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Glycoursodeoxycholic acid regulates bile acids level and alters gut microbiota and glycolipid metabolism to attenuate diabetes.

ABSTRACT: Accumulating evidence suggests that the bile acid regulates type 2 diabetes mellitus (T2DM) through gut microbiota-host interactions. However, the mechanisms underlying such interactions have been unclear. Here, we found that glycoursodeoxycholic acid (GUDCA) positively regulates gut microbiota by altering bile acid metabolism. GUDCA in mice resulted in higher taurolithocholic acid (TLCA) level and Bacteroides vulgatus abundance. Together, these changes resulted in the activation of the adipose G-protein-coupled bile acid receptor, GPBAR1 (TGR5) and upregulated expression of uncoupling protein UCP-1, resulting in elevation of white adipose tissue thermogenesis. The anti-T2DM effects of GUDCA are linked with the regulation of the bile acid and gut microbiota composition. This study suggests that altering bile acid metabolism, modifying the gut microbiota may be of value for the treatment of T2DM.

SUBMITTER: Chen B

PROVIDER: S-EPMC10054359 | biostudies-literature | 2023 Jan-Dec

REPOSITORIES: biostudies-literature

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Glycoursodeoxycholic acid regulates bile acids level and alters gut microbiota and glycolipid metabolism to attenuate diabetes.

Chen Bingting B Bai Yu Y Tong Fenglian F Yan Junlin J Zhang Rui R Zhong Yewei Y Tan Huiwen H Ma Xiaoli X

Gut microbes 20230101 1

Accumulating evidence suggests that the bile acid regulates type 2 diabetes mellitus (T2DM) through gut microbiota-host interactions. However, the mechanisms underlying such interactions have been unclear. Here, we found that glycoursodeoxycholic acid (GUDCA) positively regulates gut microbiota by altering bile acid metabolism. GUDCA in mice resulted in higher taurolithocholic acid (TLCA) level and <i>Bacteroides vulgatus</i> abundance. Together, these changes resulted in the activation of the a ...[more]

PMID: 36967529

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Project description:BackgroundBerberine (BBR) is a plant-based nutraceutical that has been used for millennia to treat diarrheal infections and in contemporary medicine to improve patient lipid profiles. Reduction in lipids, particularly cholesterol, is achieved partly through up-regulation of bile acid synthesis and excretion into the gastrointestinal tract (GI). The efficacy of BBR is also thought to be dependent on structural and functional alterations of the gut microbiome. However, knowledge of the effects of BBR on gut microbiome communities is currently lacking. Distinguishing indirect effects of BBR on bacteria through altered bile acid profiles is particularly important in understanding how dietary nutraceuticals alter the microbiome.ResultsGermfree mice were colonized with a defined minimal gut bacterial consortium capable of functional bile acid metabolism (Bacteroides vulgatus, Bacteroides uniformis, Parabacteroides distasonis, Bilophila wadsworthia, Clostridium hylemonae, Clostridium hiranonis, Blautia producta; B4PC2). Multi-omics (bile acid metabolomics, 16S rDNA sequencing, cecal metatranscriptomics) were performed in order to provide a simple in vivo model from which to identify network-based correlations between bile acids and bacterial transcripts in the presence and absence of dietary BBR. Significant alterations in network topology and connectivity in function were observed, despite similarity in gut microbial alpha diversity (P = 0.30) and beta-diversity (P = 0.123) between control and BBR treatment. BBR increased cecal bile acid concentrations, (P < 0.05), most notably deoxycholic acid (DCA) (P < 0.001). Overall, analysis of transcriptomes and correlation networks indicates both bacterial species-specific responses to BBR, as well as functional commonalities among species, such as up-regulation of Na+/H+ antiporter, cell wall synthesis/repair, carbohydrate metabolism and amino acid metabolism. Bile acid concentrations in the GI tract increased significantly during BBR treatment and developed extensive correlation networks with expressed genes in the B4PC2 community.ConclusionsThis work has important implications for interpreting the effects of BBR on structure and function of the complex gut microbiome, which may lead to targeted pharmaceutical interventions aimed to achieve the positive physiological effects previously observed with BBR supplementation.

Project description:ObjectiveTo examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism.DesignTo study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of MyD88. We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH).ResultsHepatocyte-specific deletion of MyD88 predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of MyD88 in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis.ConclusionsOur study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans.

Dataset Information

Glycoursodeoxycholic acid regulates bile acids level and alters gut microbiota and glycolipid metabolism to attenuate diabetes.

Publications

Glycoursodeoxycholic acid regulates bile acids level and alters gut microbiota and glycolipid metabolism to attenuate diabetes.

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