Understanding neuroimmune interactions in disorders of gut-brain interaction: from functional to immune-mediated disorders

Abstract

Functional gastrointestinal disorders-recently renamed into disorders of gut-brain interaction-such as irritable bowel syndrome and functional dyspepsia are highly prevalent conditions with bothersome abdominal symptoms in the absence of structural abnormalities. While traditionally considered as motility disorders or even psychosomatic conditions, our understanding of the pathophysiology has evolved significantly over the last two decades. Initial observations of subtle mucosal infiltration with immune cells, especially mast cells and eosinophils, are since recently being backed up by mechanistic evidence demonstrating increased release of nociceptive mediators by immune cells and the intestinal epithelium. These mediators can activate sensitised neurons leading to visceral hypersensitivity with bothersome symptoms. The interaction between immune activation and an impaired barrier function of the gut is most likely a bidirectional one with alterations in the microbiota, psychological stress and food components as upstream players in the pathophysiology. Only few immune-targeting treatments are currently available, but an improved understanding through a multidisciplinary scientific approach will hopefully identify novel, more precise treatment targets with ultimately better outcomes.

Keywords: FUNCTIONAL BOWEL DISORDER; FUNCTIONAL DYSPEPSIA; INTESTINAL MAST CELLS; IRRITABLE BOWEL SYNDROME; Intestinal eosinophils.

Figure 1

Rome IV criteria of functional dyspepsia and irritable bowel syndrome. EPS, epigastric pain syndrome; PDS, postprandial distress syndrome.

Figure 2

Pathophysiological mechanisms in disorders of gut–brain interaction.

Figure 3

Neuronal mechanisms of visceral hypersensitivity. 5,6-EET, 5,6-epoxyeicosatrienoic acid; ASIC, acid-sensing ion channel; CB1, cannabinoid receptor 1; DRG, dorsal root ganglion; H1R, histamine 1 receptor; P2Y1/2, purinergic receptor P2Y1/2; PAR1/2, protease-activated receptor 1/2; TRPA1, transient receptor potential ankyrin 1; TRPV1/4, transient receptor potential vanilloid 1/4.

Figure 4

Immune activation in irritable bowel syndrome and functional dyspepsia. Food and microbiota-derived antigens gain access to the subepithelial space through an impaired intestinal barrier function. These antigens and epithelium-derived proteases such as trypsin-3 can activate mast cells and eosinophils through a variety of mechanisms. Mediators from activated mast cells and eosinophils can subsequently activate sensory neurons. Finally, in conditions of psychological stress locally secreted CRH from eosinophils can activate mast cells. CRH, corticotropin-releasing hormone; CRHR1, CRH receptor 1; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; Eo, eosinophil; EPO, eosinophil peroxidase; FcERI, high-affinity IgE receptor; MBP, major basic protein; MC, mast cell; MRGPRX2, Mas-related G-protein coupled receptor member X2; NK1/2, neurokinin receptor 1/2; PAR2, Protease-activated receptor 2; SP, Substance P; TLR4, Toll-like receptor 4; VPAC1, vasoactive intestinal peptide receptor type 1. Dashed line indicates a potential link.

Figure 5

Food–microbiota interaction in visceral hypersensitivity. Bacterial histidine decarboxylase (HDC) in high-histamine producing species such as Klebsiella aerogenes metabolises dietary histidine into histamine which is stimulated by high intake of fermentable carbohydrates. Higher abundance of Lactobacilli reduces histamine production by lowering luminal pH through production of lactic acid. Bacteria-derived histamine can subsequently activate H4R on mast cells contributing to visceral hypersensitivity. FODMAPs, Fermentable Oligo-, Di-, Monosaccharides and Polyols; H1R, histamine 1 receptor; H4R, histamine 4 receptor; HDC, histidine decarboxylase; MC, mast cell; SCFA, short-chain fatty acids.

Figure 6

Treatments targeting immune activation. Solid lines: a demonstrated benefit. Dashed lines: potential benefit, but not formally tested. 5-HT₃, Serotonin 3 receptor; Eo, eosinophil; H1R, histamine 1 receptor; MC, mast cell; PPI, proton-pump inhibitor.