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

Authors: PANASEVICH, MATTHEW - University Of Missouri; MEERS, GRACE - University Of Missouri; LINDEN, MELLISA - University Of Missouri; BOOTH, FRANK - University Of Missouri; PERFIELD II, JAMES - Eli Lilly & Company; FRITSCHE, KEVIN - University Of Missouri; WANKHADE, UMESH - Arkansas Children'S Nutrition Research Center (ACNC); CHINTAPALLI, SREE - Arkansas Children'S Nutrition Research Center (ACNC); SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC); IBDAH, JAMAL - University Of Missouri; RECTOR, R SCOTT - University Of Missouri

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/7/2017
Publication Date: 1/1/2018
Citation: Panasevich, M.R., Meers, G.M., Linden, M.A., Booth, F.W., Perfield II, J.W., Fritsche, K., Wankhade, U.D., Chintapalli, S.V., Shankar, K.L., Ibdah, J.A., Rector, R. 2018. High-fat, high-fructose, high-cholesterol feeding causes severe NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine. American Journal of Physiology - Endocrinology and Metabolism. 314:E78-E92. https://doi.org/10.1152/ajpendo.00015.2017.
DOI: https://doi.org/10.1152/ajpendo.00015.2017

Interpretive Summary: With the rapid rise in childhood obesity, the incidence of co-morbidities such as type 2 diabetes, metabolic syndrome and fatty liver disease is also increasing in children. One progressive form of fatty liver disease called NASH, involves development of inflammation in the liver and can progress liver fibrosis (scarring of liver). However, no good animal models to study this form of liver disease exist in a pediatric population. In this study, we utilized feeding of high calorie diets rich in fat and high-fructose corn syrup to produce obesity and metabolic dysfunction in weanling Ossabaw pigs. Obese swine fed these diets developed insulin resistance and significant liver disease including inflammatory cells and markers of fibrosis during the study. Compared to pigs fed control diets, feeding of high fat, high fructose diets also led to dramatic changes in the composition of gut microbiota with a bloom in gram-negative, LPS containing Proteobacteria plylum. Changes in hepatic inflammation were also associated with abundance of specific taxa of bacteria. These studies provide an important new resource to study the pathophysiology of an important pediatric disease.

Technical 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.