Abatement of Forskolin-induced Intestinal Fluid Secretion by Modulation of Intracellular Camp With Penicillin

Millions of people die every year due to diarrheal related diseases, with infants and the elderly making up the majority of these deaths. Deaths are caused by excessive intestinal fluid and electrolyte secretion and are especially common in impoverished developing countries. Antibiotics have been classically used as a method to treat diarrhea-related pathologies by modulating the gut microbiome. We recently reported that penicillin may protect against disease-induced excessive fluid and electrolyte secretion via a genetics-independent, microbiome-independent mechanism in individual colonic crypt cells. In this study we investigated whether microbial-independent protective effects of penicillin against fluid secretion can be observed in the rat small intestine at the whole-tissue level. Here we report that penicillin has a significant dose-dependent protective effect against fluid secretion in induced models of diarrhea in the microbiome deficient rat small intestine. Penicillin can rapidly bring fluid secretion down to levels comparable to healthy controls. Our results suggest, for the first time, an alternative function for penicillin G as a cost-effective and fast-acting treatment against diarrheal symptoms without dependence on modulating the behavior of the existing gut microbiome.

The 5-HT3 receptor affects rotavirus-induced motility

Rotavirus infection is highly prevalent in children, and the most severe effects are diarrhea and vomiting. It is well accepted that the enteric nervous system (ENS) is activated and plays an important role, but knowledge of how rotavirus activates nerves within ENS and to the vomiting center is lacking. Serotonin is released during rotavirus infection and antagonists to the serotonin receptor subtype 3 (5-HT3 receptor) can attenuate rotavirus-induced diarrhea. In this study we used a 5-HT3 receptor knockout (KO) mouse model to investigate the role of this receptor in rotavirus-induced diarrhea, motility, electrolyte secretion, inflammatory response and vomiting reflex. The number of diarrhea days (p=0.03) and the number of mice with diarrhea were lower in infected 5-HT3 receptor KO than wildtype pups. In vivo investigation of FITC-dextran transit time showed that intestinal motility was lower in the infected 5-HT3 receptor KO compared to wildtype mice (p=0.0023). Ex vivo Ussing chamber measurements of potential difference across the intestinal epithelia showed no significant difference in electrolyte secretion between the two groups. Immediate early gene cFos expression level showed no difference in activation of the vomiting center in the brain. Cytokine analysis of the intestine indicating low effect of inflammatory response in rotavirus-infected mice lacking the 5-HT3 receptor. Our findings indicate that the 5-HT3 receptor is involved in rotavirus-induced diarrhea via its effect on intestinal motility and that the vagus nerve signaling to the vomiting center occurs also in the absence of the 5-HT3 receptor. IMPORTANCE The mechanisms underlying rotavirus-induced diarrhea and vomiting are not yet fully understood. To better understand rotavirus pathophysiology, characterization of nerve signaling within the ENS and trough vagal efferent nerves to the brain, which have been shown to be of great importance to the disease, is necessary. Serotonin (5-HT), a mediator of both diarrhea and vomiting, has been shown to be released from enterochromaffin cells in response to rotavirus infection and the rotavirus enterotoxin NSP4. Here, we investigated the role of the serotonin receptor 5-HT3, which is known to be involved in the nerve signals that regulate gut motility, intestinal secretion, and signal transduction through the vagus nerve to the brain. We show that the 5-HT3 receptor is involved in rotavirus-induced diarrhea by promoting intestinal motility. The findings shed light on new treatment possibilities for rotavirus diarrhea.