Gut microbiota dysbiosis in functional gastrointestinal disorders: Underpinning the symptoms and pathophysiology

Abstract

Functional gastrointestinal disorders (FGIDs), currently known as disorders of gut-brain interaction, are emerging microbiota-gut-brain abnormalities that are prevalent worldwide. The pathogenesis of FGIDs is heterogeneous and is intertwined with gut microbiota and its derived molecule-modulated mechanisms, including gut dysmotility, visceral hypersensitivity, gut immune abnormalities, abnormal secretion, and impaired barrier function. There has been phenomenal progress in understanding the role of gut microbiota in FGIDs by underpinning the species alternations between healthy and pathological conditions such as FGIDs. However, the precise gut microbiota-directed cellular and molecular pathogeneses of FGIDs are yet enigmatic. Determining the mechanistic link between the gut microbiota and gastrointestinal (GI) diseases has been difficult due to (i) the lack of robust animal models imitating the various aspects of human FGID pathophysiology; (ii) the absence of longitudinal human and/or animal studies to unveil the interaction of the gut microbiota with FGID-relevant pathogenesis; (iii) uncertainty about connections between human and animal studies; and (iv) insufficient data supporting a holistic view of disease-specific pathophysiological changes in FGID patients. These unidentified gaps open possibilities to explore pathological mechanisms directed through gut microbiota dysbiosis in FGIDs. The current treatment options for dysbiotic gut microbiota are limited; dietary interventions, antibiotics, probiotics, and fecal microbiota transplantation are the front-line clinical options. Here, we review the contribution of gut microbiota and its derived molecules in gut homeostasis and explore the possible pathophysiological mechanisms involved in FGIDs leading to potential therapeutics options.

Keywords: disorders of gut–brain interaction; fecal microbiota transplantation; gut immune dysfunction; impaired intestinal barrier function; visceral hypersensitivity.

Figure 1

Gut microbiota‐directed pathophysiological mechanisms of functional gastrointestinal disorders (FGIDs), currently known as disorders of gut–brain interaction. 5‐HTR, 5‐hydroxytryptamine receptor; BAs, bile acids; E‐cadherin, epithelial cadherin; GLP‐1R, glucagon‐like peptide‐1 receptor; ICCs, interstitial cells of Cajal; IPAN, intrinsic primary afferent neuron; NGF, nerve growth factor; PDGFRα, platelet‐derived growth factor receptor alpha; SCFAs, short‐chain fatty acids; SMCs, smooth muscle cells; TLRs, toll‐like receptors; TNF‐α, tumor necrosis factor‐alpha; TRPA1, transient receptor potential ankyrin 1; TRPV1, transient receptor potential cation channel subfamily V member 1; ZO, zonula occludens.

Figure 2

Pathophysiological mechanisms of functional gastrointestinal disorders (FGIDs), currently known as disorders of gut–brain interaction. BAs, bile acids; CH₄, methane; EC cell, enterochromaffin cell; H₂, hydrogen; H₂S, hydrogen sulfide; IBS‐C, constipation‐predominant irritable bowel syndrome; IBS‐D; diarrhea‐predominant irritable bowel syndrome; LGR5⁺, leucine‐rich repeat‐containing G‐protein coupled receptor 5; M cell, microfold cell; SCFAs, short‐chain fatty acids.