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

{"title":"Fecal microbiota transplantation mitigates cardiac remodeling and functional impairment in mice with chronic colitis.","authors":"Xiaoying S Zhong, Kevin M Lopez, Max Liu, Ying Xiao, Rongliwen Ou, Thierry Kochkarian, Don W Powell, Ken Fujise, Qingjie Li","doi":"10.1152/ajpgi.00324.2025","DOIUrl":"10.1152/ajpgi.00324.2025","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the intestines accompanied by profound extraintestinal manifestations. Although IBD shows a clear clinical association with cardiovascular derangements, whether and how chronic colitis impairs heart function remains unclear. To address this gap, we investigated the impact of chronic colitis on cardiac performance and the cardiac transcriptome using two mouse models: dextran sodium sulfate (DSS)-treated and <i>Il10^-/-</i> mice. Heart function was assessed by echocardiography and molecular characterization was performed using RNA-sequencing (RNA-Seq), reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), and Western blot. Both models exhibited significant functional cardiac impairment, characterized by reduced ejection fraction and fractional shortening along with histologically evident increase in collagen deposition, inflammation, and myofibril reorganization. Molecular analyses revealed a profibrotic cardiac environment. RNA sequencing unveiled a shared upregulation of eicosanoid-associated and inflammatory genes (<i>Cyp2e1</i>, <i>Map3k6</i>, <i>Pck1</i>, and <i>Cfd</i>) across both models, alongside model-specific alterations in pathways governing cAMP and cGMP signaling, arachidonic and linoleic acid metabolism, and immune cell responses. DSS colitis caused differential regulation of 232 cardiac genes, whereas <i>Il10^-/-</i> colitis yielded 105 dysregulated genes. Notably, reconstitution of a healthy balance of gut microbiota by therapeutic fecal microbiota transplantation (FMT), validated using quantitative polymerase chain reaction (qPCR), successfully rescued heart function and mitigated fibrosis in both models. However, <i>Il10^-/-</i> mice demonstrated relatively less cardiac recovery following FMT, highlighting interleukin-10 (IL-10)'s cardioprotective and anti-inflammatory contribution. Collectively, these findings provide evidence that chronic colitis impairs heart function, offer novel insights into colitis-induced cardiac remodeling, and suggest that FMT mitigates cardiac dysfunction by correcting gut dysbiosis, attenuating systemic inflammation, and reestablishing homeostasis along the gut-heart axis.<b>NEW & NOTEWORTHY</b> Inflammatory bowel disease (IBD) extends beyond the gut, as chronic inflammation and microbiota dysbiosis contribute to serious extraintestinal complications. This study demonstrates that chronic colitis induces cardiac remodeling and dysfunction in two mouse models, marked by reduced cardiac performance, fibrosis, and upregulated fibrotic and inflammatory genes. Importantly, fecal microbiota transplantation (FMT) alleviated cardiac injury, highlighting its therapeutic potential. These findings reveal FMT as a promising therapy against chronic inflammation contributing to cardiovascular complications in IBD.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G565-G580"},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147572087","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":"Inhibiting VTCN1 overcomes immunosuppression in colorectal cancer to activate T cells via galectin-3.","authors":"Zhihai Wu, Jiayi Zhong, Chengcheng Xu, Chengkuan Zhao, Qin Yang, Lili Zhao, Chaoxian Lin, Shuyao Zhang, Junyong Zhong","doi":"10.1152/ajpgi.00323.2025","DOIUrl":"10.1152/ajpgi.00323.2025","url":null,"abstract":"<p><p>Colorectal cancer (CRC) continues to be a major cause of cancer-related death globally, largely due to mechanisms of immune evasion that drive treatment resistance. Although multidisciplinary care has improved outcomes, how immune checkpoint molecules, particularly V-set domain-containing T-cell activation inhibitor 1 (VTCN1) and galectin-3, drive immunosuppression in CRC remains incompletely defined. In this study, we used an integrated multi-omics framework combining single-cell sequencing, transcriptomics, and proteomics to delineate the VTCN1-galectin-3 axis in CRC. We then validated its functional relevance using the VTCN1 inhibitor SGN-B7H4 in vitro and in vivo by assessing T cell function and tumor progression. Our results show that inhibiting VTCN1 markedly downregulates galectin-3 expression in T cells (<i>P</i> < 0.01), promoting T cell activation, as reflected by a 42% increase in CD25+CD69+ populations. Consequently, CRC cell proliferation was reduced by 58%, migration by 72% in scratch assays, and invasion by 65% in Transwell assays. In mouse models, SGN-B7H4 administration suppressed tumor growth by 63% relative to controls. These outcomes identify the VTCN1-galectin-3 axis as a pivotal mediator of immune suppression in CRC and highlight the therapeutic promise of targeting this pathway. Our work underscores the potential of VTCN1 inhibitors as part of combined treatment modalities, especially for immunotherapy-resistant CRC.<b>NEW & NOTEWORTHY</b> This study identifies the V-set domain-containing T-cell activation inhibitor 1 (VTCN1)-galectin-3 axis as a key immunosuppressive pathway in colorectal cancer (CRC). We show that inhibiting VTCN1 downregulates galectin-3 in T cells, reversing their dysfunction and reactivating antitumor immunity. Therapeutically, the VTCN1 inhibitor SGN-B7H4 restricted tumor progression by enhancing T-cell activity and impairing cancer cell proliferation, migration, and invasion. These findings reveal a novel immune checkpoint mechanism and establish VTCN1 as a promising target to overcome immunotherapy resistance in CRC.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G615-G632"},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147347126","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":"Panaxynol mitigates chemotherapy-induced intestinal mucositis by improving the colonic microenvironment in murine models.","authors":"Brooke M Bullard, Brandon N VanderVeen, Thomas D Cardaci, Sierra J McDonald, Arianna V Bastian, Nathaniel B Willis, Mingming Xu, Jie Li, Joseph F Pierre, Lorne J Hofseth, Daping Fan, E Angela Murphy","doi":"10.1152/ajpgi.00035.2026","DOIUrl":"https://doi.org/10.1152/ajpgi.00035.2026","url":null,"abstract":"<p><p>Chemotherapy-induced mucositis (CIM) is a debilitating side-effect impacting as many as 90% of cancer patients undergoing treatment. Patients receiving 5-Fluorouracil (5FU), a first-line chemotherapeutic in colorectal cancer, experience significant gastrointestinal distress that perpetuates poor patient quality of life and reduces treatment tolerance, efficacy, and survival. Natural compounds have shown promise in improving CIM through their pleiotropic actions, including immune and mucosal regulation. We examined whether panaxynol, a bioactive compound isolated from American ginseng, can alleviate murine CIM symptomology and severity. Intestinal mucositis was induced in C57BL/6J male and female mice by 5 consecutive intraperitoneal injections of 5FU (35 mg/kg/day); PBS was used as the control. Vehicle or panaxynol (2.5 mg/kg/day) was administered via oral gavage every other day, starting on Day -1, for a total of 4 treatments. Panaxynol significantly improved overall mucositis symptomology, attenuated 5FU-induced cytopenia and anemia, ameliorated the 5FU-induced loss of goblet cells per crypt, suppressed pro-inflammatory immune cells in the colonic lamina propria, and altered microbial diversity and taxonomy. Sex differences were observed, with panaxynol exerting a stronger effect in males, significantly reducing the relative percentage of colonic macrophages and neutrophils. Panaxynol treatment was associated with sex-dependent alterations in gut microbial community structure and modulation of specific taxa, including <i>Dubosiella</i> and <i>Bifidobacterium</i>, alongside male-specific increases in <i>Romboutsia</i> and <i>Alistipes</i>; <i>Akkermansia</i> abundance was primarily influenced by 5FU treatment. These preclinical findings support the potential of panaxynol as a therapeutic candidate for the treatment of CIM and highlight the importance of considering sex as a biological variable.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809678","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":"Publisher's note.","authors":"","doi":"10.1152/ajpgi.00107.2026_NOT","DOIUrl":"https://doi.org/10.1152/ajpgi.00107.2026_NOT","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"330 5","pages":"G657"},"PeriodicalIF":3.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832819","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":"IP6K1 interacts with the syndecan SDC4 to support secretory granule biogenesis in gastric chief cells.","authors":"Jayraj Sen, Pranjali Pore, Rashna Bhandari","doi":"10.1152/ajpgi.00342.2025","DOIUrl":"https://doi.org/10.1152/ajpgi.00342.2025","url":null,"abstract":"<p><p>Inositol hexakisphosphate kinases (IP6Ks) catalyze the synthesis of the inositol pyrophosphate 5-InsP₇, and regulate diverse physiological processes. <i>Ip6k1^-/-</i> mice display reduced body weight despite normal food intake, elevated fecal protein, and reduced skeletal muscle mass compared to <i>Ip6k1^+/+</i> mice, suggesting that IP6K1 may support protein digestion. IP6K1 is expressed throughout the mouse gastrointestinal tract, and is especially enriched in the cytoplasm of chief cells in the stomach, which are responsible for the storage and secretion of digestive enzymes. Pepsinogen C (PGC) containing granules were sparse, and gastric lipase F granules were completely absent in the gastric glands of <i>Ip6k1^-/-</i> mice, despite normal expression levels of these enzymes, implicating IP6K1 in digestive enzyme granule biogenesis. The level of the active protease pepsin C was decreased in the gastric lumen of <i>Ip6k1^-/-</i> mice compared with <i>Ip6k1^+/+</i> mice. CRISPR/Cas9-mediated deletion of IP6K1 in the gastric adenocarcinoma cell line AGS recapitulated the phenotype of reduced PGC granules seen in gastric chief cells of <i>Ip6k1^-/-</i> mice. PGC granule formation was restored in <i>IP6K1^-/-</i> AGS cells by the reintroduction of catalytically active or inactive IP6K1, indicating that IP6K1 supports the formation of secretory granules independent of its enzymatic activity. The proteoglycan SDC4, identified as an interactor of IP6K1, was seen to co-localize and co-migrate with PGC granules in <i>IP6K1^+/+</i> but not in <i>IP6K1^-/-</i> AGS cells. Our findings identify IP6K1 as a novel regulator of secretory granule biogenesis in gastric chief cells, to influence protein digestion in the mammalian stomach.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759927","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":"The Protease Inhibitor Darunavir Prevents Esophagitis and Impairments in Esophageal Barrier Function in a Mouse Model of GERD.","authors":"Thiago Meneses Araújo Leite Sales, Ananda Moara Lima Daniel, Lara Mara Gomes da Silva, Álvaro Xavier Franco, Humberto Barbosa da Costa Filho, Carlos Eduardo da Silva Monteiro, Antonia Beatriz Alves Ferreira, Sarah Antonieli Carneiro Alicrim, Antonielle de Sousa Lopes, Marco Antonio de Freitas Clementino, Antonio Carlos Pereira de Oliveira, Lucas Antonio Duarte Nicolau, Alexandre Havt, Pedro Marcos Gomes Soares, Stuart Jon Spechler, Rhonda Frances Souza, Marcellus Henrique Loiola Ponte de Souza","doi":"10.1152/ajpgi.00058.2025","DOIUrl":"https://doi.org/10.1152/ajpgi.00058.2025","url":null,"abstract":"<p><p>Gastric reflux induces esophageal mucosal inflammation, partially mediated by the activation of hypoxia inducible factor 2α (HIF-2α). Pepsin, present in the refluxate, amplifies this inflammatory process and exacerbates tissue injury. Therefore, pepsin inhibition represents a promising strategy to reduce inflammation and preserve esophageal mucosal integrity. In this study, we evaluated the effects of darunavir, a protease inhibitor presently used to treat human immunodeficiency virus infection, in a gastroesophageal reflux disease (GERD) model in Swiss mice. Animals were anesthetized (ketamine and xylazine) and subjected to partial pyloric ligation and total ligation of the gastric fundus. Four experimental groups were established: sham (control), Sham+darunavir, GERD and GERD+darunavir. After three days, animals were euthanized, and the esophagus was collected to measure wet weight (edema), myeloperoxidase (MPO) activity, and keratinocyte-derived cytokines (KC). Western blot was performed for HIF-2α and tight junction proteins zonula occludens-1 (ZO-1) and occludin (OCLD). Histology with analysis of dilation of the intercellular space (DIS). Esophageal barrier function was assessed by transepithelial electrical resistance and fluorescein as an index of paracellular permeability. Darunavir's anti-peptic activity was also demonstrated <i>in vitro</i>. GERD induced inflammation, with significant increases in edema, MPO, KC, DIS, histological changes and HIF-2α, and disrupted barrier function, reducing ZO-1 and OCLD levels. All these alterations were significantly reversed in darunavir-treated animals. These findings demonstrate that darunavir, a clinically available drug with anti-pepsin properties, inhibits GERD-induced inflammation and HIF-2α activation, preserving tight junction proteins and mucosal integrity. Thus, darunavir could be repurposed as a novel therapeutic option for GERD.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759884","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":"Therapeutic Efficacy, Biomarker Signatures and Translatability of Semaglutide in the Liver Biopsy-Confirmed GAN DIO-MASH Mouse Model.","authors":"Jens Bjelke Kristensen, Jacob Nøhr-Meldgaard, Susanne E Pors, Jenny Norlin, Sanne S Veidal, Kristian Moss Bendtsen, Kristoffer Niss, Maja W Andersen, Lea M Harder, Mathilde Teilmann Dalhoff, Martin Rønn Madsen, Kristoffer Voldum-Clausen, Markus Latta, Lotte Bjerre Knudsen, Michael Feigh, Henrik H Hansen","doi":"10.1152/ajpgi.00011.2026","DOIUrl":"https://doi.org/10.1152/ajpgi.00011.2026","url":null,"abstract":"<p><p>Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). Importantly, semaglutide was recently approved as the first GLP-1 based treatment for people with MASH with moderate-to-severe fibrosis. Translational models that recapitulate human MASH are critical for guiding early-stage drug discovery, enabling rigorous efficacy evaluation and facilitating the progression of drug candidates into clinical development. In this study, we investigated the efficacy of semaglutide across an extensive series of experiments in the liver biopsy-confirmed GAN DIO-MASH mouse model, benchmarking outcomes against those from pivotal clinical trials of semaglutide in MASH. Treatment outcomes in the GAN DIO-MASH mouse closely mirrored clinical findings, particularly for hepatic steatosis and inflammation endpoints. Longer semaglutide treatment durations (≥16 weeks) led to pronounced and consistent improvements in quantitative fibrosis histology across studies. In comparison, the response rate for fibrosis stage improvement with semaglutide was modest and largely independent of treatment duration. Importantly, the GAN DIO-MASH mouse recapitulated many human MASH-associated changes in circulating proteins and semaglutide-responsive biomarkers. Collectively, these results support the therapeutic effects of semaglutide in MASH and underscore the reproducibility and clinical translatability of multiple disease-relevant features of the GAN DIO-MASH mouse model, highlighting its applicability as a robust platform for preclinical drug development.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669813","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":"Brown adipose tissue inactivation exacerbates alcohol-induced liver steatosis, inflammation, and fibrosis.","authors":"Qing Zhang, Zhiguo Zhang, Liangyou Rui","doi":"10.1152/ajpgi.00336.2025","DOIUrl":"10.1152/ajpgi.00336.2025","url":null,"abstract":"<p><p>Alcohol-induced liver fibrosis is a devastating manifestation of alcohol-related liver disease (ALD). However, conventional mouse models fail to recapitulate this fibrotic phenotype, limiting their translational relevance. Mice develop and retain robust brown adipose tissue (BAT) for thermoregulation, which confers protection against hepatic steatosis. Here, we identify BAT as a key protective tissue against alcohol-induced liver fibrosis in mice. BAT was inactivated in mice via denervation or surgically ablated, followed by 8 wk of chronic plus binge alcohol exposure. Both BAT denervation and ablation markedly exacerbated hepatic steatosis, injury, and inflammation compared with sham controls. Remarkably, BAT inactivation or ablation induced robust hepatic stellate cell (HSC) activation and liver fibrosis in both sexes, as evidenced by increased α-smooth muscle actin expression, enhanced Sirius red and Masson's trichrome staining, and elevated hydroxyproline content. These fibrotic changes were absent in sham-operated controls. Mechanistically, BAT-conditioned medium-containing BAT-secreted batokines-induced lipid accumulation, oxidative stress, and cell injury in hepatocyte cultures. Furthermore, batokines directly targeted cultured macrophages and HSCs and suppressed their activities. Collectively, these results unveil a hepatoprotective role of BAT and batokines in ALD progression and establish a physiologically and translationally relevant mouse model of ALD by combining BAT inactivation with chronic plus binge alcohol exposure.<b>NEW & NOTEWORTHY</b> Brown adipose tissue confers resistance to alcohol-related liver disease through secreting batokines. Inactivation of brown fat exacerbates alcohol-induced liver steatosis, inflammation, and fibrosis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G381-G396"},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13020465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146163675","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":"A pilot, randomized, placebo-controlled trial of rimegepant on visceral sensation and symptoms in nonconstipation IBS pain.","authors":"Houssam Halawi, Ayah Matar, Iris Wang, Kara J Jencks, Irene Busciglio, Deborah Eckert, William S Harmsen, Michael Camilleri","doi":"10.1152/ajpgi.00394.2025","DOIUrl":"10.1152/ajpgi.00394.2025","url":null,"abstract":"<p><p>Visceral hypersensitivity is a pivotal mechanism in pain associated with irritable bowel syndrome (IBS). Calcitonin gene-related peptide (CGRP) is expressed by visceral afferents. The aim of this study was to evaluate the efficacy of rimegepant, a CGRP antagonist, on abdominal pain, rectal compliance and sensation, gut transit, and safety in participants with nonconstipation IBS with pain. We conducted a pilot, randomized, double-blind, placebo-controlled, parallel-group design trial (NCT06221111) of oral rimegepant 75 mg every other day (as approved for migraine prophylaxis) in adults with nonconstipation IBS pain. The trial consisted of three periods: 2-wk run-in, 4-wk treatment, and 4-wk post-treatment with diary recording of daily abdominal pain (primary endpoint) and bowel movements (BMs). Rectal compliance and sensation were measured using barostat distensions and gastrointestinal and colonic transit by scintigraphy. Statistical analysis compared rimegepant with placebo using analysis of covariance with sex, level of anxiety, and baseline measurements as covariates. Twenty-four participants were randomized to rimegepant (<i>n</i> = 12) or placebo (<i>n</i> = 12); baseline demographics, rectal sensation, and compliance were similar between the groups. Rimegepant did not significantly reduce abdominal pain, daily BM frequency, or BM consistency relative to baseline. Compared with placebo, rimegepant significantly reduced sensations of gas, urgency, and pain during 24 mmHg, and gas and urgency sensations during 36 mmHg rectal distension (all <i>P</i> ≤ 0.05 unadjusted). Rimegepant decreased rectal compliance. No significant effects were noted during washout. There were no serious adverse events or adverse events of ≥ Grade 3 severity. Rimegepant's effects on rectal sensation suggest further studies in nonconstipation IBS pain are warranted. Clinical Trial Registry Number: NCT06221111.<b>NEW & NOTEWORTHY</b> This pilot, randomized, double-blind trial in a relatively small sample of patients with IBS-related pain shows rimegepant significantly reduced sensations of gas, urgency, and pain during rectal distention and decreased rectal compliance. Decrease in compliance implies that changes in physical properties or distensibility of rectum did not contribute to alterations in rectal sensation. Same dose of rimegepant did not significantly impact daily abdominal pain, BM frequency, or colonic transit. There were no serious adverse events.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G369-G380"},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117686","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":"SGK1 signaling: an important modulator of CFTR function and early immune response in mouse intestine.","authors":"Caroline Muiler, Anderson Santos, Nadia A Ameen","doi":"10.1152/ajpgi.00400.2025","DOIUrl":"10.1152/ajpgi.00400.2025","url":null,"abstract":"<p><p>Glucocorticoid (GC) and stress-induced serum- and glucocorticoid-inducible kinase 1 (SGK1) signaling rapidly modulate intestinal epithelial transport, yet whether epithelial SGK1 is required to couple GC signaling to functional cystic fibrosis transmembrane conductance regulator (CFTR) output in vivo has remained unclear. We examined this question using <i>Villin-Cre;Sgk1</i>^flox/flox conditional knockout (<i>Sgk1</i>cKO) and littermate heterozygous controls (<i>Sgk1</i>cHET) mice treated with dexamethasone (DEX; 2 mg/kg ip) for 1 or 4 h. Outcomes included CFTR protein abundance, immunolocalization (immunoblotting and immunofluorescence), CFTR-ion transport measured by short-circuit current (<i>I</i>_sc) in Ussing chambers, epithelial <i>Sgk1/2/3</i> expression, intestinal loop fluid accumulation, and CD45⁺ cell signal as a readout of early immune engagement. Acute DEX treatment activated SGK1 signaling and elevated CFTR protein in <i>Sgk1</i>cHET but also in <i>Sgk1</i>cKO. However, only <i>Sgk1</i>cHET exhibited a rise in CFTR-dependent Δ<i>I</i>_sc, whereas <i>Sgk1</i>cKO failed to increase secretion despite higher total CFTR. <i>Sgk2</i> and <i>3</i> were upregulated in <i>Sgk1</i>cKO but did not restore function. CD45⁺ signal rose transiently at 1 h and normalized by 4 h, consistent with early, self-limited immune engagement. In an intestinal loop assay, short-term DEX treatment did not exacerbate cGMP-evoked fluid accumulation. Together, these data identify epithelial SGK1 signaling as a necessary node that translates acute stress-induced CFTR stabilization into functional secretion and a transient epithelial-immune response. These findings help reconcile expression-function discrepancies and suggest that targeting SGK1 or its downstream steps may be required to achieve functional CFTR gains under acute stress in the intestine.<b>NEW & NOTEWORTHY</b> Glucocorticoids rapidly boost intestinal CFTR expression, function, and trafficking through SGK1 and link stress signaling to epithelial secretion and immune control. Deleting <i>Sgk1</i> blocked glucocorticoid-driven CFTR activation and altered early immune cell recruitment, uncovering SGK1 as a critical regulator of intestinal adaptation to acute stress.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G487-G494"},"PeriodicalIF":3.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218547","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}