Volume 31, Issue S1 p. 887.1-887.1
Physiology
Free Access

Long-term Western Diet Feeding Causes Severe NASH and Cecal Dysbiosis in Juvenile Ossabaw Swine

Matthew R Panasevich

Matthew R Panasevich

Research Service-Harry S Truman Memorial VA Hospital, Columbia, MO

Nutrition and Exercise Physiology, University of Missouri, Columbia, MO

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Grace M Meers

Grace M Meers

Research Service-Harry S Truman Memorial VA Hospital, Columbia, MO

Medicine-Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO

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Melissa A Linden

Melissa A Linden

Research Service-Harry S Truman Memorial VA Hospital, Columbia, MO

Nutrition and Exercise Physiology, University of Missouri, Columbia, MO

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Jamal A Ibdah

Jamal A Ibdah

Research Service-Harry S Truman Memorial VA Hospital, Columbia, MO

Medicine-Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO

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Frank W Booth

Frank W Booth

Biomedical Sciences, University of Missouri, Columbia, MO

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James W Perfield II

James W Perfield II

Nutrition and Exercise Physiology, University of Missouri, Columbia, MO

Food Science, University of Missouri, Columbia, MO

Eli Lilly and Company, Indianapolis, IN

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Kartik Shankar

Kartik Shankar

Arkansas Children's Nutrition Center, Little Rock, AR

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R Scott Rector

R Scott Rector

Research Service-Harry S Truman Memorial VA Hospital, Columbia, MO

Nutrition and Exercise Physiology, University of Missouri, Columbia, MO

Medicine-Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO

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Abstract

Pediatric obesity and nonalcoholic fatty liver disease (NAFLD) 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 continued western diet (WD)-feeding on NAFLD and cecal dysbiosis in juvenile Ossabaw swine. Female Ossabaw swine (5 weeks old) were fed WD (43.0% fat; 17.8% high fructose corn syrup; 2% cholesterol) or low-fat control diet (CON; 10.5% fat) for 16 or 36 wks. We observed progressive obesity, lower physical activity, dyslipidemia, and systemic insulin resistance through 36 wks of WD feeding (P<0.05). In addition, WD-fed pigs developed a progressive form of severe nonalcoholic steatohepatitis (NASH), with significant hepatic steatosis, hepatocyte ballooning, inflammatory cell infiltration, fibrosis, and elevated liver enzymes. WD-fed pigs also had elevated hepatic expression of inflammatory genes TNFα, TGFβ, IL-1β, TLR4, TLR9, and F4/80 (P<0.05), as well as increased (P<0.05) hepatic protein content of fibrosis marker α-SMA and JNK1 at 16 and 36 wks. WD feeding also significantly reduced hepatic OXPHOS proteins in complexes I, III and V at 16 and 36 weeks. Assessment of the microbiome in WD-fed animals for 36 wks revealed dysbiosis showing higher (P<0.05) cecal relative abundance of Proteobacteria, and families and genera within (i.e. Enterobacteriaceae, Succinivibrionaceae, Desulfovrobrionaceae, Succinvibrio, and Desulfovbrio). Furthermore, LPS-producing Desulfovbrionaceae and Desulfovbrio, were positively correlated with hepatic TLR4 expression (r=0.7997 and r=0.9130, P=0.01, respectively). Consistent with human high fat diet feeding and obesity and suggestive of increased energy harvest, long term WD-feeding also resulted in an increased (P<0.05) Firmicutes to Bacteroidetes ratio and exhibited a tendency (r=0.6503, P=0.08) to be positively correlated with biochemical hepatic TAG concentrations. The changes observed in the microbiome are consistent with LPS-induced transcriptional activation of pro-inflammatory status in the liver and resemble the human NAFLD/NASH phenotype. Overall, WD-fed Ossabaw swine developed cecal dysbiosis, a pro-inflammatory signature, and NAFLD progressing to NASH similar to the pediatric/adolescent and young adult populations.

Support or Funding Information

This work was supported by grants from Mizzou Advantage, The Allen Foundation, and partially supported by VA Grant VHA-CDA2 IK2BX001299.