Correction of hypertriglyceridemia by intestinal microbiota remodeling alleviates NASH and atherosclerosis in severe combined hyperlipidemia disease

Abstract Background Combined hyperlipidemia (CHL), characterized by elevated cholesterol and triglyceride levels in circulation, is a common risk factor of cardiovascular disease (CVD) accompanied by obesity, insulin resistance and fatty liver. Emerging lines of evidence demonstrate that intestinal microbiota plays a central role in the development of metabolic disease and the application of antibiotics can influence microbial homeostasis in gut, suggesting that modulation of microbiota profiling by antibiotics could improve metabolic abnormalities. However, the beneficial consequence of CHL yielded by antibiotic-mediated remodeling of intestinal microbiota has not been investigated yet and whether intestinal microbiota can be a potential therapeutic target for CHL is still unknown so far. Results Intermittent antibiotic treatment and transfer of gut microbiota through cohousing approach could effectively change gut microbial composition and functions but didn't affect microbiota abundance in low density lipoprotein receptor deficient (LDLR−/−) hamsters fed an HFHC diet compared to placebo-treated control group. Modulating gut microbiota significantly reduced body weight gain, lowered plasma triglyceride levels without affecting cholesterol concentration, restrained adipocyte hypertrophy and brown adipocyte whitening, eventually alleviating obesity, non-alcoholic steatohepatitis (NASH) and atherosclerosis. Further omic analysis of intestinal microbiota showed that along with sequentially increased bacterial richness, Lactobacillus, Clostridia_UCG-014, Bifidobacterium and Eubacterium_coprostanoligenes_group were key four species that droved severe CHL-associated NASH progression. Additionally, we observed that Fusobacterium, Blautia, Parasutterella, and Methanosphaera genera were enriched in antibiotic treated LDLR−/− hamsters with mitigating aberrant intestinal absorption, NASH and atherosclerotic lesions. Conclusion Remodeling gut microbiota by antibiotics and transfer gut microbiota via cohousing approach effectively corrects hypertriglyceridemia in HFHC diet-fed LDLR−/− hamsters, which is sufficient to improve obesity, non-alcoholic steatohepatitis (NASH) and atherosclerosis caused by refractory CHL, further confirming that hypertriglyceridemia is the important risk factor for CVD and then suggesting that intestinal microbiota exert a therapeutic potential in CHL disease.