Adenosine from high-fat-diet-tolerant monkey-derived Limsolactobacillus reuteri MacFasB02 modulates cholesterol metabolism to alleviate hyperlipidemia and inflammation

Hyperlipidemia is a leading global health challenge, limited by the safety liabilities of current pharmacotherapies. Here, we isolated a novel Limosilactobacillus reuteri strain, MacFasB02, from fecal samples of cynomolgus monkeys tolerant to chronic high-fat diet (HFD). This study aimed to systematically evaluate its probiotic properties and therapeutic potential against hyperlipidemia. In vitro, MacFasB02 exhibited robust growth, acid production, and tolerance to acidic and bile environments. In HFD-fed mice, 13-week MacFasB02 administration reduced weight gain, serum triglycerides, low-density lipoprotein cholesterol and total cholesterol, while ameliorating hepatic steatosis and inflammation, as well as restoring intestinal barrier integrity by enhanced villus architecture, goblet cell function, and tight junction proteins expression. Metagenomic analysis revealed gut microbiota remodeling. Transcriptomic profiling coupled with in vivo validation demonstrated upregulation of Apoa1 and Pltp in cholesterol metabolism. Untargeted metabolomics integrated with whole-genome sequencing and supernatant metabolite profiling identified adenosine as a key MacFasB02-derived metabolite in purine metabolism. Consistently, In vitro experiments showed that adenosine reduced lipid accumulation and inflammation in hepatocytes by regulating Apoa1 and Pltp to modulate cholesterol metabolism. Collectively, MacFasB02 exerts dual lipid-lowering and anti-inflammatory effects probably via adenosine-mediated modulation of cholesterol metabolism, promising potential as a live biopharmaceutical agent for hyperlipidemia.