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Immunoregulation of Intrahepatic Bone Marrow Monocyte–Derived Macrophages by Dietary Nitrate Prevents Nonalcoholic Fatty Liver Disease

ABSTRACT: Although nonalcoholic fatty liver disease (NAFLD) is one of the leading causes of liver disease worldwide, no efficient treatment has been approved yet. We investigated whether oral nitrate administration prevents development of diet-induced NAFLD in two mouse models. Nitrate exerted its protective effect mainly through rebalancing of pro- and anti-inflammatory bone marrow monocyte–derived macrophages (MoMFs) in the liver. Using an NAFLD model in relatively germ-free mice and bone marrow–transplanted mice with a heritable Slc17a5 mutation, we showed that nitrate can prevent NAFLD by direct regulation of MoMFs through sialin, besides via the classical nitric oxide pathway. In vitro studies revealed that nitrate directly regulates mouse and human macrophages through the sialin-Sema4A pathway. Our work demonstrated for the first time nitrate’s ability to prevent NAFLD by directly modulating the homeostasis of hepatic pro- and anti-inflammatory macrophages, which indicates a novel strategy for potential clinical application in NAFLD.

ORGANISM(S): Mus musculus

PROVIDER: GSE204856 | GEO | 2025/08/05

REPOSITORIES: GEO

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Project description:Background & Aims: Non-alcoholic fatty liver disease (NALFLD)-associated changes in gut microbiota are important drivers of disease progression toward fibrosis. Therefore, reversing microbiota alterations could ameliorate NAFLD progression. Oat beta-glucan, a non-digestible polysaccharides, has shown promising therapeutic effects on hyperlipidemia associated with NAFLD, but its impact on gut microbiota and most importantly NAFLD fibrosis remains unknown. Methods: We performed detailed metabolic phenotyping including body composition, glucose tolerance, and lipid metabolism as well as comprehensive characterization of the gut-liver axis in a western-style diet (WSD)-induced model of NAFLD and assessed the effect of a beta-glucan intervention on early and advanced liver disease. Gut microbiota was modulated using broad-spectrum antibiotic (Abx) treatment. Results: Oat beta-glucan supplementation did not affect WSD-induced body weight gain, glucose intolerance, and the metabolic phenotype remained largely unaffected. Interestingly, oat beta-glucan dampened NAFLD inflammation, associated with significantly reduced monocyte-derived macrophages (MoMFs) infiltration, fibroinflammatory gene expression, and strongly reduced fibrosis development. Mechanistically, this protective effect was not mediated by changes in bile acid composition or signaling, but was dependent on gut microbiota and was lost upon Abx treatment. Specifically, oat beta-glucan partially reversed unfavorable changes in gut microbiota, resulting in an expansion of protective taxa, including Ruminococcus, and Lactobacillus followed by reduced translocation of TLR ligands. Conclusions: Our findings identify oat beta-glucan as a highly efficacious food supplement that dampens inflammation and fibrosis development in diet-induced NAFLD. These results, along with its favorable dietary profile, suggest that it may be a cost-effective and well-tolerated approach to preventing NAFLD progression and should be assessed in clinical studies.

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Immunoregulation of Intrahepatic Bone Marrow Monocyte–Derived Macrophages by Dietary Nitrate Prevents Nonalcoholic Fatty Liver Disease

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