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

{"title":"Dissecting neuromuscular transmission in the gastrointestinal tract: from single cell RNA analysis to function and pharmacology.","authors":"Pere Guzman, Mihaela Penchova, Patri Vergara, Marcel Jimenez","doi":"10.1152/ajpgi.00434.2025","DOIUrl":"https://doi.org/10.1152/ajpgi.00434.2025","url":null,"abstract":"<p><p>Gastrointestinal (GI) motility is coordinated by multiple neurotransmitter systems acting on distinct post-junctional cells within the smooth muscle-interstitial cell-PDGFRα⁺ (SIP) syncytium. This study integrates physiological, pharmacological, and single-cell transcriptomic data to define the cellular mechanisms underlying inhibitory and excitatory neuromuscular transmission in the human colon. Inhibitory signaling involves purinergic (P2Y₁) and adrenergic (α₁A) receptors, which activate SKCa channels in PDGFRα⁺ cells, while nitrergic (nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP) pathways are primarily mediated by interstitial cells of Cajal (ICCs) and smooth muscle cells (SMCs). VIPergic signaling also contributes to relaxation through cAMP-dependent mechanisms possibly located in PDGFRα⁺ cells. Excitatory transmission is mainly driven by muscarinic M3 and M2 receptors expressed in ICCs and SMCs, leading to calcium-dependent contractions. Pharmacologically, hyoscine butylbromide (HBB) reduces acetylcholine (ACh)-induced contractions by blocking M2/M3 receptors, whereas neostigmine enhances cholinergic transmission to restore motility. Blockade of voltage-gated calcium channels (Cav1.2, CACNA1C) by agents such as otilonium bromide further contributes to spasmolytic effects. These findings provide an integrated framework linking receptor expression, cellular mechanisms, and drug actions that modulate GI motility.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832704","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":"Lactotransferrin reduction as a target mechanism of postnatal intestinal vulnerability in murine preeclampsia models.","authors":"Tomohiro Ohtani, Mari Ichinose, Takayuki Iriyama, Miho Irie, Yu Ariyoshi, Eriko Yano, Seisuke Sayama, Nobumi Suzuki, Yoku Hayakawa, Keiichi Kumasawa, Takeshi Nagamatsu, Miyuki Harada, Yasushi Hirota","doi":"10.1152/ajpgi.00401.2025","DOIUrl":"https://doi.org/10.1152/ajpgi.00401.2025","url":null,"abstract":"<p><p>Fetal growth restriction (FGR) and preeclampsia (PE) are associated with placental insufficiency. Although FGR increases the risk of postnatal intestinal disorders, the mechanisms by which intrauterine stress causes these disorders and the intestinal alterations underlying their pathogenesis remain unclear. In this study, we investigated the underlying molecular mechanisms and potential preventive strategies. Pregnant mice were administered angiotensin II or recombinant soluble fms-like tyrosine kinase-1 to induce PE with FGR. Offspring intestines were collected on embryonic day 18.5 for RNA sequencing and on postnatal days (P) 7 and 21 for histological analyses. At P21, enteritis was induced using lipopolysaccharide and platelet-activating factors. Offspring from the PE model (PE offspring) exhibited shorter intestinal lengths and fewer secretory cells than the controls. RNA sequencing identified 226 differentially expressed genes, with lactotransferrin (<i>Ltf</i>), a protective secretory protein, downregulated in PE offspring. Immunohistochemistry demonstrated increased epithelial Ltf expression from P7 to P21, which was impaired in PE offspring. Following enteritis induction, the PE offspring showed increased severity, which was markedly mitigated by prophylactic LTF supplementation. These findings highlight the importance of risk-based preventive strategies for postnatal intestinal disorders in infants exposed to placental insufficiency-induced intrauterine stress.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832839","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":"Fibroblast-specific <i>Gpx4</i> deletion exacerbates IBD via lipid peroxidation.","authors":"Yuezhong Zhang, Yinzhi Ying, Wesley Huang, Zoe A Rosenfeld, Marwa O El-Derany, Zheng Hong Lee, Cristina Castillo, Tae Gyu Oh, Joel K Greenson, Yatrik M Shah","doi":"10.1152/ajpgi.00387.2025","DOIUrl":"10.1152/ajpgi.00387.2025","url":null,"abstract":"<p><p>Broad antioxidant strategies in inflammatory bowel disease (IBD) have had limited success, likely because they indiscriminately quench both harmful and physiological reactive oxygen species. In our recent work, we demonstrated that fibroblast-specific overexpression of acyl-CoA synthetase long-chain family member 4 reprogrammed lipid metabolism and sensitized adjacent epithelial cells to ferroptosis in IBD models, pointing to heterocellular lipid cross talk as a driver of epithelial injury. Building on that insight, here we test the hypothesis that fibroblast glutathione peroxidase 4 (GPX4), a key enzyme detoxifying lipid hydroperoxides, is critical in restraining fibroblast-mediated lipid peroxidation and consequent epithelial ferroptosis during colitis. We generated tamoxifen-inducible fibroblast-specific GPX4 knockout mice and subjected them to acute dextran sulfate sodium (DSS) colitis. Fibroblast-specific GPX4 deletion did not alter basal colon morphology but significantly aggravated DSS-induced injury. It increased histological scores and led to greater weight loss and colon shortening compared with littermate control mice. In vitro, GPX4-deficient fibroblasts exhibited elevated lipid peroxidation in response to ferroptosis inducers, reversible by liproxstatin-1. Critically, liproxstatin-1 treatment rescued colitis severity in fibroblast-GPX4-deficient animals, restoring colon length, weight loss, and histologic injury. Together, these findings identify fibroblast GPX4 as a gatekeeper that limits stromal lipid peroxidation and suppresses epithelial ferroptosis under inflammatory stress. Targeting fibroblast-mediated lipid peroxidation may offer a refined therapeutic axis in IBD.<b>NEW & NOTEWORTHY</b> Fibroblast-specific GPX4 deletion promotes IBD progression. Lipid peroxidation could be a potential therapeutic target of IBD.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G591-G600"},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643630","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":"Fecal DPP4 concentration reflects colonic injury in the TNBS-induced rat model of colitis.","authors":"Sandra F Gomes, Mariana Ferreira-Duarte, Patrícia Dias-Pereira, Joana Couto, Margarida Duarte-Araújo, Manuela Morato, Fernando Magro","doi":"10.1152/ajpgi.00030.2026","DOIUrl":"10.1152/ajpgi.00030.2026","url":null,"abstract":"<p><p>Dipeptidyl peptidase 4 (DPP4) is involved in intestinal homeostasis and immune regulation. However, its distribution across biological matrices during intestinal inflammation remains poorly characterized. This study investigated DPP4 concentrations in feces, colonic tissue, and serum in a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced rat model of colitis and assessed host and/or microbiota contribution to fecal DPP4 in knockout and germ-free mice. Colitis was induced in male Wistar rats by intrarectal administration of an ethanolic solution of TNBS. Disease severity was assessed using clinical evaluation, macroscopic scoring, and histopathological indices. DPP4 concentrations were quantified by ELISA in serum, proximal and distal colonic tissue, luminal content, and cage-collected feces. Colonic DPP4 location was assessed by immunohistochemistry. To explore host and microbiota contributions, fecal DPP4 concentration was also measured in DPP4 knockout and germ-free mice. TNBS-induced colitis resulted in regionally heterogeneous inflammation, predominantly affecting the distal colon. In healthy rats, colonic DPP4 showed a proximal-to-distal gradient that was lost during inflammation. Fecal DPP4 concentrations were significantly increased in TNBS-treated animals, exhibited a proximal-to-distal increase, and reached highest levels in cage fecal pellets. Fecal DPP4 correlated with macro- and microscopic scores and with distal colonic DPP4 levels, whereas serum DPP4 did not differ between groups. Fecal DPP4 levels were reduced in DPP4 knockout and germ-free mice, suggesting a modulation of fecal DPP4 by a host-microbiota cross talk. DPP4 distribution is context- and matrix-dependent. Fecal DPP4 reflects regional and histological features of experimental colitis, by integrating local intestinal injury with luminal shedding.<b>NEW & NOTEWORTHY</b> This study broadens current views of DPP4 in intestinal inflammation by showing that its regulation extends beyond tissue and circulation into the intestinal lumen. By mapping DPP4 across colonic regions and biological compartments in experimental colitis, we highlight feces as a window into spatial features of mucosal injury and into host-microbiota influences on enzyme regulation during intestinal inflammation.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G645-G656"},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147637910","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":"Single-cell transcriptomics reveals that air-liquid interface culture promotes goblet cell differentiation and inhibits glycolysis in organoid cell monolayers.","authors":"Tania Malonga, Emeline Lhuillier, Christelle Marrauld, Deborah Fourmy, Elodie Riant, Cedric Cabau, Nathalie Vialaneix, Martin Beaumont","doi":"10.1152/ajpgi.00251.2025","DOIUrl":"10.1152/ajpgi.00251.2025","url":null,"abstract":"<p><p>Faithfully recapitulating the cellular heterogeneity of the intestinal epithelium is essential when using organoid models. Air-liquid interface (ALI) culture has been shown to promote secretory cell differentiation, but its impact on gene expression in each epithelial cell type remains unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize the cellular heterogeneity of rabbit cecum-derived organoid monolayers grown under immerged or ALI conditions. We then compared these organoid cell type-specific gene expression profiles to a scRNA-seq atlas of the rabbit cecal epithelium in vivo. We selected the rabbit model notably because, unlike mice, it possesses BEST4⁺ epithelial cells, a newly discovered subset of mature absorptive cells. Our analysis revealed a high degree of transcriptomic similarity between in vivo and organoid-derived stem and transit-amplifying cells. ALI culture markedly enhanced the differentiation of the secretory lineage, especially goblet cells, whose transcriptome closely resembled that of in vivo goblet cells. Furthermore, ALI was the only condition allowing the detection of enteroendocrine cells. BEST4⁺ cells, however, were absent from organoids in immerged or ALI conditions despite their presence in vivo. In addition, ALI culture led to a consistent downregulation of hypoxia and glycolysis-associated genes across all cell types, which suggests a metabolic shift likely driven by increased oxygen availability in ALI conditions. Cell-cell communication analyses further indicated that ALI more closely mirrored in vivo patterns than immerged condition. Altogether, these results demonstrate that ALI culture allows for better recapitulation of the in vivo cellular heterogeneity and molecular signatures of the intestinal epithelium.<b>NEW & NOTEWORTHY</b> Using single-cell RNA sequencing, this study shows that air-liquid interface (ALI) culture enhances secretory lineage differentiation of intestinal organoid cell monolayers and improves transcriptomic similarity to the native epithelium. ALI reduced hypoxia-associated gene expression and better recapitulates in vivo-like cell-cell interactions, supporting its value for modeling intestinal epithelial heterogeneity in organoids.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G513-G531"},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147455262","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":"Improvement of glucose homeostasis during leptin treatment does not alter the intestinal microbiome in male diabetic UC Davis type-2 diabetes mellitus rats.","authors":"Manuel Martínez-Ruiz, Leslie Tabor-Simecka, James L Graham, Christopher Randolph, Renee Fox, Renny Lan, Lindsay Pack, Tanya LeRoith, Kimber L Stanhope, Laxmi Yeruva, Peter J Havel, Brian D Piccolo","doi":"10.1152/ajpgi.00412.2025","DOIUrl":"10.1152/ajpgi.00412.2025","url":null,"abstract":"<p><p>Gut dysbiosis contributes to type 2 diabetes mellitus (T2DM) progression according to the preclinical evidence. Alterations in gut microbiome, energy metabolism, and barrier function were observed in individuals with obesity and insulin resistance. However, it remains unclear whether therapeutic interventions can reverse these alterations. This study aimed to evaluate whether improvements of glucose homeostasis resulting from leptin administration can lead to changes in colonic epithelial metabolism and barrier function in male UC Davis type 2 diabetic mellitus (UCD-T2DM) rats. Male UCD-T2DM rats (age: 173 ± 41 days) with 6 wk postonset of diabetes were randomized to receive daily subcutaneous injections of either phosphate buffer solution (control; <i>n</i> = 12) or recombinant leptin (0.5 mg/kg; <i>n</i> = 12) for 4 wk. Metabolic and intestinal outcomes were assessed, including glucose tolerance, insulin sensitivity, glucagon-like protein 1 levels, gut permeability, microbiota composition, short-chain fatty acids content, colon epithelial hypoxia, intestinal morphology, and gene/protein expression. Leptin treatment significantly reduced food intake and improved glucose homeostasis and insulin sensitivity without affecting body weight. No changes were observed in microbiome composition, gut permeability, or colon epithelial hypoxic gradients. Ileal villus height was decreased, whereas colonic crypt depth was not different between leptin-treated rats and control rats. Butyric, isocaproic, and valeric acids levels were increased in colonic content, colonic gene expression of <i>Pparg</i> and <i>Ldha</i> was downregulated, whereas PHD2 and Occludin protein levels were upregulated in leptin-treated compared with control. Despite improvements of glucose homeostasis, chronic leptin treatment did not modify gut microbiota or barrier function markers and colonic metabolic gene expression showed no clear adaptive shift.<b>NEW & NOTEWORTHY</b> Our data indicate that chronic administration of recombinant leptin in diabetic UCD-T2DM rats does not change the gut microbiome, despite improvements in food intake, glucose homeostasis, and insulin sensitivity.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G549-G564"},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13104595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508816","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":"Regulatory T cells are induced by gut microbiota through differentially regulating costimulatory molecules of enteric glial cells.","authors":"Jiahui Yang, Qishan Zeng, Min Zou, Jiao Nie, Huatian Gan","doi":"10.1152/ajpgi.00032.2025","DOIUrl":"10.1152/ajpgi.00032.2025","url":null,"abstract":"<p><p>Probiotics have been proven to be effective in inducing and maintaining remission of inflammatory bowel disease (IBD). However, their precise mechanisms remain unclear. Interactions between the gut microbiota and enteric glial cells (EGCs) have gained increasing attention. We aimed to investigate whether and how <i>Bifidobacterium longum</i> (B.l), as a typical probiotic, exerts anti-inflammatory effects by acting on EGCs. Herein, we demonstrate that EGCs possess bacterial phagocytosis and antigen-presenting functions, and their costimulatory molecule expression is differentially regulated by bacteria. Specifically, B.l significantly upregulates EGC expression of programmed death-ligand 1 (PD-L1), while enterohemorrhagic <i>Escherichia coli</i> (EHEC) markedly increases CD86 expression. B.l ameliorates dextran sulfate sodium (DSS)-induced experimental colitis by activating the p38 MAPK signaling pathway, upregulating PD-L1 expression in EGCs, and inducing the conversion of CD4⁺ cells into regulatory T (Treg) cells through the PD-L1/PD-1 pathway. This process promotes Treg cell expansion, inhibits pathogenic T-helper type 17 (Th17) cells, increasing IL-10 production, and reduces TNF-α and IL-1β production. Notably, ablation of EGCs significantly diminishes the efficacy of B.l in alleviating experimental colitis. In conclusion, our findings suggest that B.l induces the conversion of CD4⁺ cells into Treg cells by acting on EGCs and alleviating intestinal inflammation. These findings support the notion that EGCs are not only neural cells but also potential immune cells, which exert immune regulatory functions depending on the type of bacteria and which signaling molecules are being expressed. This study provides new data for elucidating the mechanisms of probiotics in the treatment of IBD.<b>NEW & NOTEWORTHY</b> The interactions between gut microbiota and enteric glial cells (EGCs) are increasingly recognized. This study reveals that EGCs possess bacterial phagocytosis and antigen-presentation functions, which are modulated differently by various bacteria. Specifically, <i>Bifidobacterium longum</i> (B.l) relieves DSS-induced colitis by enhancing PD-L1 expression on EGCs and promoting Treg cell differentiation through EGC-mediated immune regulation. Understanding the dual role of EGCs as both neural and immune cells expands our comprehension of gut microbiota-neural-immune interaction in intestinal health.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G532-G548"},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224750","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":"TNF-α alters dedifferentiation of enterochromaffin cells, redirecting toward neuroendocrine tumors.","authors":"Yoshitatsu Sei, Jianying Feng, Xilin Zhao, Stephen A Wank","doi":"10.1152/ajpgi.00407.2025","DOIUrl":"10.1152/ajpgi.00407.2025","url":null,"abstract":"<p><p>Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting, well-differentiated neuroendocrine tumors of enterochromaffin (EC) cell origin. However, EC cell-derived tumorigenesis remains poorly understood. Prior studies using TPH1 Cre-ERT2-driven RPM mice [EC cell-targeted RB1 (R) and Trp53 (P) loss and Myc (M) gain] showed nonendocrine adenocarcinomas in the small intestine through dedifferentiation of EC cells to intestinal stem cells, which are prone to transformation. However, these studies were limited by early death from tumors at other sites, leaving the potential for SI-NET development unclear over longer periods. To circumvent this time-limited off-target effect, the present study used intestinal enteroids from RPM mice to examine the effect of RB1 and Trp53 loss with or without gain of Myc function on EC cell-derived tumors. Initial results confirmed the previous in vivo induction of nonendocrine adenoma/adenocarcinoma. However, the addition of TNF-α to the enteroid media induced EC cell clusters in multiple crypts and well-differentiated neuroendocrine tumor versus carcinoma in the absence and presence of gain of Myc function, respectively. These findings suggest that TNF-α blocked EC cell dedifferentiation to intestinal stem cells, promoting their survival and expansion and shifting their fate from intestinal adenoma/carcinoma to a differentiated neuroendocrine tumor type. The present study thus highlights the crucial role of the microenvironment in influencing EC cell-derived tumorigenesis and provides insights into SI-NET development.<b>NEW & NOTEWORTHY</b> Small intestinal neuroendocrine tumors are of putative enterochromaffin (EC) cell origin and are the most common malignancy in the small intestine. However, the tumorigenesis of these specified tumor types remains poorly understood. The present organoid studies show that the addition of TNF-α to the microenvironment maintains the specificity of EC cells during their transformation to neuroendocrine tumors while blocking their dedifferentiation to ISC-derived adenomas.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G581-G590"},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147572120","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":"Measuring autonomic influence on gastrointestinal contractility: development and preliminary validation of novel capsule-based indices.","authors":"Mitali Mehta, Zhan Zhao, Asala Erekat, Jack Semler, Niyati Neupane, Bridget R Mueller, Kaitlyn Coyle, Gabriela Cedillo, Jessica Robinson-Papp","doi":"10.1152/ajpgi.00006.2026","DOIUrl":"10.1152/ajpgi.00006.2026","url":null,"abstract":"<p><p>The migrating motor complex (MMC) is a key feature of fasting gastrointestinal (GI) motility, but its disruption in neuropathic conditions remains poorly characterized. Wireless motility capsules (WMCs) offer a noninvasive means of collecting motility data, facilitating study of larger cohorts. We aimed to develop WMC-derived metrics to identify neuropathic dysmotility and its associations with autonomic nervous system (ANS) function. We analyzed WMC data from 98 controls and 71 people living with human immunodeficiency virus (HIV; PWH) in whom autonomic neuropathy (AN) and delayed small bowel transit time (dSBTT) are common. We studied nine contractility metrics, including established and novel metrics targeting rhythmic bursts of sustained contractile activity. Autonomic function, summarized as Modified Composite Autonomic Severity Score (MCASS), was used to draw associations with contractility measures. All contractility metrics were higher in PWH compared with controls (<i>P</i> ≤ 0.01 for all). Among PWH, those with AN showed the highest contractility, whereas those with dSBTT had the lowest. In controls, rhythmic bursts were more clustered, especially in the later portions of the small bowel recording, and had less variability in contraction amplitude and timing, potentially indicating greater organization. Overall, worse autonomic function was associated with higher contractility. WMC-derived metrics effectively capture fasting small bowel motility and may distinguish neuropathic patterns, which appear to progress from increased, disorganized contractility to decreased contractility as dSBTT develops. Future studies should validate these findings in other WMCs and populations to clarify their potential in advancing understanding of the pathophysiology of gut-brain-axis disorders.<b>NEW & NOTEWORTHY</b> This study introduces novel WMC-derived contractility indices to quantify gastrointestinal motility, enabling noninvasive characterization of neuropathic dysmotility. In PWH, hypercontractility and disorganized rhythmic bursts were observed despite autonomic neuropathy and delayed transit, suggesting a spectrum in which inefficient high-amplitude contractions initially may preserve transit before progressive delay ensues. Leveraging raw pressure data from WMC technology, these indices are linkable to extrinsic autonomic biomarkers and may advance understanding of gut-brain axis disorder pathophysiology.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G633-G644"},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13150863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669831","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":"Site-specific bidirectional regulation of <i>Fgf15</i> transcription in the mouse ileum.","authors":"Takeshi Katafuchi, Akira Honda, Makoto Makishima","doi":"10.1152/ajpgi.00026.2026","DOIUrl":"10.1152/ajpgi.00026.2026","url":null,"abstract":"<p><p>Fibroblast growth factor 15 (FGF15) plays a crucial role in the negative feedback loop of bile acid (BA) production by reducing mRNA levels of hepatic <i>Cyp7a1</i>, a rate-limiting enzyme of BA synthesis. Here, we investigated the postprandial regulation of <i>Fgf15</i> mRNA levels in the ileum to unveil the physiological regulation of FGF15 production by feeding in mice. The postprandial <i>Fgf15</i> mRNA level reached the minimum level in the distal ileum following starvation for 20 h and subsequent feeding for 3 h. In mice lacking tauro-β-muricholic acid, which is an endogenous antagonist for the farnesoid-X-receptor (FXR), the <i>Fgf15</i> mRNA level in the distal ileum was still 3 h-postprandially reduced. We further explored the postprandial regulation of <i>Fgf15</i> transcription in various sites of the ileum and found that the 3 h-postprandial <i>Fgf15</i> levels were reduced in the distal ileum while elevated in the proximal ileum. Furthermore, the 3 h-postprandial plasma FGF15 level was reduced despite the elevated <i>Fgf15</i> mRNA level in the proximal ileum. In mice lacking <i>Fxr</i> in the intestine, the relative amount of 3 h-postprandial <i>Fgf15</i> mRNA level was still reduced in the distal ileum, whereas the 3 h-postprandial elevation was blunt in the proximal ileum. Oral administration of soybean oil, fatty acids, and PPARγ agonist pioglitazone reduced <i>Fgf15</i> expression in the distal ileum, indicating that PPARγ signaling is involved in the negative regulation of <i>Fgf15</i> mRNA level. Collectively, our data show the complicated regulation of plasma FGF15 concentration by bidirectional change in <i>Fgf15</i> mRNA levels by food intake in different sites of the ileum.<b>NEW & NOTEWORTHY</b> It is considered that feeding stimulates the release of bile acids, which ultimately bind to FXR to increase the <i>Fgf15</i> transcription in the ileum. However, we found that <i>Fgf15</i> mRNA levels were postprandially reduced, particularly in the distal ileum, and this reduction was mediated through fatty acid-PPARγ signaling. In the proximal ileum, however, we observed that <i>Fgf15</i> mRNA levels were postprandially elevated through bile acid-FXR signaling, which was consistent with the current idea.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G601-G614"},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147697198","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}