(P19-043-25) Effects of High Fat Diet on Gut Microbiota in Diet-induced (C57BL/6J) and Genetically (TALLYHO/Jng) Obese Mice

Objectives: Obesity is a chronic multifactorial disease that elevates the risk of metabolic comorbidities. Adipose tissue remodeling contributes to chronic inflammation, impacting systemic metabolism in obesity. Gut dysbiosis, disrupted intestinal barrier integrity, and elevated bacterial lipopolysaccharide (LPS) levels, are all hallmarks of obesity-related disorders. Previously we showed that high fat (HF) diet significantly increased plasma IL-6 levels, a pro-inflammatory cytokine, in TALLYHO/Jng (TH) polygenic female mice compared to low-fat (LF) diet. We hypothesized that HF diet adversely alters gut microbiota composition, and markers of intestinal barrier integrity, and exacerbates inflammation in both diet-induced C57BL/6J (B6) and polygenic TH obese mice.

Methods: Four-week-old male and female B6 and TH mice were fed LF or HF diets for 14 weeks and were metabolically phenotyped in a previous study. As this study focused on changes in gut microbiota and intestinal markers, we used terminally collected cecal and colon tissue samples for 16S rRNA sequencing to evaluate changes in gut bacteria composition and colon tissue to measure changes in markers of intestinal barrier integrity using qRT-PCR.

Results: In B6 mice, HF diet significantly reduced the relative abundance of Bacteroidaceae in males (p = 0.03) and females (p = 0.047), compared to the LF group, at the family level. Similarly, in TH mice, the HF diet significantly decreased the relative abundance of Lactobacillaceae in both males (p = 0.037) and females (p = 0.007). Moreover, beta diversity analyses revealed distinct clustering patterns between diet groups in all cohorts (p < 0.05). In B6 and TH female mice, HF diet significantly reduced the mRNA expression level of Ocln, (B6: p = 0.04; TH: p = 0.02) and Zo1 (TH: p = 0.0009, B6: p = 0.04), with no significant changes in males, consistent with previously reported diet, sex and genotype effects on circulating Il-6 levels.

Conclusions: HF diet negatively remodeled gut microbiota and positively increased expression of intestinal barrier integrity markers, particularly in females. These findings highlight strain and sex-specific responses to HF diets, warranting further translational studies to determine sex-dependent changes in gut integrity in human obesity.

Funding Sources: USDA NIFA AFRI award # 2019-67017-29247