylamine N-oxide as an accelerator of gallstone disease accompanied by early neoplastic alterations in mice.","authors":"Vipin Yadav, Deepti Sharma, Vaishali Yadav, Ragini Kilambi, Nihar Mohapatra, Ankit Bhardwaj, Nilesh S Patil, Shridhar V Sasturkar, Archana Rastogi, Garima Bhatia, Anupama Kumari, Nagarajan Perumal, Khushboo Agrawal, Jaswinder Singh Maras, Nirupama Trehanpati, Viniyendra Pamecha, Shiv K Sarin, Gayatri Ramakrishna","doi":"10.1152/ajpgi.00413.2025","DOIUrl":"10.1152/ajpgi.00413.2025","url":null,"abstract":"<p><p>India accounts for 10% of the global gallstone disease (GSD) and gallbladder cancer (CaGB) burden. CaGB's poor prognosis necessitates early detection of biomarkers. We used targeted/untargeted plasma metabolomics in human and mouse models to identify metabolite biomarkers for gallbladder disease. LC-MS-based metabolomics was performed on plasma samples in the discovery cohort (14 healthy controls, 30 GSD, and 56 CaGB). The identified metabolite signature was validated in 45 samples, and the candidate metabolite was further examined using targeted LC-MS in an independent cohort (<i>n</i> = 30). Trimethylamine N-oxide (TMAO) emerged as a significant metabolite that was evaluated in female C57BL/6 mice fed a lithogenic diet. Untargeted metabolomics from the discovery cohort identified 172 significantly altered metabolites (<i>P</i> < 0.05), with a 20-metabolite signature discriminating groups with high accuracy [area under the curve (AUC): GSD 0.98, CaGB 0.93; validation: GSD 0.87, CaGB 0.95]. TMAO was significantly elevated in GSD and CaGB (<i>P</i> < 0.001), with predictive values (AUC: GSD 0.96, CaGB 0.85). Targeted analysis confirmed twofold higher plasma TMAO in patients (<i>P</i> < 0.001). Female C57BL/6 mice fed on lithogenic diet (LD) with 0.3% TMAO (LD + TMAO) showed higher prevalence with early onset at 12 wk. TMAO induced epithelial metaplasia, hyperplasia, and altered mRNA expression of bile acid regulators [ATP-binding cassette subfamily C member 3 (ABCC3), 3 farnesoid X receptor (FXR), and Takeda G protein-coupled receptor 5 (TGR5)] and IL-10. Immunohistochemistry in mouse gallbladder tissue showed increased FXR and reduced TGR5 expression, following TMAO treatment. TMAO is a key metabolite associated with GSD and CaGB. TMAO supplementation with lithogenic diet accelerated gallstone formation, accompanied by preneoplastic changes, and disrupted bile acid regulation.<b>NEW & NOTEWORTHY</b> TMAO as a predictor of gallstone disease and accelerator of gallstone formation.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G140-G154"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148136421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}