High fat, high fructose, high cholesterol feeding causes severe NASH and cecal microbiota dysbiosis in juvenile ossabaw swine. - GreenMedInfo Summary

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 model. 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 weeks 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 wks (n=6 each) or 36 wks (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 weeks, with further exacerbation of histological inflammation and fibrosis after 36 wks 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 Succinvibrio), LPS-containing Desulfovbrionaceae and Desulfovbrio, 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 high fat, high fructose, high cholesterol diet develop obesity and severe microbiota dysbiosis with a pro-inflammatory signature and a NASH phenotype directly relevant to the pediatric/adolescent and young adult population.