ABSTRACT The overall goal of our laboratory's research is to determine the mechanisms by which gut microbiota and their products alter gastrointestinal (GI) tract luminal physiology and to develop microbiota-based therapeutic manipulations to correct altered physiology in diseases like irritable bowel syndrome (IBS) associated with alterations in gut microbiota. Our preliminary studies have identified the gene tryptophan decarboxylase which converts dietary tryptophan to tryptamine in common human gut commensal bacteria like Ruminococcus gnavus and Clostridium sporogenes. Furthermore our preliminary data show that tryptamine increases short circuit current (representing ionic flux; surrogate for secretion) across the colonic epithelium in vitro in Ussing chamber studies and this effect can be inhibited by serotonin receptor4 (5HT4R) antagonists and is absent in 5HT4R knock out mice. Interestingly genetically engineered bacteria with the gene tryptophan decarboxylase produce tryptamine in vivo in gnotobiotic mice and accelerate whole gut transit, when diet is supplemented with tryptophan. Our overall hypothesis is that dietary tryptophan driven production of bacterial tryptamine increases 5HT4R-mediated intestinal secretion modulating GI function in health and disease. In order to determine the mechanism of action of tryptamine we will first determine if the effect of exogenous tryptamine on intestinal secretion is dependent on 5HT4R and identify specific downstream pathways responsible for secretion. We will then investigate the effect of dietary tryptophan on bacteria produced tryptamine and 5HT4R mediated intestinal secretion and whole gut transit as well as its application in a preclinical model of constipation. The results from this study will potentially contribute to the development of novel engineered probiotics capable of producing a bioactive metabolite such as tryptamine to correct the altered physiology such as constipation in diseases like IBS.
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