Mechanisms Underlying Food-Triggered Symptoms in Disorders of Gut-Brain Interactions

Abstract

There has been a dramatic increase in clinical studies examining the relationship between disorders of gut-brain interactions and symptoms evoked by food ingestion in the upper and lower gastrointestinal tract, but study design is challenging to verify valid endpoints. Consequently, mechanistic studies demonstrating biological relevance, biomarkers and novel therapeutic targets are greatly needed. This review highlights emerging mechanisms related to nutrient sensing and tasting, maldigestion, physical effects with underlying visceral hypersensitivity, allergy and immune mechanisms, food-microbiota interactions and gut-brain signaling, with a focus on patients with functional dyspepsia and irritable bowel syndrome. Many patients suffering from disorders of gut-brain interactions exhibit these mechanism(s) but which ones and which specific properties may vary widely from patient to patient. Thus, in addition to identifying these mechanisms and the need for further studies, biomarkers and novel therapeutic targets are identified that could enable enriched patient groups to be studied in future clinical trials examining the role of food in the generation of gut and non-gut symptoms.

Figure 1.

Sequence of physiological events related to the presence and sensing of nutrients in the gastrointestinal tract. Potential sites of upregulation or sensitization leading to visceral hypersensitivity are indicated by red stars. Created with BioRender.com. CNS, central nervous system.

Figure 2.

Hypothetical mechanisms involved in allergy-like reactions to food in the gastrointestinal tract in disorders of gut-brain interactions (DGBIs), as hypothesized for food reactions mainly in irritable bowel syndrome (IBS) and functional dyspepsia (FD). Increased mucosal permeability is proposed as an underlying alteration, allowing food proteins in the lumen to activate mast cells and/or eosinophils in DGBI patients. The latter may lead to release of cytokines and other signaling molecules in the circulation, recruitment of inflammatory cells and altered neural (e.g., through eosinophil-derived neurotoxin) and hormonal control of gastrointestinal sensorimotor function, triggering nutrient-induced symptoms. The mechanism through which food proteins activate mast cells or eosinophils in DGBIs remains to be established. Proposed pathways involve locally produced immunoglobulin E (IgE) acting on the FceR receptor, immunoglobulin G (IgG) acting on the FcgR receptor or non-Ig mediated activation of mast cells through pattern recognition receptors (PRRs) or the mas-related G-protein coupled receptor X2 (MRGPRX2). Mast cells can also be activated by corticotrophin releasing hormone (CRH). The submucosal inflammatory cells can be inactivated through sialic acid-binding immunoglobulin-type lectin (SIGLEC) receptors. Further studies will be required to identify the contribution of these putative pathways in (subgroups of) specific DGBIs.

Figure 3.

Food evokes and amplifies visceral hypersensitivity via mast cell dependent (1) and mast cell-independent pathways (2). Ingestion of high FODMAP foods (and other poorly absorbed sugars) leads to bacterial fermentation predominantly in the colon, producing gas and osmotically active metabolites that can distend the colon and amplify pre-existing visceral hypersensitivity. Specific bacteria also produce neuroactive mediators that evoke or amplify visceral hypersensitivity via mast cell dependent and independent pathways. Intermediary cells (e.g., enterocytes, enteroendocrine cells or other immune cells) may also contribute to either pathway. Re-exposure to food antigens following loss of oral tolerance caused by an acute self-limiting infectious colitis or psychological stress could also lead to IgE-dependent mast cell activation and visceral hypersensitivity. 5-HT, 5-hydroxytryptamine; FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides and polyols; LPS, lipopolysaccharide.

Figure 4.

A hypothetical central mechanism to explain different responses to meals in healthy individuals and patients with functional gastrointestinal disorders. Gastrointestinal tract communicates with the brain through neural, immune and hormonal pathways, and the microbiota plays a key role in this gut-brain axis. While in healthy subjects, meal induced distension activates “default mode network” in the midbrain, in patients the gut distension activates pain-responsive regions.