<i>Lactobacillus murinus</i> Alleviates High Fructose‐Induced <scp>MASLD</scp> by Boosting Arginine Production

Over the past few years, the prevalence of high-fructose diets has become a significant inducer of metabolic dysfunction-associated steatotic liver disease (MASLD). The effects and pathological mechanisms of high dietary fructose on gut microbiota and its subsequent role in MASLD remain unclear. Here, we investigated the impact of fructose supplementation on MASLD progression in wild-type C57BL/6 mice using both high-fructose drinking water and a high-fructose diet. Through 16S rDNA sequencing, we observed that long-term fructose exposure significantly reduced the abundance of <i>Lactobacillus murinus</i> (<i>L. murinus</i>) in the intestines of mice. We aim to further elucidate the role and underlying mechanisms of <i>L. murinus</i> in high-fructose-induced MASLD. Logically, we supplemented <i>L. murinus</i> exogenously in the high-fructose mouse model and found that <i>L. murinus</i> significantly alleviated fructose-induced MASLD symptoms, characterized by reduced liver ballooning, inflammation, hepatic cholesterol, triglycerides, as well as decreased blood cholesterol, triglycerides, ALT and AST levels. To further investigate the mechanistic basis of <i>L. murinus</i>-mediated protection, we conducted serum and fecal metabolomic analyses. These studies identified arginine as the sole metabolite exhibiting marked reductions in both serum and intestinal compartments. Integrated multi-omics analysis revealed a strong positive correlation between gut <i>L. murinus</i> abundance and arginine levels. ELISA demonstrated that exogenous administration of <i>L. murinus</i> effectively restored circulating arginine concentrations in high-fructose-fed mice. Importantly, direct arginine supplementation produced similar therapeutic benefits as <i>L. murinus</i>. Specifically, it improved key features of MASLD, including reduced liver ballooning, less liver inflammation, lower buildup of cholesterol and triglycerides in the liver and blood, and decreased ALT/AST levels. These data revealed a novel mechanism underlying fructose-induced MASLD by decreasing the abundance of gut <i>L. murinus</i>, which disrupts arginine metabolism. <i>L. murinus</i> and arginine could serve as potential therapeutic strategies against fructose-induced MASLD.