Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Single Cell Profiling in the Sox10^Dom Hirschsprung Mouse Implicates Hox genes in Enteric Neuron Trajectory Allocation.","authors":"Justin A Avila, Joseph T Benthal, Jenny C Schafer, David K Flaherty, E Michelle Southard-Smith","doi":"10.1016/j.jcmgh.2025.101590","DOIUrl":"10.1016/j.jcmgh.2025.101590","url":null,"abstract":"<p><strong>Background & aims: </strong>Enteric nervous system (ENS) development requires migration, proliferation, and differentiation of progenitors for normal gastrointestinal (GI) motility. Sox10 deficit causes aganglionosis, modeling Hirschsprung disease (HSCR), and disrupts ratios of postnatal enteric neurons in proximal ganglionated bowel. How Sox10 deficiency alters enteric neuron ratios is unclear. Sox10's prominent expression in enteric neural crest-derived progenitors (ENCP) and lack of this gene in mature enteric neurons led us to examine Sox10^Dom effects in early ENS development.</p><p><strong>Methods: </strong>Immunohistochemistry localized SOX10 in the developing ENS relative to HuC/D. ENS progenitors, developing neurons, and enteric glia were isolated from Sox10^+/+ and Sox10^Dom/+ littermates for single-cell RNA sequencing (scRNA-seq). scRNA-seq data was processed to identify cell type-specific markers, differentially expressed genes, cell fate trajectories, and gene regulatory network activity between genotypes. Hybridization chain reaction (HCR) coupled with immunohistochemistry validated expression changes.</p><p><strong>Results: </strong>SOX10 protein was detected in early ENS neurons. scRNA-seq profiles detected three neuronal trajectories emerging via two transition pathways accompanied by elevated activity of Hox gene regulatory networks (GRN). Sox10^Dom/+ scRNA-seq profiles exhibited a novel progenitor cluster, reduced numbers of cells in transitional states, and shifts in cell abundance between neuronal trajectories. Hoxa6 was differentially expressed in the neuronal trajectories impacted in Sox10^Dom/+ mutants and HCR identified altered Hoxa6 expression in early developing neurons of Sox10^Dom/+ ENS.</p><p><strong>Conclusions: </strong>Sox10^Dom/+ mutation shifts enteric neuron types by altering neuronal trajectories early in ENS development. Multiple neurogenic transcription factors are reduced in Sox10^Dom/+ scRNA-seq profiles. This work is the first to correlate changes in Hox expression, notably Hoxa6, with alterations in enteric neuron trajectories.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101590"},"PeriodicalIF":7.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700443","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":"Intermittent fasting reduces obesity-driven oxidative stress in the male mouse colon via changes in gut microbiota.","authors":"Citlally Condado-Huerta, Adriana López-Barradas, Alan Hernández-Melgar, Rommel A Carballo-Castañeda, Raúl De la Torre-Baez, Maria R Encarnacion-Garcia, Mónica Sánchez-Tapia, Omar Granados-Portillo, Lilia G Noriega, Natalia Vázquez-Manjarrez, Martha Guevara-Cruz, Nimbe Torres, Juan Carlos León-Contreras, Guillermina Juliana Baay-Guzman, Oscar Rodríguez-Lima, Abraham Landa, Porfirio Nava, Aldo Moreno-Ulloa, Armando R Tovar, Francisco Flores-Murrieta, Laura A Velazquez-Villegas","doi":"10.1016/j.jcmgh.2025.101592","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101592","url":null,"abstract":"<p><strong>Background and aims: </strong>Obesity impairs colon homeostasis by increasing oxidative stress, which is associated with damage to the epithelial barrier and the development of intestinal diseases. Intermittent fasting (IF) improves mitochondrial activity (MA) in metabolic tissues and positively modifies gut microbiota composition, suggesting that this intervention may exert beneficial effects on colon homeostasis. The aim of this study was to evaluate the effect of IF on MA in the colon and its modulation by gut microbiota in a diet-induced obesity mouse model.</p><p><strong>Methods: </strong>C57BL/6 male mice were fed a control (CNT) diet or high-fat/high-sucrose diet (HFSD) for 12 weeks, followed by 4 weeks of IF intervention or continued HFSD, with or without antibiotic (AB) treatment. We evaluated MA in colonic mitochondria determined by the oxygen consumption rate (OCR) and reactive oxygen species (ROS) production, together with gut microbiota composition and metabolome from feces.</p><p><strong>Results: </strong>Mice who underwent IF intervention had a significant decrease in colonic mitochondria OCR and ROS compared to the HFSD group, parameters that were sharply increased by AB administration. Moreover, IF improved colon morphology and epithelial barrier integrity via changes in gut microbiota composition and the metabolome profile, an effect that was modulated by mitochondrial activity and ROS production and not preserved upon AB administration.</p><p><strong>Conclusions: </strong>We conclude that IF reduces MA in the colon via changes in bacterial taxonomy and metabolites abundance to decrease oxidative stress caused by obesity, establishing a close connection between host MA and gut microbiota.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101592"},"PeriodicalIF":7.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700442","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":"FMO5 plays a sex-specific role in goblet cell maturation and mucus barrier formation.","authors":"Megan L Schaller, Madeline M Sykes, Joy Mecano, Sumeet Solanki, Wesley Huang, Ryan J Rebernick, Safa Beydoun, Emily Wang, Amara Bugarin-Lapuz, Yatrik M Shah, Scott F Leiser","doi":"10.1016/j.jcmgh.2025.101591","DOIUrl":"10.1016/j.jcmgh.2025.101591","url":null,"abstract":"<p><strong>Background and aims: </strong>The intestine plays a key role in metabolism, nutrient and water absorption, and provides both physical and immunological defense against dietary and luminal antigens. The protective mucosal lining in the intestine is a critical component of intestinal barrier that when compromised, can lead to increased permeability, a defining characteristic of inflammatory bowel disease (IBD), among other intestinal diseases. Here, we define a new role for the flavin-containing monooxygenase (FMO) family of enzymes in maintaining a healthy intestinal epithelium.</p><p><strong>Methods: </strong>Using Caenorhabditis elegans we measure intestinal barrier function, actin expression, and intestinal damage response. In mice, we utilize an intestine-specific, tamoxifen-inducible knockout model of the mammalian homolog of Cefmo-2, Fmo5, and assess histology, mucus barrier thickness, and goblet cell physiology. We also treat mice with the ER chaperone Tauroursodeoxycholic acid (TUDCA).</p><p><strong>Results: </strong>In nematodes, we find Cefmo-2 is necessary and sufficient for intestinal barrier function, intestinal actin expression, and is induced by intestinal damage. In mice, we find striking changes to the intestine within two weeks following FMO5 disruption. Alterations include sex-dependent changes in colon epithelial histology, goblet cell localization, and mucus barrier formation. These changes are significantly more severe in female mice, mirroring differences observed in IBD patients. Furthermore, we find increased protein folding stress in FMO5 knockout animals and successfully rescue the severe female phenotype with addition of a chemical ER chaperone.</p><p><strong>Conclusions: </strong>Together, our results identify a highly conserved and novel role for FMO5 in the mammalian intestine and support a key role for FMO5 in maintenance of ER/protein homeostasis and proper mucus barrier formation.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101591"},"PeriodicalIF":7.1,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683587","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":"Hepatic ketogenesis regulates lipid homeostasis via ACSL1-mediated fatty acid partitioning.","authors":"Raja Gopal Reddy Mooli, Yerin Han, Ericka J Fiorenza, Karthik Balakrishnan, Jitendra Singh Kanshana, Suchita Kumar, Fiona M Bello, Anoop R Nallanagulagari, Shreya Karra, Junyan Tao, Evan R Delgado, Lihong Teng, Alison B Kohan, Aatur D Singhi, Michael Jurczak, Sadeesh K Ramakrishnan","doi":"10.1016/j.jcmgh.2025.101593","DOIUrl":"10.1016/j.jcmgh.2025.101593","url":null,"abstract":"<p><strong>Background and aims: </strong>Liver-derived ketone bodies play an essential in energy homeostasis during fasting by supplying fuel to both the brain and peripheral tissues. Ketogenesis also helps to remove excess acetyl-CoA generated from fatty acid oxidation, thereby protecting against diet-induced hepatic steatosis. Despite this, the role of ketogenesis in fasting-associated hepatocellular lipid metabolism has not been thoroughly investigated.</p><p><strong>Methods: </strong>We utilized mice with liver-specific knockout of HMGCS2 mice to determine how ACSL1-mediated esterification contributes to fasting-induced steatosis and performed biochemical assays, gene expression profiling, Western blotting, and histological analyses. We further investigated the association between HMGCS2 expression, lipid re-esterification, and steatosis using human primary hepatocytes and liver samples from MASH patients.</p><p><strong>Results: </strong>We show that ketogenic insufficiency, achieved through disrupting hepatic HMGCS2, worsens liver steatosis in both fasted chow-fed and high-fat-fed mice. Our findings indicate that hepatic steatosis arises from increased fatty acid partitioning to the endoplasmic reticulum (ER) for re-esterification, a process mediated by acyl-CoA synthetase long-chain family member 1 (ACSL1). Mechanistically, the accumulation of acetyl-CoA due to impaired hepatic ketogenesis drives the elevated translocation of ACSL1 to the ER. Furthermore, our study reveals heightened ER-localized ACSL1 and lipid re-esterification in human MASH cases exhibiting impaired hepatic ketogenesis. We also demonstrate that L-carnitine, which buffers excess acetyl-CoA, reduces ER-associated ACSL1 and alleviates hepatic steatosis.</p><p><strong>Conclusion: </strong>Hepatic ketogenesis plays a crucial role in maintaining intracellular acetyl-CoA balance, regulating lipid partitioning, and preventing the development of fasting-induced hepatic steatosis.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101593"},"PeriodicalIF":7.1,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683588","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":"Targeting hepatic stellate cell PD-L1 alters liver inflammation and fibrosis in CCl₄ liver injury mouse model.","authors":"Bing Bai, Wenming Bao, Yuanguo Wang, Aurpita Shaha, Tatiana Kisseleva, Lianping He, Liankang Sun, Sofia Jerez, Vijay H Shah, Xianghu Wang, Ningling Kang","doi":"10.1016/j.jcmgh.2025.101587","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101587","url":null,"abstract":"<p><strong>Background and aims: </strong>PD-L1 on hepatic stellate cell (HSC) is required for HSC activation and suppressing T and B lymphocytes. We tested whether targeting HSC PD-L1 influenced liver inflammation and fibrosis in CCl₄ injury mouse model.</p><p><strong>Methods: </strong>HSC-specific PD-L1 knockout (PD-L1^HSCKO) mice were created by crossing Cd274 floxed mice to Collagen1A1-Cre mice. CCl₄ was injected into PD-L1^HSCKO and PD-L1^HSCWT mice twice weekly for 6 weeks. Liver fibrosis was assessed by Trichrome and Picrosirius Red staining; HSC activation was determined by immunofluorescence and Western blot for HSC activation markers; liver inflammation was studied by multiplex immunofluorescence and cytokine profiling. Multiomics was leveraged to determine how targeting PD-L1 altered HSC producing collagens and cytokines/chemokines.</p><p><strong>Results: </strong>Collagen deposition was reduced in CCl₄-injured PD-L1^HSCKO livers compared to CCl₄-injured PD-L1^HSCWT livers; myofibroblast density was lower in CCl₄-injured PD-L1^HSCKO livers compared to CCl₄-injured PD-L1^HSCWT livers. CCl₄-injured PD-L1^HSCKO livers had higher lymphocyte densities (GranzymeB+, CD8a+, CD20+) but lower Kupffer and myeloid cell densities (F4/80+ and CD11b+) compared to CCl₄-injured PD-L1^HSCWT livers. Serum AST and ALT, however, were similarly elevated by CCl₄ in both groups. Spatial and bulk-cell transcriptomics revealed a global transcriptomic change of HSCs induced by PD-L1 targeting. A targeted proteomics identified that HSC secretion of a group of cytokines/chemokines, including growth/differentiation factor 15, GM-CSF, CXC and CC chemokines, was altered upon PD-L1 targeting, highlighting the role of HSC PD-L1 in HSC/Kupffer and HSC/myeloid cell interactions during HSC activation and fibrosis development.</p><p><strong>Conclusions: </strong>Targeting HSC PD-L1 altered HSC transcriptome and liver inflammation, and suppressed liver fibrosis, representing a potential therapeutic strategy for liver fibrosis.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101587"},"PeriodicalIF":7.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669061","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":"Differential protective roles of c-Jun N-terminal kinase-2 in non-parenchymal liver cells and hepatocytes during cholestasis.","authors":"Mohamed Ramadan Mohamed, Gang Zhao, Ines Volkert, Antonio Molinaro, Carolin V Schneider, Pavel Strnad, Jan G Hengstler, Chi Xu, Roger J Davis, Kai Markus Schneider, Francisco Javier Cubero, Christian Trautwein","doi":"10.1016/j.jcmgh.2025.101588","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101588","url":null,"abstract":"<p><strong>Background and aims: </strong>Cell-type specific mechanisms are crucial in determining liver disease progression e.g. during cholestasis. Here we defined the role of c-Jun N-terminal kinases 2 (JNK2) in cholestasis. Specifically, we studied differential JNK2 functions for controlling bile acid (BA) homeostasis and inflammation.</p><p><strong>Methods: </strong>Mice lacking Jnk2 function, either specifically in hepatocytes (Jnk2^Δhepa), globally (Jnk2^-/-) or in combination with hepatocyte-specific Jnk1 deletion (Jnk1^Δhepa/2^-/-), were subjected to bile duct ligation (BDL). Parameters of liver injury, inflammation, BA composition, synthesis and transport, and fibrosis were studied. Additionally, bone marrow transplantation (BMT) experiments were performed. Furthermore, primary cultured hepatocytes were incubated with hyper-IL6, and hepatic BA transporters were analysed.</p><p><strong>Results: </strong>Jnk2^-/- mice triggered increased liver injury, inflammation, and fibrosis compared to WT and Jnk2^Δhepa mice after BDL. However, Jnk1^Δhepa/2^-/- mice exhibited an aggravated phenotype compared with Jnk2^-/- livers as indicated by enhanced hepatic damage, ductular reaction, inflammatory response and fibrogenesis. BMT experiments excluded BM-derived cells and indicated that non-parenchymal liver cells (NPCs) play a critical role in driving the Jnk1^Δhepa/2^-/--dependent severe phenotype after BDL. Furthermore, in vivo and in vitro analysis demonstrated a pivotal role for JNK signalling in hepatocytes in the regulation of BA homeostasis and transport.</p><p><strong>Conclusions: </strong>Besides in hepatocytes, JNK2 in NPCs - but not in BM-derived cells - confers protection during cholestasis. After BDL, a JNK2-dependent mechanism directs the inflammatory response involved in regulating biliary transporters. Hence, our data define JNK2 as a critical target during cholestasis in NPCs.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101588"},"PeriodicalIF":7.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669059","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 PXR Signaling Exacerbates Ethanol-Induced Liver Injury in Females: Evidence from Mouse Models and Human ALD Cohorts.","authors":"Malvin Ofosu-Boateng, Sora Choi, Sarah Kim, Elizabeth Twum, Daniel O Nnamani, Lidya H Gebreyesus, Suryakant Niture, Nour Yadak, Deepak Kumar, Frank J Gonzalez, Suthat Liangpunsakul, Julia Yue Cui, Maxwell A Gyamfi","doi":"10.1016/j.jcmgh.2025.101589","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101589","url":null,"abstract":"<p><strong>Background & aims: </strong>Alcohol-associated liver disease (ALD), resulting from excessive alcohol consumption, manifests with greater severity in females. The pregnane X receptor (PXR), a xenobiotic nuclear receptor critical for toxin defense, has been implicated in ALD; however, the mechanisms underlying its role, particularly in sex differences, remain unclear. Due to species-specific ligand differences, PXR-humanized (hPXR) mouse models are essential for investigating PXR's contribution to sexual dimorphism in human ALD.</p><p><strong>Methods: </strong>Male and female C57BL/6N Tac wild-type (WT) and hPXR mice were subjected to the 10-day chronic-plus-binge ethanol (NIAAA) model. Assessments included hepatotoxicity, liver histopathology, protein expression, hepatic transcriptomics, and bioinformatic analyses. Complementary gene expression and tissue microarray (TMA) analyses were performed on human ALD liver samples.</p><p><strong>Results: </strong>Ethanol-induced hepatotoxicity was most pronounced in female hPXR mice. Microarray profiling identified 442 genes uniquely regulated by ethanol in female hPXR mice, highlighting significant pathway alterations. Quantitative analyses revealed that hepatotoxicity correlated with increased hepatic mRNA levels of Pparg (1.9-fold), its target Fsp27/Cidec (31-fold), liver-specific Fsp27β (66-fold), and the CAR/PXR target Cyp2b10, all implicated in ethanol-induced liver injury. Pro-inflammatory markers Tnfrsf12a (2.7-fold) and Fgf21 (14.6-fold) were also elevated. In female ALD patients, hepatic mRNA levels of CIDEC (13.8-fold), CYP2B6 (the human ortholog of Cyp2b10, 3.7-fold), FGF21 (4.5-fold), and TNFRSF12A (3-fold) were significantly increased. TMA analyses further demonstrated elevated expression of CYP2B6 and PXR1 in patients with alcohol-associated hepatitis.</p><p><strong>Conclusion: </strong>These data indicate that hPXR-transgenic mice serve as a valuable in vivo model to elucidate mechanisms driving sexual dimorphism in ethanol-induced hepatotoxicity.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101589"},"PeriodicalIF":7.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669060","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":"CMGH Reviews: From Comprehensive Narratives to Concise Insights.","authors":"Michele A Battle, Jonathan P Katz","doi":"10.1016/j.jcmgh.2025.101564","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2025.101564","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101564"},"PeriodicalIF":7.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144661113","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":"Histopathologic Evaluation and Single-cell Spatial Transcriptomics of the Colon Reveal Cellular and Molecular Abnormalities Linked to J-Pouch Failure in Patients with Inflammatory Bowel Disease.","authors":"Andrea D Olivas, Paul Chak Mou Ngai, Emily Schahrer, Junjie Xing, Mobarakeh Ghadiri, Kinga S Olortegui, John F Cursio, Shintaro Akiyama, Eugene B Chang, Le Shen, Konstantin Umanskiy, David T Rubin, David Zemmour, Christopher R Weber","doi":"10.1016/j.jcmgh.2025.101563","DOIUrl":"10.1016/j.jcmgh.2025.101563","url":null,"abstract":"<p><strong>Background & aims: </strong>Total abdominal colectomy (TAC) with a staged ileal pouch-anal anastomosis (IPAA) is a common surgical treatment for ulcerative colitis (UC). However, a significant percentage of patients experience pouch failure, leading to morbidity. This retrospective case-control study identified histopathologic features of the TAC specimen associated with pouch failure and investigated the molecular mechanisms of this susceptibility using single-cell spatial transcriptomics.</p><p><strong>Methods: </strong>We analyzed a cohort of 417 patients who underwent IPAA between 2000 and 2010 at the University of Chicago Medical Center for up to 18 years. Histologic examination of TAC specimens focused on disease activity, depth of inflammation, and specific features, including granulomas and deep ulcers. A subset of patients was profiled using single-cell spatial transcriptomics to map gene expression and immune cell interactions in relation to the risk of pouch failure.</p><p><strong>Results: </strong>The 18-year pouch failure risk was 23%, with post-procedure clinical features of Crohn's disease as a major risk factor (hazard ratio [HR], 4.3; 95% confidence interval [CI], 2.3-8.1) as well as high-risk histologic features, including deep chronic inflammation (HR, 21; 95% CI, 11-41) and severe disease activity (HR, 14; 95% CI, 5.7-32) in TAC specimens. Spatial transcriptomics showed immune infiltration of T and myeloid cells, reduced myocyte-glial interactions, and cytokine signaling pathways such as interleukin (IL)-10, IL-1β, and type I/II interferons, associated with an increased risk of pouch failure. CD68 immunohistochemistry confirmed that deep CD68⁺ macrophage infiltration is associated with increased risk of future pouch failure.</p><p><strong>Conclusion: </strong>Histologic features including CD68 immunohistochemisty and spatial molecular profiling are predictive of IPAA failure. These findings support the use of histologic evaluation and targeted molecular analysis of the TAC specimen to identify high-risk patients and improve IPAA outcomes.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101563"},"PeriodicalIF":7.1,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144509578","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":"Phosphocreatine Rescues Intestinal Epithelial Metabolic Dysfunction Related to Creatine Kinase Loss and is Protective in Murine Colitis.","authors":"Geetha Bhagavatula, Corey S Worledge, Ciara Schaepe, Emily M Murphy, Rane M Neuhart, J Scott Lee, Ian Cartwright, Sean P Colgan, Caroline H T Hall","doi":"10.1016/j.jcmgh.2025.101557","DOIUrl":"10.1016/j.jcmgh.2025.101557","url":null,"abstract":"<p><strong>Background & aims: </strong>Inflammatory bowel disease is associated with intestinal energetic derangements, including reduced creatine kinase (CK) expression. CK is critical to cellular energetics, catalyzing bidirectional transfer of high-energy phosphate between creatine and ATP, and phosphocreatine (PCr) and ADP. However, the impact of CK loss on intestinal epithelial cells (IECs) remains unclear. We aimed to characterize energetic and functional consequences of CK deficiency in IECs and identify a treatment to circumvent CK loss.</p><p><strong>Methods: </strong>The CK-brain isoform was knocked down (CKB KD) in T84 cells. Colonoids were derived from CK-brain/mitochondrial isoform knockout (CK dKO) mice. Cell lines were characterized by quantitative polymerase chain reaction, immunoblot, high-performance liquid chromatograph, Seahorse assays, transepithelial electrical resistance, wound healing, immunofluorescence, and proliferation assays, and in the presence of supplemental PCr. CK dKO mice treated with PCr in the setting of colitis were evaluated by clinical and histologic disease scoring.</p><p><strong>Results: </strong>CKB KD T84s and CK dKO colonoids demonstrated signs of energy deficiency, including reduced ATP levels and oxidative phosphorylation capacity. This was associated with diminished IEC function, most notably proliferation, and impaired barrier formation and scratch-wound healing. Supplementing PCr normalized ATP levels, proliferation, and barrier formation. Oral PCr supplementation during murine colitis resulted in improved disease activity.</p><p><strong>Conclusions: </strong>Loss of CK, a change that occurs in inflammatory bowel disease, causes defective energy metabolism and IEC functioning. PCr supplementation rescues many detrimental effects of CK loss and serves as a protective mechanism in murine colitis. These findings may provide insight into pathogenic mechanisms and a novel therapeutic modality in inflammatory bowel disease.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101557"},"PeriodicalIF":7.1,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144499453","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}