The metabolic impact of small intestinal nutrient sensing

Abstract

The gastrointestinal tract maintains energy and glucose homeostasis, in part through nutrient-sensing and subsequent signaling to the brain and other tissues. In this review, we highlight the role of small intestinal nutrient-sensing in metabolic homeostasis, and link high-fat feeding, obesity, and diabetes with perturbations in these gut-brain signaling pathways. We identify how lipids, carbohydrates, and proteins, initiate gut peptide release from the enteroendocrine cells through small intestinal sensing pathways, and how these peptides regulate food intake, glucose tolerance, and hepatic glucose production. Lastly, we highlight how the gut microbiota impact small intestinal nutrient-sensing in normal physiology, and in disease, pharmacological and surgical settings. Emerging evidence indicates that the molecular mechanisms of small intestinal nutrient sensing in metabolic homeostasis have physiological and pathological impact as well as therapeutic potential in obesity and diabetes.

Fig. 1. An integrated hormonal-dependent metabolic network that is activated by small intestinal nutrient sensing.

Glucose, lipids, and protein from ingested foods are taken up by small intestinal enterocytes for cellular metabolism and absorption. Preabsorptive nutrients also activate enteroendocrine cells, triggering the release of GLP-1 and CCK. CCK and GLP-1 enter the circulation and act directly on peripheral organs to regulate metabolism. In parallel, CCK and GLP-1 act on the vagus nerve innervating the small intestine or portal vein as well as interact with the enteric nervous system to regulate glucose and energy homeostasis. In this context, the central nervous system can receive neuronal and/or direct hormonal signals to regulate feeding and maintain plasma glucose levels.

Fig. 2. Mechanisms of small intestinal nutrient sensing.

a Mechanisms of small intestinal lipid sensing. Small intestinal long-chain fatty acids are taken up (via CD36/FATP4 and/or simple diffusion) by enterocytes to form triglycerides and eventually packaged into chylomicrons released on the basolateral side. LCFA are also taken up by enteroendocrine cells to undergo ACSL3-dependent metabolism and activate PKCs to potentially stimulate CCK and/or GLP-1 release. Luminal LCFA may activate GPR40/120 to stimulate peptide release. The hydrolysis of chylomicrons by nearby enterocytes on the basolateral membrane may lead to increased LCFAs that can activate basolateral GPR40 to induce peptide release. In the setting of a high-fat diet or obesity, GPRs/ACSL3 expression, the release of GLP-1/CCK, and CCK signaling are reduced, leading to a disruption of fatty acid sensing. b Mechanisms of small intestinal carbohydrate sensing. Luminal glucose and fructose are transported into upper small intestinal enterocytes and/or enteroendocrine cells via SGLT1 and GLUT5, respectively. Through SGLT1, glucose directly and/or indirectly (via cellular metabolism) stimulates the release of gut peptides and regulates feeding and systemic glucose control in the upper small intestine. However, ileal glucose sensing may stimulate the release of GLP-1 independent of SGLT1. In response to high-fat feeding or obesity, small intestinal SGLT1 expression is reduced, leading to an impairment of glucose sensing, GLP-1 secretion, and glucose control. c Mechanisms of small intestinal protein sensing. Luminal small oligopeptides and amino acids are taken up by PepT1 and amino acid transporters, respectively, into the enterocyte and enteroendocrine cells. Small intestinal protein sensing stimulates the release of CCK and GLP-1 and regulates feeding and glucose homeostasis potentially via PepT1 dependent mechanisms. In addition, amino acids stimulate peptide release via the membrane-bound calcium-sensing receptor, the umami taste receptor, and G-protein-coupled receptor 6A. However, the downstream mechanism mediating the peptide release remains elusive. In parallel, amino acids are also transported to the basolateral side, and studies implicated that they may activate the calcium-sensing receptor to stimulate GLP-1 secretion.

Fig. 3. Interaction of gut microbiota and small intestinal nutrient sensing.

We put forward a working hypothesis for the mechanistic links between small intestinal nutrient-sensing, microbiota, peptide release, and metabolic regulation. (From Left to Right of the Schematic): Bacterial species can directly and/or indirectly impact epithelial GPRs to alter GLP1 expression and release. Bacterial by-products such as LPS can impair lipid and glucose sensing and potentially disrupt ACSL3 and SGLT1 dependent pathways that regulate glucose and energy homeostasis. Bile salt hydrolase of bacteria contributes to the bile acid pool and regulates bile acid metabolism. As a result, changes in bile acids can alter GLP-1 release and metabolic regulation via intestinal FXR and TGR5 signaling. High-fat feeding reduces the abundance of small intestinal Lactobacillus species (e.g., L. gasseri) and consequently inhibits ACSL3 expression and impairs lipid sensing. Lastly, metformin increases the abundance of upper small intestinal Lactobacillus and enhances SGLT1 expression and glucose sensing, while also reducing the abundance of Bacteroides fragilis that results in ileal FXR inhibition and improvement in glucose metabolism. Bariatric surgery enhances small intestinal nutrient sensing mechanisms and consequently lowers glucose levels, while changes in bile acid metabolism and FXR are necessary for the glucose-lowering effect of bariatric surgery.