Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"Triazine thiols decrease Apolipoprotein B secretion from hepatocytes through inhibition of human carboxylesterase 1.","authors":"Josef Blaszkiewicz, Yu-Lin Jiang, Jui-Tung Liu, Carla Martinez-Morant, Troy Dearth, Casper van Altena, Mary Paige Lamprecht, Christiana Kappler, Mi-Hye Lee, Jennifer R Bethard, Lauren E Ball, Stephen A Duncan","doi":"10.1016/j.jcmgh.2026.101796","DOIUrl":"https://doi.org/10.1016/j.jcmgh.2026.101796","url":null,"abstract":"<p><strong>Background and aims: </strong>Homozygous familial hypercholesterolemia (HoFH) is an autosomal genetic disorder that generates increased levels of low-density lipoproteins (LDL) in the serum. Elevated LDL results in hypercholesterolemia leading to potentially fatal cardiovascular disease. HoFH patients are often refractory to standard cholesterol-lowering treatments. Some available pharmaceuticals developed specifically for HoFH can elevate hepatic lipid levels and in other cases have limited accessibility. Previously, we identified a family of triazine thiol compounds that effectively reduce apolipoprotein B-100 (APOB) secretion by hepatocytes. In mice with humanized livers, triazine thiols effectively lowered serum cholesterol, triglycerides, low-density lipoproteins and lipoprotein(a) (Lp(a)). Despite their effectiveness, the mode of action of triazine thiols was unknown.</p><p><strong>Methods and results: </strong>Using affinity-based mass spectrometry we identify Carboxylesterase 1 (CES1) as a triazine thiol binding protein. Through biochemical assays, we show that triazine thiols are slow-binding, allosteric, covalent CES1-specific inhibitors. We use molecular modeling to identify a predicted binding site within CES1 near cysteine 390 and demonstrate that loss of this cysteine leads to resistance to triazine thiol-mediated inhibition. Moreover, we show that hepatocyte-like cells derived from CES1^-/- induced human pluripotent stem cells have a significant reduction in APOB secretion, mimicking the effect of treating hepatocytes with triazine thiols.</p><p><strong>Conclusions: </strong>This study establishes triazine thiols as novel, highly specific CES1 inhibitors, providing insight into their mechanism and highlighting CES1 inhibition as an approach for treating hypercholesterolemia.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101796"},"PeriodicalIF":7.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147823930","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":"Interleukin-13 Promotes Accumulation of Esophageal Epithelial Mitochondria With Translational Implications for Eosinophilic Esophagitis.","authors":"Jazmyne L Jackson, Reshu Saxena, Mary Grace Murray, Abigail J Staub, Courtney Worrell, Jasmine Cruz, No'ad Shanas, Alena Klochkova, Travis H Bordner, John M Crespo, Annie D Fuller, William Nazario-Lugo, Grace Davis, Hailey Golden, Andres J Klein-Szanto, Tatiana A Karakasheva, Adam Karami, John W Elrod, Gary W Falk, Zachary Wilmer Reichenbach, Melanie Ruffner, Amanda B Muir, Kelly A Whelan","doi":"10.1016/j.jcmgh.2026.101782","DOIUrl":"10.1016/j.jcmgh.2026.101782","url":null,"abstract":"<p><strong>Background & aims: </strong>Metabolic and mitochondrial dysfunction have recently been implicated in eosinophilic esophagitis (EoE) pathogenesis. However, there is a need to define the influence of EoE-associated inflammatory cues upon mitochondrial biology, mechanisms mediating these effects, and the clinical significance of mitochondrial alterations in EoE.</p><p><strong>Methods: </strong>Mitochondria were evaluated in human biopsies, MC903/ovalbumin-induced murine EoE, and human esophageal keratinocytes stimulated with EoE-relevant cytokines. Mitochondrial mediators were assessed via quantitative reverse transcription polymerase reaction and Western blotting. Metabolism, mitochondrial membrane potential, and apoptosis were measured. Mitochondrial DNA (mtDNA)-encoded genes, ND1 and ND6 were assessed by quantitative polymerase chain reaction in DNA from culture media and circulating nucleic acids from human serum samples. Effects of Janus kinase (JAK) inhibitor ruxolitinib or genetic inhibition of signal transducer and activator of transcription (STAT)3 or STAT6 on mitochondria were assessed in vitro.</p><p><strong>Results: </strong>We identified evidence of increased mitochondria in esophageal mucosa of patients with EoE and mice with EoE-like inflammation. Interleukin (IL)-13 consistently induced mitochondrial accumulation in esophageal keratinocytes in vitro, and this response was associated with increased expression of mediators of mitochondrial biogenesis, fusion, and mitophagy. IL-13 suppressed mitochondrial respiration and adenosine triphosphate (ATP) production, without impacting membrane polarization or apoptosis. Patients with active EoE exhibited elevated serum mtDNA levels and upregulation of mediators of mtDNA-associated inflammatory signaling. Increased mitochondrial mass and accumulation of extracellular mtDNA in IL-13-treated esophageal keratinocytes were dependent on JAK/STAT signaling.</p><p><strong>Conclusions: </strong>We identify IL-13 as a mediator of increased mitochondrial mass in EoE through JAK/STAT signaling. We further demonstrate that IL-13 promotes accumulation of extracellular mtDNA and that circulating mtDNA is elevated in patients with EoE.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101782"},"PeriodicalIF":7.1,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147647686","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":"Microbial Monotherapy With Leuconostoc sp LB-P8 Improves Inflammation and Fibrosis in Mouse Primary Sclerosing Cholangitis by Inhibiting Transforming Growth Factor β1/SMAD Signaling.","authors":"Kihyoun Park, Joon Yong Kim, Seong Woon Roh, Bansi P Savaliya, Carys A Turner, Nicholas E Pirius, Nicholas F LaRusso, Kyoungsub Song, Steven P O'Hara","doi":"10.1016/j.jcmgh.2026.101789","DOIUrl":"10.1016/j.jcmgh.2026.101789","url":null,"abstract":"<p><strong>Background & aims: </strong>Primary sclerosing cholangitis (PSC) is a prototypical disease with an impaired gut-liver axis, frequently associated with inflammatory bowel disease, and linked to microbial dysbiosis. However, how microbes influence PSC progression remains unclear. We identified a novel L sp. (LB-P8) with potential anti-fibrotic properties via inhibition of transforming growth factor beta-1 (TGF-β)/SMAD signaling and investigated its therapeutic efficacy and mechanisms in mouse PSC models.</p><p><strong>Methods: </strong>Human intestinal cells were cultured with or without LB-P8 to assess metabolite profiles (untargeted ultra-performance liquid chromatography-tandem mass spectrometry) and gene expression in co-cultured myofibroblasts and macrophages (reverse transcription-quantitative polymerase chain reaction). LB-P8 was orally gavaged following disease onset in three cholestatic models: bile duct ligation (BDL), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding, and the Mdr2^-/- mouse. Hepatic injury, inflammation, and fibrosis were assessed by serum alanine aminotransferase and alkaline phosphatase, histology, immunofluorescence, Picrosirius red staining, and reverse transcription-quantitative polymerase chain reaction. Nanostring GeoMX spatial transcriptomic analysis was performed on DDC-fed liver. LB-P8 was also tested in dextran sodium sulfate (DSS)-induced colitis.</p><p><strong>Results: </strong>Metabolomic profiling of LB-P8 cultures revealed increased detection of 10 metabolites involved in anti-fibrosis and anti-inflammation. RNA sequencing analysis of hepatic stellate cells showed downregulation of TGF-β, epithelial-mesenchymal transition (EMT,) and integrin signaling pathways. LB-P8 reduced liver fibrosis in BDL, DDC-fed, and Mdr2^-/- mouse models as evident by ∼50% lower Picrosirius red staining and decreased expression of Col1a1 and Timp1. In Mdr2^-/- and DDC-fed mice, LB-P8 reduced periportal macrophage number (F4/80; ∼30%). GeoMX spatial transcriptomics revealed reduced TGF-β1 in cholangiocyte and myofibroblast regions. Finally, LB-P8 suppressed expression of colonic markers of inflammation and fibrosis in the DSS model of bowel injury.</p><p><strong>Conclusions: </strong>LB-P8 ameliorates cholestatic liver disease progression by reducing TGF-β-mediated fibroblast activation, and periportal accumulation of macrophages. Targeting the gut-liver axis with LB-P8 may represent a novel therapeutic strategy for PSC.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101789"},"PeriodicalIF":7.1,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147719275","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":"Maternal High-Fat Diet Worsens Necrotizing Enterocolitis via Effects on Mitochondrial Function in Newborn Mice.","authors":"Koichi Tsuboi, Hee-Seong Jang, Pranav Prakash, Brian Kwon, Sanxia Wang, Menghan Wang, Thomas Prindle, William B Fulton, Chhinder P Sodhi, David J Hackam","doi":"10.1016/j.jcmgh.2026.101786","DOIUrl":"10.1016/j.jcmgh.2026.101786","url":null,"abstract":"<p><strong>Background & aims: </strong>Necrotizing enterocolitis (NEC) is a life-threatening intestinal disease of preterm infants that causes epithelial injury and necrosis. Prematurity and postnatal formula administration are known contributors, but maternal nutrition may also influence offspring gut susceptibility. The biological relationship between maternal diet and neonatal intestinal vulnerability remains unclear.</p><p><strong>Methods: </strong>A maternal high-fat diet (HFD) mouse model with a neonatal NEC model were used to investigate how maternal HFD affects offspring outcomes. Bulk RNA sequencing of ileal tissue before NEC induction was used to assess baseline transcription profiles. Following NEC, survival rate was assessed with ileal histological injury, epithelial reactive oxygen species, and mitochondrial membrane depolarization, as well as ultrastructural characteristics on transmission electron microscopy.</p><p><strong>Results: </strong>Compared with standard diet, offspring born from HFD mothers showed altered mitochondria-related gene expression, shorter villi, and reduced MUC2⁺ goblet cells. Transmission electron microscopy showed region-specific mitochondria abnormalities, with crypt enterocytes showing reduced mitochondrial volume density and size, and increased mitochondria-endoplasmic reticulum contact site after NEC induction. Strikingly, HFD increased mortality and elevated epithelial reactive oxygen species after the induction of NEC, linking maternal dietary risk factors with NEC development.</p><p><strong>Conclusions: </strong>Maternal HFD disrupts mitochondrial architecture and transcriptional programming in the neonatal intestine, promoting a pre-injured state that increases NEC susceptibility, suggesting that maternal diet may be a modifiable target for early NEC prevention.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101786"},"PeriodicalIF":7.1,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147719213","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":"Gastric Cancer-Associated Immunomodulatory Fibroblasts Persist Following Helicobacter pylori Eradication: The Need to Douse a Smoldering Fire.","authors":"Jennifer M Noto, Richard M Peek","doi":"10.1016/j.jcmgh.2026.101787","DOIUrl":"10.1016/j.jcmgh.2026.101787","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101787"},"PeriodicalIF":7.1,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147678935","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":"Mesothelin/Mucin 16 Signaling in Activated Portal Fibroblasts Drives the Development of Cholestatic Fibrosis and Hepatocellular Carcinoma in Aged Female Multidrug Resistance Protein 2 Knockout Mice.","authors":"Sadatsugu Sakane, Takahiro Nishio, Hiroaki Fuji, Se Yong Park, Kei Ishizuka, Charlene Miciano, Yusuke Kimura, Mojgan Hosseini, Karin Diggle, Vivian Zhang, Wonseok Lee, Hyun Young Kim, Xiao Liu, Allen Wang, David A Brenner, Tatiana Kisseleva","doi":"10.1016/j.jcmgh.2026.101785","DOIUrl":"10.1016/j.jcmgh.2026.101785","url":null,"abstract":"<p><strong>Background & aims: </strong>The contribution of activated hepatic stellate cells (aHSCs) to cholestatic fibrosis and cancer is well-documented, but the role of portal fibroblasts (PFs), and especially mesothelin (Msln)-mucin 16 (Muc16)- Thy-1 cell surface antigen (Thy-1) signaling in activated portal fibroblasts (aPFs), is unknown.</p><p><strong>Methods: </strong>The role of aPFs/mesenchymal cells in the pathogenesis of cholestatic fibrosis and hepatocellular carcinoma (HCC) was studied in aged (16 months old) multidrug resistance protein 2 knockout (Mdr2^-/-) mice, which mimic primary biliary cholangitis with biliary fibrosis.</p><p><strong>Results: </strong>Aged female Mdr2^-/- mice were more susceptible to cholestatic fibrosis and inflammation and developed 4-fold more adenomas and GPC3⁺SOX9⁺AFP⁺ HCC than age-matched male littermates. Deletion of Msln or Muc16 ameliorated cholestatic fibrosis, inflammation and HCC in Mdr2^-/-Msln^-/- and Mdr2^-/-Muc16^-/- mice, whereas Mdr2^-/- and Mdr2^-/-Thy-1^-/- mice exhibited similar phenotypes and developed severe fibrosis and HCC. Aged Mdr2^-/-Msln^-/- and Mdr2^-/-Muc16^-/- mice developed fewer HCCs and of smaller sizes. Ductular proliferation and hepatocyte and cholangiocyte senescence were suppressed in Mdr2^-/-Msln^-/- and Mdr2^-/-Muc16^-/- mice, whereas hepatocyte regeneration was markedly improved. Msln- and Muc16-deficient aPFs exhibited a less fibrogenic and inflammatory phenotype, and downregulated expression of Col1a2, Col3a1, Tgfβ1, MMP3, Cxcl9, Clcl7, Lgals1, and MMP2/3. The lack of MMP3 in Msln^-/- aPFs was linked to increased hepatocyte proliferation. Based on in vitro studies, MMP3-mediated shedding of hepatic HGFR (c-Met) was identified as one of the mechanisms by which aPFs suppress HGF-c-Met-induced phosphorylation of AKT, ERK, p38, resulting in proliferation of primary human hepatocytes. In turn, proliferation of MMP3-stimulated human hepatocytes was restored in the presence of MMP3 inhibitor.</p><p><strong>Conclusions: </strong>These findings demonstrate that aPFs mediate the crosstalk between cholangiocytes and hepatocytes, regulate hepatocyte functions, and that Msln-Muc16 signaling in aPFs is pathogenic for cholestatic fibrosis and HCC. Msln and Muc16 may become novel targets for anti-fibrotic therapy and patients with HCC and sclerosis cholangitis.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101785"},"PeriodicalIF":7.1,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147678958","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":"Bile Acid Detergency as Determinant of Liver Pathology in a Humanized Mouse Model of Progressive Familial Intrahepatic Cholestasis Type 3.","authors":"Lixin Ke, Niels L Mulder, Milaine V Hovingh, Rick Havinga, Ellen Weersing, Hilde D de Vries, Krisztina de Bruyn, Kirill Ustyantsev, Eugene Berezikov, Vincent W Bloks, Brecht Attema, Anna Worthmann, Joerg Heeren, Justina C Wolters, Rachel Tiessen-Thomas, Henkjan J Verkade, Folkert Kuipers, Jan Freark de Boer","doi":"10.1016/j.jcmgh.2026.101783","DOIUrl":"10.1016/j.jcmgh.2026.101783","url":null,"abstract":"<p><strong>Background & aims: </strong>Progressive familial intrahepatic cholestasis type 3 (PFIC3) is caused by impaired activity of ABCB4 that transports phosphatidylcholines (PC) from hepatocytes into bile. Abcb4-knockout (KO) mice have been generated, but hydrophilic muricholic acids in their bile acid (BA) pool may limit pathology and thereby hamper translation to human PFIC3. Therefore, we addressed whether Abcb4 knockdown (Abcb4-KD) in the livers of Cyp2c70-KO mice with a human-like BA composition leads to liver pathology that more closely resembles human PFIC3.</p><p><strong>Methods: </strong>Expression of Abcb4 gene was suppressed in livers of Cyp2c70-KO/L-Cas9tg mice and control-Cas9tg mice using CRISPR/Cas9-technology to assess short- and long-term consequences. The BA sequestrant colesevelam was mixed into the chow diet (2% w/w) of Cyp2c70-KO mice with or without Abcb4-KD, and the effects were evaluated after 6 weeks.</p><p><strong>Results: </strong>Abcb4-KD strongly reduced biliary phospholipid:BA ratios in both Cyp2c70-KO and control mice. However, plasma transaminases elevations, liver fibrosis, and ductular reactions were markedly aggravated by Abcb4-KD in the context of a human-like BA composition. Importantly, the biliary lipid compositions differed markedly between the 2 Abcb4-KD models. Reduced biliary PC and increased concentrations of lysophosphatidylcholine, sphingomyelin, and ceramide were associated with the severity of liver disease only in Cyp2c70-KO/Abcb4-KD mice. Gene set enrichment analysis indicated that epithelial-mesenchymal transition was induced in the livers of Cyp2c70-KO/Abcb4-KD mice compared with control Abcb4-KD mice. BA sequestration reduced biliary BA secretion rates and mitigated liver pathology in Cyp2c70-KO/Abcb4-KD mice.</p><p><strong>Conclusions: </strong>The presence of a human-like BA composition profoundly aggravates liver pathology upon Abcb4 reduction in mice, conceivably due to the augmented extrusion of non-PC phospholipids by hydrophobic BAs from membranes into bile. This humanized PFIC3 model is anticipated to accelerate the development of novel therapies for PFIC3 and potentially other cholestatic liver diseases.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101783"},"PeriodicalIF":7.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147655494","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":"Inducible POU Class 2 Homeobox 3 Expression in Human Intestinal Organoids as a Model of Human Tuft Cells.","authors":"Carolyn Bomidi, Luqiong Wang, Hoa Nguyen-Phuc, Mary K Estes, Sarah E Blutt","doi":"10.1016/j.jcmgh.2026.101784","DOIUrl":"10.1016/j.jcmgh.2026.101784","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101784"},"PeriodicalIF":7.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147647771","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":"Enteral Feeding With Omega-3 Polyunsaturated Fatty Acids Mitigates Liver Injury Following Massive Intestinal Resection.","authors":"Hannah M Phelps, Daniel Alligood, Alex Park, Ayoung Kim, Richard R Kitchen, Kerry Swanson, Ashley C King, Xiuli Liu, Evan Mayse, Naima Pyarali, Jun Guo, Brian D Muegge, Gwendalyn J Randolph, Nicholas O Davidson, Deborah C Rubin, Brad W Warner, Colin A Martin, David M Alvarado","doi":"10.1016/j.jcmgh.2026.101775","DOIUrl":"10.1016/j.jcmgh.2026.101775","url":null,"abstract":"<p><strong>Background & aims: </strong>Intestinal failure-associated liver disease results from massive small bowel resection (SBR). We assessed the impact of isocaloric enteral omega-3 (ω-3) and omega-6 (ω-6) polyunsaturated fatty acids (PUFAs) on intestinal function and liver injury following massive enterectomy.</p><p><strong>Methods: </strong>Male C57BL/6J mice underwent SBR or sham operation. Mice received either ω-3-enriched, ω-6-enriched, or a balanced saturated/monounsaturated/PUFA (control) diet postoperatively. At 10 weeks, body composition, metabolic profiles, intestinal adaptation, and liver injury were assessed. Targeted lipidomic profiling and bulk RNA sequencing of liver and intestine was completed. The role of Pparα activity was assessed in vivo by genetic deletion and pharmacologic activation.</p><p><strong>Results: </strong>ω-3-fed mice experienced improved weight recovery and more efficient energy metabolism following SBR. Compared with control mice, SBR mice fed either ω-3 or ω-6 diets showed reduced serum aspartate aminotransferase and alanine aminotransferase. Hepatic free fatty acid analysis reflected dietary intake. Hepatic steatosis and fibrosis was lowest in ω-3, intermediate in ω-6, and highest in control mice following SBR. Hepatic RNA sequencing found upregulation of fibrotic pathways in both the SBR control and SBR ω-6 with lipid metabolism upregulated in the SBR ω-3. Pparα was shown to be necessary for survival but not sufficient for hepatoprotection following SBR, which suggested that ω-3 fatty acids engage in Pparα-independent effects. RNA sequencing of the remnant ileum found ω-3 fatty acids promote upregulation of genes related to lipid metabolism and nutrient absorption consistent with a more proximal intestinal identity.</p><p><strong>Conclusions: </strong>These data suggest that enteral feeding with ω-3 PUFAs improves intestinal functional adaptation and protects the liver injury after SBR while improving weight recovery and energy expenditure.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101775"},"PeriodicalIF":7.1,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576606","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":"Intestinal Stem Cells From Patients With Inflammatory Bowel Disease Retain an Epigenetic Memory of Inflammation.","authors":"Feda H Hamdan, Mona Farhadipour, Isaiah Perez, Kimberlee Kossick, Hannah Smith, Adam Edwinson, Jose M de Hoyos-Vega, Michelle Gonzalez, David Chiang, Emily Klatt, Kristy Rumer, Mauricio Perez Pachon, Mary Sagstetter, Jessica Friton, Erin Kammer, Alana English, Lucas C S Chini, Jarl F Carnahan, Noah A Baca, Jessie Hohenstein, Rohini Mopuri, Aditya Bhagwate, Laura E Raffals, Rondell Graham, Zhifu Sun, Madhusudan Grover, Alexander Revzin, Michael Kattah, William A Faubion, Brooke R Druliner","doi":"10.1016/j.jcmgh.2026.101774","DOIUrl":"10.1016/j.jcmgh.2026.101774","url":null,"abstract":"<p><strong>Background & aims: </strong>Intestinal epithelial damage and impaired repair are hallmarks of ulcerative colitis (UC), even after inflammation resolves. Intestinal stem cells (ISCs) can retain stable epigenetic changes after inflammation, highlighting the potential for long-lived epithelial memory in the gut. Inflammatory injury in barrier tissues induces epigenetic memory in epithelial stem cells, and the tendency of UC to relapse at previously inflamed sites led us to hypothesize that ISCs from patients with inflammatory bowel disease acquire lasting memory of prior inflammation.</p><p><strong>Methods: </strong>To test this, we derived colonic organoids from inflamed (I) and noninflamed regions of the same patients with UC and propagated in long-term culture.</p><p><strong>Results: </strong>Chromatin profiling revealed 2252 accessible regions unique to I organoids, associated with stress response, repair, and inflammatory genes. Although these regions remained accessible, ∼95% of associated genes were not upregulated in I organoids, indicating a primed state. Upon inflammatory or injury re-challenge, I organoids exhibited heightened transcriptional responses and accelerated wound closure, despite reduced clonogenicity and impaired barrier function, indicating a retained inflammatory memory program.</p><p><strong>Conclusions: </strong>Our findings demonstrate that human ISCs retain a chromatin-based memory of inflammation that persists in the absence of immune cues and shapes future responses to injury. Although this may support epithelial adaptation to secondary insults, it may predispose tissue to relapse in patients with UC.</p>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":" ","pages":"101774"},"PeriodicalIF":7.1,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147576599","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}