Western Diet-Induced Dysbiosis Is Associated with Intestinal Hyperplasia and Dysregulation of FXR-FGF19 Gene Expression in Juvenile Iberian Pigs (OR26-03-19)

Abstract

ObjectivesThe Western diet has been associated with increased risk of colon cancer, partially due to changes in bile acid (BA) homeostasis. While diet-induced proliferation of intestinal mucosa has been documented in adults, it is unclear whether it can develop in pediatric populations. We hypothesize that feeding a high-fat high-fructose (HFF) diet to neonatal pigs will increase BA levels in liver and plasma, and cell proliferation in intestinal mucosa. In addition, we hypothesize that supplementation of a probiotic mixture with Pediococcus, Lactobacillus and Bacillus at 6.2 × 104 cfu/mL will ameliorate the HFF pro-proliferative effect. MethodsTo test the hypothesis we used 10-d old Iberian pigs, which have a leptin-resistant phenotype resulting in rapid development of obesity and dyslipidemia. Diets contained (g/kg body weight × d) 0 g fructose, 11 g fat and 199 kcal (CON-N; n = 8), 22 g fructose, 16 g fat and 300 kcal (HFF-N; n = 6), CON + probiotic (CON-P; n = 6), or HFF + probiotic (HFF-P; n = 6). Pigs were euthanized at 80 d of age. Liver and plasma BA levels were analyzed by LC-MS. Hyperplasia in colon and distal ileum (DI) was assessed by hematoxylin-eosin and Ki-67 staining. Bacteria in colon content were quantified at genus level by 16S ribosomal RNA analysis. Gene expression of farnesoid X receptor (FXR), small heterodimer partner (SHP), fibroblast growth factor 19 (FGF19), organic solute transporter (OST) α, apical sodium-dependent BA transporter (ASBT), tumor necrosis factor (TNF) α, tumor growth factor (TGF) β, takeda G-protein receptor (TGR) 5, and epidermal growth factor receptor (EGFR) was measured by qPCR. ResultsHFF-N an HFF-P increased taurocholate and glyocholate in liver and plasma (P ≤ 0.0001), crypt depth, villi length and Ki-67 + cells/crypt (P ≤ 0.01) in colon and DI, and Clostridium, Bacteroides, Synergistes, and Bilophila populations in colon content (P ≤ 0.05). HFF-N and HFF-P increased expression of SHP, OSTα, and ASBT and decreased FGF19 in DI (P ≤ 0.05), and increased SHP and decreased TNFα and TGFβ in colon (P ≤ 0.05). FXR, TGR5 and EGFR did not differ between groups. ConclusionsA high-fructose high-fat diet increased liver and plasma BA levels and downregulated FGF19 expression in DI. Colonic hyperplasia, proliferation of BA tolerant bacteria and changes in SHP, TNFα and TGFβ may be related to increased secondary BA in the colon. Funding SourcesARI, AcornSeekers, STRIDE.