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

{"title":"Contrasting impacts of two ABCB11 variants affecting the same residue in progressive familial intrahepatic cholestasis type 2.","authors":"Yosra Riahi, Marion Almes, Manon Banet, Elodie Mareux, Isabelle Garcin, Anne Davit-Spraul, Redouane Si-Bouazza, Sylvie Fabrega, Benjamin Boucherle, Jean-Luc Decout, Thomas Falguières, Isabelle Callebaut, Emmanuel Jacquemin, Emmanuel Gonzales, Martine Lapalus","doi":"10.1152/ajpgi.00055.2026","DOIUrl":"10.1152/ajpgi.00055.2026","url":null,"abstract":"<p><p>Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a severe autosomal recessive cholestatic liver disease due to variations in ATP-binding cassette subfamily B member 11 (<i>ABCB11</i>) gene. The clinical and molecular consequences of two missense variations affecting the same ABCB11 residue (T463) were characterized, and pharmacological strategies were investigated. Clinical and genetic data were collected from two PFIC2 patients carrying p.T463I or p.T463P substitutions. A three-dimensional (3-D) structure analysis was performed to predict substitution impacts. ABCB11^T463I and ABCB11^T463P variants were expressed in HepG2 and Madin-Darby canine kidney cells to assess their subcellular localization and functional activity. Pharmacological modulators were tested to correct the defects. The patient carrying ABCB11^T463I exhibited a mild phenotype and responded to surgical biliary diversion. Conversely, the patient carrying ABCB11^T463P required a liver transplantation before age one. 3-D structure and in vitro analyses predicted a functional defect in both variants and a folding defect for the T463P variant. In vitro, ursodeoxycholic acid combined with glycerol phenylbutyrate increased ABCB11^T463P canalicular expression (40.2 ± 7.7% of the wild type, <i>P</i> < 0.0001) and improved transport activity (32.4 ± 10.3% of the wild type, <i>P</i> < 0.0001). VX-770 and SBC040 increased ABCB11^T463I function from 37.9 ± 2.5% (DMSO) to 73.2 ± 12.3% and 76.1 ± 17.5%, respectively, of the wild-type activity (<i>P</i> < 0.0001). <i>ABCB11</i> missense variations, even affecting the same residue, can cause various molecular defects, resulting in mild to severe phenotypes. 3-D structure and in vitro analyses could be used to predict the severity of missense variants and guide the treatment of PFIC2 patients with pharmacological modulators.<b>NEW & NOTEWORTHY</b> Patients with progressive familial intrahepatic cholestasis type 2 (PFIC2) due to ATP-binding cassette subfamily B member 11 (<i>ABCB11</i>) missense variations may present various phenotypes and exhibit different response patterns to treatments. This study exemplifies this variability and provides an in silico and in vitro framework for characterizing and classifying ABCB11 missense variants. This classification could serve to guide treatment strategies, stratify patients with missense variants in clinical trials, and predict patient outcomes.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G299-G311"},"PeriodicalIF":3.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148672924","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":"Host-microbe interactions in the appendix of children with inflammatory bowel diseases.","authors":"Nazanin Arjomand Fard, John Maringa Githaka, Simona Veniamin, Le Luo Guan, Harmol Aujla, Amreen Kaur, E Paul Lerner, Deenaz Zaidi, Anissa M Armet, Joseph Andrews, Xiao Han, Bruce A Vallance, Karen L Madsen, Troy Perry, Eytan Wine","doi":"10.1152/ajpgi.00080.2026","DOIUrl":"10.1152/ajpgi.00080.2026","url":null,"abstract":"<p><p>The human appendix is traditionally considered a vestigial organ; however, clinical observations link it to inflammatory bowel diseases (IBDs), including Crohn disease (CD) and ulcerative colitis (UC), as suggested by periappendicular inflammation and the reported protective effect of appendectomy in UC. Despite these associations, its functional contribution remains poorly defined. Here, we performed a multiomics analysis of appendix tissue from pediatric patients with IBD and non-IBD surgical controls (<i>n</i> = 15) to characterize microbial composition and host molecular landscape. Metagenomic sequencing revealed Proteobacteria enrichment and reduced microbial diversity in IBD appendices. Correlations between host transcriptomes and mucus-associated microbial pathways indicated associations consistent with host-microbe interactions linked to immune activation. Fluorescence in situ hybridization confirmed bacterial localization, and functional assays of appendix-derived <i>Klebsiella variicola</i> isolates demonstrated invasive capacity in vitro. Our findings suggest that the appendix represents a distinct microbial niche in pediatric IBD and may contribute to host-microbe perturbations associated with disease.<b>NEW & NOTEWORTHY</b> Multiomics profiling of pediatric appendiceal tissue in inflammatory bowel diseases reveals reduced microbial diversity, Proteobacteria enrichment, and coordinated associations between microbial functional pathways and host immune-related transcripts. Invasive capacity of appendix-derived <i>Klebsiella variicola</i> further supports potential host-microbe interactions within this niche. These findings characterize the appendix as a distinct mucosal compartment in pediatric IBD and provide a foundation for future mechanistic investigation.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G328-G347"},"PeriodicalIF":3.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629021","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":"Integrated analyses of in vivo mouse models and liver organoids reveal MFG-E8-mediated protection against hepatocyte injury.","authors":"Heng-Fu Bu, Qianming Jiang, Hua Geng, Saravanan Subramanian, Nazeer Hussain Khan, Xiao Wang, Xiao-Di Tan","doi":"10.1152/ajpgi.00079.2026","DOIUrl":"10.1152/ajpgi.00079.2026","url":null,"abstract":"<p><p>Milk fat globule-EGF factor 8 (MFG-E8) is a multifunctional glycoprotein implicated in tissue homeostasis and repair. Although its roles in intestinal and pancreatic injury are well established, its function in hepatic regeneration remains poorly defined. In this study, we investigated MFG-E8 expression and activity using a hepatocyte-specific apoptosis model (3xTg-iHAP) and liver organoid cultures from wild-type (B6^WT) and <i>Mfge8</i> knockout (<i>Mfge8^-/-</i>) mice. In doxycycline (Dox)-treated 3xTg-iHAP mice, <i>Mfge8</i> mRNA and MFG-E8 protein were markedly upregulated, peaking at 48 h after hepatocyte injury. RNAScope-Immunostain Integrated Codetection Workflow (ICW) demonstrated that under basal conditions, <i>Mfge8</i> expression was localized to cholangiocytes, but following injury, hepatocytes exhibited robust transcriptional induction. In vitro, three-dimensional (3-D) organoids showed no overt genotype-specific differences between B6^WT and <i>Mfge8^-/-</i> mice; however, two-dimensional (2-D) monolayers derived from <i>Mfge8^-/-</i> mice exhibited cytopathic disintegration by <i>day 5</i>. This phenotype was partially rescued by recombinant MFG-E8 (rMFG-E8). Transcriptomic analysis by RNA sequencing (RNA-seq) confirmed loss of <i>Mfge8</i> expression in knockout cultures, accompanied by an approximately eight fold increase in <i>Hddc3</i>, a ferroptosis-associated gene, suggesting a potential mechanism underlying structural instability ex vivo. These findings demonstrate that MFG-E8 is indispensable for maintaining hepatic epithelial integrity. Loss of MFG-E8 sensitizes hepatocytes to ferroptosis stress, providing mechanistic insight into impaired liver repair and highlighting MFG-E8 as a potential therapeutic target to enhance hepatic regeneration.<b>NEW & NOTEWORTHY</b> This study uncovers a novel role of milk fat globule-EGF factor 8 (MFG-E8) in liver regeneration. Hepatocytes upregulate <i>Mfge8</i> after injury, shifting from its basal expression in cholangiocytes to hepatocytes. Loss of MFG-E8 destabilizes hepatocyte monolayers, a defect partially rescued by recombinant MFG-E8 (rMFG-E8). Transcriptomic analysis revealed <i>Hddc3</i> upregulation in <i>Mfge8^-/-</i> mice, linking MFG-E8 deficiency to ferroptosis. These findings identify MFG-E8 as a key regulator of hepatic epithelial integrity and a potential therapeutic target for liver repair.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G384-G397"},"PeriodicalIF":3.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757923","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":"Genetic and pharmacologic modulations elucidate NRF2 protective role in acute pancreatitis.","authors":"Olga A Mareninova, Alex G Chang, Sebastian Hernandez Malpica, Jerik A Pineda, Rami Mamita, Natalia Shalbueva, Ilya Gukovsky, Anna S Gukovskaya","doi":"10.1152/ajpgi.00032.2026","DOIUrl":"10.1152/ajpgi.00032.2026","url":null,"abstract":"<p><p>Acute pancreatitis (AP) is a potentially fatal disease of the exocrine pancreas. The disease pathogenesis remains obscure, and no effective treatment is available. Uncontrolled, deregulated inflammation is a major cause of systemic complications in AP; however, approaches to reduce inflammation in human disease by inhibiting inflammatory mediators have encountered multiple challenges and have not been successful. Oxidative stress drives inflammation in many diseases but its role in AP remains poorly understood. This study evaluates the role of nuclear factor erythroid 2-related factor 2 (NRF2), the master antioxidant defense transcription factor, in the inflammatory response and severity of experimental AP in mouse and cellular (ex vivo) models. Pancreas-specific genetic ablation of NRF2 worsened nonalcoholic and alcohol-mediated AP by downregulating antioxidant gene expression and upregulating inflammatory mediators, as shown by RNA-Seq analysis. Pancreatic NRF2 was activated in the experimental AP models; however, this activation was insufficient to prevent oxidative stress and inflammation. Additional pharmacologic NRF2 activation with sulforaphane markedly reduced oxidative stress, inflammation, and other pancreatitis responses; importantly, it ameliorated a recurrent episode of AP. The results highlight a major role of NRF2 in protecting against oxidative stress and inflammation in AP and suggest pharmacologic activation of NRF2 as a promising therapeutic strategy to mitigate inflammation and reduce the severity of pancreatitis.<b>NEW & NOTEWORTHY</b> Nonresolving inflammation is a major cause of acute pancreatitis (AP) mortality. Oxidative stress drives inflammation in various diseases, but its role in AP remains poorly understood, and targeted therapies are lacking. We show that acinar cell nuclear factor erythroid 2-related factor 2 (NRF2) activation in experimental AP was insufficient to prevent oxidative stress; however, additional NRF2 activation with sulforaphane markedly reduced oxidative stress, the inflammatory response, and disease severity. The results highlight pharmacologic NRF2 activators as a promising therapeutic approach for pancreatitis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G348-G364"},"PeriodicalIF":3.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13506221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618168","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":"E-cadherin acts as a dynamic switch in epithelial regeneration in inflammatory bowel disease.","authors":"Bereket Girma, Hammed Ayansola, Jiecheng Chen, Jain Kim, Corina Miko, Zoe Gruskin, Younggeon Jin","doi":"10.1152/ajpgi.00044.2026","DOIUrl":"10.1152/ajpgi.00044.2026","url":null,"abstract":"<p><p>Effective epithelial regeneration is crucial for mucosal healing to achieve complete remission in patients with inflammatory bowel disease (IBD). E-cadherin (<i>Cdh1</i>), a key transmembrane protein mediating epithelial cell-cell adherence, must be transiently suppressed to permit proliferation yet subsequently restored for epithelial maturation. Although its role in cancer and developmental biology has been well studied, the role of E-cadherin in intestinal epithelial repair remains unexplored. Thus, we hypothesize that a temporary reduction in E-cadherin during early repair enhances proliferation, followed by E-cadherin rebound that drives differentiation, improving mucosal healing. When we used an isopropyl-β-d-thiogalactopyranoside (IPTG)-inducible shRNA lentiviral system to induce <i>Cdh1</i> knockdown (KD), colonoids developed stem-like spheroidal shapes. This phenotype was supported by upregulated intestinal stem cell (ISC) marker (<i>Lgr5</i>) and increased proliferation (Ki67), along with increased Wnt and Hippo target gene expression levels. Consistently, transcriptomic data further confirmed the significant enrichment of ISC- and fetal-like-associated genes, as well as multiple regeneration-related pathways, in <i>Cdh1</i> KD colonoids compared with controls. In the novel inflammatory injury and repair model established by combining proinflammatory cytokines and anoxia, IPTG-treated <i>Cdh1</i> KD during the early regeneration phase enhanced the epithelial repair process. Finally, in vivo validation through colonoid transplantation in dextran sulfate sodium (DSS)-induced colitis mice demonstrated enhanced mucosal healing in the group receiving IPTG-pretreated colonoids compared with those receiving normal colonoids. These findings support a model in which transient, controlled E-cadherin downregulation promotes epithelial repair and may represent a promising therapeutic approach to promote mucosal healing in patients with IBD.<b>NEW & NOTEWORTHY</b> Mucosal healing in IBD remains inadequate despite anti-inflammatory therapies, largely because epithelial regeneration itself is not directly targeted. This study reframes E-cadherin as a dynamic regenerative switch whose transient suppression actively drives ISC-mediated repair. Using a novel dual-injury colonoid model recapitulating the IBD microenvironment, we show that precisely timed E-cadherin knockdown unlocks regenerative programs and enhances mucosal healing after transplantation in vivo, supporting epithelial junction dynamics as a new therapeutic target in IBD.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G365-G383"},"PeriodicalIF":3.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618195","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":"Radiotherapy reduces ATP-mediated relaxation in human rectal smooth muscle.","authors":"Yoon-Hye Kwon, Tae Sik Sung, Young Hyun Yun, Hyunjin Jung, Insuk So, Seung-Bum Ryoo, Kyu Joo Park","doi":"10.1152/ajpgi.00451.2025","DOIUrl":"10.1152/ajpgi.00451.2025","url":null,"abstract":"<p><p>Radiation therapy for rectal cancer often causes long-term bowel dysfunction. We investigated radiation-associated motility changes in human rectal smooth muscle, focusing on the role of platelet-derived growth factor receptor alpha-positive (PDGFRα⁺) cells and interstitial cells of Cajal (ICC). Human rectal tissues were obtained from patients undergoing surgery with (<i>n</i> = 61) or without (<i>n</i> = 51) preoperative concurrent chemoradiotherapy (CCRT). Isometric tension recordings were used to assess myogenic responses to potassium chloride (KCl), acetylcholine (ACh), sodium nitroprusside (SNP), and adenosine triphosphate (ATP). Neurogenic components were assessed using electrical field stimulation. Intracellular microelectrode recordings measured slow wave activity. Expression of interstitial cells, neuronal cells, and smooth muscle cells was assessed by immunohistochemistry and quantitative polymerase chain reaction (PCR). ATP-induced relaxation and ATP-associated suppression of slow wave activity were significantly attenuated in irradiated rectal tissue, whereas responses to KCl, ACh, and SNP were preserved. <i>PDGFRA</i> and <i>KIT</i> expression levels were markedly decreased in irradiated tissue (<i>P</i> < 0.001), whereas neuronal nitric oxide synthase 1 (<i>NOS1</i>), vesicular acetylcholine transporter (VAChT), and myosin heavy chain 11 (<i>MYH11</i>) expression levels remained unchanged. Immunostaining confirmed reduced PDGFRα⁺ cells and ICC in irradiated tissue. Pelvic irradiation delivered in the context of preoperative CCRT was associated with reduced PDGFRα⁺ cells and ICC, with associated attenuation of ATP-mediated inhibitory responses, which may contribute to rectal dysmotility. These results suggest that preserving purinergic signaling may offer a potential therapeutic approach to improve long-term bowel function after pelvic radiotherapy.<b>NEW & NOTEWORTHY</b> Pelvic irradiation is associated with attenuated adenosine triphosphate (ATP)-mediated rectal smooth muscle relaxation. The loss of platelet-derived growth factor receptor alpha-positive (PDGFRα⁺) cells is associated with altered rectal neuromodulation. PDGFRα⁺ cells and interstitial cells of Cajal (ICC) are reduced in irradiated rectal tissue. Intrinsic smooth muscle contractile responses are preserved, whereas ATP-mediated inhibitory regulation is reduced.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G287-G298"},"PeriodicalIF":3.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648219","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":"Phase-dependent disruption of microbiome-metabolome coordination is associated with diet-induced MASLD.","authors":"Arka Jyoti De, Bibek Upadhyaya, Palok Aich","doi":"10.1152/ajpgi.00163.2026","DOIUrl":"10.1152/ajpgi.00163.2026","url":null,"abstract":"<p><p>Metabolic-dysfunction-associated steatotic liver disease (MASLD) is typically attributed to caloric overload, lipotoxicity, and static gut dysbiosis, but how chronic diet alters the temporal organization of gut-liver communication remains unclear. We combined a phase-stratified multiomics framework, cecal 16S rRNA profiling, dual-compartment (cecum and serum) metabolomics, and hepatic clock and lipogenic gene expression in C57BL/6J male mice fed a high-fat, palmitate, and cholesterol-enriched (FPC) diet containing high sucrose for 22 wk. FPC feeding was associated with severe MASLD and markedly attenuated homeostatic phase-dependent differences in hepatic clock and lipogenic transcripts, consistent with a persistently lipogenic transcriptional state across the light-dark cycle. This temporal disruption coincided with reduced phase-structured ecological organization in the cecal microbiome and the emergence of a constrained, dysbiotic community dominated by a few taxa. Dual-compartment metabolomics revealed that despite retaining overall phase structure, local (cecal) and systemic (serum) metabolite pools showed misalignment: proinflammatory and bile acid species showed exaggerated luminal variations but flattened, persistently elevated profiles in serum. High-stringency covariance network analysis identified diet-associated differences in microbiome-metabolome covariance patterns. These findings are consistent with a model in which diet-induced MASLD is associated with altered spatial and phase-dependent coordination across microbiome-host metabolic and transcriptional networks, suggesting disruption of integrated microbiome-host organization beyond static dysbiosis and lipotoxic stress.<b>NEW & NOTEWORTHY</b> Using a phase-stratified multiomics framework in a murine MASLD model, we show that chronic FPC feeding is associated with altered temporal coordination between the gut and liver, beyond compositional dysbiosis. FPC reduces phase-dependent differences in hepatic clock and lipogenic gene expression, attenuates microbiome phase organization, and is associated with misaligned cecal and systemic metabolite profiles. Covariance networks reveal alteration of microbiome-metabolome-transcriptional connectivity, implicating disruption of phase-dependent gut-liver integration as an underappreciated axis of MASLD pathogenesis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G312-G327"},"PeriodicalIF":3.0,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629060","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 zinc targets dysregulated GC-C signaling and restores ileal defects in a preclinical model of familial diarrheal disease.","authors":"Avipsa Bose, Yashika Bopanna, Pallavi Shetty, Kritica Sharma, John Kandam Kulathu Mathew, Vishwas Mishra, Sanghita Bannerjee, Harini Ramani, Anna B Pulimood, Ramray Bhat, Avinash R Shenoy, Sandhya S Visweswariah","doi":"10.1152/ajpgi.00049.2026","DOIUrl":"10.1152/ajpgi.00049.2026","url":null,"abstract":"<p><p>Hyperactivating mutations in guanylyl cyclase C (GC-C) are monogenic causes of early-onset inflammatory bowel disease, familial diarrheal syndrome, and congenital secretory diarrhea. The mechanisms linking elevated cGMP levels to immune imbalance remain poorly defined. Here, using a preclinical model of a disease-associated GC-C mutation, we observe pleiotropic alterations in the small intestinal epithelium. Transcriptomic and functional analyses revealed impaired Paneth and goblet cell differentiation, compromised barrier integrity, heightened epithelial permeability, and increased proinflammatory cytokine levels. Intestinal organoids from mutant mice exhibited amplified cGMP responses to GC-C ligands and defects in secretory lineage specification, confirming cell-autonomous mechanisms. Strikingly, oral zinc administration suppressed aberrant GC-C activity, normalized cGMP levels, and restored barrier function. These findings highlight the central role of epithelial cGMP signaling in coordinating barrier integrity and immune-epithelial interactions and identify zinc as a tractable therapeutic strategy for GC-C-mediated intestinal disorders.<b>NEW & NOTEWORTHY</b> Activating mutations in <i>GUCY2C</i>, which encodes the receptor guanylyl cyclase C (GC-C), cause early-onset diarrheal disease and gastrointestinal inflammation. Knock-in mice carrying a familial diarrheal syndrome mutation exhibited impaired gut barrier function. Mutant organoids showed defective secretory lineage specification associated with reduced Wnt3 expression. Zinc administration, which lowers epithelial cGMP levels by inhibiting GC-C, reversed most pathological changes in both mice and organoids.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G125-G139"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13419675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306605","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":"Aldosterone suppresses Na⁺/H⁺ exchanger-3 expression through miR-204-5P-mediated posttranscriptional regulation in distal colon.","authors":"Karthikeyan Narayanan, Kumaran M Rajendran, Joshua Cornman-Homonoff, Mark Donowitz, Henry J Binder, Vazhaikkurichi M Rajendran","doi":"10.1152/ajpgi.00094.2026","DOIUrl":"10.1152/ajpgi.00094.2026","url":null,"abstract":"<p><p>Na⁺/H⁺ exchanger-3 (NHE3) is a major mediator of electroneutral NaCl absorption in the intestine and colon. In the distal colon, chronic aldosterone exposure suppresses NHE3 expression, but the molecular mechanism responsible for this regulation remains unclear. Here, we tested whether aldosterone represses NHE3 through microRNA-dependent posttranscriptional regulation. Transcriptomic analysis of distal colon from dietary Na⁺-depleted rats identified miR-204-5P (miR-204-5P) as markedly upregulated. Aldosterone increased miR-204-5P abundance and concomitantly reduced NHE3 mRNA, protein expression, and transport activity in rat and human distal colonic epithelium and in SK-CO15 cells. Bioinformatic and reporter analyses identified a conserved miR-204-5P binding site within the NHE3 3'-untranslated region, and miR-204-5P mimic transfection markedly suppressed NHE3 expression and transport activity without affecting other Na⁺/H⁺ exchanger isoforms. These findings identify a previously unrecognized aldosterone-microRNA signaling pathway that mediates chronic repression of NHE3 and provide new insight into hormonal regulation of colonic Na⁺ absorption.<b>NEW & NOTEWORTHY</b> This study identifies a previously unrecognized aldosterone-microRNA signaling mechanism regulating colonic Na⁺ absorption. We demonstrate that aldosterone induces miR-204-5P, which directly targets the NHE3 3'-untranslated region and suppresses NHE3 expression and transport activity in distal colonic epithelium. These findings reveal a microRNA-mediated pathway linking mineralocorticoid signaling to long-term inhibition of electroneutral NaCl absorption, providing new insight into hormonal regulation of intestinal electrolyte transport.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G277-G286"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468303","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 RNA-binding protein Imp1 promotes a Spdef transcriptional program and mucus fucosylation during necrotizing enterocolitis.","authors":"Kevin A Swift, Alexandria J Shumway, Molly Aloia, Madeline Hedges, Rachel Pung, Moqing Liu, Cariam Rodriguez Santiago, Michael T Shanahan, Alexander Drake, Melanie H Hakar, Leigh Selesner, Madeline Kuhn, Claire Yung, Praveen Sethupathy, Sarah F Andres","doi":"10.1152/ajpgi.00060.2026","DOIUrl":"10.1152/ajpgi.00060.2026","url":null,"abstract":"<p><p>Necrotizing enterocolitis (NEC) is the most deadly gastrointestinal disease in preterm neonates, with up to 50% mortality. There is no cure for NEC. Enhancing our understanding of intestinal epithelial cell (IEC) responses to NEC will provide novel therapeutic targets. The RNA-binding protein insulin-like growth factor 2 mRNA binding protein 1 (IMP1) plays roles in intestinal development and repair. Notably, roles for IMP1 in NEC are unknown. Intestinal goblet cells produce protective mucus, and their function depends on the transcription factor SAM pointed domain containing ETS transcription factor (SPDEF). Evidence suggests that goblet cell mucus glycosylation affects barrier function and inflammation. We aimed to define the role of IMP1 in NEC damage response using neonatal human enteroids and an NEC-like intestinal injury model. At postnatal day 3, wild-type mice or littermates with IEC-specific IMP1 overexpression (<i>Imp1</i>^IEC-OE) or loss (<i>Imp1</i>^ΔIEC) were assigned to control or NEC groups. NEC was induced with stress, formula feeding, bacterial exposure, and hypoxia. IMP1 effects on NEC response were assessed using RNA sequencing, Western blotting, immunostaining, and a cytokine array. We found that proinflammatory bacteria induced <i>IMP1</i> expression in neonatal human enteroids. During NEC, <i>Imp1</i>^IEC-OE mice exhibit more severe intestinal damage and priming for lytic cell death. Elevated IMP1 levels were linked to a SPDEF transcriptional signature and in silico analysis predicted IMP1 binding to <i>Spdef</i> and mucus glycosylation mediator mRNAs. Functionally, IMP1 increased fucosylation in the intestinal epithelium. Collectively, results suggest that IMP1 primes the intestine for lytic death and promotes the production of fucosylated mucus, changes which could alter the damage response.<b>NEW & NOTEWORTHY</b> Expression of the RNA-binding protein IMP1 is enhanced in neonatal human enteroids in response to NEC-associated enteric bacteria. IMP1 regulates goblet cell function in response to early intestinal inflammation in a mouse model of necrotizing enterocolitis. IMP1 enhances epithelial damage and priming for lytic cell death, while promoting a SPDEF transcriptional program through SPDEF upregulation and elevated expression of SPDEF target genes. In addition, IMP1 increases the gene expression of α(1, 2)fucosyltransferase, <i>Fut2,</i> and increases UEAI-positive cells.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G107-G124"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161341","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}