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.
LAY SUMMARY There are trillions of bacteria in our intestines which play an important part in keeping us healthy. While we have always known they are important for our health, we did not have the tools to study them. With the advent of new sequencing technology and availability of relevant animal models, we are now able to specifically address how bacteria affect our health. As a part of this project, I will study the effect of a product of bacterial metabolism on intestinal secretion. We know that bacteria rely on our diet to derive energy. Undigested dietary components are passed on to the colon where bacteria break them down further. Bacteria can produce tryptamine by utilizing tryptophan from diet. We are testing if tryptamine produced by bacteria in our gut can change secretion of fluid and electrolytes in our intestines and if so how does it do it. This will allow us to understand the role of bacteria in maintaining normal function of the gut as well as develop newer more effective probiotic treatments which will help correct underlying dysfunction in the gut in diseases like irritable bowel syndrome.
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