Bile acids are endocrine molecules that in addition to facilitating the absorption of fat-soluble nutrients regulate numerous metabolic processes, including glucose, lipid, and energy homeostasis. The signaling actions of bile acids are mediated through specific bile acid-activated nuclear and membrane bound receptors. The two major bile acid receptors that regulate host metabolism are the nuclear farnesoid X receptor (FXR) and the membrane-bound Takeda G protein-coupled receptor 5 (TGR5) and they are considered to have a large impact on the development of metabolic disorders. TGR5 is highly expressed in gallbladder, spleen, intestine, liver, placenta, lung, brown and white adipose tissue, skeletal muscle, and bone marrow. TGR5, in contrast to FXR, is activated by secondary bile acids (LCA and DCA) that are formed from primary bile acids (CDCA and CA) by gut microbiota-dependent deconjugation and dihydroxylation reactions. TGR5 is especially expressed in muscle and brown adipose tissue (BAT) where it promotes the conversion of inactive thyroxine into active thyroid hormone which induces thermogenesis and increased energy expenditure. TGR5 activation in intestinal L-cells promotes the secretion of GLP-1. INT-777, which is a derivative of CDCA and a specific TGR5 agonist, ameliorates hepatic steatosis and adiposity and improves insulin sensitivity in mice with high-fat diet-induced obesity. Of note, FXR and TGR5 seem to have opposite effects on GLP-1 signalling. Thus, when providing natural bile acids that are agonists for FXR the gut microbial metabolism may generate ligands for TGR5, which may result in unpredictable treatment responses. Rapid metabolic improvement after bariatric surgery is associated with changes in bile acid profiles. These are positively correlated with a number of metabolically active peptides, including adiponectin, peptide YY and in particular, GLP-1, which could be attributed to increased secondary bile acid mediated activation of TGR5. Vertical sleeve gastrectomy (VSG) is a major bariatric surgery procedure that nowadays is performed in about half of the patients with morbid obesity. Studies on VSG in TGR5-deficient mice showed that TGR5 is fundamental for the beneficial effect of VSG in terms of improved glucose metabolism, insulin signaling and fat accumulation in the liver, while data on postoperative body weight reduction are controversial. Studies in conventional, germ-free and gnotobiotic mice lacking either the FXR or TGR5 receptors may help to decipher the interplay between bile acids and microbiota aiming to find specific microbiota that improve metabolism by specifically activating either bile acid receptor.