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

Monica Sanchez-Tapia; Sandra Tobon-Cornejo; Martha Guevara-Cruz; Laura A. Velazquez-Villegas; Rogelio Hernandez-Pando; Adriana Lopez-Barradas; Rocio Guizar-Heredia; Otoniel Maya Lucas; Janette Furuzawa-Carballeda; Rosa Rebollar-Vega; Ariana Vargas-Castillo; Nimbe Torres; Armando R. Tovar

doi:10.1002/mnfr.70549

PPARα Dependent Regulation of Gut Microbiota: Implication for Host Metabolic Homeostasis
Journal article, 2026

The peroxisome proliferator-activated receptor alpha (PPAR alpha) 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 PPAR alpha in a mouse model or the presence of a single nucleotide polymorphism (SNP) rs6008259 of PPAR alpha in humans can modulate the gut microbiota and its association with metabolic alterations. PPAR alpha-/- and PPAR+/+ male mice were fed an AIN-93 diet for 10 days, and a human cohort (n = 177) was genotyped for the PPAR alpha SNP rs6008259. PPAR alpha-/- 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 PPAR alpha showed similar findings in blood lipids and body composition. Colonic analysis revealed reduced hypoxia in PPAR alpha-/- mice, increased inflammatory markers, and compromised barrier function. Gut microbiota analysis in PPAR alpha-/- mice and humans, carriers of the rs6008259 allele of PPAR alpha 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.

PPAR alpha

triglycerides

SNP rs6008259

colonic hypoxia

gut microbiota