Papel da Fexaramina e da metformina, agonista ou antagonista do FXR intestinal, no eixo entero-hepático em modelo experimental

Abstract

Alterations in intestinal microbiota and bile acids modulate the intestinal farnesoid X receptor (FXR) and induce intestinal inflammation and hyperpermeability. Metformin or Fexaramine act via intestinal FXR, inhibiting or activating, respectively, the intestinal microbiota, intestinal permeability, and hepatic steatosis through the gut-liver axis. 3-month-old male mice were randomly divided into 2 groups (n=30, each) and received control (C) and high-fat (HF, 50% of total lipid energy) diets for 12 weeks. Afterwards, they were subdivided for administration by orogastric gavage of Metformin (MET- 300mg/kg) or Fexaramine (FEX-5mg/kg): C, C+MET, C+FEX, HF, HF+MET, HF+FEX (n= 10, each) for 3 weeks. Body mass (BM), glucose metabolism, RT-qPCR 16s rRNA of cecum stool, ileum (morphometry, stereology, and bile acid pathways, tight junctions, inflammatory cytokines RT-qPCR), liver (stereology, bile acid pathway, lipogenesis, beta-oxidation and inflammatory cytokines RT-qPCR). The HF vs. C increased MC, area under the curve (AUC) and HOMA-IR, reduced QUICKI and the villus/crypt ratio. It increased the Firmicutes/Bacteroidetes ratio, decreased Fxr-Tgr5, Cldn-Ocldn-Zo1 gene expression and increased Tlr4-Il6-Il1beta expression in the ileum. In the hepatic gene expression, there was an increase in Srebp1c-Ppargama-Fas, Tlr4-Il6-Tnfalfa and a decrease in Pparalpha and Fxr-Shp, triggering an increase in ALT and in the density (Vv) of hepatic steatosis. The HF+MET vs. HF group reduced MC, ASC, HOMA-IR, plasma triacylglycerol (TAG), increased QUICKI and plasma adiponectin, epithelium thickness and villus width. Reduced the Firmicutes/Bacteroidetes ratio. In the ileum it reduced Fxr, increased Glp1r, Ocldn-Cldn-Zo1, IL10 and reduced Tlr4-Il6-Il1beta. In the liver, was increased Fxr, Fgfr4, Pparalpha, reduced Srebp1c-Ppargama-Fas and Tlr4-Il6-Tnfalfa, thus decreasing the Vv of hepatic steatosis. The HF+FEX vs. HF showed similar results to HF+MET vs. HF, however, showed no change in AUC, HOMA-IR, QUICKI, adipokines, villus/crypt ratio, epithelium thickness and Il10 gene expression in the ileum. Regarding the pathway of bile acids, there were also differences, in the ileum of Fxr-Fgf15, Tgr5 was increased, and in the liver, as in the HF+MET, Fxr was increased, but Fexaramine induced an increase in Shp and reduction of Cyp7a1. Metformin and Fexaramine attenuated the deleterious effects of the HF diet, such as changes in the intestinal microbiota and permeability, ileum morphology and hepatic steatosis, due to the central role of intestinal FXR in the composition of bile acids. However, Metformin has shown some benefits beyond those found by Fexaramine. However, intestinal FXR has been shown to be an efficient treatment target for metabolic diseases.