Pub Date : 2026-01-01DOI: 10.1016/j.jcmgh.2025.101672
Jieun Song , Suyeon Je , Bawool Lee , Hyuk Wan Ko
<div><h3>Background & Aims</h3><div>Intestinal development is intricately governed by epithelial-mesenchymal crosstalk, with Hedgehog (Hh) signaling playing a pivotal role. The formation of mesenchymal clusters, driven by epithelial Hh signals, is critical for villus morphogenesis. However, the specific role of primary cilia within the mesenchyme during this process remains insufficiently understood. Ciliogenesis-associated kinase 1 (Cilk1) is crucial for maintaining primary cilia required for Hh signal transduction. This study examines the role of Cilk1 in mesenchymal ciliogenesis and cluster formation during intestinal development.</div></div><div><h3>Methods</h3><div>We used both Cilk1 knockout (<em>Cilk1</em><sup><em>KO</em></sup>) and tissue-specific Cilk1 deletion models, along with conditional Ift88 knockout mice, to examine the role of primary cilia in intestinal development. Immunohistochemistry, in situ hybridization, quantitative real-time PCR (qRT-PCR), and bulk RNA sequencing (RNA-seq) were employed to evaluate the presence of primary cilia, mesenchymal cluster formation, and the expression of signaling pathway activity. The tissue-specific deletion of primary cilia was achieved by crossing Ift88 floxed mice with Cre driver lines targeting the intestinal epithelium (Villin<sup>Cre</sup>) and mesenchyme (Gli1<sup>CreERT2</sup>). Postnatal deletion experiments validated Hh responsiveness in postnatal intestinal mesenchyme.</div></div><div><h3>Results</h3><div>Our findings demonstrate that, although Cilk1 is not required for the initial formation of primary cilia in both the epithelium and mesenchyme at embryonic day 12.5 (E12.5), it is crucial for maintaining mesenchymal cilia beyond E14.5—a critical stage for villus morphogenesis. Deletion of Cilk1 led to the loss of mesenchymal cilia, resulting in impaired Hh signaling, defective mesenchymal clustering, and abnormal villus formation. Transcriptomic analysis revealed disruption of multiple signaling pathways including marked downregulation of BMP ligands, significant enrichment of Wnt pathway alterations (NES = 1.52; false discovery rate [FDR] q = 0.0038), and changes in retinoic acid signaling, whereas fibroblast growth factor (FGF) signaling remained unaffected. Tissue-specific deletion of Ift88 further confirmed the necessity of mesenchymal cilia for proper cluster formation and Hh signal transduction. Activation of Hh signaling through administration of the agonist SAG partially restored mesenchymal cluster formation in <em>Cilk1</em><sup><em>KO</em></sup> intestines, consistent with the multi-pathway disruption identified by RNA-seq. Postnatal deletion experiments confirmed that Cilk1 is required for Hh responsiveness in postnatal intestinal mesenchyme.</div></div><div><h3>Conclusions</h3><div>Cilk1 is essential for maintaining mesenchymal primary cilia and ensuring effective signaling required for intestinal villus morphogenesis. Disruption of Cilk1 impairs Hh-mediated mesen
{"title":"Cilk1 Is Essential for Mesenchymal Cilia Maintenance and Epithelial-mesenchymal Crosstalk in Intestinal Villus Morphogenesis","authors":"Jieun Song , Suyeon Je , Bawool Lee , Hyuk Wan Ko","doi":"10.1016/j.jcmgh.2025.101672","DOIUrl":"10.1016/j.jcmgh.2025.101672","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Intestinal development is intricately governed by epithelial-mesenchymal crosstalk, with Hedgehog (Hh) signaling playing a pivotal role. The formation of mesenchymal clusters, driven by epithelial Hh signals, is critical for villus morphogenesis. However, the specific role of primary cilia within the mesenchyme during this process remains insufficiently understood. Ciliogenesis-associated kinase 1 (Cilk1) is crucial for maintaining primary cilia required for Hh signal transduction. This study examines the role of Cilk1 in mesenchymal ciliogenesis and cluster formation during intestinal development.</div></div><div><h3>Methods</h3><div>We used both Cilk1 knockout (<em>Cilk1</em><sup><em>KO</em></sup>) and tissue-specific Cilk1 deletion models, along with conditional Ift88 knockout mice, to examine the role of primary cilia in intestinal development. Immunohistochemistry, in situ hybridization, quantitative real-time PCR (qRT-PCR), and bulk RNA sequencing (RNA-seq) were employed to evaluate the presence of primary cilia, mesenchymal cluster formation, and the expression of signaling pathway activity. The tissue-specific deletion of primary cilia was achieved by crossing Ift88 floxed mice with Cre driver lines targeting the intestinal epithelium (Villin<sup>Cre</sup>) and mesenchyme (Gli1<sup>CreERT2</sup>). Postnatal deletion experiments validated Hh responsiveness in postnatal intestinal mesenchyme.</div></div><div><h3>Results</h3><div>Our findings demonstrate that, although Cilk1 is not required for the initial formation of primary cilia in both the epithelium and mesenchyme at embryonic day 12.5 (E12.5), it is crucial for maintaining mesenchymal cilia beyond E14.5—a critical stage for villus morphogenesis. Deletion of Cilk1 led to the loss of mesenchymal cilia, resulting in impaired Hh signaling, defective mesenchymal clustering, and abnormal villus formation. Transcriptomic analysis revealed disruption of multiple signaling pathways including marked downregulation of BMP ligands, significant enrichment of Wnt pathway alterations (NES = 1.52; false discovery rate [FDR] q = 0.0038), and changes in retinoic acid signaling, whereas fibroblast growth factor (FGF) signaling remained unaffected. Tissue-specific deletion of Ift88 further confirmed the necessity of mesenchymal cilia for proper cluster formation and Hh signal transduction. Activation of Hh signaling through administration of the agonist SAG partially restored mesenchymal cluster formation in <em>Cilk1</em><sup><em>KO</em></sup> intestines, consistent with the multi-pathway disruption identified by RNA-seq. Postnatal deletion experiments confirmed that Cilk1 is required for Hh responsiveness in postnatal intestinal mesenchyme.</div></div><div><h3>Conclusions</h3><div>Cilk1 is essential for maintaining mesenchymal primary cilia and ensuring effective signaling required for intestinal villus morphogenesis. Disruption of Cilk1 impairs Hh-mediated mesen","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101672"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145453711","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 : 2026-01-01DOI: 10.1016/j.jcmgh.2025.101699
Sara R. Druffner , Benjamin C. Duncan , Maeve T. Morris , Jordan L. Pascoe , Tyler M. Abner , Salik Hussain , M. Blanca Piazuelo , Richard M. Peek Jr. , Melody Zhang , Richard J. DiPaolo , Jonathan T. Busada
Background & Aims
Immune responses to infection must balance pathogen clearance with minimizing tissue damage and autoimmunity. Chronic gastric inflammation caused by Heliobactor pylori damages the gastric mucosa and promotes carcinogenesis. Glucocorticoids are immunoregulatory hormones that limit immune activation in the stomach. This study aimed to determine how endogenous glucocorticoids regulate the gastric immune response to Helicobacter infection and their impact on preneoplastic lesion development.
Methods
We examined the role of endogenous glucocorticoids in shaping the gastric immune response to Helicobacter felis colonization. Gastric immune cell infiltration, atrophy, metaplasia, and preneoplastic lesion development were evaluated in adrenal-intact and adrenalectomized (ADX) mice. Auto-reactive immunoglobulin G antibodies were assessed using a mouse self-antigen array and by measuring their binding to healthy gastric tissue.
Results
Loss of endogenous glucocorticoids led to significantly increased Hfelis-induced gastric T cell infiltration and proinflammatory cytokine expression compared with intact-infected controls. Although all intact mice maintained chronic infection for up to 12 months post-colonization, nearly all ADX mice eradicated Hfelis within 2 to 3 weeks. Despite bacterial clearance, ADX mice continued to exhibit chronic gastric inflammation and developed dysplasia. Autoantibody profiling showed that both intact and ADX groups generated self-reactive immunoglobulin G during active infection. However, only ADX mice sustained autoantibody production following bacterial eradication.
Conclusions
Endogenous glucocorticoids attenuate gastric inflammation during Helicobacter infection, supporting bacterial persistence while maintaining immune tolerance. These findings suggest that heightened immune responses to Hpylori may trigger autoimmune gastritis development, which can persist after Hpylori clearance and continue to drive gastric cancer risk.
{"title":"Endogenous Glucocorticoids Moderate the Gastric Inflammatory Response to Helicobacter Infection and Protect from Autoimmunity","authors":"Sara R. Druffner , Benjamin C. Duncan , Maeve T. Morris , Jordan L. Pascoe , Tyler M. Abner , Salik Hussain , M. Blanca Piazuelo , Richard M. Peek Jr. , Melody Zhang , Richard J. DiPaolo , Jonathan T. Busada","doi":"10.1016/j.jcmgh.2025.101699","DOIUrl":"10.1016/j.jcmgh.2025.101699","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Immune responses to infection must balance pathogen clearance with minimizing tissue damage and autoimmunity. Chronic gastric inflammation caused by <em>Heliobactor pylori</em> damages the gastric mucosa and promotes carcinogenesis. Glucocorticoids are immunoregulatory hormones that limit immune activation in the stomach. This study aimed to determine how endogenous glucocorticoids regulate the gastric immune response to <em>Helicobacter</em> infection and their impact on preneoplastic lesion development.</div></div><div><h3>Methods</h3><div>We examined the role of endogenous glucocorticoids in shaping the gastric immune response to <em>Helicobacter felis</em> colonization. Gastric immune cell infiltration, atrophy, metaplasia, and preneoplastic lesion development were evaluated in adrenal-intact and adrenalectomized (ADX) mice. Auto-reactive immunoglobulin G antibodies were assessed using a mouse self-antigen array and by measuring their binding to healthy gastric tissue.</div></div><div><h3>Results</h3><div>Loss of endogenous glucocorticoids led to significantly increased <em>H</em> <em>felis-</em>induced gastric T cell infiltration and proinflammatory cytokine expression compared with intact-infected controls. Although all intact mice maintained chronic infection for up to 12 months post-colonization, nearly all ADX mice eradicated <em>H</em> <em>felis</em> within 2 to 3 weeks. Despite bacterial clearance, ADX mice continued to exhibit chronic gastric inflammation and developed dysplasia. Autoantibody profiling showed that both intact and ADX groups generated self-reactive immunoglobulin G during active infection. However, only ADX mice sustained autoantibody production following bacterial eradication.</div></div><div><h3>Conclusions</h3><div>Endogenous glucocorticoids attenuate gastric inflammation during <em>Helicobacter</em> infection, supporting bacterial persistence while maintaining immune tolerance. These findings suggest that heightened immune responses to <em>H</em> <em>pylori</em> may trigger autoimmune gastritis development, which can persist after <em>H</em> <em>pylori</em> clearance and continue to drive gastric cancer risk.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 4","pages":"Article 101699"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844563","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 : 2026-01-01DOI: 10.1016/j.jcmgh.2025.101713
Joydeep Aoun , Ahmed Kabrah , Malini Ahuja , Benjamin Leblanc , Changyu Zhang , Li Li , Yan Wang , Shmuel Muallem
Background & Aims
Oral and gut health are tightly connected through their microbiome and immunity, including in disease states. The oral adaptive immunity contributes to the severity of inflammatory bowel disease (IBD). However, the role of oral innate immunity, and more specifically the saliva, in gut microbiome and IBD is poorly understood.
Methods
We used 2 mouse models with reduced saliva, nonobese diabetic (NOD) and aquaporin 5 (Aqp5)-/- mice, and recovery of salivation in the NOD mice by treatment with a cystic fibrosis transmembrane regulator corrector to examine the role of salivation in oral and gut microbiome, IBD, and survival.
Results
Analysis of the oral microbiome at various conditions revealed that the saliva has a minimal role in shaping the oral microbiome. However, salivation affected the composition of the gut microbiome. Moreover, the lack of saliva significantly delayed development of dextran sodium sulphate-induced colitis, but resulted in a later, age-dependent, rapidly developed weight loss and death. The dual roles of the saliva were caused by 2 immunomodulatory peptides secreted by salivary glands. Fractionation and mass spectroscopy analysis identified trefoil factor 2 (TFF2) as a protective component and the cytokine macrophage migration inhibitory factor (MIF) as the damaging component of the saliva. The effects of the salivary fluid, TFF2, and MIF were primarily due to control of the gut barrier, rather than the gut microbiome. Scavenging salivary TFF2 and MIF with antibodies resulted in exacerbating and protection, respectively, of IBD.
Conclusions
The oral innate immunity has a major role in shaping the gut microbiome through secretion of MIF and TFF2. Control of MIF and TFF2 can benefit the treatment of colitis.
{"title":"Role of Innate Oral Immunity and the Salivary Fluid in Inflammatory Bowel Disease","authors":"Joydeep Aoun , Ahmed Kabrah , Malini Ahuja , Benjamin Leblanc , Changyu Zhang , Li Li , Yan Wang , Shmuel Muallem","doi":"10.1016/j.jcmgh.2025.101713","DOIUrl":"10.1016/j.jcmgh.2025.101713","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Oral and gut health are tightly connected through their microbiome and immunity, including in disease states. The oral adaptive immunity contributes to the severity of inflammatory bowel disease (IBD). However, the role of oral innate immunity, and more specifically the saliva, in gut microbiome and IBD is poorly understood.</div></div><div><h3>Methods</h3><div>We used 2 mouse models with reduced saliva, nonobese diabetic (NOD) and aquaporin 5 (Aqp5)<sup>-/-</sup> mice, and recovery of salivation in the NOD mice by treatment with a cystic fibrosis transmembrane regulator corrector to examine the role of salivation in oral and gut microbiome, IBD, and survival.</div></div><div><h3>Results</h3><div>Analysis of the oral microbiome at various conditions revealed that the saliva has a minimal role in shaping the oral microbiome. However, salivation affected the composition of the gut microbiome. Moreover, the lack of saliva significantly delayed development of dextran sodium sulphate-induced colitis, but resulted in a later, age-dependent, rapidly developed weight loss and death. The dual roles of the saliva were caused by 2 immunomodulatory peptides secreted by salivary glands. Fractionation and mass spectroscopy analysis identified trefoil factor 2 (TFF2) as a protective component and the cytokine macrophage migration inhibitory factor (MIF) as the damaging component of the saliva. The effects of the salivary fluid, TFF2, and MIF were primarily due to control of the gut barrier, rather than the gut microbiome. Scavenging salivary TFF2 and MIF with antibodies resulted in exacerbating and protection, respectively, of IBD.</div></div><div><h3>Conclusions</h3><div>The oral innate immunity has a major role in shaping the gut microbiome through secretion of MIF and TFF2. Control of MIF and TFF2 can benefit the treatment of colitis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 4","pages":"Article 101713"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828890","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 : 2026-01-01DOI: 10.1016/j.jcmgh.2025.101695
Wendong Li , Tongtong Wu , Hao Li , Zhenyu Guan , Mingjie Ding , Wenzhi Guo
Background & Aims
Hepatic ischemia-reperfusion injury (HIRI) is one of the common complications of liver transplantation. Rhomboid 5 homolog 2 (Rhbdf2) plays a crucial role in apoptosis, inflammation, and liver injury, but its role and regulatory mechanism in HIRI remain unclear. The aim of this study was to investigate the role of Rhbdf2 in HIRI and elucidate its molecular mechanism.
Methods
Rhbdf2 expression levels were detected in pre-ischemia–reperfusion (Pre) and post-ischemia–reperfusion (Post) livers. Western blot analysis, flow cytometry, quantitative real-time polymerase chain reaction, and immunofluorescence staining were used to investigate the effects of Rhbdf2 on hepatic ischemia-reperfusion (HI/R). The potential molecular mechanisms of the effects of Rhbdf2 on HI/R were investigated by combining RNA sequencing and mass spectrometry analysis, as well as co-immunoprecipitation and in vitro ubiquitination assays.
Results
The level of Rhbdf2 protein was significantly increased in HI/R. Overexpression of Rhbdf2 in mice exacerbated HI/R-induced liver injury, apoptosis, and the inflammatory response, whereas knockdown of Rhbdf2 produced the opposite results. Mechanistically, overexpression of Rhbdf2 promoted the phosphorylation of mitogen-activated protein kinase kinase kinase 7 (MAP3K7, also known as TAK1), thereby activating the JNK/p38 signaling pathway and ultimately exacerbating HIRI. Mass spectrometry analysis, co-immunoprecipitation, and in vitro ubiquitination assays revealed that the E3 ubiquitin ligase constitutive photomorphogenic 1 (Cop1) interacts with Rhbdf2 and mediates its degradation through K48-linked ubiquitination, thereby inhibiting the TAK1- JNK/p38 axis and reducing HIRI.
Conclusions
This study revealed that Rhbdf2 exacerbates HIRI by activating the TAK1- JNK/p38 axis, whereas Cop1-mediated Rhbdf2 ubiquitination and degradation can significantly inhibit this process. These findings provide potential therapeutic targets and insights for the clinical treatment of HIRI.
{"title":"Ubiquitination of Rhomboid 5 Homolog 2 by Constitutive Photomorphogenic 1 Alleviates Hepatic Ischemia-reperfusion Injury by Regulating the Transforming Growth Factor-β Activating Kinase 1-C-Jun N-terminal Kinase/p38 Signaling Pathway","authors":"Wendong Li , Tongtong Wu , Hao Li , Zhenyu Guan , Mingjie Ding , Wenzhi Guo","doi":"10.1016/j.jcmgh.2025.101695","DOIUrl":"10.1016/j.jcmgh.2025.101695","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Hepatic ischemia-reperfusion injury (HIRI) is one of the common complications of liver transplantation. Rhomboid 5 homolog 2 (Rhbdf2) plays a crucial role in apoptosis, inflammation, and liver injury, but its role and regulatory mechanism in HIRI remain unclear. The aim of this study was to investigate the role of Rhbdf2 in HIRI and elucidate its molecular mechanism.</div></div><div><h3>Methods</h3><div>Rhbdf2 expression levels were detected in pre-ischemia–reperfusion (Pre) and post-ischemia–reperfusion (Post) livers. Western blot analysis, flow cytometry, quantitative real-time polymerase chain reaction, and immunofluorescence staining were used to investigate the effects of Rhbdf2 on hepatic ischemia-reperfusion (HI/R). The potential molecular mechanisms of the effects of Rhbdf2 on HI/R were investigated by combining RNA sequencing and mass spectrometry analysis, as well as co-immunoprecipitation and in vitro ubiquitination assays.</div></div><div><h3>Results</h3><div>The level of Rhbdf2 protein was significantly increased in HI/R. Overexpression of Rhbdf2 in mice exacerbated HI/R-induced liver injury, apoptosis, and the inflammatory response, whereas knockdown of Rhbdf2 produced the opposite results. Mechanistically, overexpression of Rhbdf2 promoted the phosphorylation of mitogen-activated protein kinase kinase kinase 7 (MAP3K7, also known as TAK1), thereby activating the JNK/p38 signaling pathway and ultimately exacerbating HIRI. Mass spectrometry analysis, co-immunoprecipitation, and in vitro ubiquitination assays revealed that the E3 ubiquitin ligase constitutive photomorphogenic 1 (Cop1) interacts with Rhbdf2 and mediates its degradation through K48-linked ubiquitination, thereby inhibiting the TAK1- JNK/p38 axis and reducing HIRI.</div></div><div><h3>Conclusions</h3><div>This study revealed that Rhbdf2 exacerbates HIRI by activating the TAK1- JNK/p38 axis, whereas Cop1-mediated Rhbdf2 ubiquitination and degradation can significantly inhibit this process. These findings provide potential therapeutic targets and insights for the clinical treatment of HIRI.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 4","pages":"Article 101695"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145702997","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 : 2026-01-01DOI: 10.1016/j.jcmgh.2025.101660
Urvinder Kaur Sardarni, Jennifer M. Bailey-Lundberg
{"title":"CREB Fuels Tumorigenesis in Alcoholic Pancreatitis","authors":"Urvinder Kaur Sardarni, Jennifer M. Bailey-Lundberg","doi":"10.1016/j.jcmgh.2025.101660","DOIUrl":"10.1016/j.jcmgh.2025.101660","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101660"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338286","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 : 2026-01-01DOI: 10.1016/j.jcmgh.2025.101678
Hui Han , Jeongwoo Park , Rui Zhang , Nithyananthan Subramaniyam , Sukanta Das , Xiaodong Ge , Sai Santosh Babu Komakula , Chao Wang , Romain Desert , Wei Chen , Zhuolun Song , Dipti Athavale , Abid Anwar , Daniel Lantvit , Grace Guzman , María Dolores Frutos , Bruno Ramos-Molina , Natalia Nieto
Background & Aims
The gut-liver axis plays a critical role in metabolic dysfunction-associated steatohepatitis (MASH). Osteopontin (OPN, encoded by SPP1) is implicated in chronic liver disease; however, its expression in intestinal epithelial cells (IECs) and role in MASH remain unclear.
Methods
We evaluated intestinal OPN expression during MASH progression in patients. To determine the function of IEC-derived OPN, we generated Spp1 knock-in (Spp1KI IEC) and knock-out (Spp1ΔIEC) mice and fed them a high-fat, high-fructose, high-cholesterol diet to induce MASH.
Results
IEC OPN expression decreased with MASH progression and was inversely associated with liver injury. Loss of Spp1 in IECs exacerbated MASH, whereas overexpression or oral OPN administration was protective. Spp1ΔIEC mice exhibited increased hepatic inflammation, disrupted IEC morphology, elevated IEC apoptosis, reduced epithelial cell turnover, and heightened intestinal permeability. They also showed hepatic 16s rRNA presence and elevated conjugated bile acids (BAs), particularly taurocholic acid and taurodeoxycholic acid, in portal serum. These BAs promoted hepatocyte injury and activated liver macrophages, enhancing inflammation both in vitro and in vivo. Fecal microbiome analysis revealed reduced abundance of bile salt hydrolase-expressing bacteria. Fecal microbiota transplantation from Spp1ΔIEC mice or treatment with a bile salt hydrolase inhibitor further worsened MASH.
Conclusions
IEC-derived OPN protects against MASH by modulating BA composition and shaping the gut microbiome.
{"title":"Intestinal Epithelial Cell-derived Osteopontin Protects Against Metabolic Dysfunction–associated Steatohepatitis by Modulating Bile Acid Composition and the Gut Microbiome","authors":"Hui Han , Jeongwoo Park , Rui Zhang , Nithyananthan Subramaniyam , Sukanta Das , Xiaodong Ge , Sai Santosh Babu Komakula , Chao Wang , Romain Desert , Wei Chen , Zhuolun Song , Dipti Athavale , Abid Anwar , Daniel Lantvit , Grace Guzman , María Dolores Frutos , Bruno Ramos-Molina , Natalia Nieto","doi":"10.1016/j.jcmgh.2025.101678","DOIUrl":"10.1016/j.jcmgh.2025.101678","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The gut-liver axis plays a critical role in metabolic dysfunction-associated steatohepatitis (MASH). Osteopontin (OPN, encoded by <em>SPP1</em>) is implicated in chronic liver disease; however, its expression in intestinal epithelial cells (IECs) and role in MASH remain unclear.</div></div><div><h3>Methods</h3><div>We evaluated intestinal OPN expression during MASH progression in patients. To determine the function of IEC-derived OPN, we generated <em>Spp1</em> knock-in (<em>Spp1</em><sup>KI IEC</sup>) and knock-out (<em>Spp1</em><sup>ΔIEC</sup>) mice and fed them a high-fat, high-fructose, high-cholesterol diet to induce MASH.</div></div><div><h3>Results</h3><div>IEC OPN expression decreased with MASH progression and was inversely associated with liver injury. Loss of <em>Spp1</em> in IECs exacerbated MASH, whereas overexpression or oral OPN administration was protective. <em>Spp1</em><sup>ΔIEC</sup> mice exhibited increased hepatic inflammation, disrupted IEC morphology, elevated IEC apoptosis, reduced epithelial cell turnover, and heightened intestinal permeability. They also showed hepatic <em>16s</em> rRNA presence and elevated conjugated bile acids (BAs), particularly taurocholic acid and taurodeoxycholic acid, in portal serum. These BAs promoted hepatocyte injury and activated liver macrophages, enhancing inflammation both in vitro and in vivo. Fecal microbiome analysis revealed reduced abundance of bile salt hydrolase-expressing bacteria. Fecal microbiota transplantation from <em>Spp1</em><sup>ΔIEC</sup> mice or treatment with a bile salt hydrolase inhibitor further worsened MASH.</div></div><div><h3>Conclusions</h3><div>IEC-derived OPN protects against MASH by modulating BA composition and shaping the gut microbiome.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101678"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531026","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 : 2026-01-01DOI: 10.1016/j.jcmgh.2025.101707
Camilla Cadoli , Sania Arif , Wibke Ballhorn , Angela Brieger , Maximilian Joseph Brol , Florence Castelli , Hans-Peter Erasmus , Julia Fischer , Robert Gurke , Lisa Hahnefeld , Christophe Junot , Nico Kraus , Cristina Ortiz , Robert Schierwagen , Sara Garcia Torres , Frank Erhard Uschner , Volker Müller , Jonel Trebicka , Christoph Welsch , Volkhard A.J. Kempf
Background & Aims
Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome of acute hepatic decompensation (AD) that leads to multiorgan failure and high mortality. Bacterial infections are often implicated in ACLF pathogenesis; however, their underlying molecular mechanisms remain poorly understood. This study employed a combined in vitro-ex vivo metabolomics approach to investigate infection-associated metabolic alterations relevant to ACLF.
Methods
Gut (Caco-2) cells were infected with Acinetobacter baumannii and Klebsiella pneumoniae strains. Metabolite profiling was conducted on cell culture supernatants, and selected metabolites were tested for hepatotoxicity in vitro using liver (HepG2) cells. Metabolomic analysis of sera from 2 independent patient cohorts (AD and ACLF) was conducted to validate in vitro findings and to assess their clinical relevance.
Results
Distinct metabolic signatures were identified in Abaumannii (19 metabolites) and Kpneumoniae (15 metabolites)-infected Caco-2 cells. Four key metabolites from each bacterial species were prioritized for further experiments: α-ketoglutarate, indoleacetic acid, p-coumaric acid, uridine (Abaumannii), desthiobiotin, N8-acetylspermidine, N-acetylglutamine, and β-pinene (Kpneumoniae). Hepatotoxicity was demonstrated in liver (HepG2) cells exposed to Caco-2 infected cell-derived supernatants, infection-associated metabolites, and metabolite mixtures (in all conditions, P < .0001). Increased levels of α-ketoglutarate (P = .0002), N-acetylglutamine (P = .0153), indoleacetic acid (P < .05), and N8-acetylspermidine (P < .01) have been confirmed in the sera of patients with AD and ACLF.
Conclusions
Our findings suggest that metabolites associated with bacterial infections and hepatotoxic potential are significantly elevated in patients with AD and ACLF. These compounds may contribute to disease-related metabolic disturbances, representing promising candidates as early diagnostic biomarkers and targeted therapeutic strategies for ACLF.
{"title":"Metabolic Signatures of Acinetobacter baumannii and Klebsiella pneumoniae Infections in Acute-on-chronic Liver Failure","authors":"Camilla Cadoli , Sania Arif , Wibke Ballhorn , Angela Brieger , Maximilian Joseph Brol , Florence Castelli , Hans-Peter Erasmus , Julia Fischer , Robert Gurke , Lisa Hahnefeld , Christophe Junot , Nico Kraus , Cristina Ortiz , Robert Schierwagen , Sara Garcia Torres , Frank Erhard Uschner , Volker Müller , Jonel Trebicka , Christoph Welsch , Volkhard A.J. Kempf","doi":"10.1016/j.jcmgh.2025.101707","DOIUrl":"10.1016/j.jcmgh.2025.101707","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome of acute hepatic decompensation (AD) that leads to multiorgan failure and high mortality. Bacterial infections are often implicated in ACLF pathogenesis; however, their underlying molecular mechanisms remain poorly understood. This study employed a combined in vitro-ex vivo metabolomics approach to investigate infection-associated metabolic alterations relevant to ACLF.</div></div><div><h3>Methods</h3><div>Gut (Caco-2) cells were infected with <em>Acinetobacter baumannii</em> and <em>Klebsiella pneumoniae</em> strains. Metabolite profiling was conducted on cell culture supernatants, and selected metabolites were tested for hepatotoxicity in vitro using liver (HepG2) cells. Metabolomic analysis of sera from 2 independent patient cohorts (AD and ACLF) was conducted to validate in vitro findings and to assess their clinical relevance.</div></div><div><h3>Results</h3><div>Distinct metabolic signatures were identified in <em>A</em> <em>baumannii</em> (19 metabolites) and <em>K</em> <em>pneumoniae</em> (15 metabolites)-infected Caco-2 cells. Four key metabolites from each bacterial species were prioritized for further experiments: α-ketoglutarate, indoleacetic acid, p-coumaric acid, uridine (<em>A</em> <em>baumannii</em>), desthiobiotin, N8-acetylspermidine, N-acetylglutamine, and β-pinene (<em>K</em> <em>pneumoniae</em>). Hepatotoxicity was demonstrated in liver (HepG2) cells exposed to Caco-2 infected cell-derived supernatants, infection-associated metabolites, and metabolite mixtures (in all conditions, <em>P</em> < .0001). Increased levels of α-ketoglutarate (<em>P</em> = .0002), N-acetylglutamine (<em>P</em> = .0153), indoleacetic acid (<em>P</em> < .05), and N8-acetylspermidine (<em>P</em> < .01) have been confirmed in the sera of patients with AD and ACLF.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that metabolites associated with bacterial infections and hepatotoxic potential are significantly elevated in patients with AD and ACLF. These compounds may contribute to disease-related metabolic disturbances, representing promising candidates as early diagnostic biomarkers and targeted therapeutic strategies for ACLF.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 4","pages":"Article 101707"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752469","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 : 2026-01-01DOI: 10.1016/j.jcmgh.2025.101681
Rainelli B. Koumangoye, Mohammed Z. Ferdaus, Xenia Davis, Julia K. Bohannon, Eric Delpire
Background & Aims
Potassium and chloride efflux have been reported to regulate nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. Aberrant activation of NLRP3 inflammasome causes autoimmune and chronic inflammatory diseases. The Na+-K+-2Cl- cotransporter (NKCC1) maintains the intracellular concentrations of sodium, potassium, and chloride. Here we ask whether NKCC1 modulates NLRP3 inflammasome activation.
Methods
Mice with intestinal epithelial-specific deletion of NKCC1, CRISPR-Cas9 NKCC1-deleted Caco-2 and HT-29 cells, and human fibroblasts expressing mutant NKCC1 were used to evaluate NLRP3 inflammasome activation.
Results
We found that deletion of NKCC1 in established intestinal epithelial cells (IECs) in culture causes increased pyroptosis and interleukin (IL)-1β and IL-18 secretion upon NLRP3 inflammasome activation. Similarly, organoids derived from mice with conditional NKCC1 knockout in IECs also exhibit increased IL-1β secretion when stimulated with adenosine triphosphate (ATP). Moreover, fibroblasts from a patient with NKCC1 mutant also showed increased pyroptosis and IL-1β and IL-18 secretion. Loss of NKCC1 sensitizes IECs to changes in intracellular concentration of K+ and decreases the threshold required for NLRP3 inflammasome activation. Finally, we showed that NKCC1ΔIEC mice have increased infiltration of innate immune cells in the colon mucosa and peritoneal cavity.
Conclusions
NKCC1 functions as a negative regulator of NLRP3 inflammasome activation and this may explain why patients of loss-of-function mutations in NKCC1 are susceptible to inflammatory diseases.
背景：钾和氯的外排已被报道调节NLRP3炎性体的激活。NLRP3炎性小体的异常激活导致自身免疫性和慢性炎症性疾病。Na+- k +- 2cl -共转运体（NKCC1）维持细胞内钠、钾和氯化物的浓度。在这里，我们询问NKCC1是否调节NLRP3炎性体的激活。方法：采用肠上皮特异性缺失NKCC1的小鼠、CRISPR-Cas9缺失NKCC1的caco2和HT-29细胞以及表达突变型NKCC1的人成纤维细胞来评估NLRP3炎性体的激活。结果：我们发现在培养的小肠上皮细胞中缺失NKCC1导致NLRP3炎性体激活后的焦亡、IL-1β和IL-18分泌增加。同样，在肠上皮细胞（IECs）中NKCC1条件敲除小鼠的类器官在ATP刺激下也表现出IL-1β分泌增加。此外，NKCC1突变患者的成纤维细胞也显示出焦亡，IL-1β和IL-18分泌增加。NKCC1的缺失使IECs对细胞内K+浓度的变化敏感，并降低NLRP3炎性体激活所需的阈值。最后，我们发现NKCC1ΔIEC小鼠在结肠黏膜和腹膜腔中增加了先天免疫细胞的浸润。结论：NKCC1作为NLRP3炎性小体激活的负调节因子，这可能解释了为什么NKCC1功能缺失突变的患者易患炎性疾病。
{"title":"Loss of NKCC1 Activates the NLRP3 Inflammasome in Intestinal Epithelia","authors":"Rainelli B. Koumangoye, Mohammed Z. Ferdaus, Xenia Davis, Julia K. Bohannon, Eric Delpire","doi":"10.1016/j.jcmgh.2025.101681","DOIUrl":"10.1016/j.jcmgh.2025.101681","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Potassium and chloride efflux have been reported to regulate nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. Aberrant activation of NLRP3 inflammasome causes autoimmune and chronic inflammatory diseases. The Na<sup>+</sup>-K<sup>+</sup>-2Cl<sup>-</sup> cotransporter (NKCC1) maintains the intracellular concentrations of sodium, potassium, and chloride. Here we ask whether NKCC1 modulates NLRP3 inflammasome activation.</div></div><div><h3>Methods</h3><div>Mice with intestinal epithelial-specific deletion of NKCC1, CRISPR-Cas9 NKCC1-deleted Caco-2 and HT-29 cells, and human fibroblasts expressing mutant NKCC1 were used to evaluate NLRP3 inflammasome activation.</div></div><div><h3>Results</h3><div>We found that deletion of NKCC1 in established intestinal epithelial cells (IECs) in culture causes increased pyroptosis and interleukin (IL)-1β and IL-18 secretion upon NLRP3 inflammasome activation. Similarly, organoids derived from mice with conditional NKCC1 <em>knockout</em> in IECs also exhibit increased IL-1β secretion when stimulated with adenosine triphosphate (ATP). Moreover, fibroblasts from a patient with NKCC1 mutant also showed increased pyroptosis and IL-1β and IL-18 secretion. Loss of NKCC1 sensitizes IECs to changes in intracellular concentration of K<sup>+</sup> and decreases the threshold required for NLRP3 inflammasome activation. Finally, we showed that NKCC1<sup>ΔIEC</sup> mice have increased infiltration of innate immune cells in the colon mucosa and peritoneal cavity.</div></div><div><h3>Conclusions</h3><div>NKCC1 functions as a negative regulator of NLRP3 inflammasome activation and this may explain why patients of loss-of-function mutations in NKCC1 are susceptible to inflammatory diseases.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101681"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145558291","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 : 2026-01-01DOI: 10.1016/j.jcmgh.2025.101679
Kim H.H. Liss , Samantha Goldman , Mai He , Trevor M. Shew , Daniel Ferguson , Brian N. Finck
Background & Aims
Hepatic ischemia reperfusion injury (IRI) is unavoidable in most liver operations and is associated with poor patient and graft outcomes in the setting of liver transplantation. However, there are no pharmacological interventions available for treatment of IRI. Prior work has demonstrated that liver IRI leads to hepatic lipid accumulation, suggesting that increased adipocyte lipolytic rates may contribute to hepatic steatosis. Inhibition of adipose triglyceride lipase (ATGL), the rate-limiting enzyme involved in triglyceride hydrolysis, may be beneficial in cardiac injury and alcoholic liver disease, but its role in liver IRI has not been investigated. Our objective was to assess the effects of inhibition of adipose tissue lipolysis in the setting of liver IRI.
Methods
Wild-type mice were treated with Atglistatin, a small molecule inhibitor of ATGL, prior to IRI. Mice with hepatocyte- or adipocyte-specific deletion of Pnpla2, the gene encoding ATGL, were generated and subjected to a mouse model of IRI. Mouse hepatocytes were cultured with fatty acids in an in vitro model of IRI.
Results
We demonstrated that experimental IRI was associated with increased adipocyte lipolysis. Pharmacological and genetic inhibition of adipocyte lipolysis reduced plasma and hepatic free fatty acids and decreased circulating transaminases and liver inflammation following hepatic IRI. Furthermore, exogenous fatty acids were sufficient to increase cell death and the expression of inflammatory cytokines in in vitro IRI.
Conclusions
These data suggest that targeting adipocyte lipolysis may represent a novel therapeutic approach in the prevention of hepatic IRI, which could improve patient and graft outcomes following liver transplantation.
{"title":"Inhibition of Adipocyte Lipolysis Reduces Liver Injury in a Mouse Model of Ischemia Reperfusion Injury","authors":"Kim H.H. Liss , Samantha Goldman , Mai He , Trevor M. Shew , Daniel Ferguson , Brian N. Finck","doi":"10.1016/j.jcmgh.2025.101679","DOIUrl":"10.1016/j.jcmgh.2025.101679","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Hepatic ischemia reperfusion injury (IRI) is unavoidable in most liver operations and is associated with poor patient and graft outcomes in the setting of liver transplantation. However, there are no pharmacological interventions available for treatment of IRI. Prior work has demonstrated that liver IRI leads to hepatic lipid accumulation, suggesting that increased adipocyte lipolytic rates may contribute to hepatic steatosis. Inhibition of adipose triglyceride lipase (ATGL), the rate-limiting enzyme involved in triglyceride hydrolysis, may be beneficial in cardiac injury and alcoholic liver disease, but its role in liver IRI has not been investigated. Our objective was to assess the effects of inhibition of adipose tissue lipolysis in the setting of liver IRI.</div></div><div><h3>Methods</h3><div>Wild-type mice were treated with Atglistatin, a small molecule inhibitor of ATGL, prior to IRI. Mice with hepatocyte- or adipocyte-specific deletion of <em>Pnpla2</em>, the gene encoding ATGL, were generated and subjected to a mouse model of IRI. Mouse hepatocytes were cultured with fatty acids in an in vitro model of IRI.</div></div><div><h3>Results</h3><div>We demonstrated that experimental IRI was associated with increased adipocyte lipolysis. Pharmacological and genetic inhibition of adipocyte lipolysis reduced plasma and hepatic free fatty acids and decreased circulating transaminases and liver inflammation following hepatic IRI. Furthermore, exogenous fatty acids were sufficient to increase cell death and the expression of inflammatory cytokines in in vitro IRI.</div></div><div><h3>Conclusions</h3><div>These data suggest that targeting adipocyte lipolysis may represent a novel therapeutic approach in the prevention of hepatic IRI, which could improve patient and graft outcomes following liver transplantation.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101679"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145566188","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 : 2026-01-01DOI: 10.1016/j.jcmgh.2025.101673
Angela M. Halstead , Chinye Nwokolo , Stella Hoft , Jinsheng Yu , Lifei Zhu , Brendan Tuley , Nancy Vargas , RuiRui Liu , Francisco Ramirez Victorino , Simrin Phatak , Wandy Beatty , Chun-Kan Chen , Richard DiPaolo , Paul Cliften , Tarin M. Bigley , José B. Sáenz
Background & Aims
Recent evidence suggests that endogenously derived double-stranded RNA (dsRNA) impacts multiple cellular processes, although its role in epithelial injury remains understudied. We previously identified the response to dsRNA as the most upregulated pathway across 2 distinct murine models of spasmolytic polypeptide-expressing metaplasia (SPEM), a critical pre-neoplastic transition in the progression to gastric cancer. The aim of this study was to define how dysregulation of the dsRNA response within gastric epithelium impacts gastric pre-neoplasia.
Methods
We specifically deleted ADAR1, a central regulator of dsRNA signaling, from gastric parietal cells (Adar1ΔPC). Adar1ΔPC and age-matched controls stomachs were histologically, transcriptionally, and immunologically profiled. The source of dsRNA in Adar1ΔPC gastric epithelium was assessed by dsRNA immunoprecipitation and immuno-electron microscopy. Finally, to define the contributions of interferon (IFN) signaling, Adar1ΔPC;Ifnar1-/-and Adar1ΔPC;Ifnlr1-/- mice, defective in type I and type III IFN signaling, respectively, were characterized.
Results
Adar1ΔPC mice spontaneously developed SPEM and gastric dysplasia, in the absence of exogenous injury. Our phenotype depended on Mavs, a key dsRNA signaling hub, implying that our model of gastric pre-neoplasia was specific to dsRNA signaling. Further characterization of this pre-neoplastic environment by single-cell RNA sequencing and flow cytometry noted a chronic and sustained transcriptional upregulation of the dsRNA response throughout gastric epithelium that was independent of adaptive immunity and that depended on both type I and type III IFN signaling. Finally, we identified an enrichment of mitochondrial dsRNA within the gastric epithelium of Adar1ΔPC stomachs.
Conclusions
Our new genetic model implicates ADAR1-mediated dsRNA signaling in gastric pre-neoplasia.
{"title":"A New Model of Gastric Pre-neoplasia Induced by Aberrant ADAR1-mediated Double-stranded RNA Signaling","authors":"Angela M. Halstead , Chinye Nwokolo , Stella Hoft , Jinsheng Yu , Lifei Zhu , Brendan Tuley , Nancy Vargas , RuiRui Liu , Francisco Ramirez Victorino , Simrin Phatak , Wandy Beatty , Chun-Kan Chen , Richard DiPaolo , Paul Cliften , Tarin M. Bigley , José B. Sáenz","doi":"10.1016/j.jcmgh.2025.101673","DOIUrl":"10.1016/j.jcmgh.2025.101673","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Recent evidence suggests that endogenously derived double-stranded RNA (dsRNA) impacts multiple cellular processes, although its role in epithelial injury remains understudied. We previously identified the response to dsRNA as the most upregulated pathway across 2 distinct murine models of spasmolytic polypeptide-expressing metaplasia (SPEM), a critical pre-neoplastic transition in the progression to gastric cancer. The aim of this study was to define how dysregulation of the dsRNA response within gastric epithelium impacts gastric pre-neoplasia.</div></div><div><h3>Methods</h3><div>We specifically deleted ADAR1, a central regulator of dsRNA signaling, from gastric parietal cells (<em>Adar1</em><sup><em>ΔPC</em></sup>). <em>Adar1</em><sup><em>ΔPC</em></sup> and age-matched controls stomachs were histologically, transcriptionally, and immunologically profiled. The source of dsRNA in <em>Adar1</em><sup><em>ΔPC</em></sup> gastric epithelium was assessed by dsRNA immunoprecipitation and immuno-electron microscopy. Finally, to define the contributions of interferon (IFN) signaling, <em>Adar1</em><sup><em>ΔPC</em></sup><em>;Ifnar1</em><sup><em>-/-</em></sup> <em>and Adar1</em><sup><em>ΔPC</em></sup><em>;Ifnlr1</em><sup><em>-/-</em></sup> mice, defective in type I and type III IFN signaling, respectively, were characterized.</div></div><div><h3>Results</h3><div><em>Adar1</em><sup><em>ΔPC</em></sup> mice spontaneously developed SPEM and gastric dysplasia, in the absence of exogenous injury. Our phenotype depended on <em>Mavs</em>, a key dsRNA signaling hub, implying that our model of gastric pre-neoplasia was specific to dsRNA signaling. Further characterization of this pre-neoplastic environment by single-cell RNA sequencing and flow cytometry noted a chronic and sustained transcriptional upregulation of the dsRNA response throughout gastric epithelium that was independent of adaptive immunity and that depended on both type I and type III IFN signaling. Finally, we identified an enrichment of mitochondrial dsRNA within the gastric epithelium of <em>Adar1</em><sup><em>ΔPC</em></sup> stomachs.</div></div><div><h3>Conclusions</h3><div>Our new genetic model implicates ADAR1-mediated dsRNA signaling in gastric pre-neoplasia.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101673"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145460738","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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