Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Barrington's nucleus: a pontine defecation brain area exhibiting prompt and delayed defecation responses.","authors":"Kota Bussaka, Yoshimasa Tanaka, Kunio Kondoh, Ken-Ichiro Nakajima, Takatoshi Chinen, Xiaopeng Bai, Yosuke Minoda, Hiroko Ikeda, Kazuki Inamura, Tsubasa Takeshima, Haruei Ogino, Eikichi Ihara, Yasuhiko Minokoshi, Yoshihiro Ogawa","doi":"10.1016/j.jcmgh.2025.101635","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101635","url":null,"abstract":"<p><strong>Background & aims: </strong>Chronic constipation has attracted considerable attention because of its negative impact on quality of life. While defecation depends on local anorectal motility coordinated by the central nervous system, how it is regulated by the brain remains unclear.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"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, Hirosato Kanda, Feng Zhu, Masamichi Okubo, Taro Koike, Yoshiya Ohno, Toshiyuki Tanaka, Yukiko Harima, Kazunari Miyamichi, Hirokazu Fukui, Shinichiro Shinzaki, Yilong Cui, Koichi Noguchi, Yi Dai","doi":"10.1016/j.jcmgh.2025.101658","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101658","url":null,"abstract":"<p><strong>Background & aims: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 signalling-mediated release of eotaxin-1 from mesenchymal cells.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101658"},"PeriodicalIF":7.1,"publicationDate":"2025-10-07","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, Minyi Lee, Graham Magor, Anne-Sophie Bergot, Yaowu He, Thomas Kryza, Tashbib Khan, Veronika Schreiber, Robert J Gordon, Rachid Zagani, Sumaira Z Hasnain, Rohan Lourie, Adam Ewing, John D Hooper, Ranjeny Thomas, Timothy H Florin, Andrew Perkins, Manish Gala, Jakob Begun","doi":"10.1016/j.jcmgh.2025.101659","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101659","url":null,"abstract":"<p><strong>Background and aims: </strong>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.</p><p><strong>Methods: </strong>A multigenerational family with UC necessitating colectomy was identified. Whole exome sequencing of this kindred was performed, implicating a rare variant in OTUD3. Constitutive knock-out and intestinal specific Otud3 deficient and heterozygous mice were generated. OTUD3 expression in human colonic biopsies and intestinal organoids was assessed using qRT-PCR and immunofluorescence. Prevalence of rare, damaging variants were compared in distinct patient cohorts. Plasmids containing OTUD3 missense variants were introduced into cell lines where OTUD3 was disrupted to determine their effects on cellular response to cytokine stimulation.</p><p><strong>Results: </strong>Constitutive disruption or heterozygosity of Otud3 in mice, or intestinal-specific deletion, resulted in impaired barrier integrity, tight-junction dysregulation, increased ER 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 OTUD3. Introduction of OTUD3 variants in intestinal cell lines phenocopied the epithelial immune dysregulation observed in knockout mice. Finally, OTUD3 mRNA and epithelial protein expression were decreased in the quiescent colonic epithelial tissue of genotype-unselected individuals with UC compared to matched non-UC controls.</p><p><strong>Conclusions: </strong>Our results demonstrate that OTUD3 is required for colonic epithelial barrier function, and plays a role in the pathogenesis of UC.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101659"},"PeriodicalIF":7.1,"publicationDate":"2025-10-07","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, Henry M Sucov, Takako Makita","doi":"10.1016/j.jcmgh.2025.101657","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101657","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"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}

{"title":"Reduced intestinal GLP-1⁺ cell numbers are associated with an inflammation-related epithelial metabolic signature.","authors":"Elisabeth Urbauer, Doriane Aguanno, Katharina Kuellmer, Amira Metwaly, Nadine Waldschmitt, Mohamed Ahmed, Sevana Khaloian, Gabriele Hörmannsperger, Julien Planchais, Tobias Fromme, R Balfour Sartor, Harry Sokol, Dirk Haller, Eva Rath","doi":"10.1016/j.jcmgh.2025.101656","DOIUrl":"10.1016/j.jcmgh.2025.101656","url":null,"abstract":"<p><strong>Background & aims: </strong>Enteroendocrine cells (EECs) are known for their role in digestion and metabolism, yet their role in intestinal inflammation remains unclear. In inflammatory bowel diseases (IBD), a contribution of EECs to pathogenesis is indicated by autoantibodies affecting EEC function and general disease symptoms like insulin resistance and altered intestinal motility. Particularly, the L cell-derived hormone glucagon-like peptide 1 (GLP-1), suggested to orchestrate metabolic-inflammatory responses may influence inflammatory pathways in the intestine.</p><p><strong>Methods: </strong>We quantified numbers of GLP-1⁺ cells in 4 different mouse models of intestinal inflammation and performed transcriptional analyses of colonic epithelial cells from inflamed interleukin (IL)10-deficient mice. Using a publicly available single-cell RNA sequencing dataset including mucosal biopsies from Crohn´s disease (CD) patients, we confirmed findings from the murine models. A model of mitochondrial dysfunction (ClpP^ΔIEC mice) as well as murine and human intestinal organoids were used to study molecular mechanisms.</p><p><strong>Results: </strong>Numbers of GLP-1 expressing cells are consistently reduced at the site of active disease in mouse models and CD patients. Despite this reduction, L cells from inflamed IL-10-deficient mice remained functional regarding GLP-1 secretion. Transcriptional analyses of intestinal epithelial cells indicate altered differentiation correlating with an inflammatory metabolic fingerprint. Reduced GLP-1⁺ cells in ClpP^ΔIEC mice and inhibition of respiration in organoid cultures supports a causative role for metabolism in steering differentiation.</p><p><strong>Conclusion: </strong>Reduction of GLP-1⁺ cells represents a general feature of ileal and colonic inflammation in mice and human. Given the numerous properties of GLP-1, this reduction likely affects inflammatory processes in the mucosa and disease-related symptoms on multiple levels, and therefore, should be considered a therapeutic target in IBD.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101656"},"PeriodicalIF":7.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233609","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":"Ferroptosis: A Novel Target to Rescue CD8⁺ T Cells Against Hepatitis B Virus.","authors":"Yongyan Chen","doi":"10.1016/j.jcmgh.2025.101631","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101631","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101631"},"PeriodicalIF":7.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228714","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":"An Update on Oxidative Stress and Redoxins in Pancreatitis.","authors":"Mohamad Assi","doi":"10.1016/j.jcmgh.2025.101632","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101632","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101632"},"PeriodicalIF":7.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228728","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":"Human-length Telomeres Limit Regeneration of Liver Epithelial Cells in Mice.","authors":"Michael Y Hu, Melissa Rowe, Mark Tigue, Yitzhak Reizel, Riham Smoom, Yehuda Tzfati, Klaus H Kaestner","doi":"10.1016/j.jcmgh.2025.101655","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101655","url":null,"abstract":"<p><strong>Background & aims: </strong>Telomeres, or the ends of linear chromosomes, are critical for maintaining genomic integrity. The commonly used C57BL/6 mouse strain has telomeres about 5 times longer than those present in humans. We recently engineered the C57BL/6 \"Telomouse\" to enable the study of human length telomeres, which we used here to study the effects of shortened telomeres on liver regeneration.</p><p><strong>Methods: </strong>We performed partial hepatectomy experiments with Telomice using wild type C57BL/6 mice as controls. Staggered injections of the thymidine analogs CldU and IdU were used to analyze their incorporation into nuclear DNA during cells' S-phase to assess proliferation. In a second model, we employed a competitive hepatocyte repopulation assay in Fah (fumarylacetoacetate hydrolase) null mice.</p><p><strong>Results: </strong>We found that human-length telomeres limit the proliferative capacity of cholangiocytes and hepatocytes in short-term liver regeneration. Control mice exhibited significant cholangiocyte proliferation at 36 hours post-PHx, which remained stable at 46 hours post-PHx. In contrast, Telomice exhibited decreased cholangiocyte proliferation at 36 hours post-PHx which further decreased at 46 hours post-PHx. Both control and Telomice exhibit increased hepatocyte proliferation at 46 hours compared to 36 hours post-PHx. However, Telomice exhibit less proliferation than controls at both time points. Compared to controls, Telomice exhibit an increased DNA damage response in the liver after partial hepatectomy. In a second model, Telomice hepatocytes also exhibited reduced efficacy in a competitive repopulation study using the Fah null mouse model of conditional hepatocyte ablation.</p><p><strong>Conclusions: </strong>Short telomeres induce DNA damage in the regenerating liver, hampering its ability to accelerate cell proliferation and regenerate the liver.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101655"},"PeriodicalIF":7.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214081","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":"Activation and spatial redistribution of RNA splicing factors trigger hepatic regeneration.","authors":"Yachun An, Jiabei Lian, Wenjing Wei, Yunuo Mao, Longxin Qiao, Tingting Li, Ruijian Li, Shumin Li, Shigang Zhao, Xuena Chen, Han Zhao, Huili Hu","doi":"10.1016/j.jcmgh.2025.101654","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101654","url":null,"abstract":"<p><strong>Background and aims: </strong>Tissue injury with regenerative obstacle leads to liver failure and inevitable consequent hepatic diseases. Yet, precise spatial and molecular alterations to initiate liver regeneration remains unknown.</p><p><strong>Methods: </strong>We employ spatiotemporal sequencing of regenerating liver combined with high-throughput single-cell RNA sequencing of established hepatocyte organoids (Hep-Orgs) mimicking the regenerative start, elucidate that splicing factors (SFs) were key factors responsible for liver regeneration. Additionally, we verify the function of splicing factors in knockout mice models in vivo.</p><p><strong>Results: </strong>We observed that the up-regulation of SFs in regenerative zone of liver and pre-cycling or cycling hepatocytes subpopulation of Hep-Orgs. We demonstrated that the splicing inhibitors suppress liver regeneration by increasing ribosomal proteins. Moreover, we identified Hnrnpu as the key SF for liver regeneration benefit to preventing chronic liver disease like metabolic dysfunction-associated steatotic liver disease (MASLD) CONCLUSIONS: The spatial remodeling of upregulated RNA splicing factors drives the first regenerative wave from the periportal zone. The reprogrammed subpopulations defined by highly expressed SFs represent original repopulating hepatocytes. Inhibiting RNA splicing leads to cellular upregulation of ribosomal proteins (RPs), less proliferative signals and abnormal lipid accumulation. Knockout of SFs leads to failure of liver regeneration and zonal disorder. SF reduction marks severe MASLD in patients and knockout mouse models. Our results lay the molecular foundation for tissue repair initiation and further developing potential therapeutic target for liver disease.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101654"},"PeriodicalIF":7.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208176","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":"Long noncoding RNA uc173 is a novel regulator of mitochondrial metabolism driving intestinal mucosal growth.","authors":"Lan Xiao, Song Ah Chae, Dongyoon Yoo, Hee K Chung, Min S Kwon, Amy VanderStoep, Ting-Xi Yu, Bridgette Warner, Myriam Gorospe, Jian-Ying Wang","doi":"10.1016/j.jcmgh.2025.101653","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101653","url":null,"abstract":"<p><strong>Background & aims: </strong>Long noncoding RNA uc.173, transcribed from ultraconserved regions, modulates many cell processes central to human pathologies, but the mechanism underlying uc.173 in the homeostasis of the intestinal epithelium is underexplored. Here we investigated the role of uc.173 in regulating mitochondrial metabolism and defined the implication of altered mitochondrial activity by uc.173 in renewal of the intestinal mucosa.</p><p><strong>Methods: </strong>Studies were conducted in CRISPR-Cas9 knock-in mice, primary enterocytes, and Caco-2 cells. Mitochondrial structure and function were elucidated by measuring mitochondria-associated proteins and mitochondrial respiratory capacity. Intestinal mucosal growth was measured by Ki67 immunostaining or BrdU incorporation assays.</p><p><strong>Results: </strong>Transient and specific deletion of uc.173 in the intestinal epithelium of mice by CRISPR-Cas9 knock-in using small guide RNA decreased the levels of several mitochondria-associated proteins including PGC-1α, along with disrupted mucosal growth. Decreasing the levels of uc.173 in cultured intestinal epithelial cells also decreased mitochondrial proteins and caused defects in the mitochondrial respiratory capacity. Reinforcing mitochondrial activity by using a mitochondrial activator or by overexpressing PGC-1α rescued growth of uc.173-deficient intestinal organoids. Mechanistic studies revealed that uc.173 increased PGC-1α expression by acting as a molecular decoy for miR-29b, thereby preventing the repressive interaction of miR-29b with PGC-1α mRNA.</p><p><strong>Conclusions: </strong>These findings indicate that uc.173 is a novel regulator of mitochondrial metabolism in the intestinal epithelium and highlight a role of deregulation of uc.173, miR-29b, and PGC-1α in the suppressed renewal of intestinal mucosa in patients with critical illnesses.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101653"},"PeriodicalIF":7.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208284","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}