High-fat, high-fructose, high-cholesterol feeding causes severe NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine

Abstract

Pediatric obesity and nonalcoholic steatohepatitis (NASH) are on the rise in industrialized countries, yet our ability to mechanistically examine this relationship is limited by the lack of a suitable higher animal models. Here, we examined the effects of high-fat, high-fructose corn syrup, high-cholesterol Western-style diet (WD)-induced obesity on NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine. Juvenile female Ossabaw swine (5 wk old) were fed WD (43.0% fat; 17.8% high-fructose corn syrup; 2% cholesterol) or low-fat diet (CON/lean; 10.5% fat) for 16 wk ( n = 6 each) or 36 wk ( n = 4 each). WD-fed pigs developed obesity, dyslipidemia, and systemic insulin resistance compared with CON pigs. In addition, obese WD-fed pigs developed severe NASH, with hepatic steatosis, hepatocyte ballooning, inflammatory cell infiltration, and fibrosis after 16 wk, with further exacerbation of histological inflammation and fibrosis after 36 wk of WD feeding. WD feeding also resulted in robust cecal microbiota changes including increased relative abundances of families and genera in Proteobacteria ( P < 0.05) (i.e., Enterobacteriaceae, Succinivibrionaceae, and Succinivibrio) and LPS-containing Desulfovibrionaceae and Desulfovibrio and a greater ( P < 0.05) predicted microbial metabolic function for LPS biosynthesis, LPS biosynthesis proteins, and peptidoglycan synthesis compared with CON-fed pigs. Overall, juvenile Ossabaw swine fed a high-fat, high-fructose, high-cholesterol diet develop obesity and severe microbiota dysbiosis with a proinflammatory signature and a NASH phenotype directly relevant to the pediatric/adolescent and young adult population.