Immune requirements and inflammatory mediators in a murine model of post-infectious irritable bowel syndrome

Abstract

Post-Infectious Irritable Bowel Syndrome (PI-IBS) occurs in up to 30% of patients following an episode of bacterial gastroenteritis. A long duration of the acute diarrheal illness is a risk factor for the development of PI-IBS. This raises the possibility that the nature of the host response during the acute infection influences the development of the persistent changes in enteric neuro-muscular function in the post-infectious state. Recently we showed that primary infection of NIH/Swiss mice results in enteric neuromuscular dysfunction that persists for at least 6 weeks after infection, reminiscent of PI-IBS. In this study we have explored mechanisms underlying the persistent neuromuscular changes in this model, focussing on the host response to infection. We used RT-PCR to evaluate the expression of mediators in the neuromuscular layers of the jejunum before, during and after the infection. Infection induced the expression of the Th2 cytokines interleukins -4 and 13 during the enteric phase of infection (day 10 PI), but these cytokines did not persist beyond the duration of the infection. Studies in mice with Severe Combined Immune Deficiency (SCID) showed that acute infection and inflammation did not result in peristent neuromuscular dysfunction, indicating that at least the initiation of these events is immunologically driven. We next examined mediators responsible for the maintenance of the neuromuscular dysfunction, focussing on prostaglandins. As expected, there was no constitutive expression of inducible cycle-oxygenase COX-2 in the neuromuscular layers but the gene encoding this enzyme was expressed during the acute infection (day 10 PI). Moreover, COX-2 mRNA expression remained elevated for at least 28 days PI, together with an increased production of prostaglandin E2 in the neuromuscular layer. Since the persistently increased contractility of muscle in this model could be abrogated by indomethacin, local PGE2 production is critical for the ongoing expression of muscle hypercontractility in this model. These results demonstrate that the Th2 cytokines IL-4 and IL-13 are neccessary for the induction but not thr maintenance of post-infectious muscle hypercontractility in this model. Our results suggest that the maintainance of the hypercontractility is mediated by the local production of PGE2, possibly via COX-2. Supported by AstraZeneca and MRC Canada.