Coexpression of inducible NO synthase and soluble guanylyl cyclase in colonic enterocytes: a pathophysiologic signaling pathway for the initiation of diarrhea by gram-negative bacteria?

Infectious diarrhea is often caused by the exotoxins of gram-negative bacteria such as Escherichia coli. However, these organisms also contain lipopolysaccharide (LPS) endotoxin. LPS induces nitric oxide synthase II (NOS II, inducible NOS) in various types of cells. We now demonstrate by RNase protection analysis, Western blot, and immunohistochemistry that the expression of NOS II mRNA and protein is markedly induced in colonic enterocytes of mice that ingest LPS with their drinking water. Using the same techniques, significant levels of soluble guanylyl cyclase (GC-S), the effector enzyme of NO, were found constitutively expressed in the mucosa. This creates a pathophysiologic autocrine pathway producing increased levels of cyclic GMP and leading to hypersecretion and diarrhea. In fact, the LPS-induced diarrhea developed in parallel with the NOS II induction. Diarrhea could be controlled with orally administered dexamethasone, which prevented the LPS-stimulated induction of NOS II (RNase protection analysis and Western blot). Diarrhea was also blocked by oral aminoguanidine, an inhibitor of NOS II activity. These data suggest that in addition to the known heat-labile and heat-stable exotoxins, gram-negative bacteria may induce diarrhea through the release of endotoxins that induce a NOS II-GC-S autocrine pathway in mucosal epithelium.