Gut Microbiota and Short Chain Fatty Acids: Implications in Glucose Homeostasis

Abstract

Gut microbiota encompasses a wide variety of commensal microorganisms consisting of trillions of bacteria, fungi, and viruses. This microbial population coexists in symbiosis with the host, and related metabolites have profound effects on human health. In this respect, gut microbiota plays a pivotal role in the regulation of metabolic, endocrine, and immune functions. Bacterial metabolites include the short chain fatty acids (SCFAs) acetate (C2), propionate (C3), and butyrate (C4), which are the most abundant SCFAs in the human body and the most abundant anions in the colon. SCFAs are made from fermentation of dietary fiber and resistant starch in the gut. They modulate several metabolic pathways and are involved in obesity, insulin resistance, and type 2 diabetes. Thus, diet might influence gut microbiota composition and activity, SCFAs production, and metabolic effects. In this narrative review, we discuss the relevant research focusing on the relationship between gut microbiota, SCFAs, and glucose metabolism.

Keywords: bacteria; diet; fiber; glucose homeostasis; intestine; metabolome.

Figure 1

Pathways involved in the biosynthesis of SCFAs from dietary fiber and carbohydrate fermentation by the colonic microbiota. The three major SCFAs are: (1) acetate which originates via the Wood–Ljungdahl pathway or acetyl-CoA; (2) butyrate synthesized from two molecules of acetyl-CoA; (3) propionate from PEP involving the acrylate pathway or the succinate pathway or the propanediol pathway after microbial transformation of fucose and rhamnose. Abbreviations: PEP—phosphoenolpyruvate; DHAP—dihydroxyacetone phosphate. Adapted from Kho et al. [31].

Figure 2

Chemical formula, molecular weight, and 3D structure of the three main short chain fatty acids acetate (C2), propionate (C3), and butyrate (C4). In the 3D structure, atoms appear as hydrogen in white color, carbon as grey color, and oxygen as red color. https://pubchem.ncbi.nlm.nih.gov/ (accessed 18 January 2022).

Figure 3

Interplay between the microbiota-accessible carbohydrates (MACs), the gut microbiota, the production short chain fatty acids (SCFAs), and the enterocytes (mainly colonocytes). The main pathways involved are summarized in the two enterocytes. (1) Following initial digestion and intestinal transit, the dietary MACs meet the gut microbiota, which is characterized by high and physiological diversity and no bacterial overgrowth. (2) SCFA-producing bacteria, mainly in the colon, will digest MACs and increase the luminal content of SCFAs. (3) In this environment, the abundance of A. muciniphila increases and is associated with protective effects on mucin and tight junction integrity. (4) In addition, a diet enriched in MACs will positively stimulate the immune system, leading to plasma cell-mediated production of immunoglobulins A (IgA) with further control on microbiota function, diversity, and prevention of overgrowth. (5) In the colonocyte, SCFAs are absorbed by colonocytes via passive diffusion or via active transport mediated by H+-dependent monocarboxylate transporters (MCTs). (6) The SCFAs acetate, butyrate, and propionate are converted to acetyl-CoA or propynyl-CoA by pathways involving the acetyl-CoA carboxylases (ACSSs) and beta oxidation. (7) This step produces ATP, which contributes to the maintenance of cell homeostasis, including the function of tight junctions. (8) Via stimulation of receptors at the apical membrane, SCFAs promote the secretion of gut hormones, such as glucagon-like peptide 1 (GLP1) and peptide YY (PYY), γ-aminobutyric acid (GABA), and serotonin (5-HT). At this level, butyrate inhibits (-) histone deacetylases (HDACs) with consequent anti-inflammatory effect by reducing NF-κB-induced pro-inflammatory mediators, such as TNF-α, IL-6, IL-12, and iNOS [43]. (9) Intracellular SCFAs contribute to inhibition (-) of HDAC. Acetate activates the inflammasome nucleotide-binding oligomerization domain 3 (NLRP3) with secretion of the protective IL-18 from epithelial cells, which maintains the tight junction’s function. (10) Colon-derived SCFAs reach the systemic circulation promoting anti-inflammatory and immunomodulatory effects as well as increasing insulin secretion, maintaining energy homeostasis, and improving liver and brain function.

Figure 4

Glucose metabolism is influenced by short chain fatty acids (SCFAs), systemically, at various levels [120]. Main target organs include adipocytes, liver, pancreas, skeletal muscle, intestine, and brain where pathways govern mechanisms, which include receptors, synthesis, hormones, and perception. Abbreviations: GLP-1—glucagon-like peptide-1; GLUT-4—activated glucose transporter protein-4; GPR—G-protein-coupled receptors; PYY—peptide YY; A—acetate; P—propionate; B—butyrate.