FIG 7.

Proposed mechanism for how neurotrophic factors protect the intestinal barrier from rotavirus insult. Studies with humans and mice (4–7) have shown that the noninflammatory infection with rotavirus leaves the intestinal permeability unaffected or even reduced during diarrhea, in contrast to most bacterial infections (8, 9). Gastrointestinal permeability is regulated by the vagus nerve and the enteric nervous system (ENS), which is composed of neurons and EGCs. Rotavirus infects mature enterocytes on the top and middle of villi, which results in release of virus and at least the enterotoxin NSP4, which stimulate EC cells. 5-HT is contained in secretory granules of the EC cells and is released following stimulation by rotavirus and NSP4 (11). Released 5-HT activates EGCs to increase release of GDNF, which subsequently increase the tight junction protein ZO-1 in infected and bystander cells. It may also be that infected enterocytes in a paracrine manner stimulate increase of GDNF in bystander cells. Intrinsic enteric 5-HT₃ receptors are of importance in the regulation of barrier function during rotavirus insult, since mice lacking this receptor have an increased permeability during rotavirus infection. The proposed mechanism is based on in vitro and ex vivo studies and is modified from previous disease models (1–3).