Cellular and Molecular Gastroenterology and Hepatology最新文献

{"title":"GPR68, A Proton-sensing GPCR, Mediates Acid-induced Visceral Nociception","authors":"Luke W. Paine ,&nbsp;Rohit Gupta ,&nbsp;James P. Higham ,&nbsp;Javier Aguilera-Lizarraga ,&nbsp;Anne Ritoux ,&nbsp;Thomas Pritchard ,&nbsp;Samuel Nicholson ,&nbsp;James R.F. Hockley ,&nbsp;Tim Raine ,&nbsp;Martin Hausmann ,&nbsp;Kyle Bednar ,&nbsp;Gerhard Rogler ,&nbsp;Fraser Welsh ,&nbsp;Ewan St John Smith ,&nbsp;David C. Bulmer","doi":"10.1016/j.jcmgh.2025.101671","DOIUrl":"10.1016/j.jcmgh.2025.101671","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Localised acidification from immune cell infiltration and heightened glycolysis contributes to colitis pathology by activating acid-sensing receptors such as G protein-coupled receptor 68 (GPR68), a proton-sensing G protein-coupled receptor (GPCR) expressed on immune and stromal cells. Single-cell RNA sequencing (RNA-seq) analysis revealed GPR68 is also expressed in colonic sensory neurons, prompting us to investigate its role in acid-induced colonic nociception.</div></div><div><h3>Methods</h3><div>Expression of GPR68 in colonic nociceptors and tissue from people with colitis was confirmed by in silico analysis of our RNA-seq databases. Its contribution to disease activity was assessed using the acute dextran sulphate sodium (DSS) model of colitis. Acid-evoked sensory signalling was evaluated via colonic afferent recordings and Ca²⁺ imaging in DRG neurons from wild-type and GPR68^-/- mice, supported by pharmacological studies using Ogerin (a GPR68 positive allosteric modulator) and Ogremorphin (a GPR68 antagonist).</div></div><div><h3>Results</h3><div>RNA-seq analysis showed GPR68 is robustly expressed in <em>Trpv1</em>⁺ colonic nociceptors and upregulated in tissue from people with inflammatory bowel disease, consistent with reduced disease activity in DSS-treated GPR68^-/- mice. Genetic deletion of GPR68 abolished colonic afferent responses to acid, which were also attenuated by Ogremorphin and enhanced by Ogerin. In Ca²⁺-free buffer, dorsal root ganglion neurons from GPR68^-/- mice or those pretreated with Ogremorphin showed significantly reduced acid-evoked intracellular Ca²⁺ responses. By contrast, the colonic afferent and dorsal root ganglion Ca²⁺ response (in Ca²⁺-containing buffer) to capsaicin was comparable between tissue from wild-type and GPR68^-/- mice highlighting the involvement of divergent proton-dependent cellular signaling cascades.</div></div><div><h3>Conclusions</h3><div>These findings identify GPR68 as a key mediator of acid-induced colonic nociception and highlight its potential as a therapeutic target for the treatment of pain in colitis.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 3","pages":"Article 101671"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145460770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver Sinusoidal Endothelial Cells Promote Metabolic Dysfunction-associated Steatohepatitis Progression via Interleukin-1R1-mediated Chemokine Production Induced by Macrophage-derived Interleukin-1β","authors":"Kenji Fukumoto ,&nbsp;Hayato Hikita ,&nbsp;Yoshinobu Saito ,&nbsp;Yuki Makino ,&nbsp;Kazumasa Soma ,&nbsp;Seiya Kato ,&nbsp;Yoichi Sasaki ,&nbsp;Yuta Myojin ,&nbsp;Katsuhiko Sato ,&nbsp;Sadatsugu Sakane ,&nbsp;Kazuhiro Murai ,&nbsp;Yuki Tahata ,&nbsp;Takahiro Kodama ,&nbsp;Tomohide Tatsumi ,&nbsp;Daisuke Motooka ,&nbsp;Yoshiaki Kubota ,&nbsp;Shogo Kobayashi ,&nbsp;Hidetoshi Eguchi ,&nbsp;Tetsuo Takehara","doi":"10.1016/j.jcmgh.2025.101698","DOIUrl":"10.1016/j.jcmgh.2025.101698","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Interleukin (IL)-1β is a key cytokine in hepatitis-related inflammation, but its role in metabolic dysfunction-associated steatotic liver disease (MASLD) or steatohepatitis (MASH) remains unclear. This study investigated IL-1β-mediated interactions in nonparenchymal liver cells to elucidate their contributions to pathological MASH progression.</div></div><div><h3>Methods</h3><div>We used the THP-1 monocyte-derived macrophage line and TMNK-1 liver sinusoidal endothelial cell (LSEC) line for in vitro assays. Endothelial cell-specific Il1r1-knockout (Il1r1^ΔEC) and systemic Cxcl10-knockout (Cxcl10^-/-) mice were subjected to a Western diet (WD) to establish a MASH model. An additional WD-fed cohort received the IL1R1 antagonist anakinra during the final 4 weeks. RNA sequencing data from liver tissues from patients with MASLD and spatial transcriptomic analyses focusing on nontumor regions of MASH-related hepatocellular carcinoma samples were evaluated.</div></div><div><h3>Results</h3><div>Liver levels of mature IL-1β were elevated in WD-fed mice compared with ND-fed mice. Il1r1 was highly expressed in LSECs, and Ccl2 and Cxcl10 expression were upregulated in LSECs under WD conditions. Palmitic acid inhibited autophagy in THP-1 macrophages, increasing IL-1β secretion. IL-1β enhanced CCL2 and CXCL10 expression in TMNK-1 LSECs via JNK activation. In Il1r1^ΔEC and Cxcl10^-/- mice, WD-induced inflammatory cell infiltration and fibrosis were attenuated, and anakinra produced similar effects. In human datasets, CCL2 and CXCL10 were upregulated in MASH livers and correlated with NAFLD activity scores. Spatial transcriptomics revealed a dominant periportal macrophage-to-LSEC IL1B–IL1R1 interaction that generates chemokine-enriched LSECs, forming inflammatory–fibrotic niches that facilitate immune cell recruitment.</div></div><div><h3>Conclusions</h3><div>Macrophage-derived IL-1β promotes hepatic inflammation and fibrosis through IL1R1-dependent chemokine induction in LSECs, highlighting IL1R1 signaling as a therapeutic target in MASH.</div></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 4","pages":"Article 101698"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145679590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover","authors":"","doi":"10.1016/S2352-345X(25)00251-6","DOIUrl":"10.1016/S2352-345X(25)00251-6","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"20 2","pages":"Article 101709"},"PeriodicalIF":7.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cilk1 Is Essential for Mesenchymal Cilia Maintenance and Epithelial-mesenchymal Crosstalk in Intestinal Villus Morphogenesis","authors":"Jieun Song ,&nbsp;Suyeon Je ,&nbsp;Bawool Lee ,&nbsp;Hyuk Wan Ko","doi":"10.1016/j.jcmgh.2025.101672","DOIUrl":"10.1016/j.jcmgh.2025.101672","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We used both Cilk1 knockout (&lt;em&gt;Cilk1&lt;/em&gt;&lt;sup&gt;&lt;em&gt;KO&lt;/em&gt;&lt;/sup&gt;) 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&lt;sup&gt;Cre&lt;/sup&gt;) and mesenchyme (Gli1&lt;sup&gt;CreERT2&lt;/sup&gt;). Postnatal deletion experiments validated Hh responsiveness in postnatal intestinal mesenchyme.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;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 &lt;em&gt;Cilk1&lt;/em&gt;&lt;sup&gt;&lt;em&gt;KO&lt;/em&gt;&lt;/sup&gt; 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.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;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}

{"title":"Endogenous Glucocorticoids Moderate the Gastric Inflammatory Response to Helicobacter Infection and Protect from Autoimmunity","authors":"Sara R. Druffner ,&nbsp;Benjamin C. Duncan ,&nbsp;Maeve T. Morris ,&nbsp;Jordan L. Pascoe ,&nbsp;Tyler M. Abner ,&nbsp;Salik Hussain ,&nbsp;M. Blanca Piazuelo ,&nbsp;Richard M. Peek Jr. ,&nbsp;Melody Zhang ,&nbsp;Richard J. DiPaolo ,&nbsp;Jonathan T. Busada","doi":"10.1016/j.jcmgh.2025.101699","DOIUrl":"10.1016/j.jcmgh.2025.101699","url":null,"abstract":"<div><h3>Background &amp; 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}

{"title":"Role of Innate Oral Immunity and the Salivary Fluid in Inflammatory Bowel Disease","authors":"Joydeep Aoun ,&nbsp;Ahmed Kabrah ,&nbsp;Malini Ahuja ,&nbsp;Benjamin Leblanc ,&nbsp;Changyu Zhang ,&nbsp;Li Li ,&nbsp;Yan Wang ,&nbsp;Shmuel Muallem","doi":"10.1016/j.jcmgh.2025.101713","DOIUrl":"10.1016/j.jcmgh.2025.101713","url":null,"abstract":"<div><h3>Background &amp; 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)^-/- 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}

{"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 ,&nbsp;Tongtong Wu ,&nbsp;Hao Li ,&nbsp;Zhenyu Guan ,&nbsp;Mingjie Ding ,&nbsp;Wenzhi Guo","doi":"10.1016/j.jcmgh.2025.101695","DOIUrl":"10.1016/j.jcmgh.2025.101695","url":null,"abstract":"<div><h3>Background &amp; 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}

{"title":"CREB Fuels Tumorigenesis in Alcoholic Pancreatitis","authors":"Urvinder Kaur Sardarni,&nbsp;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}

{"title":"Intestinal Epithelial Cell-derived Osteopontin Protects Against Metabolic Dysfunction–associated Steatohepatitis by Modulating Bile Acid Composition and the Gut Microbiome","authors":"Hui Han ,&nbsp;Jeongwoo Park ,&nbsp;Rui Zhang ,&nbsp;Nithyananthan Subramaniyam ,&nbsp;Sukanta Das ,&nbsp;Xiaodong Ge ,&nbsp;Sai Santosh Babu Komakula ,&nbsp;Chao Wang ,&nbsp;Romain Desert ,&nbsp;Wei Chen ,&nbsp;Zhuolun Song ,&nbsp;Dipti Athavale ,&nbsp;Abid Anwar ,&nbsp;Daniel Lantvit ,&nbsp;Grace Guzman ,&nbsp;María Dolores Frutos ,&nbsp;Bruno Ramos-Molina ,&nbsp;Natalia Nieto","doi":"10.1016/j.jcmgh.2025.101678","DOIUrl":"10.1016/j.jcmgh.2025.101678","url":null,"abstract":"<div><h3>Background &amp; 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>^{KI IEC}) and knock-out (<em>Spp1</em>^ΔIEC) 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>^ΔIEC 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>^ΔIEC 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}

{"title":"Metabolic Signatures of Acinetobacter baumannii and Klebsiella pneumoniae Infections in Acute-on-chronic Liver Failure","authors":"Camilla Cadoli ,&nbsp;Sania Arif ,&nbsp;Wibke Ballhorn ,&nbsp;Angela Brieger ,&nbsp;Maximilian Joseph Brol ,&nbsp;Florence Castelli ,&nbsp;Hans-Peter Erasmus ,&nbsp;Julia Fischer ,&nbsp;Robert Gurke ,&nbsp;Lisa Hahnefeld ,&nbsp;Christophe Junot ,&nbsp;Nico Kraus ,&nbsp;Cristina Ortiz ,&nbsp;Robert Schierwagen ,&nbsp;Sara Garcia Torres ,&nbsp;Frank Erhard Uschner ,&nbsp;Volker Müller ,&nbsp;Jonel Trebicka ,&nbsp;Christoph Welsch ,&nbsp;Volkhard A.J. Kempf","doi":"10.1016/j.jcmgh.2025.101707","DOIUrl":"10.1016/j.jcmgh.2025.101707","url":null,"abstract":"<div><h3>Background &amp; 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> &lt; .0001). Increased levels of α-ketoglutarate (<em>P</em> = .0002), N-acetylglutamine (<em>P</em> = .0153), indoleacetic acid (<em>P</em> &lt; .05), and N8-acetylspermidine (<em>P</em> &lt; .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}