Role of gut microbiota, bile acids and their cross-talk in the effects of bariatric surgery on obesity and type 2 diabetes

Abstract

Type 2 diabetes mellitus is becoming increasingly prevalent worldwide, and has become one of the greatest threats to global health. Bariatric surgery was initially designed to achieve weight loss, and subsequently was noted to induce improvements or remission of type 2 diabetes. Currently, these bariatric operations, such as Roux-en-Y gastric bypass and sleeve gastrectomy, are the most effective procedures for the treatment of obesity and type 2 diabetes mellitus worldwide. However, the specific mechanism mediating the beneficial effects of metabolic surgery has remained largely unknown. Those mechanical explanations, such as restriction and malabsorption, are challenged by accumulating evidence from human and animal models of these procedures, which points to the weight-independent factors, such as hormones, bile acids, gut microbiota, nervous system and other potential underlying mechanisms. A growing body of evidence suggests that gut microbiota are associated with the development of several metabolic disorders, and bile acids and FXR signaling are important for the metabolic benefits of bariatric surgery. Given the close relationship between bacteria and bile acids, it is reasonable to propose that microbiota-bile acid interactions play a role in the mechanisms underlying the effects of metabolic surgery.

Keywords: Bariatric surgery; Bile acids; Gut microbiota.

Figure 1

Bile acid biosynthesis, enterohepatic circulation and potential functions through receptors in the ileum. Bile acids (BAs) are synthesized from cholesterol in the liver with the rate‐limiting enzyme 7α‐hydroxylase (CYP7A1), conjugated to taurine or glycine, secreted into the bile, discharged into the duodenum then efficiently (i.e., >95%) reabsorbed in the terminal ileum and the colon. The molecules are then further recirculated to the liver through portal vein blood. This process is known as enterohepatic circulation. In the ileum, bile acids facilitate the secretion of fibroblast growth factor 19 (FGF19; known as FGF15 in mice), which circulates to the liver and reduces the expression of CYP7A1 to inhibit hepatic bile acid synthesis through the farnesoid X receptor (FXR), and stimulates the excretion of peptide YY (PYY), glucagon‐like peptide 1 (GLP‐1) and glucagon‐like peptide 2 (GLP‐2) through a G protein‐coupled receptor (TGR5). Primary bile acids are modified by intestinal microbiota, including transformation into secondary bile acids in the colon. FGF19 binds to FGFR4 to activate c‐Jun N‐terminal kinase/extracellular signal‐regulated kinase (JNK/ERK) signaling that inhibits expression of CYP7A1. FGFR4, fibroblast growth factor receptor 4.

Figure 2

The relationship between the effects of bariatric surgery on the composition of bile acids and the gut microbiota. Bariatric surgery impacts bile acid enterohepatic circulation and increases bile acid levels, which might contribute to the metabolic effects after operations through signaling pathways. Furthermore, it also can change the pattern of intestinal microbiota, which can produce short‐chain fatty acids, such as butyrate and propionate, and improve metabolic regulation. Gut microbiota plays a key role in modulating bile acids, including their biosynthesis and biotransformation. Conversely, bile acids can directly inhibit bacterial growth as a detergent, and can indirectly regulate the composition of gut microbes through signaling pathways. FGF19 (known as FGF15 in mice), fibroblast growth factor 19; FXR, farnesoid X receptor; GLP‐1, glucagon‐like peptide 1; GLP‐2, glucagon‐like peptide 2; PYY, peptide YY; TGR5, a G protein‐coupled receptor.