PPAR_α Dependent Regulation of Gut Microbiota: Implication for Host Metabolic Homeostasis

The peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of lipid metabolism and energy homeostasis. However, its role in shaping the gut microbiota requires further investigation. Therefore, the aim of the present study was to investigate whether the lack of PPARα in a mouse model or the presence of a single nucleotide polymorphism (SNP) rs6008259 of PPARα in humans can modulate the gut microbiota and its association with metabolic alterations. PPARα^-/- and PPAR^+/+ male mice were fed an AIN-93 diet for 10 days, and a human cohort (n = 177) was genotyped for the PPARα SNP rs6008259. PPARα^-/- mice showed less body weight gain, more fat mass and reduced lean mass compared to WT, despite similar food intake. They exhibited elevated hepatic triglycerides and hyperlipidemia. In humans, carriers of the rs6008259 allele of PPARα showed similar findings in blood lipids and body composition. Colonic analysis revealed reduced hypoxia in PPARα^-/- mice, increased inflammatory markers, and compromised barrier function. Gut microbiota analysis in PPARα^-/- mice and humans, carriers of the rs6008259 allele of PPARα showed reduced alpha diversity and altered composition, including increased Blautia, Parabacteroides and Lanchoclostridium. Genetic background is important in the interpretation on the effects of diet on gut microbiota.