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

{"title":"Mass cytometric analysis of circulating monocyte subsets in a murine model of diabetic gastroparesis.","authors":"Shefaa AlAsfoor, Erik Jessen, Suraj R Pullapantula, Jennifer R Voisin, Linda C Hsi, Kevin D Pavelko, Samera Farwana, Jack A Patraw, Xin-Yi Chai, Sihan Ji, Michael A Strausbauch, Gianluca Cipriani, Lai Wei, David R Linden, Ruixue Hou, Richard Myers, Yogesh Bhattarai, Jill Wykosky, Alan J Burns, Surendra Dasari, Gianrico Farrugia, Madhusudan Grover","doi":"10.1152/ajpgi.00229.2024","DOIUrl":"10.1152/ajpgi.00229.2024","url":null,"abstract":"<p><p>Circulating monocytes (Mo) are precursors to a subset of gastric resident muscularis macrophages. Changes in muscularis macrophages (MMs) result in delayed gastric emptying (DGE) in diabetic gastroparesis. However, the dynamics of Mo in the development of DGE in an animal model are unknown. Using cytometry by time-of-flight and computational approaches, we show a high heterogeneity within the Mo population. In DGE mice, via unbiased clustering, we identified two reduced Mo clusters that exhibit migratory phenotype (Ly6C^hiCCR2^hi-intCD62L^hiLy6G^hiCD45R^hiMERTK^hiintLGALS3^intCD14^intCX3CR1^lowSiglec-H^int-low) resembling classical Mo (CMo-like). All markers enriched in these clusters are known to regulate cell differentiation, proliferation, adhesion, and migration. Trajectory inference analysis predicted these Mo as precursors to subsequent Mo lineages. In gastric muscle tissue, we demonstrated an increase in the gene expression levels of chemokine receptor C-C chemokine receptor type 2 (<i>Ccr2</i>) and its C-C motif ligand 2 (<i>Ccl2</i>), suggesting increased trafficking of classical-Mo. These findings establish a link between two CMo-like clusters and the development of the DGE phenotype and contribute to a better understanding of the heterogenicity of the Mo population.<b>NEW & NOTEWORTHY</b> Using 32 immune cell surface markers, we identified 23 monocyte clusters in murine blood. Diabetic gastroparesis was associated with a significant decrease in two circulating classical monocyte-like clusters and an upregulation of the <i>Ccr2-Ccl2</i> axis in the gastric muscularis propria, suggesting increased tissue monocyte migration. This study offers new targets by pointing to a possible role for two classical monocyte subsets connected to the <i>Ccr2</i>-<i>Ccl2</i> axis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G323-G341"},"PeriodicalIF":3.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412799","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":"Inhibition of hedgehog signaling ameliorates severity of chronic pancreatitis in experimental mouse models.","authors":"Srikanth Iyer, Mohammad Tarique, Preeti Sahay, Sagnik Giri, Ejas P Bava, JiaShiung Guan, Tejeshwar Jain, Utpreksha Vaish, Xiuwen Jin, Sabrina Moon, David K Crossman, Vikas Dudeja","doi":"10.1152/ajpgi.00212.2024","DOIUrl":"10.1152/ajpgi.00212.2024","url":null,"abstract":"<p><p>Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas with no specific cure. Research highlighting the pathogenesis and especially the therapeutic aspect remains limited. Aberrant activation of developmental pathways in adults has been implicated in several diseases. Hedgehog pathway is a notable embryonic signaling pathway, known to promote fibrosis of various organs when overactivated. The aim of this study is to explore the role of the hedgehog pathway in the progression of CP and evaluate its inhibition as a novel therapeutic strategy against CP. CP was induced in mice by repeated injections of l-arginine or caerulein in two separate models. Mice were administered with the FDA-approved pharmacological hedgehog pathway inhibitor, vismodegib during or after establishing the disease condition to inhibit hedgehog signaling. Various parameters of CP were analyzed to determine the effect of hedgehog pathway inhibition on the severity and progression of the disease. Our study shows that hedgehog signaling was overactivated during CP and its inhibition was effective in improving the histopathological parameters associated with CP. Vismodegib administration not only halted the progression of CP but was also able to resolve already-established fibrosis. In addition, inhibition of hedgehog signaling resulted in the reversal of pancreatic stellate cell activation ex vivo. Findings from our study justify conducting clinical trials using vismodegib against CP and, thus, could lead to the development of a novel therapeutic strategy for the treatment of CP.<b>NEW & NOTEWORTHY</b> Hedgehog signaling is activated in human and experimental models of CP. Inhibition of hedgehog signaling using an FDA-approved inhibitor, vismodegib, leads to the resolution of fibrosis and improves CP. This study has immense and immediate translational benefits.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G342-G363"},"PeriodicalIF":3.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581808","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":"Progesterone sulfates are enterohepatically recycled and stimulate G protein-coupled bile acid receptor 1-mediated gut hormone release.","authors":"Alice L Mitchell, Iain R Tough, Hei Man Fan, Anita Lövgren-Sandblom, Caroline Ovadia, Jenny Chambers, Patricia Fonseca Pedro, Anastasia Tsakmaki, Gavin A Bewick, Hanns-Ulrich Marschall, Helen M Cox, Catherine Williamson","doi":"10.1152/ajpgi.00211.2024","DOIUrl":"10.1152/ajpgi.00211.2024","url":null,"abstract":"<p><p>Sulfated progesterone metabolites (PMxSs) increase during gestation and are raised further in intrahepatic cholestasis of pregnancy (ICP), a disorder characterized by pruritus and elevated serum bile acids. PMxSs interact with bile acid receptor G protein-coupled bile acid receptor 1 (GPBAR1) to cause itch. We investigated whether PMxS could undergo enterohepatic recycling and stimulate intestinal GPBAR1-mediated release of gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). PMxSs were quantified in pre-/postprandial serum samples (<i>n</i> = 21) and feces (<i>n</i> = 18) by ultra performance liquid chromatography-tandem mass spectrometry in prospectively recruited third trimester of pregnancy outpatients with uncomplicated pregnancy or ICP. Ussing chambers were used to evaluate colonic ion secretion changes (Δ<i>I</i>_sc) in wildtype, <i>GPBAR1</i>^-/-, and <i>PYY</i>^-/- mice by PMxS metabolites, 5β-pregnan-3α,-20α-diol-3-sulfate (PM3S) and 5α-pregnan-3β-ol-20-one-sulfate (PM5S), and in wildtype mice with or without apical sodium bile acid transporter (ASBT) inhibition (<i>n</i> = 6/condition). PM3S/PM5S stimulation of GLP-1 release from wildtype and <i>GPBAR1</i>^-/- murine crypts and human colonoids was measured by ELISA (<i>n</i> = 3). Serum PMxSs increase postprandially in women with ICP but are unaltered in uncomplicated pregnancies. PMxSs are present in feces. Apical and basolateral PM3S and PM5S stimulated PYY-mediated -Δ<i>I</i>_sc in wildtype (<i>P</i> < 0.01) but not <i>GPBAR1</i>^-/- or <i>PYY</i>^-/- colons. PM3S and PM5S caused GLP-1 secretion in murine crypts and human colonoids (<i>P</i> < 0.001). ASBT inhibition blunted -Δ<i>I</i>_sc by 68% after apical PM3S and PM5S addition (<i>P</i> < 0.001). Serum PMxS, elevated in women with ICP and particularly postprandially, can undergo ASBT-mediated intestinal reuptake and activate GPBAR1 to stimulate gut hormone release. PMxS may therefore augment GPBAR1-mediated metabolic responses during pregnancy.<b>NEW & NOTEWORTHY</b> Sulfated progesterone species (PMxSs) increase postprandially in women with intrahepatic cholestasis of pregnancy (ICP) but not in women with uncomplicated pregnancy. PMxS can be enterohepatically recycled via active transport from the gut lumen by apical sodium-dependent bile acid transporter (ASBT) and stimulate gut hormone secretion. Active reabsorption of PMxS may play a role in the pruritus suffered by women with ICP. ASBT inhibition is a plausible therapy for ICP-associated pruritus.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G377-G385"},"PeriodicalIF":3.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063144","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":"Unresolved alterations in bile acid composition and dyslipidemia in maternal and cord blood after UDCA treatment for intrahepatic cholestasis of pregnancy.","authors":"Srijani Basu, Sarah G Običan, Enrico Bertaggia, Hannah Staab, M Concepcion Izquierdo, Cynthia Gyamfi-Bannerman, Rebecca A Haeusler","doi":"10.1152/ajpgi.00266.2024","DOIUrl":"10.1152/ajpgi.00266.2024","url":null,"abstract":"<p><p>Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated plasma bile acid levels. ICP is linked to adverse metabolic outcomes, including a reported increased risk of gestational diabetes. The standard therapeutic approach for managing ICP is treatment with ursodeoxycholic acid (UDCA) and induction of labor before 40 wk of gestation. To investigate bile acid and metabolic parameters after UDCA treatment, we enrolled 12 ICP patients with singleton pregnancies-half with and half without gestational diabetes-and 7 controls. Our study reveals that after UDCA treatment, notwithstanding a reduction in total bile acid and alanine aminotransferase levels, imbalances persist in the cholic acid (CA) to chenodeoxycholic acid (CDCA) ratio in maternal and cord blood plasma. This indicates a continued dysregulation of bile acid metabolism despite therapeutic intervention. Maternal plasma lipid analysis showed a distinct maternal dyslipidemia pattern among patients with ICP, marked by elevated cholesterol levels on VLDL particles and heightened triglyceride concentrations on LDL particles, persisting even after UDCA treatment. Cord plasma lipid profiles in patients with ICP exhibited elevated triglyceride and free fatty acid levels alongside a tendency toward increased β-hydroxybutyrate. The changes in lipid metabolism in both maternal and cord blood correlated with the high CA/CDCA ratio but not total bile acid levels or gestational diabetes status. Understanding the imbalances in maternal and cord bile acid and lipid profiles that persist after standard UDCA therapy provides insights for improving management strategies and mitigating the long-term consequences of ICP.<b>NEW & NOTEWORTHY</b> This study uncovers that despite ursodeoxycholic acid treatment, intrahepatic cholestasis of pregnancy (ICP) is associated with increases in the ratio of cholic acid to chenodeoxycholic acid in both maternal and cord blood, suggesting ongoing dysregulation of bile acid metabolism. The high cholic to chenodeoxycholic acid ratio is correlated with maternal dyslipidemia and high cord blood lipids. These findings may inform more targeted approaches to managing ICP.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G364-G376"},"PeriodicalIF":3.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412801","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":"The Spatiotemporal Development of Mesenteric Lymphatic Changes in the TNF^ΔARE/+ Mouse Model of Terminal Ileitis.","authors":"Keith Keane, Matthew Stephens, Simon Roizes, Jingna Xue, Shan Liao, Pierre-Yves von der Weid","doi":"10.1152/ajpgi.00334.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00334.2024","url":null,"abstract":"<p><p>Crohn's disease (CD) is a chronic inflammatory bowel disease which also encompasses significant alterations of the mesenteric lymphatic system. Whether these changes are a mere consequence of, or directly contribute to the inflammation is unknown. Here we characterized the spatial and temporal development of these events in the TNF^ΔARE/+ mouse, which develops CD-like ileitis and significant mesenteric lymphatic alterations. At 8-, 12-, 20-, and 28 weeks of age, specific pathogen-free (SPF), germ-free (GF) TNF^ΔARE/+ and WT mice were assessed for ileitis via myeloperoxidase activity (MPO) while mesenteric lymphatic alterations were assessed by confocal immunofluorescence imaging. Lymphatic alterations in the SPF TNF^ΔARE/+ occurred in a stepwise manner between 8 and 28 weeks of age beginning with the development of mesenteric lymphadenopathy at 8 weeks despite no significant ileitis. By 12 weeks ileal MPO significantly elevates concomitantly with lymphangiectasia of the mesenteric collecting lymphatic vessels (CLV) and clustering of CD45⁺ immune cells around them. At 20 weeks, significant lymphangiogenesis of the initials (ILV) and tertiary lymphoid organs aligned along lymphatic collectors (CA-TLOs) had developed. At 28 weeks, lymphangiectasia, lymphangiogenesis, and CA-TLOs increased. However, 28-week-old GF TNF^ΔARE/+, while displaying no ileitis, presented with mesenteric lymphadenopathy, lymphangiectasia, and lymphangiogenesis but no immune cell clustering nor CA-TLOs. The TNF^ΔARE/+ mice develop terminal ileitis and lymphatic alterations in a stepwise manner beginning with MLN lymphadenopathy and ileal inflammation, followed by CLV dilation and lymphangiogenesis. These lymphatic alterations are exacerbated by the gut microbiome, with immune cell clustering and TLO formation being entirely dependent of its presence.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584378","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":"Cinnabarinic acid protects against metabolic dysfunction-associated steatohepatitis by activating Aryl hydrocarbon Receptor-dependent AMPK signaling.","authors":"Nikhil Y Patil, Iulia Rus, Felix Ampadu, Hassan M Abu Shukair, Sarah Bonvicino, Richard S Brush, Elena Eaton, Martin-Paul Agbaga, Tae Gyu Oh, Jacob E Friedman, Aditya D Joshi","doi":"10.1152/ajpgi.00337.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00337.2024","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by accumulation of fats in liver, chronic inflammation, hepatocytic ballooning, and fibrosis. This study investigates the significance of hepatic Aryl hydrocarbon Receptor (AhR) signaling in cinnabarinic acid (CA)-mediated protection against MASH. Here, we report that livers of high-fat, high-fructose, high-cholesterol diet-fed hepatocyte-specific Aryl hydrocarbon Receptor knockout mice (AhR-hKO) exhibited aggravated steatosis, inflammation, and fibrosis compared to control AhR-floxed livers. Moreover, treatment with a tryptophan catabolite, CA reduced body weight gain and significantly attenuated hepatic steatosis, inflammation, ballooning, fibrosis, and liver injury only in AhR-floxed but not in AhR-hKO mice, strongly indicating that the CA-mediated protection against steatohepatitis is AhR-dependent. Furthermore, protection against lipotoxicity by CA-activated AhR signaling was confirmed by utilizing an <i>in vitro</i> human hepatocyte model of MASLD. Mechanistically, CA-induced AhR-dependent signaling augmented AMP-activated protein kinase (AMPK) leading to the upregulation of peroxisome proliferator-activated receptor-c coactivator-1a (PGC1α) and attenuation of sterol regulatory element-binding protein-1 (SREBP1) to regulate hepatic lipid metabolism. Collectively, our findings indicate that CA-mediated protection against MASH is dependent on hepatic AhR signaling and selective endogenous AhR agonists that regulate lipogenesis can serve as promising future therapeutics against MASLD.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584376","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":"Key Mechanisms in Alcohol-Associated Liver Disease: Hepatic ADH Deficiency, Dysregulated Hepatic Lipid Metabolism and Nonoxidative Ethanol Metabolites.","authors":"Seol Hee Park, Wonhyo Seo","doi":"10.1152/ajpgi.00076.2025","DOIUrl":"https://doi.org/10.1152/ajpgi.00076.2025","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584377","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":"DIFFERENTIAL RESPONSES TO PROSTAGLANDINS IN THE CIRCULAR AND LONGITUDINAL MUSCLE LAYERS OF THE MURINE ILEUM.","authors":"Joong Goo Kwon, Sung Jin Hwang, Elizabeth A H Beckett, Kenton M Sanders, Sean Ward","doi":"10.1152/ajpgi.00400.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00400.2024","url":null,"abstract":"<p><p>Prostaglandin E₂ (PGE₂) actions on intestinal motility are complex due the differential expression of the PGE₂ receptors EP1-EP4. We sought to determine the actions of PGE₂ on electrical pacemaker and contractile activity of the circular and longitudinal muscle layers of the murine small intestine. Intracellular microelectrode and isometric force measurements were performed to examine the effects of PGE₂ receptor activation on circular and longitudinal muscle layers. In the two muscle layers PGE₂ produced differential responses. In the circular muscle layer PGE₂ caused dose-dependent membrane hyperpolarization and reduction in slow wave amplitude, accompanied by a decrease in the amplitude of phasic contractions. Membrane hyperpolarization and the reduction in slow wave amplitude and phasic contractions were insensitive to TTX and L-NNA, but inhibited by the K_ATP channel antagonist, glibenclamide. The actions of PGE₂ on the circular muscle layer were mimicked by the selective EP₂ and EP₄ agonists ONO AE1-259 and ONO AE1-329, respectively. The actions of PGE₂ were partially inhibited by the EP4 antagonist ONO AE3-208. The EP₁ agonist ONO DI-004 produced little effect while the EP3 agonist ONO AE-248 caused dose-dependent membrane depolarization. In comparison, PGE₂ produced increased tone and phasic contractions in the longitudinal muscle layer that was mimicked by ONO DI-004 and ONO AE-248, while EP₂ and EP₄ agonists had little effect on contractile activity. These data suggest that differential expression of PGE₂ receptors on intestinal muscle layers can produce antagonistic actions on intestinal motility.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565583","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":"Dynamics of circulatory monocytes trafficking and transitioning to gastric resident macrophages in diabetic gastroparesis.","authors":"Rajan Singh","doi":"10.1152/ajpgi.00053.2025","DOIUrl":"https://doi.org/10.1152/ajpgi.00053.2025","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539965","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":"Combination of dietary fiber and exercise training improves fat loss in mice, but does not ameliorate MASLD more than exercise alone.","authors":"Artemiy Kovynev, Mikołaj M Charchuta, Amina Begtašević, Quinten R Ducarmon, Patrick C N Rensen, Milena Schönke","doi":"10.1152/ajpgi.00317.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00317.2024","url":null,"abstract":"<p><p><b>Background:</b> Lifestyle interventions, such as diet and exercise, are currently the main therapies against metabolic dysfunction-associated steatotic liver disease (MASLD). However, not much is known about the combined impact of fiber and exercise on the modulation of gut-liver axis and MASLD amelioration. Here, we studied the impact of the combination of exercise training and a fiber-rich diet on the amelioration of MASLD. <b>Methods:</b> Male APOE*3-Leiden.CETP mice were fed a high-fat high-cholesterol diet with or without the addition of fiber (10% inulin) and exercise trained on a treadmill, or remained sedentary. <b>Results:</b> Exercise training and fiber supplementation reduced fat mass gain and lowered plasma glucose levels. Only the combination treatment, however, induced fat loss, and decreased plasma triglyceride and cholesterol levels compared to sedentary control mice. Exercise training with and without the addition of fiber had a similar ameliorating effect on the MASLD score. Only exercise without fiber decreased the hepatic expression of inflammatory markers. Fiber diet was mainly responsible for remodeling the gut microbial composition, with an increase in the relative abundance of the short-chain fatty acid (SCFA)-producing genera <i>Anaerostipes</i> and <i>Muribaculaceae</i>, while, surprisingly, exercise training alone and with fiber resulted in the highest increase of SCFA production. <b>Conclusion:</b> Overall, the combination of exercise training and dietary fiber decreases fat mass and improves glucose and lipid homeostasis, but does not have an additional synergistic positive effect on liver health compared to exercise training alone.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539852","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}