The glucose-lowering effects of α-glucosidase inhibitor require a bile acid signal in mice

Abstract

Aims/hypothesis Bile-acid (BA) signalling is crucial in metabolism homeostasis and has recently been found to mediate the therapeutic effects of glucose-lowering treatments, including α-glucosidase inhibitor (AGI). However, the underlying mechanisms are yet to be clarified. We hypothesised that BA signalling may be required for the glucose-lowering effects and metabolic benefits of AGI. Methods Leptin receptor (Lepr)-knockout (KO) db/db mice and high-fat high-sucrose (HFHS)-fed Fxr (also known as Nr1h4)-KO mice were treated with AGI. Metabolic phenotypes and BA signalling in different compartments, including the liver, gut and endocrine pancreas, were evaluated. BA pool profiles were analysed by mass spectrometry. The islet transcription profile was assayed by RNA sequencing. The gut microbiome were assayed by 16S ribosomal RNA gene sequencing. Results AGI lowered microbial BA levels in BA pools of different compartments in the body, and increased gut BA reabsorption in both db/db and HFHS-fed mouse models via altering the gut microbiome. The AGI-induced changes in BA signalling (including increased activation of farnesoid X receptor [FXR] in the liver and inhibition of FXR in the ileum) echoed the alterations in BA pool size and composition in different organs. In Fxr-KO mice, the glucose-and lipid-lowering effects of AGI were partially abrogated, possibly due to the Fxr-dependent effects of AGI on decelerating beta cell replication, alleviating insulin hypersecretion and improving hepatic lipid and glucose metabolism. Conclusions/interpretation By regulating microbial BA metabolism, AGI elicited diverse changes in BA pool composition in different host compartments to orchestrate BA signalling in the whole body. The AGI-induced changes in BA signalling may be partly required for its glucose-lowering effects. Our study, hence, sheds light on the promising potential of regulating microbial BA and host FXR signalling for the treatment of type 2 diabetes. Data availability Sequencing data are available from the BioProject Database (accession no. PRJNA600345; www.ncbi.nlm.nih. gov/bioproject/600345).

Depletion of gut microbiota induces skeletal muscle atrophy by FXR-FGF15/19 signalling

“…We found that both the concentration and proportion of TβMCA were significantly elevated in caecum and ileum of Abx mice ( Figure 3(J–M) ). In addition, the ratio of TβMCA/TCA, an indicator of FXR inactivation [ 34 ], was also increased after antibiotic treatment in ileum, although it was not significant different in caecum ( Figure 3(N,O) ). Thus, deleting gut microbiota was responsible for the alterations in microbial BA metabolism, particularly in accumulating the levels of FXR antagonist TβMCA.…”

“…BAs in caecum content, ileum, liver and colon were extracted using methanol containing internal standards and measured according to previously reported methods [ 34 ]. BAs in different tissues and BA synthesis marker 7-hydroxy-4-cholesten-3-one (C4) in plasma were analysed using ultra-performance liquid chromatography (UPLC)-triple quadrupole time-off-light mass spectrometry (Waters Corp) [ 34 , 39 ]. All the BAs standards and 7-hydroxy-4-cholesten-3-one (C4) standard were purchased from Sigma-Aldrich.…”

Effect of different bile acids on the intestine through enterohepatic circulation based on FXR

“…60 However, the pleiotropic downstream effects of FXR vary across BAs, and the metabolic effects of different BA receptors in different organs are also vary. 9 The strength of the natural activators of FXR follows the order of CDCA> DCA> CA> LCA, 57 and the natural inhibitors of FXR are tauro-α-MCA (T-α-MCA), tauroβ-MCA (T-β-MCA) and UDCA. [61][62][63] Notably, glycodeoxycholic acid (GCDCA), TCA and TDCA are weak activators of FXR.…”

“…[4][5][6] In 1999, BAs were discovered to be endogenous ligands of farnesoid X receptor (FXR), 7,8 which is widely expressed in the intestine, liver, and kidney. 9,10 BAs are generated in the liver and stored in the gallbladder. Postprandially, BAs are secreted into the intestine and metabolized by the intestinal flora.…”

Habitual Dietary Intake Affects the Altered Pattern of Gut Microbiome by Acarbose in Patients with Type 2 Diabetes

“…Gu et al reported that acarbose increased the abundance of Bifidobacterium and Lactobacillus , whereas the abundance of Bacteroides was decreased at the genus level; as a result, the abundance of microbial genes, which are associated with the bile acid metabolism, and plasma bile acid composition are altered. The association between the hypoglycemic effects of acarbose and bile acid signals was studied using genetically modified murine models [ 15 ]. Zhang et al also reported that acarbose contributed to the significant increase of Bifidobacterium and Lactobacillus at the genus level.…”