Rosuvastatin ameliorates obesity-associated insulin resistance in high-fat diet-fed mice by modulating the gut microbiota and gut metabolites

Abstract

Introduction: Insulin resistance (IR) underlies metabolic diseases such as obesity and diabetes. Statins are lipid-lowering drugs that have also been studied to improve insulin resistance, but the mechanism is not well understood. Metagenomics and metabolomics were used to analyze the main species and metabolic pathways involved in intestinal microbes while improving insulin resistance in mice with rosuvastatin in this study.

Methods: C57BL/6J male mice fed a high-fat diet were used to establish the insulin resistance (IR) mouse model. Rosuvastatin (RSV) was then administered for 8 weeks. Metagenomics and metabolomics were utilized to analyze the microbial composition and short chain fatty acid metabolites in intestinal feces of mice.

Results: It was observed that insulin-resistant mice showed significant improvement in insulin resistance following treatment with RSV. In comparison to the HFD group, specific bacterial strains were significantly increased, and the levels of butyric acid, caproic acid, and isovaleric acid among the short-chain fatty acids were notably elevated in the RSV group. Through KEGG enrichment analysis, 19 dominant strains and 15 key enzymes involved in butyric acid metabolism were identified.

Conclusions: The results suggested that IR mice might enhance insulin sensitivity by promoting butyric acid synthesis via intestinal microbes following RSV treatment.

Keywords: butyric acid; insulin resistance; metabolome; metagenome; rosuvastatin.

Figure 1

Oral rosuvastatin can repair impaired glucose tolerance. (A) After oral glucose (concentration of 2 g/KG) was measured at 0,30,60,90,120,150,180 minutes, it was found that 12 weeks of high-fat diet could caused a significant abnormal oral glucose tolerance curve of mice. (B) The area under the OGTT curve increased significantly due to the high fat diet. (C) The RVS group (that is, the HFD group of mice that took rosuvastatin orally for 8 weeks) tested by OGTT and found that rosuvastatin significantly reduced the area under the oral glucose tolerance curve. (D) HOMA-IR of RVS group mice decreased significantly after 8 weeks of oral administration of rosuvastatin. ##P <0.01 vs.NC, **P <0.01 vs. HFD, *P <0.05 vs. HFD, NC, normal control; HFD, high fat diet; RVS, high fat diet + 5mg/kg rosuvastatin.

Figure 2

Changes in intestinal microbiome composition after rosuvastatin treatment. (A) Composition of gut microbes at genus level. (B) Differences in intestinal biota composition at phylum level. (C) Differences in intestinal biota composition at family level. (D) Differences in intestinal biota composition at genus level.

Figure 3

The number of genes in each pathway predicted by the metagenomic test results. (A) KEGG function annotation, (B) eggNOG function annotation, (C) CAZy function annotation.

Figure 4

Effect of rosuvastatin administration on intestinal metabolites in insulin resistant mice. (A–C) Volcano, matchstick, and heat maps of the 11 fatty acids selected. (D) Boxplot of three significantly increased SCFAs; (E) 8 fatty acids that did not change significantly. *P <0.05, **P <0.01 vs. HFD group.

Figure 5

Significantly elevated bacterial flora associated with butyric acid production. (A) Genus that was significantly elevated and could in turn promote butyric acid production. (B) species that were significantly elevated and could promote butyrate biogenesis. *: P <0.05, **: P <0.01 vs. HFD group.

Figure 6

Administration of rosuvastatin mainly affected the metabolism of carbohydrates in intestinal metabolites of insulin resistant mice. (A) The major pathways by which rosuvastatin affects carbohydrate metabolism. (B) KO IDs involved in C5-Branched dibasic acid metabolism, Butanoate metabolism and Glycolysis/Gluconeogenesis. (C) Bacterial species underlying significant KO IDs. (D) Metabolic diagram.