Use of tryptophan-synthesizing bacteria to enhance intestinal motility

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Project Summary/Abstract Functional and inflammatory disorders of the gastrointestinal tract represent a significant burden to patients and to society. These disorders are difficult to treat, and recurrence of symptoms is common. As a result, there are ongoing efforts to develop more effective treatment options. The gut microbiome is now recognized as a dynamic entity that can influence a wide variety of physiological processes, ranging from the integrity of the intestinal epithelial barrier to brain neurochemistry and behavior. The clear success of fecal microbiome transplants in the treatment of C. difficile infections has highlighted the potential of utilizing the microbiome as a means of improving health. The studies that are included in this grant application are designed to exploit specific biochemical properties of certain bacterial strains to test novel treatment strategies for functional bowel disorders. We will test the hypothesis that tryptophan-synthesizing bacteria increase active tryptophan metabolites that enhance colonic motility through the activation of 5-HT4 receptors. Tryptophan is an essential amino acid that is typically acquired from the diet, but can also be produced by enteric bacteria. In addition to being incorporated into proteins, it serves as a precursor molecule for serotonin (5-HT), or it can be enzymatically converted to form kynurenine and its derivatives. In the epithelium of the intestine, enterochromaffin cells convert tryptophan to 5-HT. When 5-HT is released from these cells it triggers enteric reflexes that increase propulsive motility and epithelial secretion. Changes in 5-HT signaling have been identified in functional and inflammatory conditions of the gut, and drugs targeting 5-HT receptors have been developed for the treatment of constipation and diarrhea. In Specific Aim 1 of this proposal, we will test the hypothesis that treatment of mice with a bacterial strain that is known to produce tryptophan, and which has been used safely in probiotic formulations, results in increased mucosal 5- HT levels and enhanced intestinal motility. Specific Aim 2 of this proposal is aimed at determining the mechanisms by which tryptophan producing bacteria promote motility. The 5-HT receptor that is most directly linked to propulsive motility is the 5-HT4 receptor. We will test whether this receptor is involved and determine what tissues express the receptor that mediate this effect. We will also examine what changes in motility patterns and neuronal activity are associated with enhanced propulsive motility, and we will test whether increasing the tryptophan metabolite, tryptamine, can enhance the motility augmenting effect of tryptophan-producing bacteria. The results of these studies could provide a predictive translational strategy for the use of probiotic bacteria, with known biochemical features, for the treatment of constipation.