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Long‐term Western Diet Feeding Causes Severe NASH and Cecal Dysbiosis in Juvenile Ossabaw Swine
Author(s) -
Panasevich Matthew R,
Meers Grace M,
Linden Melissa A,
Ibdah Jamal A,
Booth Frank W,
Perfield James W,
Shankar Kartik,
Rector R Scott
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.887.1
Subject(s) - medicine , steatosis , dysbiosis , endocrinology , nonalcoholic fatty liver disease , fatty liver , insulin resistance , dyslipidemia , fibrosis , obesity , biology , disease
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.