Fenofibrate Ameliorated Systemic and Retinal Inflammation and Modulated Gut Microbiota in High-Fat Diet-Induced Mice

Abstract

Fenofibrate, as a lipid-lowering drug, has been reported to have a protective effect on the retina independent with plasma lipid levels. This study aimed to investigate that the ameliorative effects of fenofibrate on systemic and retinal inflammation, as well as gut microbiota dysbiosis in high-fat diet (HFD)-induced mice. C57BL/6J mice were randomly allocated into four groups: standard diet (SD) group; HFD group; SD plus fenofibrate (SD_ Fe) group; HFD plus fenofibrate (HFD_ Fe) group. After successfully establishing models (5 months), indicators associated with lipid, gut barrier, inflammation and gut microbiota were investigated. Our results showed that supplementing the HFD with fenofibrate decreased body weight gain, alleviated dyslipidemia and reversed the downregulation of short-chain fatty acid (SCFAs) in serum, retina and feces. Fenofibrate ameliorated intestinal barrier function damage in HFD-induced mice. Fenofibrate coadministration inhibited the levels of inflammatory factor and lipopolysaccharide (LPS) in the serum and attenuated inflammatory response in the retina of HFD-induced mice. Systemic LPS was positively correlated with a series of inflammatory factors in serum and retina, respectively. Fenofibrate supplementation down-regulated the abundances of LPS-associated bacteria in HFD mice, including Firmicutes and Proteobacteria at the phylum level, Desulfovibrionaceae at the family level, as well as unclassified_ Desulfovibrionaceae, Acetatifactor, Flavonifractor, Oscillibacter and Anaerotruncus at the genus level. However, fenofibrate treatment up-regulated the abundances of SCFA-associated bacteria in HFD mice, including Bacteroidetes at the phylum level, Porphyromonadaceae at the family level, as well as unclassified_Porphyromonadaceae, Barnesiella, Alloprevotella and Bifidobacterium at the genus level. In conclusion, our results confirmed fenofibrate could attenuate HFD-induced systemic and retinal inflammation, accompanying with restoration of intestinal barrier damage and modulation of gut microbiota/metabolites. This work provided an explanation for the ameliorative effects of fenofibrate on HFD-induced systemic and retinal inflammation might be partially related with the modulation of gut microbiota and its metabolites.

Fenofibrate enhances lipid deposition via modulating PPARγ, SREBP-1c, and gut microbiota in ob/ob mice fed a high-fat diet

“…In C57BL/6J mice fed a high-fat diet, long-term fenofibrate intervention (30 mg/kg, 20 weeks) can decrease the expression of Fsp27 by 51% accompanied with reductions in hepatic TG and epididymal fat without affecting serum TG ( 42 ). Fenofibrate also reduces the body weight and the adipose tissue weight in male C57BL/6J mice fed a high-fat diet, but not in the mice fed a standard-fat diet ( 36 , 38 ). Furthermore, 21 weeks′ fenofibrate intervention (0.05% w/w) significantly decreases body weight, adipose tissue weight, hepatic TG, and the number of ballooned hepatocyte, in female ovariectomized C57BL/6J mice ( 37 ).…”

“…In this study, fenofibrate reduced the abundance of Bacteroidetes and increased the abundance of Firmicutes . On the contrary, fenofibrate (0.1% w/w) is found to reverse the reduced ratio of Bacteroidetes / Firmicutes in C57BL/6J mice fed a high-fat diet ( 36 ). Furthermore, the reduction of Actinobacteria and increase of Clostridium ( Firmicutes ) are also associated with adipogenesis, and the increase of Erysipelotrichaceae and Allobaculum is correlated with reduction of weight gain ( 59 , 61 ).…”

“…Another study finds that fenofibrate can significantly reduce HDL-C by ~30% in C57Bl mice ( 35 ). In a recent comparative study, fenofibrate (0.1% w/w) reduces plasma levels of TG, TC, and LDL/VLDL-C, in male C57BL/6J mice fed a high-fat diet, but not in the mice fed a standard-fat diet ( 36 ). Furthermore, 21 weeks′ fenofibrate intervention (0.05% w/w) significantly decreases the plasma levels of TG and TC in female ovariectomized C57BL/6J mice ( 37 ).…”

“…Although fenofibrate treatment decreased the abundance of Micrococcaceae , it significantly increased the relative abundance of Ruminococcaceae and Lachnospiraceae at the family level. On the contrary, fenofibrate reduces the abundance of Ruminococcaceae and Lachnospiraceae in C57BL/6J mice fed a high-fat diet ( 36 ). The depletion of Gordonibacter at the genus level may also contribute to the adipogenesis effect of fenofibrate ( 64 , 65 ).…”

“…However, fenofibrate reduced the relative abundance of Bacteroidia, Actinobacteria, Allobaculum , and Anaplasmataceae , which are also involved in SCFAs production ( 59 , 68 ). A recent study demonstrates that fenofibrate enhances the production of SCFAs, including acetic acid, propionic acid, and butyric acid, more efficiently in male C57BL/6J mice fed a high-fat diet than those fed a standard-fat diet through modulation of the gut microbiota, thereby ameliorating inflammation ( 36 ). However, whether fenofibrate can promote the production of SCFAs in ob/ob mice need to be further investigated in the future because fenofibrate exhibits different modulatory effects on the gut microbiota in ob/ob mice compared to that in C57BL/6J mice ( 36 ).…”