Pub Date : 2026-01-01Epub Date: 2025-10-09DOI: 10.1016/j.jcmgh.2025.101659
Rabina Giri , Minyi Lee , Graham W. 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
Background & Aims
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.
Methods
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 quantitative reverse transcription polymerase chain reaction 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.
Results
Constitutive disruption or heterozygosity of Otud3 in mice, or intestinal-specific deletion, resulted in impaired barrier integrity, tight-junction dysregulation, increased endoplasmic reticulum stress, and penetration of luminal bacteria deep into the colonic crypts that preceded a spontaneous progressive colitis. Analysis of distinct UC cohorts demonstrated enrichment of rare, damaging variants in 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 with matched non-UC controls.
Conclusions
Our results demonstrate that OTUD3 is required for colonic epithelial barrier function, and plays a role in the pathogenesis of UC.
{"title":"Pathogenic OTUD3 Mutations Predispose to Ulcerative Colitis Due to Barrier Dysfunction","authors":"Rabina Giri , Minyi Lee , Graham W. 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":"10.1016/j.jcmgh.2025.101659","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The contribution of common genetic polymorphisms to ulcerative colitis (UC) pathogenesis is modest; however, families with severe colitis may harbor rare variants with large effect sizes that highlight unrecognized pathways.</div></div><div><h3>Methods</h3><div>A multigenerational family with UC necessitating colectomy was identified. Whole exome sequencing of this kindred was performed, implicating a rare variant in <em>OTUD3</em>. Constitutive knock-out and intestinal specific <em>Otud3</em> deficient and heterozygous mice were generated. OTUD3 expression in human colonic biopsies and intestinal organoids was assessed using quantitative reverse transcription polymerase chain reaction and immunofluorescence. Prevalence of rare, damaging variants were compared in distinct patient cohorts. Plasmids containing <em>OTUD3</em> missense variants were introduced into cell lines where <em>OTUD3</em> was disrupted to determine their effects on cellular response to cytokine stimulation.</div></div><div><h3>Results</h3><div>Constitutive disruption or heterozygosity of <em>Otud3</em> in mice, or intestinal-specific deletion, resulted in impaired barrier integrity, tight-junction dysregulation, increased endoplasmic reticulum stress, and penetration of luminal bacteria deep into the colonic crypts that preceded a spontaneous progressive colitis. Analysis of distinct UC cohorts demonstrated enrichment of rare, damaging variants in <em>OTUD3</em>. Introduction of <em>OTUD3</em> variants in intestinal cell lines phenocopied the epithelial immune dysregulation observed in knockout mice. Finally, <em>OTUD3</em> mRNA and epithelial protein expression were decreased in the quiescent colonic epithelial tissue of genotype-unselected individuals with UC compared with matched non-UC controls.</div></div><div><h3>Conclusions</h3><div>Our results demonstrate that OTUD3 is required for colonic epithelial barrier function, and plays a role in the pathogenesis of UC.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101659"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","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}
Pub Date : 2026-01-01Epub Date: 2025-09-03DOI: 10.1016/j.jcmgh.2025.101623
Piumi B. Wickramasinghe , Alexandre Caron , Preethi Parupalli , Junyu Liu , Sreeja Eadha , Sarvani Ganapavarapu , Joel K. Elmquist , Chen Liu , Lin Jia
Background & Aims
Binge drinking causes fat accumulation in the liver and is a known risk factor for more severe forms of alcohol-associated liver disease (ALD). Although adipocyte-released free fatty acids (FFA) have been shown to contribute to alcohol-induced liver damage, the signaling pathways that trigger lipolytic activity in adipose tissues following acute alcohol overconsumption is largely unknown. Notably, activation of sympathetic nerve-β3 adrenergic receptor (Adrb3) plays a central role in sustained adipocyte lipolysis. However, whether this pathway is involved in acute alcohol-induced lipolysis remains unclear. We aimed to explore the effect of the sympathetic nerve-Adrb3-mediated pathway on adipocyte lipolytic action and fatty liver development following acute alcohol exposure.
Methods
C57BL/6J male mice were administered a single binge of alcohol to model acute alcohol exposure. 6-hydroxydopamine (6-OHDA) was injected systemically or locally to ablate sympathetic nerves. Male mice lacking Adrb3 selectively in fat tissues (Adrb3FKO) were generated. White adipose tissue lipolysis, fatty liver development, and liver damage were investigated.
Results
A single alcohol binge in C57BL/6J mice led to significant increases in white adipose tissue (WAT) norepinephrine (NE) content and plasma FFA levels, accompanied by the development of alcoholic hepatic steatosis. Acute alcohol-induced adipose tissue lipolysis and ALD were significantly mitigated by 6-OHDA-mediated systemic and fat tissue-specific sympathetic nerve ablation. Deletion of Adrb3 in adipocytes protected mice from acute alcohol-induced adipose tissue lipolysis, hepatic fat accumulation, and liver injury.
Conclusions
Our data indicates that binge drinking leads to the development of fatty liver and liver damage by activating adipose tissue sympathetic nerve-Adrb3-mediated lipolysis in mice.
{"title":"Ablation of Sympathetic Nerve-β3 Adrenergic Receptor-mediated Adipose Tissue Lipolysis Attenuates Alcohol-induced Liver Injury in Mice","authors":"Piumi B. Wickramasinghe , Alexandre Caron , Preethi Parupalli , Junyu Liu , Sreeja Eadha , Sarvani Ganapavarapu , Joel K. Elmquist , Chen Liu , Lin Jia","doi":"10.1016/j.jcmgh.2025.101623","DOIUrl":"10.1016/j.jcmgh.2025.101623","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Binge drinking causes fat accumulation in the liver and is a known risk factor for more severe forms of alcohol-associated liver disease (ALD). Although adipocyte-released free fatty acids (FFA) have been shown to contribute to alcohol-induced liver damage, the signaling pathways that trigger lipolytic activity in adipose tissues following acute alcohol overconsumption is largely unknown. Notably, activation of sympathetic nerve-β3 adrenergic receptor (Adrb3) plays a central role in sustained adipocyte lipolysis. However, whether this pathway is involved in acute alcohol-induced lipolysis remains unclear. We aimed to explore the effect of the sympathetic nerve-Adrb3-mediated pathway on adipocyte lipolytic action and fatty liver development following acute alcohol exposure.</div></div><div><h3>Methods</h3><div>C57BL/6J male mice were administered a single binge of alcohol to model acute alcohol exposure. 6-hydroxydopamine (6-OHDA) was injected systemically or locally to ablate sympathetic nerves. Male mice lacking Adrb3 selectively in fat tissues (Adrb3<sup>FKO</sup>) were generated. White adipose tissue lipolysis, fatty liver development, and liver damage were investigated.</div></div><div><h3>Results</h3><div>A single alcohol binge in C57BL/6J mice led to significant increases in white adipose tissue (WAT) norepinephrine (NE) content and plasma FFA levels, accompanied by the development of alcoholic hepatic steatosis. Acute alcohol-induced adipose tissue lipolysis and ALD were significantly mitigated by 6-OHDA-mediated systemic and fat tissue-specific sympathetic nerve ablation. Deletion of Adrb3 in adipocytes protected mice from acute alcohol-induced adipose tissue lipolysis, hepatic fat accumulation, and liver injury.</div></div><div><h3>Conclusions</h3><div>Our data indicates that binge drinking leads to the development of fatty liver and liver damage by activating adipose tissue sympathetic nerve-Adrb3-mediated lipolysis in mice.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 1","pages":"Article 101623"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006982","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}
Pub Date : 2026-01-01Epub Date: 2025-09-05DOI: 10.1016/j.jcmgh.2025.101625
Sheng Li , Fangqing Zhu , Yao Xie , Teng Ben , Ke Liu , Xinlong Lin , Qian Zhou , Yin Zhang , Xinyue Zhang , Yeling Chen , Yuexin Ren , Xianfei Wang , Fachao Zhi , Gao Tan
Background & Aims
Over-activation of pyroptosis, recently reidentified as Gasdermin D (GSDMD)-mediated proinflammatory cell death, results in severe inflammation-related disorders. Intestinal fibrosis, an inflammation-related disorder, remains one of the most common and intractable complications of Crohn’s disease (CD). However, it is unknown whether excessive pyroptosis contributes to the development of intestinal fibrosis in CD.
Methods
Immunofluorescence costaining of CD11b and the pyroptosis-inducing fragment GSDMD-N terminal (GSDMD-NT) was performed in stenotic ileocecal valve tissues from patients with CD. A 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced mouse CD model was established. J744a.1 macrophages pretreated with imperatorin (IMP) were transfected with lipopolysaccharides (LPS) plus poly (dA: dT) to explore potential regulatory mechanisms controlling GSDMD-mediated pyroptosis in vitro.
Results
GSDMD-NT+ CD11b+ macrophages were significantly increased in stenotic ileocecal valve tissues from patients with CD compared with that in normal ileocecal valve tissues, reflecting that GSDMD-mediated pyroptosis in macrophages is excessively activated in CD-associated intestinal fibrosis. In the TNBS-induced model, Gsdmd-/- mice had decreased intestinal fibrosis compared with their wild-type littermates. We also found that imperatorin (IMP), a natural furocoumarin, not only alleviated TNBS-induced intestinal fibrosis, but also inhibited TNBS-induced increase of AIM2 expression, Caspase-1 activation, and GSDMD cleavage in the colon. In vitro, we revealed IMP acting as a new regulatory factor that negatively controlled the AIM2 inflammasome via downregulating AIM2 expression, thereby avoiding excessive GSDMD-mediated pyroptosis in J744a.1 macrophages.
Conclusions
IMP negatively controls GSDMD-mediated pyroptosis via inhibiting the AIM2 pathway in macrophages. Thus, IMP enema may be a potential therapeutic approach for CD-associated intestinal fibrosis.
背景与目的：焦亡的过度激活，最近被重新鉴定为Gasdermin D （GSDMD）介导的促炎细胞死亡，导致严重的炎症相关疾病。肠纤维化是一种炎症相关疾病，是克罗恩病（CD）最常见和最棘手的并发症之一。方法：对CD患者狭窄回盲瓣组织进行CD11b和诱导焦亡片段GSDMD-N末端（GSDMD-NT）的免疫荧光共染色。建立2,4,6-三硝基苯磺酸（TNBS）致小鼠CD模型。J744a。用脂多糖（LPS）加聚（dA: dT）转染经欧前胡素（IMP）预处理的巨噬细胞，探讨gsdmd介导的巨噬细胞焦亡的体外调控机制。结果：与正常回盲瓣组织相比，CD患者狭窄回盲瓣组织中GSDMD-NT+ CD11b+巨噬细胞明显增加，反映gsdmd介导的巨噬细胞焦亡在CD相关肠纤维化中被过度激活。在tnbs诱导的模型中，Gsdmd-/-小鼠与野生型小鼠相比，肠道纤维化减少。我们还发现，欧前胡素（IMP），一种天然的紫红色香豆素，不仅可以减轻tnbs诱导的肠道纤维化，还可以抑制tnbs诱导的AIM2表达，Caspase-1激活和结肠GSDMD切割的增加。在体外，我们发现IMP作为一种新的调控因子，通过下调AIM2表达负向控制AIM2炎性体，从而避免了gsdmd介导的J744a过度焦亡。1巨噬细胞。结论：IMP通过抑制巨噬细胞AIM2通路负性控制gsdmd介导的巨噬细胞焦亡。因此，IMP灌肠可能是一种潜在的治疗cd相关肠纤维化的方法。
{"title":"Imperatorin Alleviates Intestinal Fibrosis by Suppressing AIM2-mediated GSDMD Pyroptosis in Macrophages","authors":"Sheng Li , Fangqing Zhu , Yao Xie , Teng Ben , Ke Liu , Xinlong Lin , Qian Zhou , Yin Zhang , Xinyue Zhang , Yeling Chen , Yuexin Ren , Xianfei Wang , Fachao Zhi , Gao Tan","doi":"10.1016/j.jcmgh.2025.101625","DOIUrl":"10.1016/j.jcmgh.2025.101625","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Over-activation of pyroptosis, recently reidentified as Gasdermin D (GSDMD)-mediated proinflammatory cell death, results in severe inflammation-related disorders. Intestinal fibrosis, an inflammation-related disorder, remains one of the most common and intractable complications of Crohn’s disease (CD). However, it is unknown whether excessive pyroptosis contributes to the development of intestinal fibrosis in CD.</div></div><div><h3>Methods</h3><div>Immunofluorescence costaining of CD11b and the pyroptosis-inducing fragment GSDMD-N terminal (GSDMD-NT) was performed in stenotic ileocecal valve tissues from patients with CD. A 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced mouse CD model was established. J744a.1 macrophages pretreated with imperatorin (IMP) were transfected with lipopolysaccharides (LPS) plus poly (dA: dT) to explore potential regulatory mechanisms controlling GSDMD-mediated pyroptosis in vitro.</div></div><div><h3>Results</h3><div>GSDMD-NT<sup>+</sup> CD11b<sup>+</sup> macrophages were significantly increased in stenotic ileocecal valve tissues from patients with CD compared with that in normal ileocecal valve tissues, reflecting that GSDMD-mediated pyroptosis in macrophages is excessively activated in CD-associated intestinal fibrosis. In the TNBS-induced model, <em>Gsdmd</em><sup>-/-</sup> mice had decreased intestinal fibrosis compared with their wild-type littermates. We also found that imperatorin (IMP), a natural furocoumarin, not only alleviated TNBS-induced intestinal fibrosis, but also inhibited TNBS-induced increase of AIM2 expression, Caspase-1 activation, and GSDMD cleavage in the colon. In vitro, we revealed IMP acting as a new regulatory factor that negatively controlled the AIM2 inflammasome via downregulating AIM2 expression, thereby avoiding excessive GSDMD-mediated pyroptosis in J744a.1 macrophages.</div></div><div><h3>Conclusions</h3><div>IMP negatively controls GSDMD-mediated pyroptosis via inhibiting the AIM2 pathway in macrophages. Thus, IMP enema may be a potential therapeutic approach for CD-associated intestinal fibrosis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 1","pages":"Article 101625"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014490","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}
Pub Date : 2026-01-01Epub Date: 2025-09-22DOI: 10.1016/j.jcmgh.2025.101638
Steven J. Wilhelm , Grace E. Curry , Neel Matiwala , Jianguo Lin , Tran Quach , Mark.E. Lowe , Miklós Sahin-Tóth , Xunjun K. Xiao
Background & Aims
Increasing evidence suggests that protein misfolding and proteotoxicity is an important mechanism of chronic pancreatitis (CP) in patients with genetic variants. Two mouse models carrying misfolding digestive enzyme variants, CPA1 N256K and PNLIP T221M, recapitulate the human CP phenotype. We hypothesized that both models develop CP through similar disease mechanisms.
Methods
We conducted a comprehensive analysis of mice aged 1 to 6 months using histology, immunohistochemistry, protein immunoblotting, quantitative polymerase chain reaction (qPCR), transmission electron microscopy (TEM), and RNA sequencing (RNA-seq) analysis to characterize pancreatic pathological changes.
Results
Both homozygous models exhibited CP hallmarks, including progressive acinar cell loss, inflammation, fibrosis, and fatty replacement. CP progression was slower and less severe in Cpa1 N256K mice compared with Pnlip T221M mice, and heterozygous mice showed slower CP development than homozygotes. Both mutant proteins misfolded in the pancreas, inducing endoplasmic reticulum stress and activating the unfolded protein response. RNA-seq analysis revealed slight differences in altered pathways at 1 month, but these differences disappeared by 3 months. Notably, apoptosis pathways were among the top upregulated pathways, confirmed by qPCR and immunohistochemistry. Differential expression and pathway analyses indicated early activation of both intrinsic and extrinsic apoptosis pathways elicited through multiple mechanisms.
Conclusions
Our study demonstrates that Cpa1 N256K and Pnlip T221M mice develop CP through similar mechanisms with slight differences in progression and severity. Both models could serve as invaluable tools for developing and testing CP therapies. Targeting cell death pathways for therapy may be unfeasible given their redundancy. Instead, effective therapeutic strategies should focus on reducing the burden of misfolded digestive enzymes in the pancreas.
{"title":"Diverse Misfolding Mutant Digestive Enzymes Cause Chronic Pancreatitis Through Common Pathways","authors":"Steven J. Wilhelm , Grace E. Curry , Neel Matiwala , Jianguo Lin , Tran Quach , Mark.E. Lowe , Miklós Sahin-Tóth , Xunjun K. Xiao","doi":"10.1016/j.jcmgh.2025.101638","DOIUrl":"10.1016/j.jcmgh.2025.101638","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Increasing evidence suggests that protein misfolding and proteotoxicity is an important mechanism of chronic pancreatitis (CP) in patients with genetic variants. Two mouse models carrying misfolding digestive enzyme variants, <em>CPA1</em> N256K and <em>PNLIP</em> T221M, recapitulate the human CP phenotype. We hypothesized that both models develop CP through similar disease mechanisms.</div></div><div><h3>Methods</h3><div>We conducted a comprehensive analysis of mice aged 1 to 6 months using histology, immunohistochemistry, protein immunoblotting, quantitative polymerase chain reaction (qPCR), transmission electron microscopy (TEM), and RNA sequencing (RNA-seq) analysis to characterize pancreatic pathological changes.</div></div><div><h3>Results</h3><div>Both homozygous models exhibited CP hallmarks, including progressive acinar cell loss, inflammation, fibrosis, and fatty replacement. CP progression was slower and less severe in <em>Cpa1</em> N256K mice compared with <em>Pnlip</em> T221M mice, and heterozygous mice showed slower CP development than homozygotes. Both mutant proteins misfolded in the pancreas, inducing endoplasmic reticulum stress and activating the unfolded protein response. RNA-seq analysis revealed slight differences in altered pathways at 1 month, but these differences disappeared by 3 months. Notably, apoptosis pathways were among the top upregulated pathways, confirmed by qPCR and immunohistochemistry. Differential expression and pathway analyses indicated early activation of both intrinsic and extrinsic apoptosis pathways elicited through multiple mechanisms.</div></div><div><h3>Conclusions</h3><div>Our study demonstrates that <em>Cpa1</em> N256K and <em>Pnlip</em> T221M mice develop CP through similar mechanisms with slight differences in progression and severity. Both models could serve as invaluable tools for developing and testing CP therapies. Targeting cell death pathways for therapy may be unfeasible given their redundancy. Instead, effective therapeutic strategies should focus on reducing the burden of misfolded digestive enzymes in the pancreas.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101638"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139453","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}
Pub Date : 2026-01-01Epub Date: 2025-11-29DOI: 10.1016/j.jcmgh.2025.101689
Michael Schonfeld, Kruti Nataraj, Samson Mah, Wei Zhong, Steven A. Weinman, Irina Tikhanovich
Background & Aims
Abstinence is beneficial for patients with alcohol-associated liver disease (ALD), but disease resolution after alcohol cessation occurs slowly and only in a subset of patients. We aimed to study the mechanisms of ALD resolution using spatial transcriptomics.
Methods
Mice were fed Western diet with 20% alcohol in the drinking water for 20 weeks followed by chow diet with plain water for 4 weeks. Livers were analyzed by 1000-plex CosMx spatial transcriptomics assay (Nanostrings). To assess the role of serum amyloid A (SAA), mice were treated with recombinant SAA or SAA-rich high-density lipoprotein (HDL).
Results
Using a mouse model of ALD after alcohol cessation we performed spatial transcriptomics and identified a discrete multicellular fibrogenic and fibrolytic niches. Fibrolytic niches contained a unique subpopulation of hepatocytes that express SAA. SAA expression correlated with fibrolytic genes in mice after alcohol cessation and in human liver samples. In vitro analysis confirmed that Saa1/2high hepatocytes induced matrix metalloproteinase and lysosomal enzyme (Ctsd, Psap) gene expression in liver macrophages in an SAA and FPR2-dependent way. Moreover, after alcohol cessation, SAA was enriched on circulating HDL and the SAA pro-resolving function required SR-BI-mediated HDL uptake by macrophages. In vivo recombinant SAA or SAA-enriched HDL promoted fibrosis resolution after alcohol cessation in mice. SAA expression itself was mediated by IL-22R signaling in hepatocytes regulated by KDM5B demethylase and C/EBPβ. Hepatocyte-specific Kdm5b or Cebpb knockout promoted Il22a1 expression, Saa1/2 upregulation and collagen remodeling, facilitating fibrosis resolution after alcohol cessation.
Conclusions
Acute phase response activation after alcohol cessation triggers intrahepatic cell-cell communication changes for efficient fibrosis resolution.
{"title":"Acute Phase Response-driven Hepatic Niche Remodeling Promotes Fibrosis Resolution After Alcohol Cessation","authors":"Michael Schonfeld, Kruti Nataraj, Samson Mah, Wei Zhong, Steven A. Weinman, Irina Tikhanovich","doi":"10.1016/j.jcmgh.2025.101689","DOIUrl":"10.1016/j.jcmgh.2025.101689","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Abstinence is beneficial for patients with alcohol-associated liver disease (ALD), but disease resolution after alcohol cessation occurs slowly and only in a subset of patients. We aimed to study the mechanisms of ALD resolution using spatial transcriptomics.</div></div><div><h3>Methods</h3><div>Mice were fed Western diet with 20% alcohol in the drinking water for 20 weeks followed by chow diet with plain water for 4 weeks. Livers were analyzed by 1000-plex CosMx spatial transcriptomics assay (Nanostrings). To assess the role of serum amyloid A (SAA), mice were treated with recombinant SAA or SAA-rich high-density lipoprotein (HDL).</div></div><div><h3>Results</h3><div>Using a mouse model of ALD after alcohol cessation we performed spatial transcriptomics and identified a discrete multicellular fibrogenic and fibrolytic niches. Fibrolytic niches contained a unique subpopulation of hepatocytes that express SAA. SAA expression correlated with fibrolytic genes in mice after alcohol cessation and in human liver samples. In vitro analysis confirmed that <em>Saa1/2</em><sup>high</sup> hepatocytes induced matrix metalloproteinase and lysosomal enzyme (<em>Ctsd, Psap</em>) gene expression in liver macrophages in an SAA and FPR2-dependent way. Moreover, after alcohol cessation, SAA was enriched on circulating HDL and the SAA pro-resolving function required SR-BI-mediated HDL uptake by macrophages. In vivo recombinant SAA or SAA-enriched HDL promoted fibrosis resolution after alcohol cessation in mice. SAA expression itself was mediated by IL-22R signaling in hepatocytes regulated by KDM5B demethylase and C/EBPβ. Hepatocyte-specific <em>Kdm5b</em> or <em>Cebpb</em> knockout promoted <em>Il22a1</em> expression, <em>Saa1/2</em> upregulation and collagen remodeling, facilitating fibrosis resolution after alcohol cessation.</div></div><div><h3>Conclusions</h3><div>Acute phase response activation after alcohol cessation triggers intrahepatic cell-cell communication changes for efficient fibrosis resolution.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101689"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145650209","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}
Pub Date : 2026-01-01Epub Date: 2025-12-19DOI: 10.1016/j.jcmgh.2025.101712
Binu Prakash, Sujith Rajan, Bhargavi Gangula, Thomas Palaia, Chandana Prakashmurthy, Pradeep Kumar Yadav, Swati Valmiki, Xiaoyue Pan, M. Mahmood Hussain
Background & Aims
Lipoprotein assembly in the small intestine and liver is critical for the transport of dietary and endogenous lipids. Pla2g12b has recently been shown to play a role in lipoprotein assembly in mice livers and zebrafish larvae. Pla2g12b knockout and mutant (MUT) mice with the C129Y missense mutation have low plasma cholesterol levels. However, the role of Pla2g12b in the intestine and the reason why C129Y mutation decreases plasma lipids are unknown.
Methods
Both male and female 3-month-old chow fed Pla2g12bhlb218/hlb218 (Pla2g12bmt/mt) and WT control mice were used in parallel to study plasma lipids and lipoproteins, lipid absorption and hepatic lipoprotein production studies. Transmission electron microscopy was used to visualize lipid transit through enterocytes.
Results
We observed that Pla2g12b expression was the highest in the duodenum. Furthermore, male and female chow fed 3-month-old MUT mice and wildtype (WT) mice expressed similar amounts of Pla2g12b protein and several genes in lipid metabolism. Nonetheless, the MUT mice had significantly lower plasma triglyceride (TG), cholesterol, HDL-C, LDL-C, apoB48, and apoB100 levels than WT mice. Several mechanisms for lower plasma lipids and lipoproteins in MUT mice were investigated. C129Y mutation had no effect on the expression of Pla2g12b and several other proteins necessary for lipid transport. Therefore, the low plasma lipid levels in MUT mice were neither due to the absence of Pla2g12b protein nor due to reductions in critical proteins in lipid transport. Next, we addressed the role of Pla2g12b in hepatic lipid mobilization and intestinal lipid absorption. MUT livers exhibited normal TG synthesis, defective TG secretion, and enhanced fat accumulation. MUT mice also showed defective intestinal TG absorption, intracellular lipid accumulation, and elevated TG excretion in the feces.
Conclusions
We propose that C129 in Pla2g12b is critical for the assembly and secretion of lipoproteins by the liver and intestine.
{"title":"Cysteine 129 in Pla2g12b Is Critical for Intestinal and Hepatic Lipoprotein Secretion in Mice","authors":"Binu Prakash, Sujith Rajan, Bhargavi Gangula, Thomas Palaia, Chandana Prakashmurthy, Pradeep Kumar Yadav, Swati Valmiki, Xiaoyue Pan, M. Mahmood Hussain","doi":"10.1016/j.jcmgh.2025.101712","DOIUrl":"10.1016/j.jcmgh.2025.101712","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Lipoprotein assembly in the small intestine and liver is critical for the transport of dietary and endogenous lipids. Pla2g12b has recently been shown to play a role in lipoprotein assembly in mice livers and zebrafish larvae. Pla2g12b knockout and mutant (MUT) mice with the C129Y missense mutation have low plasma cholesterol levels. However, the role of Pla2g12b in the intestine and the reason why C129Y mutation decreases plasma lipids are unknown.</div></div><div><h3>Methods</h3><div>Both male and female 3-month-old chow fed <em>Pla2g12b</em><sup><em>hlb218</em></sup><em>/</em><sup><em>hlb218</em></sup> (<em>Pla2g12b</em><sup><em>mt</em></sup><em>/</em><sup><em>mt</em></sup>) and WT control mice were used in parallel to study plasma lipids and lipoproteins, lipid absorption and hepatic lipoprotein production studies. Transmission electron microscopy was used to visualize lipid transit through enterocytes.</div></div><div><h3>Results</h3><div>We observed that Pla2g12b expression was the highest in the duodenum. Furthermore, male and female chow fed 3-month-old MUT mice and wildtype (WT) mice expressed similar amounts of Pla2g12b protein and several genes in lipid metabolism. Nonetheless, the MUT mice had significantly lower plasma triglyceride (TG), cholesterol, HDL-C, LDL-C, apoB48, and apoB100 levels than WT mice. Several mechanisms for lower plasma lipids and lipoproteins in MUT mice were investigated. C129Y mutation had no effect on the expression of Pla2g12b and several other proteins necessary for lipid transport. Therefore, the low plasma lipid levels in MUT mice were neither due to the absence of Pla2g12b protein nor due to reductions in critical proteins in lipid transport. Next, we addressed the role of Pla2g12b in hepatic lipid mobilization and intestinal lipid absorption. MUT livers exhibited normal TG synthesis, defective TG secretion, and enhanced fat accumulation. MUT mice also showed defective intestinal TG absorption, intracellular lipid accumulation, and elevated TG excretion in the feces.</div></div><div><h3>Conclusions</h3><div>We propose that C129 in Pla2g12b is critical for the assembly and secretion of lipoproteins by the liver and intestine.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 5","pages":"Article 101712"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805439","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}
Pub Date : 2026-01-01Epub Date: 2026-01-05DOI: 10.1016/j.jcmgh.2025.101704
Michael S. Poslusney , Qian Li , Ingrid P. Buchler , Yifang Huang , Liansheng Liu , Yaohui Zhu , Subhash Kulkarni , Gregory Carr , Adrienne DeBrosse , Noelle White , Diane Peters , James C. Barrow , Pankaj J. Pasricha
Background & Aims
Visceral pain is a cardinal symptom of many disorders affecting the gut and other abdominal organs. Modulators of gamma-aminobutyric acid (GABA) such as benzodiazepines may attenuate such pain but the specific contribution of peripheral GABA-A receptors (GABRAs) remains unclear as current agonists have prominent central effects.
Methods
Using medicinal chemistry optimization of the benzodiazepine scaffold, we developed a novel and potent positive allosteric modulator (PAM), LI-633, with no significant central nervous system (CNS) penetration.
Results
The locomotor activity of rats placed in an open field was unchanged with LI-633 at doses up to 30 mg/kg, confirming its lack of a CNS effect. LI-633 produced robust potentiation of GABA-induced inward current, with EC50 values ranging from 8 nM (α5β2γ2) to 128 nM (α3β2γ2). In vitro electrophysiological studies confirmed its ability to reduce excitability of human dorsal root ganglion (DRG) neurons by GABA. LI-633 potentiated muscimol-induced GABAergic currents in rat DRG neurons in a dose-dependent manner, with an EC50 of 70.4 nM. In vivo, LI-633 significantly attenuated visceral hypersensitivity and pain behavior in a rat model of irritable bowel syndrome (IBS) and functional dyspepsia (FD), indicating the presence of physiologically relevant concentrations of GABA in the colon and stomach. In the IBS model, administration of the drug also resulted in decreased excitability of colon-specific DRG neurons and significantly reduced the colonic afferent response to balloon distention as measured by recordings of neural activity in dorsal ganglia rootlets.
Conclusions
These findings highlight the potential of targeting peripheral GABRAs for pain management in disorders associated with visceral hypersensitivity.
{"title":"Development of a Novel Benzodiazepine to Delineate Peripheral GABA-A Signaling Mechanisms in Visceral Pain Syndromes","authors":"Michael S. Poslusney , Qian Li , Ingrid P. Buchler , Yifang Huang , Liansheng Liu , Yaohui Zhu , Subhash Kulkarni , Gregory Carr , Adrienne DeBrosse , Noelle White , Diane Peters , James C. Barrow , Pankaj J. Pasricha","doi":"10.1016/j.jcmgh.2025.101704","DOIUrl":"10.1016/j.jcmgh.2025.101704","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Visceral pain is a cardinal symptom of many disorders affecting the gut and other abdominal organs. Modulators of gamma-aminobutyric acid (GABA) such as benzodiazepines may attenuate such pain but the specific contribution of peripheral GABA-A receptors (GABRAs) remains unclear as current agonists have prominent central effects.</div></div><div><h3>Methods</h3><div>Using medicinal chemistry optimization of the benzodiazepine scaffold, we developed a novel and potent positive allosteric modulator (PAM), LI-633, with no significant central nervous system (CNS) penetration.</div></div><div><h3>Results</h3><div>The locomotor activity of rats placed in an open field was unchanged with LI-633 at doses up to 30 mg/kg, confirming its lack of a CNS effect. LI-633 produced robust potentiation of GABA-induced inward current, with EC50 values ranging from 8 nM (α5β2γ2) to 128 nM (α3β2γ2). In vitro electrophysiological studies confirmed its ability to reduce excitability of human dorsal root ganglion (DRG) neurons by GABA. LI-633 potentiated muscimol-induced GABAergic currents in rat DRG neurons in a dose-dependent manner, with an EC<sub>50</sub> of 70.4 nM. In vivo, LI-633 significantly attenuated visceral hypersensitivity and pain behavior in a rat model of irritable bowel syndrome (IBS) and functional dyspepsia (FD), indicating the presence of physiologically relevant concentrations of GABA in the colon and stomach. In the IBS model, administration of the drug also resulted in decreased excitability of colon-specific DRG neurons and significantly reduced the colonic afferent response to balloon distention as measured by recordings of neural activity in dorsal ganglia rootlets.</div></div><div><h3>Conclusions</h3><div>These findings highlight the potential of targeting peripheral GABRAs for pain management in disorders associated with visceral hypersensitivity.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 4","pages":"Article 101704"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919405","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}
Dietary fat increases the risk of intestinal cancer, but the effect of the fatty acid composition on tumorigenesis is unclear. The aim of this study is to investigate the impact of diets with different fatty acids on carcinogenesis in the intestine.
Methods
Mice were fed a linoleic acid (LA)-rich or stearic acid (SA)-rich high-fat diet (HFD) from the age of 4 weeks. The ApcMin/+ mice and an azoxymethane- and a dextran sulfate sodium-induced colorectal cancer (CRC) mouse model were used to examine the effects of different dietary fatty acids on CRC development. Fatty acid-binding protein 5 (FABP5) knockout mice and SBFI-26, an inhibitor of FABP5, were used to assess its contribution.
Results
We found that an SA-rich HFD more strongly accelerated tumorigenesis in murine CRC models than an LA-rich HFD, with fewer obesity phenotypes compared with LA-rich HFD-fed mice. Dietary SA more strongly promoted epithelial cell proliferation and Paneth cell differentiation than LA, whereas no differences in the numbers of leucine-rich repeat-containing G protein-coupled receptor 5+ and B lymphoma Mo-MLV insertion region 1 homolog+ intestinal stem cells were detected between the groups. In murine and human intestinal organoids, SA promoted crypt formation. We found that FABP5 was expressed in a small population of Ki67+ proliferative cells in crypts, and the number of Ki67+ FABP5+ cells was increased by SA-rich HFD feeding. FABP5 inhibition suppressed SA-induced epithelial cell proliferation, Paneth cell differentiation, and tumorigenesis.
Conclusions
Dietary SA can promote CRC via FABP5 without promoting obesity.
{"title":"Dietary Stearic Acid Accelerates Intestinal Tumorigenesis via Fatty Acid-binding Protein 5 Without Promoting Obesity","authors":"Kazuaki Nakata , Seiga Komiyama , Keisuke Sekine , Motoyoshi Nagai , Takuma Okawa , Wakana Ohashi , Kenta Nakano , Tadashi Okamura , Takuma Kozono , Nobuyuki Takemura , Kazuhiko Yamada , Norihiro Kokudo , Taeko Dohi , Koji Hase , Yuki I. Kawamura","doi":"10.1016/j.jcmgh.2026.101740","DOIUrl":"10.1016/j.jcmgh.2026.101740","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Dietary fat increases the risk of intestinal cancer, but the effect of the fatty acid composition on tumorigenesis is unclear. The aim of this study is to investigate the impact of diets with different fatty acids on carcinogenesis in the intestine.</div></div><div><h3>Methods</h3><div>Mice were fed a linoleic acid (LA)-rich or stearic acid (SA)-rich high-fat diet (HFD) from the age of 4 weeks. The <em>Apc</em><sup><em>Min/+</em></sup> mice and an azoxymethane- and a dextran sulfate sodium-induced colorectal cancer (CRC) mouse model were used to examine the effects of different dietary fatty acids on CRC development. Fatty acid-binding protein 5 (FABP5) knockout mice and SBFI-26, an inhibitor of FABP5, were used to assess its contribution.</div></div><div><h3>Results</h3><div>We found that an SA-rich HFD more strongly accelerated tumorigenesis in murine CRC models than an LA-rich HFD, with fewer obesity phenotypes compared with LA-rich HFD-fed mice. Dietary SA more strongly promoted epithelial cell proliferation and Paneth cell differentiation than LA, whereas no differences in the numbers of leucine-rich repeat-containing G protein-coupled receptor 5<sup>+</sup> and B lymphoma Mo-MLV insertion region 1 homolog<sup>+</sup> intestinal stem cells were detected between the groups. In murine and human intestinal organoids, SA promoted crypt formation. We found that FABP5 was expressed in a small population of Ki67<sup>+</sup> proliferative cells in crypts, and the number of Ki67<sup>+</sup> FABP5<sup>+</sup> cells was increased by SA-rich HFD feeding. FABP5 inhibition suppressed SA-induced epithelial cell proliferation, Paneth cell differentiation, and tumorigenesis.</div></div><div><h3>Conclusions</h3><div>Dietary SA can promote CRC via FABP5 without promoting obesity.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 5","pages":"Article 101740"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095002","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}
Pub Date : 2026-01-01Epub Date: 2025-09-02DOI: 10.1016/j.jcmgh.2025.101626
Damra Camat , Diana Nakib , Sai W. Chung , Manmeet Sekhon , Yijia Liu , Patricia Lumanto , Sharon J. Hyduk , Catia T. Perciani , Agata M. Bartczak , Michael L. Cheng , Olivia I. Pezzutti , Melina Kaltagian , Fatima Altaf , Sadaf M. Jafari , Justin Manuel , Cornelia Thoeni , Shinchiro Ogawa , Xue-Zhong Ma , Ian D. McGilvray , Sonya A. MacParland
Background & Aims
Interleukin-4 (IL-4) is a key contributor to liver regeneration, but its effects remain poorly understood due to a lack of models that preserve the complex cellular interactions of the liver. Here, we use murine precision-cut liver slices (PCLS), a 3-dimensional tissue culture system that maintains both parenchymal and non-parenchymal cells, to investigate the role of IL-4 in hepatic cell reprogramming. Through longitudinal single-cell transcriptomics and protein-level validation, we demonstrate the proregenerative potential of IL-4.
Methods
We performed longitudinal single nucleus RNA sequencing on PCLS from 8- to 10-week-old C57BL/6 mice over 5 days of culture in the presence and absence of IL-4. We assessed intracellular ATP output to demonstrate slice viability. We further performed orthogonal evaluations of the impact of IL-4 treatment via immunhistochemical staining to confirm proliferation and cell identity within the slices. We then assessed the impact of IL-4 exposure in slices generated from the diseased livers (hepatonecrosis/fibrosis) of mice treated with thioacetamide.
Results
IL-4 induced transcriptional changes, including increased expression of tissue repair-associated markers in myeloid cells, expansion of hepatocyte and cholangiocyte progenitors, and inhibition of fibroblast activation. Additionally, IL-4 treatment significantly increased Ki67 protein expression and intracellular ATP production, indicating enhanced proliferation and viability. Notably, IL-4 also improved cellular viability in slices from thioacetamide-treated mice, highlighting its potential proregenerative effects in injured liver tissue.
Conclusions
Our study highlights the potential of IL-4-driven modulation of the liver microenvironment, paving the way for cytokine-based therapeutic strategies to enhance immune-mediated hepatic regeneration.
{"title":"Interleukin-4-mediated Pro-Regenerative Cellular Reprogramming in 3-dimensional Liver Culture","authors":"Damra Camat , Diana Nakib , Sai W. Chung , Manmeet Sekhon , Yijia Liu , Patricia Lumanto , Sharon J. Hyduk , Catia T. Perciani , Agata M. Bartczak , Michael L. Cheng , Olivia I. Pezzutti , Melina Kaltagian , Fatima Altaf , Sadaf M. Jafari , Justin Manuel , Cornelia Thoeni , Shinchiro Ogawa , Xue-Zhong Ma , Ian D. McGilvray , Sonya A. MacParland","doi":"10.1016/j.jcmgh.2025.101626","DOIUrl":"10.1016/j.jcmgh.2025.101626","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Interleukin-4 (IL-4) is a key contributor to liver regeneration, but its effects remain poorly understood due to a lack of models that preserve the complex cellular interactions of the liver. Here, we use murine precision-cut liver slices (PCLS), a 3-dimensional tissue culture system that maintains both parenchymal and non-parenchymal cells, to investigate the role of IL-4 in hepatic cell reprogramming. Through longitudinal single-cell transcriptomics and protein-level validation, we demonstrate the proregenerative potential of IL-4.</div></div><div><h3>Methods</h3><div>We performed longitudinal single nucleus RNA sequencing on PCLS from 8- to 10-week-old C57BL/6 mice over 5 days of culture in the presence and absence of IL-4. We assessed intracellular ATP output to demonstrate slice viability. We further performed orthogonal evaluations of the impact of IL-4 treatment via immunhistochemical staining to confirm proliferation and cell identity within the slices. We then assessed the impact of IL-4 exposure in slices generated from the diseased livers (hepatonecrosis/fibrosis) of mice treated with thioacetamide.</div></div><div><h3>Results</h3><div>IL-4 induced transcriptional changes, including increased expression of tissue repair-associated markers in myeloid cells, expansion of hepatocyte and cholangiocyte progenitors, and inhibition of fibroblast activation. Additionally, IL-4 treatment significantly increased Ki67 protein expression and intracellular ATP production, indicating enhanced proliferation and viability. Notably, IL-4 also improved cellular viability in slices from thioacetamide-treated mice, highlighting its potential proregenerative effects in injured liver tissue.</div></div><div><h3>Conclusions</h3><div>Our study highlights the potential of IL-4-driven modulation of the liver microenvironment, paving the way for cytokine-based therapeutic strategies to enhance immune-mediated hepatic regeneration.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101626"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145002001","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}
Pub Date : 2026-01-01Epub Date: 2025-11-29DOI: 10.1016/j.jcmgh.2025.101690
Benjamin C. Duncan, Maeve T. Morris, Jordan L. Pascoe, Stuti Khadka, Lei Wang, Gangqing Hu, Jonathan T. Busada
Background & Aims
Gastric cancer is the fifth most common cancer worldwide. Men are disproportionately affected by gastric cancer, which ranks as the fourth most common cancer in men compared with eighth in women. Chronic inflammation driven by Helicobacter pylori infection remains the leading gastric cancer risk factor. Evidence suggests that sex hormones shape sex differences in infection outcomes and cancer susceptibility. This study investigates how androgens influence the gastric inflammatory response to Helicobacter infection and contribute to sex disparities in pre-dysplastic disease progression.
Methods
Male and female mice were colonized with Helicobacter felis. Androgen levels were manipulated by bilateral castration in males and dihydrotestosterone (DHT) treatment in females. Single-cell RNA sequencing was used to identify androgen-responsive leukocyte populations and to establish cell communication networks between leukocyte clusters. The functional roles of these cells were further defined using type 2 innate lymphoid cell (ILC2)- and T cell-deficient mouse models.
Results
Infected female mice developed significantly more severe gastric inflammation, atrophy, and metaplasia infection compared with males. Androgen depletion by castration increased gastric inflammation and accelerated preneoplastic lesion development, whereas these pathological features were reduced by DHT treatment. Androgen-responsive ILC2s were key initiators of gastric inflammation, and ILC2 depletion abolished the sex differences in H felis pathogenesis.
Conclusions
This study reveals that androgens protect from Helicobacter-induced gastric inflammation by modulating ILC2 activation. These findings indicate that ILC2s serve as master regulators of Helicobacter-driven gastric inflammation and highlight their role in directing sex differences in the progression of pre-dysplastic disease.
{"title":"Androgen Signaling in ILC2s Drives Sex Differences in Helicobacter-induced Gastric Inflammation and Atrophy","authors":"Benjamin C. Duncan, Maeve T. Morris, Jordan L. Pascoe, Stuti Khadka, Lei Wang, Gangqing Hu, Jonathan T. Busada","doi":"10.1016/j.jcmgh.2025.101690","DOIUrl":"10.1016/j.jcmgh.2025.101690","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Gastric cancer is the fifth most common cancer worldwide. Men are disproportionately affected by gastric cancer, which ranks as the fourth most common cancer in men compared with eighth in women. Chronic inflammation driven by <em>Helicobacter pylori</em> infection remains the leading gastric cancer risk factor. Evidence suggests that sex hormones shape sex differences in infection outcomes and cancer susceptibility. This study investigates how androgens influence the gastric inflammatory response to <em>Helicobacter</em> infection and contribute to sex disparities in pre-dysplastic disease progression.</div></div><div><h3>Methods</h3><div>Male and female mice were colonized with <em>Helicobacter felis</em>. Androgen levels were manipulated by bilateral castration in males and dihydrotestosterone (DHT) treatment in females. Single-cell RNA sequencing was used to identify androgen-responsive leukocyte populations and to establish cell communication networks between leukocyte clusters. The functional roles of these cells were further defined using type 2 innate lymphoid cell (ILC2)- and T cell-deficient mouse models.</div></div><div><h3>Results</h3><div>Infected female mice developed significantly more severe gastric inflammation, atrophy, and metaplasia infection compared with males. Androgen depletion by castration increased gastric inflammation and accelerated preneoplastic lesion development, whereas these pathological features were reduced by DHT treatment. Androgen-responsive ILC2s were key initiators of gastric inflammation, and ILC2 depletion abolished the sex differences in <em>H felis</em> pathogenesis.</div></div><div><h3>Conclusions</h3><div>This study reveals that androgens protect from <em>Helicobacter</em>-induced gastric inflammation by modulating ILC2 activation. These findings indicate that ILC2s serve as master regulators of <em>Helicobacter-</em>driven gastric inflammation and highlight their role in directing sex differences in the progression of pre-dysplastic disease.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101690"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145650291","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}
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