Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"A Dual-compartment Scaffolding Role for Receptor for Activate C Kinase 1 in Hepatic Glucagon Signaling and Gluconeogenesis","authors":"Cancan Lyu ,&nbsp;Ling Yang ,&nbsp;Songhai Chen","doi":"10.1016/j.jcmgh.2025.101666","DOIUrl":"10.1016/j.jcmgh.2025.101666","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The hepatic glucagon–protein kinase A (PKA)–cAMP response element-binding protein (CREB) signaling axis plays a central role in regulating gluconeogenesis and maintaining glucose homeostasis during fasting. However, the mechanisms that govern the spatial coordination and substrate specificity of this pathway remain incompletely understood. This study determines the role of the scaffolding protein RACK1 (Receptor for Activated C Kinase 1) in orchestrating glucagon signaling to regulate hepatic gluconeogenesis.</div></div><div><h3>Methods</h3><div>RACK1 was acutely deleted in mouse liver and primary hepatocytes. Metabolic phenotypes were assessed by glucose, pyruvate, glucagon and insulin tolerance tests, as well as hepatocyte glucose production assays. Protein interactions were examined by coimmunoprecipitation, glutathione S-transferase (GST) pulldown, and miniTurbo-ID-mediated proximity labeling. Subcellular localization and signaling events were assessed by Western blotting, confocal microscopy, and cellular fractionation. Functional rescue was achieved by hepatic expression of a constitutively active PKA catalytic subunit (PKAcα^W196R).</div></div><div><h3>Results</h3><div>Acute hepatic RACK1 deficiency caused fasting hypoglycemia, impaired gluconeogenesis, and improved glucose, pyruvate, and glucagon tolerance without affecting insulin signaling. RACK1 directly bound glucagon receptor (GCGR) and PKA regulatory (RIIα) and catalytic (PKAcα) subunits, as well as CREB, functioning as a dual-compartment scaffold assembling GCGR–PKA complexes at the plasma membrane and PKAcα–CREB complexes in the nucleus. Loss of RACK1 impaired PKAcα translocation, CREB phosphorylation, and gluconeogenic gene expression. These defects were rescued by PKAcα^W196R expression. Overexpression of RACK1 WD1–2 and WD3–4 domains, which mediate PKA, GCGR, and CREB interactions, similarly disrupted PKA signaling and gluconeogenesis.</div></div><div><h3>Conclusions</h3><div>RACK1 functions as a dual-compartment scaffold, assembling GCGR–PKA at the plasma membrane and PKAcα–CREB in the nucleus, enabling precise glucagon signaling and gluconeogenesis while sparing insulin pathways, thereby ensuring compartmentalized regulation of hepatic glucose homeostasis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101666"},"PeriodicalIF":7.1,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial Metabolism Meets LncRNA Biology: The Role of uc.173 in Intestinal Homeostasis.","authors":"Hua Geng, Joann Romano-Keeler, Xiao-Di Tan","doi":"10.1016/j.jcmgh.2025.101662","DOIUrl":"10.1016/j.jcmgh.2025.101662","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101662"},"PeriodicalIF":7.1,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Intestinal Cues Promoting Serotonin Release From the Human Gut.","authors":"Sara C Di Rienzi","doi":"10.1016/j.jcmgh.2025.101664","DOIUrl":"10.1016/j.jcmgh.2025.101664","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101664"},"PeriodicalIF":7.1,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probiotics Mitigate High-cholesterol Diet-driven Fatty Liver and Pancreatic Cancer by Restoring Macrophage Homeostasis","authors":"Deepti Parida ,&nbsp;Swayambara Mishra ,&nbsp;Amlan Priyadarshee Mohapatra ,&nbsp;Manisha Sethi ,&nbsp;Kirti Ranjan Das ,&nbsp;Salona Kar ,&nbsp;Voddu Suresh ,&nbsp;Shrikrishna Jayaram Bhagat ,&nbsp;Amruta Mohapatra ,&nbsp;Supriya Halder ,&nbsp;Shantibhusan Senapati","doi":"10.1016/j.jcmgh.2025.101644","DOIUrl":"10.1016/j.jcmgh.2025.101644","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>High dietary cholesterol is a known risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD) and its associated hepatic carcinogenesis; however, its effect on pancreatic ductal adenocarcinoma (PDAC) is yet to be investigated. The current study explored the mechanistic association between high dietary cholesterol, MASLD, and PDAC. Importantly, we aimed to evaluate the effect of a multi-strain probiotic formulation on hypercholesterolemia-driven MASLD and PDAC.</div></div><div><h3>Methods</h3><div>In this study, wild-type (C57BL/6) and KC (Pdx-1 Cre; Kras^LSL-G12D) mice were fed either with regular diet or high cholesterol and cholic acid diet (HCCD) and received an oral probiotic consortium LR+F15 (<em>Lactobacillus rhamnosus</em> GG and <em>Lactiplantibacillus plantarum</em> ILSF15). Additionally, we also used a syngeneic orthotopic murine PDAC model to evaluate the efficacy of this probiotic consortium. For mechanistic studies, pancreas, liver, intestine, peri-pancreatic fats, peritoneal cells/lavage, and blood were evaluated for metabolic, inflammatory, and malignant changes through histology, enzyme-linked immunosorbent assay, flow cytometry, and quantitative reverse transcription polymerase chain reaction.</div></div><div><h3>Results</h3><div>HCCD induced nonobese MASLD and PDAC progression, which was eased upon probiotics intervention. Importantly, it also increased the survival of the HCCD-fed KC mice. The probiotic intervention protected against HCCD-induced leaky gut, gut microbiota translocation, and inflammatory milieu in different tissues. Interestingly, HCCD significantly increased the population of pro-inflammatory/pro-tumorigenic peritoneal macrophages, which got normalized upon probiotic administration.</div></div><div><h3>Conclusions</h3><div>The probiotic formulation LR+F15 significantly suppressed HCCD-induced MASLD and PDAC progression partly through suppressing leaky gut and normalizing peritoneal macrophages’ inflammatory properties. These findings encourage evaluation of the potential benefits of this probiotic consortium in combination with the existing therapies against PDAC in the future.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101644"},"PeriodicalIF":7.1,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145330944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CREB Fuels Tumorigenesis in Alcoholic Pancreatitis.","authors":"Urvinder Kaur Sardarni, Jennifer M Bailey-Lundberg","doi":"10.1016/j.jcmgh.2025.101660","DOIUrl":"10.1016/j.jcmgh.2025.101660","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101660"},"PeriodicalIF":7.1,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"When Liver Slices Meet Single-cell Technology.","authors":"Mi Jeong Heo, Kang Ho Kim","doi":"10.1016/j.jcmgh.2025.101661","DOIUrl":"10.1016/j.jcmgh.2025.101661","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101661"},"PeriodicalIF":7.1,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Barrington’s Nucleus: A Pontine Defecation Brain Area Exhibiting Prompt and Delayed Defecation Responses","authors":"Kota Bussaka ,&nbsp;Yoshimasa Tanaka ,&nbsp;Kunio Kondoh ,&nbsp;Ken-ichiro Nakajima ,&nbsp;Takatoshi Chinen ,&nbsp;Xiaopeng Bai ,&nbsp;Yosuke Minoda ,&nbsp;Hiroko Ikeda ,&nbsp;Kazuki Inamura ,&nbsp;Tsubasa Takeshima ,&nbsp;Haruei Ogino ,&nbsp;Eikichi Ihara ,&nbsp;Yasuhiko Minokoshi ,&nbsp;Yoshihiro Ogawa","doi":"10.1016/j.jcmgh.2025.101635","DOIUrl":"10.1016/j.jcmgh.2025.101635","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Chronic constipation has attracted considerable attention because of its negative impact on quality of life. Although defecation depends on local anorectal motility coordinated by the central nervous system, how it is regulated by the brain remains unclear.</div></div><div><h3>Methods</h3><div>Brain areas responsible for defecation, known as the defecation brain area (DBA), were identified using a trans-synaptic tracing virus, pseudorabies virus (PRV). Candidate DBAs were assessed using opto- and chemogenetic methods and in vivo monitoring of neural activity.</div></div><div><h3>Results</h3><div>A significant number of PRV-infected cells were observed in the Barrington’s nucleus (Bar), locus coeruleus (LC), ventrolateral periaqueductal gray (vlPAG), and paraventricular hypothalamic nucleus (PVH) following virus infection in the distal colon. Opto- and chemogenetic activation studies revealed that vesicular glutamate transporter 2 (VGluT2) neurons in the Bar and LC, and corticotropin-releasing hormone (CRH) neurons in the Bar exhibit prompt (short-acting) and delayed (long-lasting) contractions in the distal colon, respectively. Their neural activities increased and peaked during spontaneous defecation. In contrast, activation of tyrosine hydroxylase neurons in the LC, which co-express VGluT2, exhibited no response. PRV experiments revealed that PVH^VGluT2 and vlPAG^CRH neurons are upstream neurons that connect to Bar^VGluT2 neurons, and their optogenetic activation resulted in a contraction of the distal colon.</div></div><div><h3>Conclusions</h3><div>The study is the first to show that the Bar works as the pontine DBA, where Bar^VGluT2 and Bar^CRH neurons exert prompt and delayed defecation activity, respectively. PVH^VGluT2 and vlPAG^CRH neurons are candidates for upstream neurons that regulate defecation through Bar^VGluT2 neurons.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 1","pages":"Article 101635"},"PeriodicalIF":7.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sympathetic Overactivation Drives Colonic Eosinophil Infiltration Linked to Visceral Hypersensitivity in Irritable Bowel Syndrome","authors":"Shaoqi Duan ,&nbsp;Hirosato Kanda ,&nbsp;Feng Zhu ,&nbsp;Masamichi Okubo ,&nbsp;Taro Koike ,&nbsp;Yoshiya Ohno ,&nbsp;Toshiyuki Tanaka ,&nbsp;Yukiko Harima ,&nbsp;Kazunari Miyamichi ,&nbsp;Hirokazu Fukui ,&nbsp;Shinichiro Shinzaki ,&nbsp;Yilong Cui ,&nbsp;Koichi Noguchi ,&nbsp;Yi Dai","doi":"10.1016/j.jcmgh.2025.101658","DOIUrl":"10.1016/j.jcmgh.2025.101658","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Mucosal immune alteration is a characteristic clinical manifestation of irritable bowel syndrome (IBS), and its symptoms are often triggered by psychological stress. The present study aimed to investigate the impact of early life stress-associated dysfunction of the sympathetic nervous system (SNS) on mucosal immune changes in the gastrointestinal tract (GI) and its contribution to visceral hypersensitivity of IBS.</div></div><div><h3>Methods</h3><div>We utilized a traditional animal model of IBS with maternal separation (MS) and evaluated colorectal hypersensitivity, immune alteration, and SNS activity in adult rats with MS. We conducted a series of experiments to manipulate peripheral SNS activity pharmacologically and chemogenetically to explore the interaction between SNS activity and GI events.</div></div><div><h3>Results</h3><div>The MS-induced IBS model exhibited visceral hypersensitivity and eosinophilic infiltration in the colonic mucosa, along with SNS overactivation. Degeneration of the SNS using 6-OHDA neurotoxin decreased eosinophil infiltration and visceral hypersensitivity in the MS model. Notably, specific chemogenetic activation of the peripheral SNS induced eosinophil infiltration in the intestinal mucosa through the noradrenergic signaling-mediated release of eotaxin-1 from mesenchymal cells.</div></div><div><h3>Conclusions</h3><div>This study highlights the critical role of SNS overactivation in eotaxin-1-driven eosinophil infiltration in the colon, leading to the development of visceral hypersensitivity in IBS. The results provide important insights into the mechanistic links among increased sympathetic activity, mucosal immune alteration, and visceral hypersensitivity in individuals with IBS, suggesting potential therapeutic approaches.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101658"},"PeriodicalIF":7.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathogenic OTUD3 Mutations Predispose to Ulcerative Colitis Due to Barrier Dysfunction","authors":"Rabina Giri ,&nbsp;Minyi Lee ,&nbsp;Graham W. Magor ,&nbsp;Anne-Sophie Bergot ,&nbsp;Yaowu He ,&nbsp;Thomas Kryza ,&nbsp;Tashbib Khan ,&nbsp;Veronika Schreiber ,&nbsp;Robert J. Gordon ,&nbsp;Rachid Zagani ,&nbsp;Sumaira Z. Hasnain ,&nbsp;Rohan Lourie ,&nbsp;Adam Ewing ,&nbsp;John D. Hooper ,&nbsp;Ranjeny Thomas ,&nbsp;Timothy H. Florin ,&nbsp;Andrew Perkins ,&nbsp;Manish Gala ,&nbsp;Jakob Begun","doi":"10.1016/j.jcmgh.2025.101659","DOIUrl":"10.1016/j.jcmgh.2025.101659","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The contribution of common genetic polymorphisms to ulcerative colitis (UC) pathogenesis is modest; however, families with severe colitis may harbor rare variants with large effect sizes that highlight unrecognized pathways.</div></div><div><h3>Methods</h3><div>A multigenerational family with UC necessitating colectomy was identified. Whole exome sequencing of this kindred was performed, implicating a rare variant in <em>OTUD3</em>. Constitutive knock-out and intestinal specific <em>Otud3</em> deficient and heterozygous mice were generated. OTUD3 expression in human colonic biopsies and intestinal organoids was assessed using quantitative reverse transcription polymerase chain reaction and immunofluorescence. Prevalence of rare, damaging variants were compared in distinct patient cohorts. Plasmids containing <em>OTUD3</em> missense variants were introduced into cell lines where <em>OTUD3</em> was disrupted to determine their effects on cellular response to cytokine stimulation.</div></div><div><h3>Results</h3><div>Constitutive disruption or heterozygosity of <em>Otud3</em> in mice, or intestinal-specific deletion, resulted in impaired barrier integrity, tight-junction dysregulation, increased endoplasmic reticulum stress, and penetration of luminal bacteria deep into the colonic crypts that preceded a spontaneous progressive colitis. Analysis of distinct UC cohorts demonstrated enrichment of rare, damaging variants in <em>OTUD3</em>. Introduction of <em>OTUD3</em> variants in intestinal cell lines phenocopied the epithelial immune dysregulation observed in knockout mice. Finally, <em>OTUD3</em> mRNA and epithelial protein expression were decreased in the quiescent colonic epithelial tissue of genotype-unselected individuals with UC compared with matched non-UC controls.</div></div><div><h3>Conclusions</h3><div>Our results demonstrate that OTUD3 is required for colonic epithelial barrier function, and plays a role in the pathogenesis of UC.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101659"},"PeriodicalIF":7.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Placode Lineage Contributes to the Enteric Nervous System: A Caution for Cell Transplantation Therapy for Hirschsprung Disease","authors":"Shigeru Sato,&nbsp;Henry M. Sucov,&nbsp;Takako Makita","doi":"10.1016/j.jcmgh.2025.101657","DOIUrl":"10.1016/j.jcmgh.2025.101657","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101657"},"PeriodicalIF":7.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}