Mechanisms of alteration of gastrointestinal physiology by gut microbes

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 K08 funded research into mechanisms by which gut microbiota products affect GI physiology identified a role for the bacteria-derived metabolite tryptamine.Data from my current K08 show that Ruminococcus gnavus and Clostridium sporogenes, found in the gut of healthy individuals, carry the enzyme tryptophan decarboxylase which can convert dietary tryptophan to tryptamine. Furthermore our preliminary studies 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 (5-HT) receptor 4 antagonists. Our overall aim is to determine the effect of tryptamine, on intestinal secretion. We propose to determine the role of exogenous tryptamine in regulation of intestinal secretion in hypothesis 1, the role of bacterial-derived tryptamine in hypothesis 2 and the mechanism of action of tryptamine in hypothesis 3. These experiments, while foundationally linked to previous work, are a new but logical extension of the work associated with the K08 and can be completed in the defined award period. The results from this study will potentially contribute to development of novel engineered probiotics capable of producing a metabolite of interest to correct the altered physiology in diseases like IBS.