Deletion of the PPAR gene exacerbates high-fat diet-induced nonalcoholic fatty liver disease in mice through the gut-liver axis

Gut microbiota dysbiosis is an essential factor contributing to non-alcoholic fatty liver disease (NAFLD), in which the gut-liver axis plays a crucial role. Peroxisome proliferator-activated receptor delta (PPAR delta) is considered a new direction for the research on NAFLD due to its positive regulation of glucose and lipid metabolism. Our experiment aimed to investigate the effect of PPAR delta gene deletion on gut microbiota and NAFLD through the gut-liver axis. PPAR delta-/- mice and wild-type mice were randomly divided into high-fat diet (HFD) groups and normal diet groups. In each group, six mice were sacrificed at weeks 4, 8, and 12. Metabolic indicators and inflammation indicators were measured, and the degree of liver steatosis and the ileum mucosa integrity were evaluated. Additionally, fecal samples were subjected to 16S rDNA gene sequencing and analysis of gut microbiota. Deletion of the PPAR delta gene exhibited exacerbated effects on HFD-induced NAFLD and displayed more severe liver inflammation and intestinal mucosal barrier injuries. The HFD reduced the abundance of short-chain fatty acid (SCFA)-producing bacteria and increased the abundance of intestinal endotoxin-rich bacteria in mice. Deletion of the PPAR delta gene exacerbated this trend, resulting in decreased abundances of norank_f_Eubacterium_coprostanoligenes_group and Alloprevotella and increased abundances of Acidibacunclassified_f_Caulobacteraceae, unclassified_c_Bacteroidia and Bosea. Spearman's correlation analysis found Lachnoclostridium, unclassified_f_Rhizobiaceae, Allobaculum, Acinetobacter, Romboutsia, norank_f_ Muribaculaceae and Dubosiella showed some correlations with metabolic indicators, inflammation indicators, NAS and occludin. Deletion of the PPAR delta gene exacerbated HFD-induced gut microbiota dysbiosis and affected NAFLD through the gut-liver axis.