The Relationship Between A High-Fat Diet, Gut Microbiome, and Systemic Chronic Inflammation: Insights from Integrated Multi-Omics Analysis

Background: The detrimental effects of a high-fat diet (HFD) extend beyond metabolic consequences and include systemic chronic inflammation (SCI), immune dysregulation, and gut health disruption.

Objectives: In this study, we used Mendelian randomization (MR) to investigate the relationship between HFD and gut microbiota, and SCI.

Methods: Genetic variants associated with dietary fat were utilized to explore causal relationships. GWAS data for the analyses of the gut microbiota, inflammatory cytokines, immune cell characteristics and serum metabolites were obtained from European individuals. Mediation analysis was used to reveal potential mediating factors. The GMrepo database was used to analyze the bacterial composition in different groups. Transcriptomic and single-cell sequencing analyses were used to explore inflammation and barrier function in colonic tissue.

Results: HFD consumption was linked to changes in the abundance of 3 bacterial families and 11 bacterial genera. Combined with the GMrepo database, the increased abundance of genus.Lachnospiraceae_FCS020group and the decreased abundance of genus.Bacteroides and genus.Barnesiella are consistent with the MR results. Transcriptomic and single-cell sequencing analyses revealed intestinal inflammation and mucosal barrier dysfunction in HFD-fed mice. MR revealed a link between HFD consumption and increased levels of interleukin (IL)-18 (OR=3.64, 95%CI: 1.24-10.69, P=0.02), MIG (OR=3.14, 95%CI: 1.17-8.47, P=0.02), IL-13 (OR=3.21, 95%CI:1.08-9.52, P=0.04), and IL-2RA (OR=2.93, 95%CI: 1.01-8.53, P=0.049). Twenty-nine immune cell signatures, including altered monocyte and T-cell subsets, were affected by HFD consumption. Twenty-six serum metabolites that are linked to HFD consumption, particularly lipid and amino acid metabolites, were identified. The positive gut microbiota exhibits extensive associations with inflammatory cytokines. In particular, Lachnospiraceae_FCS020 group (OR=1.93, 95% CI: 1.11-3.37, P=0.02) may play a mediating role in HFD-induced increases in IL-2RA levels.

Conclusions: Microbial dysbiosis appears to be an important mechanism for HFD-induced SCI. The Lachnospiraceae_FCS020 group may act as a key genus in HFD-mediated elevation of IL-2RA.