Immune responses in the irritable bowel syndromes: time to consider the small intestine

Abstract

Background: Irritable bowel syndrome (IBS) is considered a disorder of gut-brain interaction (DGBI), presenting as chronic abdominal pain and altered defaecation. Symptoms are often food related. Much work in the field has focused on identifying physiological, immune and microbial abnormalities in the colon of patients; however, evidence of small intestinal immune activation and microbial imbalance has been reported in small studies. The significance of such findings has been largely underappreciated despite a growing body of work implicating small intestinal homeostatic imbalance in the pathogenesis of DGBIs.

Main text: Small intestinal mechanosensation is a characteristic feature of IBS. Furthermore, altered small intestinal barrier functions have been demonstrated in IBS patients with the diarrhoea-predominant subtype. Small intestinal bacterial overgrowth and increased populations of small intestinal mast cells are frequently associated with IBS, implicating microbial imbalance and low-grade inflammation in the pathogenesis of IBS. Furthermore, reports of localised food hypersensitivity responses in IBS patients implicate the small intestine as the site of immune-microbial-food interactions.

Conclusions: Given the association of IBS symptoms with food intake in a large proportion of patients and the emerging evidence of immune activation in these patients, the current literature suggests the pathogenesis of IBS is not limited to the colon but rather may involve dysfunction of the entire intestinal tract. It remains unclear if regional variation in IBS pathology explains the various symptom phenotypes and further work should consider the intestinal tract as a whole to answer this question.

Keywords: Disorders of gut-brain interaction; Functional gastrointestinal disorders; Immune; Irritable bowel syndrome; Small intestine.

Fig. 1

Regional specificity of selected immune and microbial components in the gastrointestinal tract. There is a distinct variation in the abundance of immune and microbial factors that mediate homeostasis in conjunction with physiological function throughout the small intestine and colon. Because of the role of the small intestine in nutrient absorption, the proximal segments (duodenum and jejunum) have longer, finger-like villi to increase the available surface area. The distal small intestine, the ileum, has shorter villi. Functionally, the colon primarily reabsorbs water and processes unabsorbable waste as faeces for elimination and does not have the finger-like projections of the small intestine. In the colon, immune homeostasis is primarily focused on tolerating the high commensal burden. As such, there is a higher abundance of Th type 17 cells in the duodenum that decreases towards the distal colon, corresponding with an inverse abundance of FoxP3⁺ regulatory T cells. Nutrient absorption capacity is greatest in the duodenum and decreases towards the colon. This corresponds with the small intestinal immune systems focus on oral tolerance to food antigens and production of anti-microbial peptide production and secretory IgA. Eosinophils are a normal constituent of the gastrointestinal tract. Their abundance increases towards the distal small intestine, peaking in the terminal ileum and proximal colon before decreasing towards the rectum [–18]. The image was created using BioRender.com

Fig. 2

Hypothesised immune mechanisms potentially involved in small intestinal dysfunction in IBS. The small intestinal immune system actively modulates tolerance to commensal microbes and food components to maintain homeostasis, in conjunction with the mucosal barrier and mucus layer. In this process, antigens are sampled by dendritic cells and presented to naïve T cells. The differentiation of these cells to regulatory T cells results in the release of interleukin-10 and transforming growth factor beta, which actively suppresses inflammatory immune responses. In contrast, physiological abnormalities in the composition of the mucus layer, coupled with altered mucosal permeability and changed microbial community composition in IBS patients may allow for increased antigen contact with the mucosa and a dysregulated or increased stress response. In this environment, antigen presentation may result in the activation of T cell subsets that drive B cell maturation and specific antibody production that is likely localised to the gastrointestinal tract. The activation of the adaptive immune system may drive the recruitment of eosinophils and mast cells, which degranulate and release inflammatory mediators. The release of these mediators near enteric nerves is likely to promote abnormal signalling and may result in visceral pain. Altered or enhanced stress signalling may also enhance this eosinophil and mast cell response to further contribute to immune activation. However, these pathways require further investigation in IBS patients compared to controls to demonstrate the mechanisms underlying intestinal immune activation. The image was created using BioRender.com