Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Disruption of the Circadian Rhythm Induces Acute Pancreatitis via Amino Acid Metabolism-Mediated Macrophage Infiltration.","authors":"Haitao Li, Xiaomei Zhang, Zhili He, Wei Tong, Weijian Liu, Siyang Ma, Jianbo Lv, Danyang Ling, Qi Wang, Jian Wang, Jianwei Zheng","doi":"10.1016/j.jcmgh.2026.101777","DOIUrl":"10.1016/j.jcmgh.2026.101777","url":null,"abstract":"<p><strong>Background & aims: </strong>Circadian rhythms play a key role in regulating physiological processes, including inflammatory responses. Disruption of these rhythms has been associated with a variety of inflammatory diseases, but it is not known whether disrupted circadian rhythms directly trigger pancreatitis.</p><p><strong>Methods: </strong>We conducted a population-based cohort study using data from the UK Biobank to assess the association between circadian rhythm disruption and the risk of pancreatitis. In addition, a mouse model of circadian rhythm disruption was generated by exposing mice to continuous light. Expression levels of circadian rhythm genes, inflammatory factors, and digestive enzyme levels were analyzed using real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Hematoxylin and eosin staining and immunohistochemical staining were introduced to assess histopathological changes and macrophage infiltration. RNA sequencing was performed to identify differentially expressed genes as well as the mechanisms involved. In addition, we investigated whether administration of melatonin could alleviate this disorder.</p><p><strong>Results: </strong>This population-based study revealed that individuals with disrupted circadian rhythms are at a significantly higher risk of developing pancreatitis. In our circadian rhythm disorder mouse model, the incidence of acinar vacuolization increased with exposure to light. This was accompanied by a significant rise in intrapancreatic trypsin levels as well as serum digestive enzyme levels and activity. Interestingly, increased infiltration of M1-type macrophages was observed in the circadian rhythm disorder group. RNA sequencing analysis indicated that, under conditions of continuous light exposure, there was a significant enrichment of gene expression related to amino acid metabolism in pancreatic tissue, particularly genes involved in the glycine, serine, and threonine metabolic pathways. The use of the threonine dehydrogenase inhibitor QC1 effectively promoted the polarization of RAW264.7 cells towards the M2-type macrophage phenotype. Furthermore, treatment with melatonin inhibited the expression of threonine dehydrogenase in pancreatic tissue, reduced the levels of inflammatory cytokines, and promoted the M2 polarization of macrophages, thus relieving the circadian disruption-induced pancreatic disorder.</p><p><strong>Conclusions: </strong>Our study establishes a link between circadian disruption and an elevated risk of pancreatitis and suggests a potential therapeutic effect of melatonin treatment.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101777"},"PeriodicalIF":7.1,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576619","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":"Conserved Ductular Reaction Mechanisms in Biliary Atresia and Primary Sclerosing Cholangitis Derived From Single-Cell and Spatial Transcriptomics.","authors":"Annabelle Schofield, Binita M Kamath, Sonya A MacParland, Michael Trauner, Palak Trivedi, Jake Peter Mann","doi":"10.1016/j.jcmgh.2026.101778","DOIUrl":"10.1016/j.jcmgh.2026.101778","url":null,"abstract":"<p><p>Primary sclerosing cholangitis (PSC) and biliary atresia (BA) both demonstrate the ductular reaction (DR), including biliary ductules, immune infiltration, and fibroblast activation. Advances in single-cell RNA sequencing and spatial transcriptomics have revolutionized our understanding of the DR fibro-inflammatory niche of these disorders. Recent studies using these techniques have also demonstrated that there are conserved mechanisms of fibro-inflammation across diseases and organ systems. Notably, epithelial, mesenchymal, and innate immune processes in the DR are shared between BA and PSC, including pro-fibrogenic hepatocyte-to-cholangiocyte transdifferentiation, increased cholangiocyte senescence, accumulation of scar-/lipid-associated macrophages, Kupffer cell dysfunction, and activation of portal fibroblasts. In contrast, adaptive immune processes differ between the 2 disorders, including: transdifferentiation of Th17 into Th1 cells in BA, dominance of the Th17 axis in PSC, reduced CX3CR1 CD8/NKT-cells in BA, and gut-priming with liver-homing of lymphocytes in PSC. Future work needs to include a range of early- and late-stage disease samples, particularly non-cirrhotic PSC, and the use of single-cell spatial transcriptomic technologies will allow higher confidence in prediction of ligand-receptor interactions. These observations facilitate identification of therapeutic targets against conserved mechanisms of the DR applicable to multiple fibro-inflammatory disorders.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101778"},"PeriodicalIF":7.1,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576579","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":"Colon-Restricted Phosphatase and Tensin Homolog Deleted From Chromosome 10 Haploinsufficiency Models Phosphoinositide 3-Kinase Pathway-Driven Invasion in Colorectal Cancer.","authors":"Haruki Sada, Hiroaki Niitsu, Yuji Urabe, Hikaru Nakahara, Masatoshi Kochi, Naoya Sakamoto, Yusuke Sotomaru, Hirotaka Tashiro, Shiro Oka, Hideki Ohdan, Eric R Fearon, Takao Hinoi","doi":"10.1016/j.jcmgh.2026.101773","DOIUrl":"10.1016/j.jcmgh.2026.101773","url":null,"abstract":"<p><strong>Background & aims: </strong>The multistep accumulation of driver gene mutations is associated with early-stage colorectal tumorigenesis. To observe the phenotype-genotype correlation, we developed a series of genetically engineered mouse models based on Apc inactivation led by CDX2P-Cre and found invasive adenocarcinomas developed by inducing the loss of one Pten copy with Apc inactivation in the colonic epithelium. Here, we aimed to study the mechanisms underlying Pten haploinsufficiency and its clinical relevance.</p><p><strong>Methods: </strong>Tumor number, volume, and histology were compared between CDX2P-Cre;Apc^flox/+ (CPC;Apc) and CDX2P-Cre;Apc^flox/+;Pten^flox/+ (CPC;ApcPten) mice, and a multi-omics analysis was used to investigate the mechanism of the invasive phenotype in CPC;ApcPten mice. Rapamycin was administered to tumor organoids and in vivo to evaluate its dependency on the ATK serine-threonine protein kinase (AKT)- mechanistic target of rapamycin complex 1 (mTORC1) pathway. We also performed phylogenetic analysis of tumor evolution during human colorectal carcinogenesis using multiple targeted biopsies.</p><p><strong>Results: </strong>A greater number of tumors developed in CPC;ApcPten mice, half of which invaded the submucosal layer. Although both Apc alleles were inactivated by Cre-LoxP recombination and loss of heterozygosity in tumors, a wild-type Pten allele remained in the tumors of CPC;ApcPten mice, suggesting the haploinsufficient effect of Pten on tumorigenesis. Loss of one Pten copy decreased Pten expression levels and induced downstream activation of the AKT-mTORC1 signaling pathway in CPC;ApcPten mice. Rapamycin administration markedly inhibited tumorigenesis in CPC;ApcPten and CPC;Apc mice. In clinical biopsies, phosphoinositide 3-kinase (PI3K) genetic alteration was predominantly observed during the transition from tubular adenoma to adenocarcinoma.</p><p><strong>Conclusions: </strong>The effect of Pten haploinsufficiency on colonic tumor formation in mice reaffirms the significance of PI3K alterations in tumor evolution in human colorectal cancers.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101773"},"PeriodicalIF":7.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147534409","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":"Mex-3 RNA Binding Family Member A Modulates Peroxisome Proliferator-Activated Receptor Gamma Pathway Activity and Colorectal Cancer Growth.","authors":"Ana R Silva, Alexandre Coelho, Vanessa Machado, Morgana Russel, Dalila Mexieiro, Ana L Amaral, Bruno Cavadas, Nuno Mendes, Carina Carvalho-Maia, Davide Gigliano, Carmen Jerónimo, Raquel Almeida, Bruno Pereira","doi":"10.1016/j.jcmgh.2026.101771","DOIUrl":"10.1016/j.jcmgh.2026.101771","url":null,"abstract":"<p><strong>Background & aims: </strong>RNA-binding proteins (RBPs) are major effectors of post-transcriptional regulation. Recently, we described the role of Mex-3 RNA binding family member A (MEX3A) in maintaining leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5)+ intestinal stem cells identity and epithelial renewal. This work aimed to study MEX3A functional impact in colorectal cancer (CRC).</p><p><strong>Methods: </strong>We characterized MEX3A expression profile in CRC mouse models and a cohort of CRC cases (n = 172). Mouse CRC tissues were used for the establishment of tumoroids and CRISPR/Cas9-mediated MEX3A knockout was performed in patient-derived CRC tumoroids to further understand its biological and therapeutic relevance. Simultaneously, we implemented the high-throughput technique HyperTRIBE to uncover MEX3A RNA targets.</p><p><strong>Results: </strong>Intestinal adenomas from Apc^+/fl mice have increased Mex3a expression, and Apc^+/fl;Mex3a^+/- animals presented a significant reduction in tumor burden. Apc^+/fl;Kras^+/G12D;Mex3a^+/- compound mice exhibited reduced tumor area, whereas corresponding tumoroids had reduced growth ability and enhanced differentiation potential associated with increased peroxisome proliferator-activated receptor gamma (PPARγ) signaling. MEX3A overexpression was observed in 85% of human CRC cases, whereas 72% presented PPARγ downregulation, with a significant inverse correlation (P = .039). Accordingly, MEX3A-depleted patient-derived CRC tumoroids showed decreased LGR5 expression, accompanied by increased PPARγ expression and higher sensitivity to 5-fluorouracil/oxaliplatin (FOLFOX)-based chemotherapy. HyperTRIBE results revealed a direct interaction between MEX3A and PPARG transcripts.</p><p><strong>Conclusions: </strong>MEX3A contributes to colorectal carcinogenesis, in association with PPARγ signaling modulation, impacting tumor development and therapeutic response.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101771"},"PeriodicalIF":7.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147516755","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":"Guiding Principles: Reporting Elements for Gastrointestinal Organoid Research.","authors":"Kelli L VanDussen, Tatiana A Karakasheva, Maxime M Mahe, Joseph Burclaff, Luis F Arrieta-Viana, Ian Williamson, Heather A McCauley, Andrés J García, Scott T Magness, Kathryn E Hamilton","doi":"10.1016/j.jcmgh.2026.101772","DOIUrl":"10.1016/j.jcmgh.2026.101772","url":null,"abstract":"<p><p>Gastrointestinal (GI) organoids are now widely used for disease modeling, drug discovery, regenerative-, and precision medicine. As publications using GI organoids have increased exponentially, methodological reporting across GI organoid studies remains inconsistent, making results difficult to interpret, compare, and reproduce. To address this, we present community-informed guidance for reporting key experimental details in GI organoid research. Our recommendations were developed by integrating established biomedical reporting frameworks, organoid-focused resources from international organizations, and structured input from the GI organoid community through an expert panel survey. These inputs informed a core set of reporting items, including stem cell source and donor context, media and supplement composition, extracellular matrix type, culture configuration, and other parameters essential for replication. We provide an \"Organoid Reporting Toolkit\" containing practical checklists and templates intended to help authors, reviewers, editors, and journals. Together, these resources aim to improve transparency and reproducibility, facilitate cross-study comparison, and streamline communication in the GI organoid field while preserving flexibility for methodological innovation.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101772"},"PeriodicalIF":7.1,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147500813","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":"Immune Patterns Shape Liver Hepatocellular Carcinoma Prognosis.","authors":"Yi-Jie Zhang, Ning Liu","doi":"10.1016/j.jcmgh.2026.101767","DOIUrl":"10.1016/j.jcmgh.2026.101767","url":null,"abstract":"<p><strong>Background & aims: </strong>Patterns of immune cell infiltration (ICI) and tumor genetic variability are key factors affecting liver hepatocellular carcinoma (LIHC) outcomes and treatment response. Yet, their precise roles remain unclear. This study investigates how these immune and genetic factors shape LIHC progression and identifies regulatory genes that could enhance immunotherapy effectiveness.</p><p><strong>Methods: </strong>We analyzed LIHC datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), applying CIBERSORT and ESTIMATE algorithms to evaluate the tumor immune microenvironment (TIME) and calculate tumor mutational burden (TMB). ICI scoring was performed to identify survival-associated patterns, and gene set enrichment analysis, weighted gene coexpression network analysis (WGCNA), and machine learning were employed to uncover immunoregulatory genes. The role of CST7 in ICI and PD-1 blockade response was validated in mouse models.</p><p><strong>Results: </strong>ICI analysis revealed distinct survival-associated clusters, with patients in Cluster B showing significantly improved survival. Gene subtype A was linked to prolonged survival with enhanced M1 macrophage infiltration. CST7 was identified as a key regulator, promoting CD8⁺ T cell infiltration and demonstrating synergy with programmed cell death protein 1 (PD-1) antibody therapy. TMB was positively correlated with ICI patterns and served as an independent prognostic marker for LIHC outcomes.</p><p><strong>Conclusions: </strong>CST7 contributes to enhanced ICI and boosts the efficacy of PD-1 immunotherapy, suggesting its potential as a therapeutic option for LIHC.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101767"},"PeriodicalIF":7.1,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147470372","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":"Color Graphics: Can Everyone See Them?","authors":"Yutong Geng, Vivian Ortiz","doi":"10.1016/j.jcmgh.2026.101766","DOIUrl":"10.1016/j.jcmgh.2026.101766","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101766"},"PeriodicalIF":7.1,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147461025","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":"Ungluing the Mystery of Postoperative Ileus: Enteric Glial Connexin 43 Promotes the Development of Inflammation.","authors":"Keith A Sharkey","doi":"10.1016/j.jcmgh.2026.101761","DOIUrl":"10.1016/j.jcmgh.2026.101761","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101761"},"PeriodicalIF":7.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147357798","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":"Vacuolar Membrane Protein 1 and Transmembrane Protein 41B in Action: At the Right Place, With the Right Strength.","authors":"Xiao-Ming Yin","doi":"10.1016/j.jcmgh.2026.101763","DOIUrl":"10.1016/j.jcmgh.2026.101763","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101763"},"PeriodicalIF":7.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147357784","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":"Support Cells to Stem Cells: The Promise of Enteric Glia in Treating Gut Neuropathies.","authors":"Tim J Hibberd, Nick J Spencer","doi":"10.1016/j.jcmgh.2026.101764","DOIUrl":"10.1016/j.jcmgh.2026.101764","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101764"},"PeriodicalIF":7.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147357702","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}