IL-34 ameliorates MASLD by regulating the synthesis of gut microbiota-derived metabolites LPS and IMP

Previous studies have established that metabolic dysfunction-associated steatotic liver disease (MASLD) disrupts the intestinal barrier, allowing harmful microbial metabolites such as lipopolysaccharide (LPS) to translocate to the liver via the gut-liver axis and accelerate disease progression. While the conventional view holds that IL-34 plays a pro-inflammatory role in various diseases, our findings using IL-34 knockout mice under a high-fat diet (HFD) challenge this assumption, Contrary to expectations, IL-34 deficiency exacerbated both hepatic lipid accumulation and intestinal barrier damage compared to wild-type controls. Furthermore, IL-34 knockout led to a significant reduction in gut microbial diversity and an altered ratio of detrimental to beneficial bacterial populations. Notably, antibiotic intervention ameliorated the aggravated MASLD phenotype in IL-34-deficient mice, a protective effect not observed with macrophage depletion. Metabolomic analysis of portal vein serum revealed a significant increase in imidazole propionate (IMP), a microbiota-derived metabolite, following IL-34 ablation. Functional assays demonstrated that IMP directly promotes free fatty acid-induced lipid accumulation in AML12 and HepG2 hepatocyte cell lines. To our knowledge, this study is the first to elucidate that elevated serum IL-34 plays a protective role in MASLD by modulating the gut microbiota and preserving intestinal barrier integrity, thereby limiting the portal influx of deleterious gut microbial metabolites such as IMP and LPS. These findings uncover a previously unrecognized mechanism by which IL-34 regulates MASLD progression through the gut microbial metabolic network, highlighting its potential as a therapeutic target for metabolic liver diseases.