Background Cystic fibrosis (CF) has multiple effects on the gastrointestinal system, including altered motility. The Cftr knockout mouse model of CF has impaired small intestinal transit but the mechanism is unknown. Methods Behavior of circular smooth muscle was studied in an organ bath. Expression levels of prostaglandin (PG) degradative genes was measured by quantitative RT-PCR, and PGE2 levels were measured by enzyme immunoassay. Key Results CF circular muscle activity was erratic and had variable frequency of contractions, as compared to WT. The CF tissue was nonresponsive to cholinergic stimulation or direct KCl depolarization. PGE2 and PGF2α are significantly elevated in the CF mouse small intestine, and we hypothesized these contribute to impaired smooth muscle activity. After inhibition of PG synthesis, the CF circular muscle exhibited greater cholinergic responsiveness, which was reversed by exogenous PGE2. PGF2α enhanced activity of CF tissue only after inhibition of PG synthesis. The enteric microbiota was implicated in PGE2 mediated dysmotility because broad spectrum antibiotic treated WT mice, which have slowed transit, exhibit impaired circular muscle activity. This was accompanied by decreased expression of PG degradative genes and increased intestinal PGE2 levels. Furthermore, administration of oral laxative, which eradicates bacterial overgrowth and improves transit in CF mice, increased expression of PG degradative genes, decreased PGE2 levels, and improved CF muscle activity. Conclusions and Inferences These results suggest that the enteric microbiota modulates PGE2 levels in a complex manner, which affects enteric smooth muscle activity and contributes to slower small intestinal transit in CF.

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BackgroundCystic fibrosis (CF) has many effects on the gastrointestinal tract and a common problem in this disease is poor nutrition. In the CF mouse there is an innate immune response with a large influx of mast cells into the muscularis externa of the small intestine and gastrointestinal dysmotility. The aim of this study was to evaluate the potential role of mast cells in gastrointestinal dysmotility using the CF mouse (Cftrtm1UNC, Cftr knockout).MethodologyWild type (WT) and CF mice were treated for 3 weeks with mast cell stabilizing drugs (ketotifen, cromolyn, doxantrazole) or were treated acutely with a mast cell activator (compound 48/80). Gastrointestinal transit was measured using gavage of a fluorescent tracer.ResultsIn CF mice gastric emptying at 20 min post-gavage did not differ from WT, but was significantly less than in WT at 90 min post-gavage. Gastric emptying was significantly increased in WT mice by doxantrazole, but none of the mast cell stabilizers had any significant effect on gastric emptying in CF mice. Mast cell activation significantly enhanced gastric emptying in WT mice but not in CF mice. Small intestinal transit was significantly less in CF mice as compared to WT. Of the mast cell stabilizers, only doxantrazole significantly affected small intestinal transit in WT mice and none had any effect in CF mice. Mast cell activation resulted in a small but significant increase in small intestinal transit in CF mice but not WT mice.ConclusionsThe results indicate that mast cells are not involved in gastrointestinal dysmotility but their activation can stimulate small intestinal transit in cystic fibrosis.

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