Post-infectious irritable bowel syndrome: mechanistic insights into chronic disturbances following enteric infection

Abstract

Irritable bowel syndrome (IBS) is a commonly encountered chronic functional gastrointestinal (GI) disorder. Approximately 10% of IBS patients can trace the onset of their symptoms to a previous a bout of infectious dysentery. The appearance of new IBS symptoms following an infectious event is defined as post-infectious-IBS. Indeed, with the World Health Organization estimating between 2 and 4 billion cases annually, infectious diarrheal disease represents an incredible international healthcare burden. Additionally, compounding evidence suggests many commonly encountered enteropathogens as unique triggers behind IBS symptom generation and underlying pathophysiological features. A growing body of work provides evidence supporting a role for pathogen-mediated modifications in the resident intestinal microbiota, epithelial barrier integrity, effector cell functions, and innate and adaptive immune features, all proposed physiological manifestations that can underlie GI abnormalities in IBS. Enteric pathogens must employ a vast array of machinery to evade host protective immune mechanisms, and illicit successful infections. Consequently, the impact of infectious events on host physiology can be multidimensional in terms of anatomical location, functional scope, and duration. This review offers a unique discussion of the mechanisms employed by many commonly encountered enteric pathogens that cause acute disease, but may also lead to the establishment of chronic GI dysfunction compatible with IBS.

Keywords: Enteric pathogen; Immune alterations; Infectious diarrhea; Inflammatory disorders; Post-infectious irritable bowel syndrome.

Figure 1

Illustration representing the interaction of several pathogens with the intestinal epithelium and resident immune cells, and their contribution to the development of post-infectious-irritable bowel syndrome. A: Giardia duodenalis disrupts tight junctional proteins in the epithelium, in addition to resulting in a decrease in 5-HT-producing enterochromaffin cells; B: Salmonella enterica serovar Typhimurium invades enterocytes and makes its way to resident macrophages, where upon being phagocytosed it causes interleukin (IL)-18 release, which further stimulates interferon (IFN)-γ release from nearby immune cells, i.e., lamina propria dendritic cells, and macrophage pyroptosis. This pathogen is also able to disrupt the resident microbiota; C: Campylobacter jejuni causes disruptions in TLR9 signaling to make epithelial cells more susceptible (would sensitive apply here instead of susceptible) even to mild pro-inflammatory cytokines. It also activates the NF-κB pathway to result in an IL-1β and IL-8 release. C. jejuni has also been shown, particularly in cases of post infectious (Pi)-IBS, to cause a reduction of resident CD68⁺ macrophages; D: Shigella flexneri crosses the epithelium through the M cell and is taken up resident macrophages, where it causes IL-1β and IL-18 release, and pyroptosis in these macrophages. S. flexneri has also been associated with increased number of mast cells, secretions of which MCT can activate the enteric nervous system; E: EPEC results in TNF-α, IFN-γ, and IL-1β release via NF-κB and ERK-1/2 activation. Both EPEC and EHEC result in MLCK-dependent tight junctional disruption. Intriguingly, G. duodenalis (A) and C. jejuni (C) have been implicated in the modification of the intestinal microbiota; however, the effects of this modification remain unclear[90]. A variety of combinations of these factors may contribute to the pathogenesis of PI-IBS. MCT: Mass cell tryptase.