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

{"title":"Lymphatic alterations in Crohn's disease: the villain or victim.","authors":"Geoffrey E Hespe, Raghu P Kataru","doi":"10.1152/ajpgi.00134.2025","DOIUrl":"10.1152/ajpgi.00134.2025","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G186-G188"},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958118","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":"Mouse models of eosinophilic esophagitis: molecular and translational insights.","authors":"Jazmyne L Jackson, Abigail J Staub, Annie D Fuller, John M Crespo, Travis H Bordner, Courtney Worrell, No'ad Shanas, Danielle Waheed, Tatiana A Karakasheva, Melanie Ruffner, Amanda B Muir, Kelly A Whelan","doi":"10.1152/ajpgi.00396.2024","DOIUrl":"10.1152/ajpgi.00396.2024","url":null,"abstract":"<p><p>Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease of the esophagus that exerts a significant clinical and financial burden in developed countries. Despite an emerging interest in this disease, the cellular and molecular mechanisms driving EoE pathogenesis remain elusive. Addressing this knowledge gap is critical to guide the development of novel approaches for diagnosis, monitoring, and therapy in patients with EoE. As EoE is an allergic inflammatory disorder that results in esophageal inflammation and tissue remodeling, in vivo studies are critical to develop a better understanding of this disease. Here, we provide a review of murine models of EoE, highlighting the mechanistic and translational insights into EoE pathogenesis and therapeutic approaches that studies using these models have uncovered. We further discuss the strengths and limitations of EoE mouse models, as well as opportunities for future in vivo approaches to study EoE. Overall, this article reviews the progress, challenges, unmet needs, and opportunities in murine modeling of EoE.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G215-G231"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214686","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":"Generation of gastric proton pump <i>atp4a</i> knockouts in <i>Astyanax mexicanus</i>: a fish model for insights into the mechanisms of acidification by oxynticopeptic cells.","authors":"Patrícia G Ferreira, A Wayne Vogl, L Filipe C Castro, Jonathan M Wilson","doi":"10.1152/ajpgi.00382.2024","DOIUrl":"10.1152/ajpgi.00382.2024","url":null,"abstract":"<p><p>The gastric proton pump H⁺/K⁺-ATPase (HKA) is the highly conserved acid secretory mechanism of the gnathostome stomach. HKA is a heterodimeric pump composed of α and β-subunits. In this study, we have explored the involvement of this enzyme in the transcriptional regulation of pathways linked to acid secretion (Cl^- and K⁺ movement across the cell membrane) and peptic digestion (pepsinogens) in the stomach of the teleost <i>Astyanax mexicanus</i>. To this end, we generated the first nonmammalian knockout line for the gastric proton pump, <i>atp4a</i> (HKA-α-subunit), in <i>A. mexicanus</i> using CRISPR-Cas9 gene editing. Homozygous mutant <i>atp4a</i>^-/- fish appeared healthy but were achlorhydric. The transcript and protein levels of the HKA-β-subunit remained unaltered despite the absence of α-subunit protein. Pepsinogen (<i>pga</i> and <i>pgc</i>) transcript levels were reduced, together with <i>kcne2</i>, <i>kcc4</i> (involved in apical K⁺ recycling), and <i>clcn2</i> (involved in the acid-coupled Cl^- secretion mechanism) mRNA levels. The <i>cftr</i> and <i>slc4a2b</i> transcript levels were significantly increased in knockout stomachs. The gastric morphology and cytology of <i>atp4a</i>^-/- characterized through bright-field and electron microscopy show that the lumen of the gastric glands of <i>atp4a</i>^-/- fish was dilated and the oxynticopeptic cells had large cytoplasmic inclusions that were absent in wild-type animals. The tubulovesicular system of knockouts was less developed relative to wild-type animals. Our findings provide novel evidence of the highly conservative nature of the gastric acid-peptic pathways across diverse vertebrates. Furthermore, this work highlights the potential for the use of nontraditional models in biomedical research.<b>NEW & NOTEWORTHY</b> We have knocked out stomach acidification in a nonmammalian gnathostome for the first time using CRISPR-Cas9 gene editing in the teleost fish <i>Astyanax mexicanus</i> targeting the gastric proton pump. This offers a novel and insightful alternative to murine models, having larger offspring numbers, rapid development, and ease of maintenance. In accordance, we present the first demonstration in a knockout animal of how diverse chloride and potassium transporters dynamically respond to-and are directly altered by-acidification.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G88-G101"},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075441","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":"Gly-βMCA modulates bile acid metabolism to reduce hepatobiliary injury in <i>Mdr2</i> KO mice.","authors":"Mohammad Nazmul Hasan, Huaiwen Wang, Wenyi Luo, Yanhong Du, Tiangang Li","doi":"10.1152/ajpgi.00044.2025","DOIUrl":"10.1152/ajpgi.00044.2025","url":null,"abstract":"<p><p>Cholestasis results from impaired bile flow that causes accumulation of hepatic bile acid and injury. Alleviating bile acid hepatobiliary toxicity is a major therapeutic goal in cholestasis. Our recent study revealed a potent anticholestasis effect of glycine-conjugated β-muricholic acid (Gly-βMCA) in <i>Cyp2c70</i> knockout (KO) mice with humanized hydrophobic bile acid composition. To better understand the mechanisms and human relevance of the therapeutic benefits of Gly-βMCA, we investigated the effects of Gly-βMCA on bile acid metabolism and biliary injury in <i>Mdr2</i> KO mice, a cholestasis model with a hydrophilic murine bile acid composition. Gly-βMCA significantly reduced serum alkaline phosphatase (ALP), ductular reaction, and liver cytokine expression in female mice but offered little benefits in male mice. Consistently, Gly-βMCA reduced hepatic bile acids and total bile acid pool size in female but not male mice, due to its ability to promote fecal bile acid excretion. However, the endogenous taurine-conjugated muricholic acid (T-MCA) limited the ability of Gly-βMCA to further enrich the bile acid pool with Gly-βMCA-derived T-βMCA to reduce bile acid hydrophobicity. Overall, Gly-βMCA showed diminished therapeutic efficacy in <i>Mdr2</i> KO mice than <i>Cyp2c70</i> KO mice, which may be due to differences in bile acid hydrophobicity and disease etiology in the two cholestasis models. These findings suggest that the benefits of Gly-βMCA are mediated by its unique pharmacokinetics, which allows for simultaneous reduction of bile acid pool size and hydrophobicity. Gly-βMCA may be a promising therapy for treating human cholestasis, despite its reduced efficacy in improving the toxicity profile of murine bile acid pool.<b>NEW & NOTEWORTHY</b> Gly-βMCA decreases liver injury in female but not male <i>Mdr2</i> KO mice. Gly-βMCA blocks bile acid absorption to reduce bile acid pool in female <i>Mdr2</i> KO mice. Gly-βMCA reduces bile acid hydrophobicity by causing T-βMCA enrichment in bile, but this therapeutic benefit was partially masked by a murine bile acid composition due to abundantly synthesized T-MCA in <i>Mdr2</i> KO mice. Gly-βMCA alleviates bile acid hepatobiliary toxicity by reducing both bile acid pool size and hydrophobicity.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G45-G57"},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148879","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":"Contribution of neuroligin and neurexin alternative splicing to the establishment of enteric neuronal synaptic specificity.","authors":"Fabien D'Autréaux, Alcmène Chalazonitis, Dena Arumugam, Timothy Gershon, Michael D Gershon","doi":"10.1152/ajpgi.00408.2024","DOIUrl":"10.1152/ajpgi.00408.2024","url":null,"abstract":"<p><p>The enteric nervous system (ENS) is unique among components of the peripheral nervous system due to its complexity in structure and neurotransmitter phenotype diversity. In this complexity, the ENS resembles the central nervous system (CNS). Although the ENS is derived from the neural crest rather than the neural tube, similar mechanisms may generate complex connectivity in both the ENS and the CNS. Neuroligins and neurexins are cell adhesion molecules that participate in regulating CNS synaptogenesis. We investigated whether these molecules also play a role in establishing enteric synapses. We found that neuroligins and neurexins were expressed in mouse, rat, and human gut. Transcripts of both types of molecule were extensively spliced in the bowel during fetal and adult life. When transfected into non-neuronal cells, neuroligins and neurexins were sufficient to recruit, respectively, presynaptic and postsynaptic elements. Engineered soluble neurexin, which interferes with endogenous neurexin-neuroligin binding, inhibited enteric synapse formation/stabilization and recruitment of neurotransmitter receptors. Finally, we demonstrated that alternative splicing of neuroligin and neurexin contributes to ENS synaptic specificity. Some isoforms preferentially induced cholinergic synapses, whereas others promoted serotonergic synaptogenesis.<b>NEW & NOTEWORTHY</b> We found that neuroligins and neurexins play roles in establishing ENS synapses. Both are extensively spliced in the fetal and adult gut. When expressed in non-neuronal cells, both neuroligins and neurexins are sufficient to recruit, respectively, presynaptic and postsynaptic elements. Soluble neurexin inhibits enteric synapse formation and recruitment of neurotransmitter receptors by interfering with endogenous neurexin/neuroligin binding. The neurexin/neuroligin splice code contributes physiologically to ENS synaptic specificity, promoting for example, cholinergic or serotonergic synaptogenesis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G140-G158"},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12224031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956343","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":"Glucose metabolism through the hexosamine biosynthetic pathway drives hepatic de novo lipogenesis via promoting <i>N</i>-linked protein glycosylation.","authors":"Yanhui Li, Qing Song, Rui Guo, Yanyu Qian, Yuwei Jiang, Zhenyuan Song","doi":"10.1152/ajpgi.00056.2025","DOIUrl":"10.1152/ajpgi.00056.2025","url":null,"abstract":"<p><p>De novo lipogenesis (DNL) converts excess glucose into lipids, whereas the hexosamine biosynthetic pathway (HBP), a glycolytic branch, generates UDP-<i>N</i>-acetylglucosamine for protein glycosylation, including <i>O</i>-GlcNAcylation and <i>N</i>-linked glycosylation. Both pathways are active in hepatocytes and integral to glucose metabolism; however, their functional interplay remains unclear. Here, we investigated the role of HBP in hepatic DNL activation using both in vitro and in vivo models. AML12 hepatocytes were cultured in low- and high-glucose media with or without HBP blockade, both pharmacologically and genetically. For in vivo studies, male C57BL/6J mice were subjected to a fasting-refeeding regimen with or without intraperitoneal administration of azaserine, a competitive inhibitor of glutamine-fructose-6-phosphate transaminase 1 (GFPT1), the rate-limiting enzyme of the HBP. Our results demonstrated that, in AML12 cells, glucose exposure activated both DNL and HBP, leading to triacylglycerol (TAG) accumulation, whereas HBP inhibition ameliorated DNL and TAG accumulation. In mice, refeeding after a 24-h fasting induced hepatic DNL, which was abolished by HBP inhibition, indicating its mechanistic involvement in glucose-driven lipogenesis. Mechanistically, we identified ATF4 as a key regulator of GFPT1 upregulation under high-glucose conditions. As expected, both glucose-treated hepatocytes and livers from fasting-refed mice exhibited increased protein glycosylation. Notably, blocking <i>N</i>-linked glycosylation, but not <i>O</i>-GlcNAcylation, abolished glucose-induced DNL activation, indicating that HBP is essential for glucose-induced DNL pathway activation via promoting <i>N</i>-linked glycosylation, independent of <i>O</i>-GlcNAcylation. In conclusion, our findings establish that an intact HBP is required for glucose-induced hepatic DNL activation, primarily through promoting protein <i>N</i>-linked glycosylation.<b>NEW & NOTEWORTHY</b> High-glucose exposure activates both hepatic HBP and DNL pathways. The glucose metabolism into HBP is essential for the activation of the DNL pathway. ATF4 activation plays a mechanistic role in high glucose-induced HBP activation. HBP drives high glucose-induced hepatic DNL activation via promoting <i>N</i>-linked protein glycosylation.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G746-G759"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962803","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":"Enteric glia promotes the survival of CD4 and CD8 T cells in plexitis: a new player in Crohn's disease recurrence?","authors":"Catherine Le Berre, Tony Durand, Julie Pabois, Rodrigue Brossaud, Laetitia Aymeric, Michel Neunlist, Arnaud Bourreille, Philippe Naveilhan, Isabelle Neveu","doi":"10.1152/ajpgi.00377.2024","DOIUrl":"10.1152/ajpgi.00377.2024","url":null,"abstract":"<p><p>The accumulation of immune cells in and around enteric ganglia, called plexitis, is associated with postoperative recurrence in Crohn's disease. Interaction between T cells and enteric glia is increased at the proximal resection margin in patients with Crohn's disease who suffer from postoperative recurrence. However, little is known about the T cells that interact with enteric glia and contribute to the formation of plexitis. In this work, the number of CD4 and CD8 T cells interacting with enteric glia was quantified in sections of the proximal (ileal) resection margin of patients with Crohn's disease, and in cocultures prepared with rat and human enteric glia. The molecules implicated in these interactions were investigated, as well as the impact of enteric glia on T cell survival. Analyses indicated that both CD4 and CD8 cells were present and in contact with enteric glia in plexitis in patients with Crohn's disease. In vitro studies demonstrated that the adhesion of both human and rat CD4 and CD8 cells to enteric glia was increased after pretreatment of the glial cells with IL1β/TNFα, and that this adhesion was lymphocyte function-associated antigen 1 (LFA-1)-dependent. The interactions between T cells and enteric glia increased the survival of CD4 and CD8 T cells in an ICAM-1/LFA-1-independent manner. In conclusion, both CD4 and CD8 T lymphocytes are present and in contact with enteric glia in plexitis. The in vitro studies demonstrate that they adhere to human and rat enteric glia through LFA-1 and show that interactions with enteric glia promote their survival, independently of LFA-1.<b>NEW & NOTEWORTHY</b> Both CD4 and CD8 T cells adhere to enteric glial cells in patients with Crohn's disease, contributing to the development of plexitis associated with postoperative recurrence. The adhesion of CD4 and CD8 T cells to enteric glial cells is dependent on ICAM-1/LFA-1. Enteric glial cells promote the survival of CD4 and CD8 T cells independently of ICAM-1/LFA-1.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G861-G871"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075391","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":"Saturated phosphatidic acids induce mTORC1-driven integrated stress response contributing to glucolipotoxicity in hepatocytes.","authors":"Rui Guo, Yanhui Li, Yuwei Jiang, Md Wasim Khan, Brian T Layden, Zhenyuan Song","doi":"10.1152/ajpgi.00027.2025","DOIUrl":"10.1152/ajpgi.00027.2025","url":null,"abstract":"<p><p>Hepatic glucolipotoxicity, characterized by the synergistic detrimental effects of elevated glucose levels combined with excessive lipid accumulation in hepatocytes, plays a central role in the pathogenesis of various metabolic liver diseases. Despite recent advancements, the precise mechanisms underlying this process remain unclear. Using cultured AML12 and HepG2 cells exposed to excess palmitate, with and without high glucose, as an in vitro model, we aimed to elucidate the cellular and molecular mechanisms underlying hepatic glucolipotoxicity. Our data showed that palmitate exposure induced the integrated stress response (ISR) in hepatocytes, evidenced by increased eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation (serine 51) and upregulated activating transcription factor 4 (ATF4) expression. Moreover, we identified mammalian target of rapamycin complex 1 (mTORC1) as a novel upstream kinase responsible for palmitate-triggered ISR induction. Furthermore, we showed that either mTORC1 inhibitors, ISRIB (an ISR inhibitor), or ATF4 knockdown abolished palmitate-induced cell death, indicating that the mTORC1-eIF2α-ATF4 pathway activation plays a mechanistic role in mediating palmitate-induced hepatocyte cell death. Our continuous investigations revealed that glycerol-3-phosphate acyltransferase (GPAT4)-mediated metabolic flux of palmitate into the glycerolipid synthesis pathway is required for palmitate-induced mTORC1 activation and subsequent ISR induction. Specifically, we uncovered that saturated phosphatidic acid production contributes to palmitate-triggered mTORC1 activation. Our study provides the first evidence that high glucose enhances palmitate-induced activation of the mTORC1-eIF2α-ATF4 pathway, thereby exacerbating palmitate-induced hepatotoxicity. This effect is mediated by the increased availability of glycerol-3-phosphate, a substrate essential for phosphatidic acid synthesis. In conclusion, our study highlights that the activation of the mTORC1-eIF2α-ATF4 pathway, driven by saturated phosphatidic acid overproduction, plays a mechanistic role in hepatic glucolipotoxicity.<b>NEW & NOTEWORTHY</b> Integrated stress response (ISR) activation contributes to palmitate-induced lipotoxicity in hepatocytes. mTORC1 acts as an upstream kinase essential for palmitate-mediated ISR activation and hepatocyte death. The formation of saturated phosphatidic acid mechanistically regulates hepatic mTORC1 activation induced by palmitate. Glucose-enhanced generation of saturated phosphatidic acid amplifies palmitate-induced hepatotoxicity, contributing to glucolipotoxicity.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"328 6","pages":"G663-G676"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963869","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":"Indole-3-propionic acid protects medium-diversity colitic mice via barrier enhancement preferentially over anti-inflammatory effects.","authors":"Kristoff M Nieves, Kyle L Flannigan, Elizabeth Hughes, Matthew Stephens, Andrew J Thorne, Ameline Delanne-Cuménal, Kathryn Strayer, Darasimi Kola-Ilesanmi, Senya Wickramasinghe, Niloofar Mirzadzar, Grace Baruta, Braedon McDonald, Eduardo R Cobo, Björn Petri, Sridhar Mani, Simon A Hirota","doi":"10.1152/ajpgi.00256.2024","DOIUrl":"10.1152/ajpgi.00256.2024","url":null,"abstract":"<p><p>Metabolites generated from the intestinal microbiota regulate local and distant tissues. One important metabolite generated from l-tryptophan is indole-3-propionic acid (IPA), which has been shown previously to regulate intestinal mucosal homeostasis in specific pathogen-free (SPF)-colonized animals through distinct receptor-mediated events. Interestingly, IPA levels are reduced in patients with inflammatory bowel disease (IBD). In the current study, we assessed whether IPA could improve colitis outcomes in the absence of its production by the microbiota. To do this, colitis was induced by dextran sulfate sodium (DSS) in gnotobiotic mice colonized with the 12-member stable defined moderately diverse microbiota mouse 2 (sDMDMm2) microbial consortium, which lacks the genes required for IPA generation. We found that these mice were exquisitely sensitive to DSS compared with SPF-colonized mice. However, IPA treatment significantly increased survival. Infiltrating immune cells in the colon were not altered by IPA treatment nor were there any remarkable changes in local and systemic inflammatory mediator levels. Nevertheless, IPA treatment changed the composition of the fecal microbiota and enhanced intestinal barrier function, demonstrated by a reduction in FITC-dextran flux and retainment of a bioluminescent <i>Escherichia coli</i> within the lumen of colitic mice. Together, our data suggest that IPA treatment in the context of its systemic depletion enhances barrier function and enhances survival in the presence of established inflammation. These data support continued assessment of IPA as a potential treatment for IBD.<b>NEW & NOTEWORTHY</b> Indole-3-propionic acid (IPA) is a metabolite produced by the intestinal microbiota that has been shown to elicit beneficial effects in the gastrointestinal (GI) tract that include regulating intestinal barrier function, reducing inflammation, and controlling immune responses that lead to fibrosis. In patients with inflammatory bowel disease (IBD), IPA levels are reduced. In the current study, we found that treating mice with IPA at the peak of intestinal inflammation improved clinical outcomes and disease.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G696-G715"},"PeriodicalIF":3.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955608","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":"Functional roles of interstitial cells of Cajal in the GI tract of rats.","authors":"Sung Jin Hwang, Joong Goo Kwon, Elizabeth A H Beckett, Minkyung Kim, Tom Herbert, Kenton M Sanders, Sean M Ward","doi":"10.1152/ajpgi.00036.2025","DOIUrl":"10.1152/ajpgi.00036.2025","url":null,"abstract":"<p><p>Interstitial cells of Cajal (ICC) are distributed through the gastrointestinal (GI) tract, but the functional role of these cells comes primarily from studies of mice. Whether the functions of ICC are similar in larger animals is largely speculative. We investigated whether the <i>Kit</i> mutation in <i>Ws/Ws</i> rats had consequences on ICC populations in the stomach, small intestine, and colon and whether loss of ICC resulted in functional defects similar to <i>Kit</i> mutations in mice. Immunohistochemical labeling with c-KIT or ANO1 antibodies revealed loss of intramuscular ICC (ICC-IM) and reduced myenteric ICC (ICC-MY) in the stomachs of <i>Ws/Ws</i> mutants. Disruption of ICC-MY networks but not ICC within the deep muscular plexus (ICC-DMP) was observed in the small intestine. ICC in the proximal colon was reduced, but no population was absent. ICC loss in the stomach caused loss of spontaneous transient depolarizations, reduced pacemaker activity, and reduced responses to cholinergic and nitrergic nerve stimulation. Loss of ICC-MY in the small intestine resulted in abnormal pacemaker activity, but neural responses appeared to be normal. In the proximal colon, tonic inhibition due to ongoing nitrergic neural inputs was reduced, spontaneous spike complexes were less rhythmic, and nitrergic neural responses were reduced. Apamin-sensitive inhibitory neural responses were retained throughout the GI tract. In summary, <i>Ws/Ws</i> rats have lesions in ICC and functional deficits similar to, but not identical to, <i>Kit</i> mutant mice. These larger animals with more robust GI muscles may be useful for investigations into the role of ICC in normal and abnormal GI motility.<b>NEW & NOTEWORTHY</b> The physiological roles of interstitial cells of Cajal (ICC) throughout the gastrointestinal (GI) tract have been derived predominantly from studies of mice. We sought to determine whether reduction in ICC in the rat, a commonly used animal for studies of GI motor functions, leads to functional deficits. <i>Ws/Ws</i> rats display reduced ICC leading to a disruption in pacemaker activity and neuroeffector responses. Our results provide additional evidence for the functions of ICC in the GI tract.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"328 6","pages":"G677-G695"},"PeriodicalIF":3.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961356","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}