Tryptophan (Trp) is an essential amino acid and a precursor of several metabolites involved in key physiological processes. Metabolic pathways leading to serotonin (5-hydroxytryptamine) and other metabolites from Trp are under the direct or indirect control of the microbiota.
A new review led by Prof. Harry Sokol, a gastroenterologist and researcher from the French National Institute for Agricultural Research (INRA) and the French Medical Research Institute (INSERM), clarifies how the gut microbiota regulates Trp metabolism and identifies the underlying molecular mechanisms of these interactions, based on the pathogenesis of human diseases and potential new treatments.
Dr. Sokol corresponded with GMFH editors about the significance of the work.
Why did you conduct the review? What gap in the impact of the gut microbiota on host physiology is this review filling?
There have been several studies pointing to the role of the gut microbiota in many diseases associated with western life style. In parallel, many data also show the role of Trp metabolites in the same diseases. We know that the gut microbiota has a major impact on the tryptophan metabolism in the gut. In this paper, we reviewed the data linking the gut microbiota to the tryptophan metabolism in health and disease and generated new concepts regarding the interactions between the different pathways and the therapeutic potential of intervention on the gut microbiota to modulate them.
Which pathways are involved in the intestinal Trp metabolism and how do they affect host physiology in terms of clinical relevance?
Trp metabolism follows three major pathways in the gastrointestinal tract: (i) the direct transformation by the gut microbiota of Trp into several molecules, including ligands of the aryl hydrocarbon receptor (AhR); (ii) the kynurenine pathway in both immune and epithelial cells via indoleamine 2,3-dioxygenase 1 (IDO1); and (iii) the serotonin production pathway in enterochromaffin cells via Trp hydroxylase 1 (TpH1). The metabolites of these three pathways have major effects on the host and notably on immunity and metabolism (all 3 pathways), intestinal barrier (AhR pathway particularly), and intestinal transit (serotonin pathway).
In which diseases is Trp metabolism perturbed and to what extent could Trp metabolites be used as biomarkers for specific diseases and conditions?
Currently, it is clearly demonstrated that Trp metabolism is perturbed in intestinal diseases (such as inflammatory bowel disease and irritable bowel syndrome), but also in some non-intestinal diseases such as neuropsychiatric conditions and metabolic diseases.
What strategies can be used for modulating the gut microbiota to restore the perturbed Trp equilibrium?
There is nothing currently available. However, if the microorganisms involved in Trp metabolism control are identified, it will open up the possibility of using them as next generation probiotics. For example, we identified a Lactobacilus reuterii strain with a strong and natural ability to produce AhR agonists from Trp metabolism. In mice with dysbiotic microbiota, this strain exhibits anti-inflammatory effects in colitis models.
Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe. 2018; 23(6):716-24. doi: 10.1016/j.chom.2018.05.003.