Tryptophan bacterial metabolism by intestinal microbes and its benefits.

Tryptophan is an essential amino acid that is supplied in the diet. Dietary tryptophan is primarily catabolized through endogenous metabolism included kynurenine pathway and serotonin pathway, and direct bacterial metabolism. However, recent studies have revealed that tryptophan bacterial metabolism can directly or indirectly influence the endogenous tryptophan metabolism. Tryptophan metabolites generated by gut microbiota are important contributors to intestinal homeostasis and they regulate the intestinal homeostasis by activating aryl hydrocarbon receptor (AhR), which is a cytosolic ligand-activated transcription factor that regulate the intestinal immunity and inflammation.¹ In addition, some tryptophan bacterial metabolites may also promote intestinal epithelial barrier function by acting as ligands for pregnane X receptor (PXR).² Several tryptophan bacterial metabolites, including indole, indole acetic acid, indole propionic acid, skatole, indole-3-aldehyde, and tryptamine, have been proven to be AhR and/or PXR ligands, and they are considered to play important roles in preventing inflammatory bowel diseases and gastrointestinal infections.³

Aim
l  To study the role of food matrix in tryptophan conversion by gut microbiota.
l   To study the contribution of specific species of colon bacteria to the generation of tryptophan metabolites.
l   To investigate the role of tryptophan metabolites in the activation of AhR and PXR, and its contribution to intestinal health and function.

Approach
We will use in vitro fermentation models (e.g. batch fermentation, SHIME (Simulator of the Human Intestinal Microbial Ecosystem), and Mucosa-SHIME) to study tryptophan bacterial metabolism. Bioinformatic tools and pathway analysis will be employed to predict microbial metabolism of tryptophan. Intestinal organoids will be used to study the effect of tryptophan bacterial metabolites on intestinal epithelial barrier function, as well as the transport of tryptophan metabolites through the colon epithelium. Tryptophan bacterial metabolites during fermentation will be characterized by LC-MS/MS and AhR/PXR activation will be tested on HepG2-Lucia-AhR cells for AhR and DPX2^TM cells for PXR. In vivo study may also include in this research to validate findings from in vitro experiments.

References
^{1. Lamas, B., Natividad, J. M., & Sokol, H. (2018). Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunology, 11, 1024-1038.}

^{2. Roager, H. M., & Licht, T. R. (2018). Microbial tryptophan catabolites in health and disease. Nature Communications, 9(1), 3294.}

^{3. Allison, A., Julien, P., & Harry, S. (2018). Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host & Microbe, 23(6), 716-724.}