Bile acids as a key target: traditional Chinese medicine for precision management of insulin resistance in type 2 diabetes mellitus through the gut microbiota-bile acids axis

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease caused by insulin resistance (IR) and insufficient insulin secretion. Its characteristic pathophysiological processes involve the interaction of multiple mechanisms. In recent years, globally, the prevalence of T2DM has shown a sharp rise due to profound changes in socio-economic structure, the persistent influence of environmental factors, and the complex role of genetic background. It is worth noting that most T2DM patients show significant IR, which further exacerbates the difficulty of disease progression and prevention. In the process of extensively exploring the pathogenesis of T2DM, the dynamic equilibrium of gut microbes and its diverse metabolic activities have increasingly emphasized its central role in the pathophysiological process of T2DM. Bile acids (BAs) metabolism, as a crucial link between gut microbes and the development of T2DM, not only precisely regulates lipid absorption and metabolism but also profoundly influences glucose homeostasis and energy balance through intricate signaling pathways, thus playing a pivotal role in IR progression in T2DM. This review aims to delve into the specific mechanism through which BAs contribute to the development of IR in T2DM, especially emphasizing how gut microbes mediate the metabolic transformation of BAs based on current traditional Chinese medicine research. Ultimately, it seeks to offer new insights into the prevention and treatment of T2DM. Diet, genetics, and the environment intricately sculpt the gut microbiota and BAs metabolism, influencing T2DM-IR. The research has illuminated the significant impact of single herbal medicine, TCM formulae, and external therapeutic methods such as electroacupuncture on the BAs pool through perturbations in gut microbiota structure. This interaction affects glucose and lipid metabolism as well as insulin sensitivity. Additionally, multiple pathways including BA-FXR-SHP, BA-FXR-FGFR15/19, BA-FXR-NLRP3, BA-TGR5-GLP-1, BAs-TGR5/FXR signaling pathways have been identified through which the BAs pool significantly alter blood glucose levels and improve IR. These findings offer novel approaches for enhancing IR and managing metabolic disorders among patients with T2DM.

Keywords: bile acids; insulin resistance; the gut-liver axis; traditional Chinese medicine; type 2 diabetes mellitus.

Figure 1

The synthesis and metabolic cycle of bile acids (BAs) involve the liver, intestine, and gut microbiota. BAs are synthesized in hepatocytes via the classic pathway and the alternative pathway, and are primarily conjugated with glycine and taurine before being transported to the bile duct by transporters such as bile salt export pump (BSEP). They are stored in the gallbladder and further transformed by gut microbiota into secondary bile acids like lithocholic acid (LCA), deoxycholic acid (DCA), and ursodeoxycholic acid (UDCA), increasing their diversity and complexity. Most bile acids are reabsorbed through passive diffusion or active transport via apical sodium-dependent bile acid transporter (ASBT) in the ileum, entering the portal circulation through the heterodimeric organic solute transporter (OSTα/β), and then transported back to hepatocytes by Sodium/taurocholic acid cotransport polypeptide (NTCP) and organic anion transporting polypeptide (OATP), completing the enterohepatic circulation. Unabsorbed bile acids are excreted in feces and urine.

Figure 2

Relevance of gut microbiota-mediated BAs metabolism in the development of IR in individuals with type 2 diabetes mellitus(By Figdraw). Patients with type 2 diabetes mellitus often exhibit intestinal inflammation, resulting in increased intestinal permeability that allows bacterial lipopolysaccharides and BAs to directly enter the liver through the portal vein. Within the intestinal microecosystem, a series of biochemical processes such as uncoupling, dehydrogenation, dehydroxylation, and differential isomerization convert BAs into secondary BAs. As the primary organ responsible for BAs synthesis and metabolism, the liver may alter its synthesis and secretion under inflammatory stimulation, thereby influencing the metabolic balance of BAs. Disordered BAs metabolism can lead to elevated glucose levels and IR, further exacerbating pathological progression.

Figure 3

The molecular mechanism of BAs receptors ameliorate T2DM-IR.(By Figdraw)FXR and TGR5 are key BAs receptors that are highly expressed in tissues such as the liver and intestine, responding to bile acid pool composition and inhibiting inflammation, helping to prevent insulin resistance. These metabolites can act on the gut and liver through different signaling pathways, thus triggering different physiological and biochemical reactions.