Mechanisms controlling hormone secretion in human gut and its relevance to metabolism

Abstract

The homoeostatic regulation of metabolism is highly complex and involves multiple inputs from both the nervous and endocrine systems. The gut is the largest endocrine organ in our body and synthesises and secretes over 20 different hormones from enteroendocrine cells that are dispersed throughout the gut epithelium. These hormones include GLP-1, PYY, GIP, serotonin, and CCK, each of whom play pivotal roles in maintaining energy balance and glucose homeostasis. Some are now the basis of several clinically used glucose-lowering and weight loss therapies. The environment in which these enteroendocrine cells exist is also complex, as they are exposed to numerous physiological inputs including ingested nutrients, circulating factors and metabolites produced from neighbouring gut microbiome. In this review, we examine the diverse means by which gut-derived hormones carry out their metabolic functions through their interactions with different metabolically important organs including the liver, pancreas, adipose tissue and brain. Furthermore, we discuss how nutrients and microbial metabolites affect gut hormone secretion and the mechanisms underlying these interactions.

Figure 1

The role of gut hormones in metabolically important organs. Gut hormones are implicated in the regulation in glucose homeostasis through their differential actions on the liver and endocrine pancreas. They also play important roles in maintaining energy balance by modulating nutrient absorption, mobilization of fat stores from adipose tissue and appetite regulation. 5-HT, serotonin; CCK, cholecystokinin; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide 1; INSL5, insulin-like peptide 5; PYY, peptide YY; OXM, oxyntomodulin; BAT, brown adipose tissue; WAT, white adipose tissue.

Figure 2

Activation of enteroendocrine (EE) cells. Carbohydrates in the gut lumen such as simple sugars are sensed by sodium-glucose transporters (SGLTs), glucose transporters (GLUTs) and sweet taste receptors (T1R2/3). Lipids are sensed basolaterally, with medium- and long-chain fatty acids activating free fatty acid receptors (FFARs) 1 and 4 and lipid amides activating G-protein receptor 119 (GPR119). EE cell secretion is also differentially regulated by individual bile acids, which signal through the GPCR, Takeda G-protein receptor 5 (TGR5) on the basolateral membrane and through the nuclear receptor, Farnesoid X receptor (FXR). Short-chain fatty acids (SCFAs) derived from bacterial fermentation of indigestible polysaccharides, also influence EE cell secretion through activating FFARs 2 and 3 and inhibiting histone deacetylases (HDACs).