Peroxisome Proliferator-Activated Receptor α and Synthetic Agonist WY14643 Alter Gut Microbiome Composition and Metabolism
Restricted (Penn State Only)
- Author:
- Gandy, Katrin
- Graduate Program:
- Biochemistry, Microbiology, and Molecular Biology
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- March 09, 2023
- Committee Members:
- Andrew Patterson, Thesis Advisor/Co-Advisor
Jordan Bisanz, Committee Member
Wendy Hanna-Rose, Program Head/Chair
Jeffrey Maurice Peters, Thesis Advisor/Co-Advisor - Keywords:
- PPAR
PPARα
gut microbiome
WY14643
metabolomics
trimethylamine - Abstract:
- Peroxisome proliferator-activated receptor α (PPARα) is a ligand activated transcription factor that regulates gene expression related to several processes including fatty acid metabolism, cell proliferation, and inflammation. As such, it has been studied as a target in ameliorating diseased states including metabolic disease and cancer. The gut microbiome is known to interact with nuclear receptors, although its relationship with PPARα function is not fully understood. Here, 16S rRNA sequencing and 1H NMR metabolomics are used to examine how gut microbiome composition and metabolic output is shaped by the constitutive activity and ligand activation of PPARα. The role of PPARα basal expression is evaluated using intestine-specific (PparaΔIE) and hepatocyte-specific (PparaΔHep) conditional knockout mouse models, and ligand activation is achieved through feeding of 0.1% WY14643 for five days. While large shifts in microbiome composition and metabolism due to constitutive PPARα alone were not observed, several changes were documented upon ligand activation with WY14643. Beta diversity analysis of sequencing data indicates that both genotype and treatment status influence microbial composition. Most notably, cecal trimethylamine was reduced by WY14643 in Pparafl/fl and PparaΔHep mice which may be due to the large decreases in the abundance of members of the Lachnospiraceae family also observed in these mice. Additionally, activation of intestinal PPARα was found to prevent the expansion of multiple taxa in the Erysipelotrichaceae family. These substantial shifts in microbial populations due to WY14643 treatment have not been accounted for despite the common use of this compound to study PPARα and are important to understand as they may contribute to host phenotype.