Diammonium Glycyrrhizinate Ameliorates Obesity Through Modulation of Gut Microbiota-Conjugated BAs-FXR Signaling

Abstract

Obesity is a worldwide epidemic metabolic disease. Gut microbiota dysbiosis and bile acids (BAs) metabolism disorder are closely related to obesity. Farnesoid X-activated receptor (FXR), served as a link between gut microbiota and BAs, is involved in maintaining metabolic homeostasis and regulating glucose and lipid metabolism. We previously reported that diammonium glycyrrhizinate (DG) could alter gut microbiota and prevent non-alcoholic fatty liver disease. However, it remains ambiguous how DG affects the gut microbiota to regulate host metabolism. In this present study, 16S rRNA Illumina NovaSeq and metabolomic analysis revealed that DG treatment suppressed microbes associated with bile-salt hydrolase (BSH) activity, which, in turn, increased the levels of taurine-conjugated BAs accompanied by inhibition of ileal FXR-FGF15 signaling. As a result, several obesity-related metabolism were improved, like lower serum glucose and insulin levels, increased insulin sensitivity, few hepatic steatosis and resistance to weight gain. Additionally, decreased level of serum lipopolysaccharide was observed, which contributed to a strengthened intestinal barrier. The effect of DG on weight loss was slightly enhanced in the antibiotics-treated obese mice. Collectively, the efficacy of DG in the treatment of obesity might depend on gut microbiota-conjugated BAs-FXR axis. Hence, it will provide a potential novel approach for the treatment of obesity.

Farnesoid X Receptor, Bile Acid Metabolism, and Gut Microbiota

“…However, this hypothesis is in contrast with the assumption of FXR activation being beneficial during NAFLD [ 69 ]. Thus, intestinal FXR antagonists are considered for the treatment of metabolic diseases: the glycine-beta-muricholic acid (namely, a tauro-beta-muricholic acid derivative) is used in experimental models of NAFLD, producing a reduction in obesity, insulin resistance, and liver fibrosis/inflammation grading [ 70 , 71 , 72 ].…”

Gut Microbiota and Sex Hormones: Crosstalking Players in Cardiometabolic and Cardiovascular Disease

“…PBAs appear to play a role in preventing the development of atherosclerosis through activation of the farnesoid X receptor (FXR) signaling cascade, which improves lipid profile and regulates gluconeogenesis and intestinal barrier function [14]. In addition, PBAs inhibit the NF-kB-dependent activation of Takeda-G protein 5 receptors (TGR5), resulting in a decreased production of proinflammatory cytokines [10,15].…”

Glycyrrhizic Acid and Its Derivatives: Promising Candidates for the Management of Type 2 Diabetes Mellitus and Its Complications

“…At a later stage, the pancreatic β-cells cannot compensate for the high demand of insulin; therefore, this eventually leads to β-cell dysfunction and defect in insulin secretion, and hyperglycemia occurs [ 58 ]. Studies have shown that GL, GA, and DG could improve insulin sensitivity in diabetic rodents [ 28 , 30 , 31 , 33 , 54 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ].…”

“…Moreover, it also reduced the adipocyte size and area in the subcutaneous WAT of rats [ 65 , 68 ]. Similarly, GL and DG could reduce the weights of WAT in HFD-induced obese rodents [ 30 , 61 ]. Furthermore, peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor, which is highly expressed in adipose tissue [ 76 ].…”