American journal of physiology. Gastrointestinal and liver physiology最新文献

{"title":"Association between interlobular pancreatic adipose tissue and low glucose-induced insulin secretion by β-cells.","authors":"Adeline Divoux, Hayley Nielsen, Charles Rowe, Richard E Pratley, Anna Casu","doi":"10.1152/ajpgi.00116.2026","DOIUrl":"10.1152/ajpgi.00116.2026","url":null,"abstract":"<p><p>The potential role of pancreatic fat on human β-cell dysfunction and its association with fibrosis are controversial. From the PANC-DB database, we estimated β-cell function with glucose-stimulated insulin secretion (GSIS) and quantified fat infiltration and fibrosis using pancreatic histology sections from 45 organs from cadaveric organ donors. In the donors without diabetes, high fat infiltration and adipocyte size in the pancreatic septum were associated with lower GSIS. Low GSIS in fatty pancreas was confirmed in living pancreatic tissue slices. This association is dependent on age and global adiposity and independent of fibrosis. These results suggest that the localization and phenotype of fat infiltration in the pancreas are important factors to determine the role of adipose tissue on pancreatic endocrine function.<b>NEW & NOTEWORTHY</b> Adipose tissue infiltration in the pancreas and its potential implication in the development or maintenance of diabetes has been and is still intensively investigated. In this short communication, we showed negative association between pancreatic fat infiltration and glucose-stimulated insulin secretion (GSIS), specifically in T2D. In addition, interlobular adipocyte size correlated positively with body mass index, age, and HbA1c, and negatively with GSIS. This suggests that adipocyte phenotype, rather than fat quantity alone, may influence β-cell function.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G102-G106"},"PeriodicalIF":3.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibiotics treatment promotes squamocolumnar junction tumor progression via tumor immune evasion in K19-Wnt1/C2mE mice fed high-fat diet and acidic bile salts.","authors":"Koya Ogasawara, Kaname Uno, Toru Tamahara, Naoki Asano, Koichiro Sudo, Keisuke Kusano, Mizuki Tanabe, Yumiko Kaise, Takafumi Shindo, Yusuke Shimoyama, Takeshi Kanno, Tomoyuki Koike, Ritsuko Shimizu, Atsushi Masamune","doi":"10.1152/ajpgi.00056.2026","DOIUrl":"10.1152/ajpgi.00056.2026","url":null,"abstract":"<p><p>Clinical studies suggested that antibiotics (ABx) administration might increase esophagogastric junction adenocarcinoma risk, but the underlying mechanisms remain unclear. We previously demonstrated that the administration of a high-fat diet (HFD) and acid bile salts (ABS) to K19-Wnt1/C2mE mice might promote the metabolic-driven tumor growth at the squamocolumnar junction (SCJ) cooperatively with gut dysbiosis. To clarify whether ABx-induced dysbiosis promotes tumorigenesis, we evaluated the effects of HFD + ABS ± ABx treatment on tumor immune evasion in mice. In HFD + ABS + ABx-treated mice, SCJ tumor growth with increased tumor cell proliferation and infiltration of inflammatory cells positive for CD8, programmed cell death protein 1, and programmed cell death-ligand 1 (PD-L1) was observed, along with apoptosis suppression. Protein expressions of interferon-gamma (IFNγ) and phosphorylated signal transducer and activator of transcription (p-STAT) 3 were upregulated in the tumors of the HFD + ABS + ABx group, whose p-STAT1 expression was equivalent to that of the control group. The mice exhibited insulin resistance and metabolic endotoxemia, and metagenomic analysis of their ileal excrement revealed dysbiosis with a decrease in butyrate-producing bacteria and bacterial butanoate metabolism activity. Moreover, IFNγ stimulation of human-derived NUGC-4 cells increased the protein expression of PD-L1, p-STAT1, and p-STAT3, all of which decreased in response to STAT inhibitors. Transfection with small interfering RNA targeting <i>STAT1</i> or <i>STAT3</i> did not attenuate PD-L1 induction, which was inhibited by the combined knockdown. Therefore, oral HFD + ABS + ABx administration to K19-Wnt1/C2mE mice may promote SCJ tumors through tumor immune evasion via IFNγ-STAT1/STAT3-PD-L1 signaling, along with metabolic endotoxemia.<b>NEW & NOTEWORTHY</b> Coadministration of antibiotics with a high-fat diet and acid bile salts exacerbated dysbiosis, insulin resistance, and systemic inflammation, thereby promoting tumor progression via tumor immune evasion at the squamocolumnar junction (SCJ) in K19-Wnt1/C2mE mice. In the tumor, interferon-gamma-induced programmed death-ligand 1 through the activation of signal transducer and activator of transcription 1 (STAT1) and STAT3. Understanding the link between dysbiosis and tumor immunity might aid in the development of new immunotherapies for SCJ tumors.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G38-G59"},"PeriodicalIF":3.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage-specific autotaxin deficiency promotes hepatic steatosis and inflammation in diet-induced MASLD.","authors":"Soyeong Park, Sihyun Jeong, Yunna Lee, Gwangbeom Heo, Yuju Kim, Doyeon Lee, Sang Hoon Rhee, Eunok Im","doi":"10.1152/ajpgi.00462.2025","DOIUrl":"10.1152/ajpgi.00462.2025","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder in which dysregulated inflammation plays a central role. We previously reported that macrophage-specific deletion of autotaxin (ATX) exacerbates inflammatory responses, including lipopolysaccharide -induced peritonitis and interleukin-10 deficiency-mediated colitis in mice. Moreover, circulating ATX levels are elevated in patients with MASLD. This study aimed to determine whether macrophage-specific ATX deficiency influences MASLD progression. To this end, MASLD was induced using amylin liver nonalcoholic steatohepatitis (AMLN) diet in macrophage-specific ATX knockout (Atx^ΔME/ΔME) and wild-type (Atx^+/+) mice. ATX deficiency in macrophages promoted lipid droplet deposition in hepatocytes and hepatic triglyceride accumulation, thereby aggravating liver steatosis. Serum alanine aminotransferase, aspartate transaminase, and total cholesterol levels were significantly higher in Atx^ΔME/ΔME AMLN mice compared with Atx^+/+ AMLN mice. In addition, ATX deletion increased proinflammatory cytokine production in both Kupffer cells and hepatocytes. Notably, the expression of sterol regulatory element-binding transcription factor 1 and carbohydrate-responsive element-binding protein was elevated in Atx^ΔME/ΔME AMLN mice. Collectively, these findings demonstrate that macrophage-specific ATX deficiency accelerates MASLD progression by enhancing inflammation and upregulating lipogenic transcription factors, leading to increased hepatic lipid accumulation.<b>NEW & NOTEWORTHY</b> This study reveals a protective role of macrophage-derived autotaxin (ATX) in liver homeostasis, demonstrating that its cell-specific deletion exacerbates hepatic steatosis, inflammation, and injury in a diet-induced metabolic dysfunction-associated steatotic liver disease model. Mechanistically, loss of ATX enhances proinflammatory cytokine production in Kupffer cells and hepatocytes, while upregulating lipogenic transcription factors, such as <i>Srebf1</i> and <i>Chrebp</i>. These findings highlight macrophage-derived ATX as a critical regulator of hepatic lipid metabolism by restraining inflammation-driven lipogenesis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G60-G72"},"PeriodicalIF":3.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148025711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AXL and MERTK in macrophages restore pancreatic exocrine function after severe acute pancreatitis by modulating acinar-to-ductal metaplasia formation.","authors":"Kaixin Peng, Xiuli Zhang, Yonghao Chen, Siqi Xiao, Haoru Li, Jie Wu, Bin Li, Li Wen","doi":"10.1152/ajpgi.00057.2026","DOIUrl":"10.1152/ajpgi.00057.2026","url":null,"abstract":"<p><p>Severe acute pancreatitis (SAP) often leads to incomplete tissue repair and prolonged exocrine dysfunction. Acinar-to-ductal metaplasia (ADM) is a critical regenerative process postinjury, but persistent ADM impedes functional recovery. Axl and Mertk belong to the TAM family of receptor tyrosine kinases, which are expressed primarily in macrophages to mediate efferocytosis and promote pro-resolving macrophage polarization, and have been implicated in tissue repair. However, their roles in resolving ADM and restoring exocrine function remain unclear. We utilized cerulein-induced SAP models in mice with either global or cell-specific deletion of <i>Axl</i> and <i>Mertk</i>. Pancreatic repair was assessed by histology, transcriptomics, and functional assays. Coculture of primary acinar cells with bone marrow-derived macrophages. The expression of AXL and MERTK in the pancreas was upregulated on <i>Day 4</i> during pancreatic repair after SAP. Global deletion of <i>Axl</i> and <i>Mertk</i> similarly delayed tissue repair, resulting in persistent ADM, impaired acinar redifferentiation, and defective restoration of exocrine function. Transcriptomics revealed aberrant activation of developmental signaling pathways, including Hedgehog, Wnt, and Notch, and sustained suppression of acinar digestive enzyme genes. In vitro coculture experiments showed that M2 macrophages lacking <i>Axl</i> and <i>Mertk</i> promoted persistent ADM, in contrast to M1 macrophages. AXL and MERTK in macrophages are crucial regulators of pancreatic regeneration after SAP, facilitating ADM resolution and exocrine recovery through interactions between acinar cells and M2 macrophages. These findings highlight that macrophage AXL and MERTK could act as a potential therapeutic target for enhancing long-term restoration of pancreatic function following SAP.<b>NEW & NOTEWORTHY</b> Deleting Axl and Mertk in myeloid cells disrupts the healing process, resulting in persistent ductal structures and failure to recover exocrine function. This repair failure is linked to the abnormal persistence of developmental signaling pathways and is mediated by interactions between acinar cells and macrophages, emphasizing the importance of AXL and MERTK in macrophages in pancreatic functional recovery.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G12-G26"},"PeriodicalIF":3.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissecting neuromuscular transmission in the gastrointestinal tract: from single-cell RNA analysis to function and pharmacology.","authors":"Pere Guzman, Mihaela Penchova, Patri Vergara, Marcel Jimenez","doi":"10.1152/ajpgi.00434.2025","DOIUrl":"10.1152/ajpgi.00434.2025","url":null,"abstract":"<p><p>Gastrointestinal (GI) motility is coordinated by multiple neurotransmitter systems acting on distinct postjunctional cells within the smooth muscle-interstitial cell-platelet derived growth factor receptor alpha-positive (PDGFRα⁺) (SIP) syncytium. This study integrates physiological, pharmacological, and single-cell transcriptomic data to define the cellular mechanisms underlying inhibitory and excitatory neuromuscular transmission in the human colon. Inhibitory signaling involves purinergic (P2Y₁) and adrenergic (α₁A) receptors, which activate small-conductance calcium-activated potassium channels in PDGFRα⁺ cells, whereas nitrergic [nitric oxide (NO)-soluble guanylate cyclase-cGMP] pathways are primarily mediated by interstitial cells of Cajal (ICCs) and smooth muscle cells (SMCs). VIPergic signaling also contributes to relaxation through cAMP-dependent mechanisms possibly located in PDGFRα⁺ cells. Excitatory transmission is mainly driven by muscarinic M3 and M2 receptors expressed in ICCs and SMCs, leading to calcium-dependent contractions. Pharmacologically, hyoscine butylbromide reduces acetylcholine-induced contractions by blocking M2/M3 receptors, whereas neostigmine enhances cholinergic transmission to restore motility. Blockade of voltage-gated calcium channels (Ca_v1.2, CACNA1C) by agents such as otilonium bromide further contributes to spasmolytic effects. These findings provide an integrated framework linking receptor expression, cellular mechanisms, and drug actions that modulate GI motility.<b>NEW & NOTEWORTHY</b> In this manuscript, we correlate data from single-cell RNA analysis with previously published physiological findings. Based on this correlation, we discuss the mechanisms of action of clinically relevant drugs and reevaluate their effects within the context of the smooth muscle, interstitial cells, and PDGFRα⁺ cell (SIP) syncytium. This work also has translational relevance, providing clinicians with a more comprehensive understanding of drug mechanisms of action.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G27-G34"},"PeriodicalIF":3.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling anastomotic leak: biological mechanisms underlying intestinal healing after resection.","authors":"Christie S Catley, Emily C Hoedt, Peter Pockney, Simon Keely, Kateleen E Hedley","doi":"10.1152/ajpgi.00071.2026","DOIUrl":"10.1152/ajpgi.00071.2026","url":null,"abstract":"<p><p>Understanding intestinal healing following resection and anastomosis is a challenging topic due to the complexity of underlying mechanisms. Anastomotic healing follows the fundamental phases of normal wound repair; however, the intestinal anastomosis represents a unique biological environment in which factors such as the structure of the intestines, as well as the microbiome, may modify the healing process. Disruptions in any of the healing phases, such as the inflammatory, proliferative, and remodeling phase, may result in severe complications, characterized by the intraluminal contents leaking out into the extraluminal space, termed an anastomotic leak (AL). Despite decades of surgical advancements, we are still no closer to understanding the underlying AL etiology. It is clear that ALs are multifactorial in nature and contribute to by patient-, technical-, and biological-related factors; however, emerging evidence suggests that biological mechanisms may play a more significant role in AL pathology than originally believed. Evidence points to an interplay between epithelial healing, tissue oxygenation, and the resident microbiome in influencing mucosal healing at the anastomotic site. However, the precise contribution of these factors to failed anastomotic healing and AL etiology remains unclear. In this review, we examine the phases of healing, discuss the existing literature on biological factors affecting anastomotic healing, and describe the advancements made to improve AL rates by targeting the healing response.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G1-G11"},"PeriodicalIF":3.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wnt regulates cellular differentiation and retinoid metabolism genes in the mouse stomach.","authors":"Elizabeth Delgado, Elise S Hibdon, Theresa M Keeley, Christopher Quoc Huynh, Justin A Colacino, Linda C Samuelson","doi":"10.1152/ajpgi.00012.2026","DOIUrl":"10.1152/ajpgi.00012.2026","url":null,"abstract":"<p><p>Although recognized as a key regulator of gastrointestinal tissues, Wnt signaling pathway function in the stomach is poorly understood. This study aimed to define Wnt functions and identify Wnt-regulated genes in the stomach. Reporter mouse analysis localized Wnt signaling to the base and proliferative region in both the corpus and the antrum. Canonical Wnt inhibition in vivo using <i>Sox2-CreER^T2</i>; <i>Ctnnb1^fl^/^fl</i> mice reduced epithelial cell proliferation with loss of gastric stem cells. Wnt-regulated genes and potential effector pathways were studied by bulk RNA sequencing (RNA-Seq) analysis of corpus and antral organoids 24 h after Wnt inhibition in vitro. Cell signature analysis revealed that gastric organoids adopt a surface cell transcriptional profile following Wnt inhibition instead of a basal cell profile. Furthermore, retinoid metabolism terms were differentially expressed after Wnt inhibition, with decreased expression of retinoic acid target genes. Inhibition of retinoic acid signaling in corpus and antral organoids showed a marked increase in surface cell marker expression, consistent with the effects of Wnt inhibition. In the mouse, immunostaining showed differential localization of retinoid metabolic components in luminal pit cells (ALDH3A1) and basal chief/deep mucous cells (STRA6), with expression changes after β-catenin deletion in <i>Sox2-CreER^T2</i>; <i>Ctnnb1^fl/fl</i> mice, consistent with the Wnt-regulated cell fate changes observed in organoids. Together, these studies showed that Wnt signaling is required for gastric stem cell survival and promotes differentiation of cell types at the gland base. We identified retinoid metabolism as a candidate Wnt-regulated pathway, with cell-specific expression of key components, and regulation of surface cell marker expression by retinoic acid signaling.<b>NEW & NOTEWORTHY</b> Using mouse genetic and organoid models, we show that canonical Wnt signaling promotes gastric epithelial cell proliferation and regulates differentiation along the base-lumen gland axis in the stomach. Transcription profiling of Wnt-inhibited gastric organoids identified retinoic acid signaling as a potential Wnt-regulated effector pathway in the stomach. Accordingly, manipulation of retinoic acid signaling in organoids altered differentiated marker expression consistent with Wnt inhibition, supporting the presence of a Wnt-retinoic acid signaling axis in the stomach.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G85-G101"},"PeriodicalIF":3.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13417362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148222530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"circRET-mediated regulation of <i>RET</i> influences enteric neural crest cell development in Hirschsprung disease.","authors":"Yingnan Yan, Juping Wang, Fangzheng Zhao, Yang Wang","doi":"10.1152/ajpgi.00041.2026","DOIUrl":"10.1152/ajpgi.00041.2026","url":null,"abstract":"<p><p>Hirschsprung disease (HSCR) is a life-threatening congenital disorder characterized by defective migration and proliferation of enteric neural crest cells (ENCCs), a process in which the receptor tyrosine kinase <i>RET</i> plays a central regulatory role. However, the regulatory mechanisms governing <i>RET</i> expression remain incompletely understood. In the present study, we identify the circular RNA circRET (hsa_circ_0093651) as a critical translational regulator of its parental gene <i>RET</i> and explore its role in HSCR pathogenesis. We demonstrate that circRET is significantly downregulated in the colonic tissues from patients with HSCR and directly binds <i>RET</i> mRNA, modulating RET protein synthesis at the translational level without altering mRNA abundance. Notably, circRET interacts with the coding region of <i>RET</i> mRNA, potentially facilitating its translation. circRET knockdown suppresses <i>RET/AKT</i> signaling and impairs ENCC migration, proliferation, and distal colon colonization. Our study uncovers a novel circRET-mediated regulatory mechanism of its parental gene <i>RET</i>, with potential implications for therapeutic targeting in HSCR.<b>NEW & NOTEWORTHY</b> Hirschsprung disease (HSCR) results from impaired enteric neural crest cell development, in which <i>RET</i> plays a central role. Here, we identify circRET as a translational regulator of <i>RET</i>. circRET is downregulated in HSCR tissues and modulates RET protein by directly binding <i>RET</i> mRNA without affecting mRNA levels. Loss of circRET suppresses <i>RET</i>/AKT signaling and ENCC migration, highlighting a novel regulatory mechanism with therapeutic relevance.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G73-G84"},"PeriodicalIF":3.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148222559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction for Gershner et al., volume 329, 2025, p. G344-G359.","authors":"","doi":"10.1152/ajpgi.00342.2024_COR","DOIUrl":"https://doi.org/10.1152/ajpgi.00342.2024_COR","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":"330 6","pages":"G727"},"PeriodicalIF":3.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic efficacy, biomarker signatures, and translatability of semaglutide in the liver biopsy-confirmed GAN DIO-MASH mouse model.","authors":"Jens Bjelke Kristensen, Jacob Nøhr-Meldgaard, Susanne E Pors, Jenny Norlin, Sanne S Veidal, Kristian Moss Bendtsen, Kristoffer Niss, Maja W Andersen, Lea M Harder, Mathilde Teilmann Dalhoff, Martin Rønn Madsen, Kristoffer Voldum-Clausen, Markus Latta, Lotte Bjerre Knudsen, Michael Feigh, Henrik H Hansen","doi":"10.1152/ajpgi.00011.2026","DOIUrl":"10.1152/ajpgi.00011.2026","url":null,"abstract":"<p><p>Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). Importantly, semaglutide was recently approved as the first GLP-1-based treatment for people with MASH with moderate-to-severe fibrosis. Translational models that recapitulate human MASH are critical for guiding early-stage drug discovery, enabling rigorous efficacy evaluation, and facilitating the progression of drug candidates into clinical development. In this study, we investigated the efficacy of semaglutide across an extensive series of experiments in the liver biopsy-confirmed GAN diet-induced obese MASH (GAN DIO-MASH) mouse model, benchmarking outcomes against those from pivotal clinical trials of semaglutide in MASH. Treatment outcomes in the GAN DIO-MASH mouse closely mirrored clinical findings, particularly for hepatic steatosis and inflammation endpoints. Longer semaglutide treatment durations (≥16 wk) led to pronounced and consistent improvements in quantitative fibrosis histology across studies. In comparison, the response rate for fibrosis stage improvement with semaglutide was modest and largely independent of treatment duration. Notably, pooling data from long-term intervention studies revealed more favorable effects on fibrosis stage. Importantly, the GAN DIO-MASH mouse recapitulated many human MASH-associated changes in circulating proteins and semaglutide-responsive biomarkers. Collectively, these results support the therapeutic effects of semaglutide in MASH and underscore the reproducibility and clinical translatability of multiple disease-relevant features of the GAN DIO-MASH mouse model, highlighting its applicability as a robust platform for preclinical drug development.<b>NEW & NOTEWORTHY</b> Translational preclinical models that faithfully recapitulate human MASH are essential for guiding early-stage drug discovery by enabling rigorous efficacy assessment. In this study, we demonstrate that the biopsy-confirmed GAN DIO-MASH mouse model replicates semaglutide treatment responses across metabolic, biochemical, and histological endpoints, as well as key biomarker signatures observed in pivotal clinical trials in people with MASH. These findings strongly support the model's clinical translatability to facilitate efficient progression of therapeutic candidates into clinical development.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G659-G683"},"PeriodicalIF":3.0,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147669813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}