Molecular Mechanisms of Microbiota-Mediated Pathology in Irritable Bowel Syndrome

Abstract

Irritable bowel syndrome (IBS) is one of the most prevalent functional gastrointestinal disorders, and accumulating evidence gained in both preclinical and clinical studies indicate the involvement of enteric microbiota in its pathogenesis. Gut resident microbiota appear to influence brain activity through the enteric nervous system, while their composition and function are affected by the central nervous system. Based on these results, the term "brain-gut-microbiome axis" has been proposed and enteric microbiota have become a potential therapeutic target in IBS cases. However, details regarding the microbe-related pathophysiology of IBS remain elusive. This review summarizes the existing knowledge of molecular mechanisms in the pathogenesis of IBS as well as recent progress related to microbiome-derived neurotransmitters, compounds, metabolites, neuroendocrine factors, and enzymes.

Keywords: PI-IBS; SIBO; bile acids; histamine; serotonin; short-chain fatty acids.

Figure 1

Overview of pathogenesis related to IBS. IBS is a multifactorial disorder affected by various genetic and environmental factors. Altered diet, aberrant usage of antibiotics, or exposure to severe enterocolitis induce gut dysbiosis, resulting in mucosal immune activation and low-grade inflammation, as well as gut barrier dysfunction through increased epithelial permeability. These pathways along with psychological factors influence the brain-gut-microbiome axis, which is mediated by aberrant neuroendocrine factors, transmitters, and metabolites, resulting in altered gut motility and visceral hypersensitivity. Chronic status of such gut dysfunctions shapes IBS symptoms including abnormal bowel movements and visceral pain. TLR, Toll-like receptor; CRH/HPA, corticotropin-releasing hormone/hypothalamic-pituitary-adrenal axis; ENS, enteric nervous system; CNS, central nervous system.

Figure 2

Mechanisms of dysbiosis-mediated intestinal dysfunction in IBS. In dysbiosis related to IBS, both the quality and quantity of microbial metabolites (BA, SCFAs, Vit D, B6, Trp-related), neurotransmitters (His, Glu, GABA, NA, DA, ACh), compounds (TLR ligands), neuroendocrine factors (GLP-1, PYY), and protases are significantly altered as compared with those in a healthy condition. In addition, activated 5-HT with weakened Ind and Kyn signaling can be observed in the Trp pathway. These alternations potentially increase mucosal permeability, while microbial products (TLR ligands, etc.) or antigens can easily penetrate into sub-mucosal areas and stimulate immune cells, thus inducing low-grade inflammation. Prolonged mucosal inflammation and some microbial products directly or indirectly influence ENS and CNS functions through CRH/HPA, GI motility alteration, and hypersensitivity as part of the pathogenesis of IBS. BA, bile acids; SCFA, short-chain fatty acids; Vit, vitamin; Trp, tryptophan; QS, quorum sensing; 5-HT, 5-hydroxytryptamine; Ind, indole; Kyn, kynurenine; His, histamine; Glu, glutamine; GABA, γ-aminobutyric acid; NA, noradrenaline; DA, dopamine; Ach, acetylcholine; GLP-1, glucagon-like peptide-1; PYY, Peptide YY; AhR, aryl hydrocarbon receptor; PARs, protease activated receptors; TJ, tight junction; TLRs, toll-like receptors; EC cells, enterochromaffin cells; CRH/HPA, corticotropin-releasing hormone/hypothalamic-pituitary-adrenal axis; ENS; enteric nervous system; CNS; central nervous system.