Periodic Reporting for period 4 - MODulATE (Gut microbiota-dependent tryptophan metabolism: role in disease pathogenesis and therapeutic target)
Okres sprawozdawczy: 2021-09-01 do 2022-08-31
Tryptophan (Trp) is an essential amino acid required for protein biosynthesis and is also a biochemical precursor of metabolites which have major effects on human physiology. In the gastrointestinal tract, Trp metabolism can follow three major pathways, all of which are under the control of the gut microbiota: (i) the kynurenin pathway in immune and epithelial cells via indoleamine 2,3-Dioxygenase 1, (ii) the serotonin production pathway in enterochromaffin cells via Trp hydroxylase 1 and (iii) the direct use of Trp by the microorganisms of the gut microbiota into several molecules including ligands of the Aryl Hydrocarbon Receptor. The end products of these pathways play key roles in modulating the immune response, intestinal and metabolic functions and behaviour. Several diseases which involve the gut microbiota in their pathogenesis are also impacted by Trp metabolite. This suggests that the effect of the microbiota in these diseases could be at least partially mediated by impaired Trp metabolism. We recently observed that impaired Trp metabolism by the gut microbiota is involved in inflammatory bowel disease pathogenesis and preliminary data suggest a potential role in other major human diseases.
The aims of the current proposal are (i) to identify the components of the gut microbiota, including both bacteria and fungi, involved in the control of the 3 Trp metabolism pathways in the gut, (ii) to decipher the reciprocal equilibrium between the pathways and to evaluate the potential of its modulation as a therapeutic target, and finally (iii) to assess the relevance of these phenomena in human patients.
This challenging project involves multi-disciplinary aspects, from microbiology to metabolism, inflammation and medicine, the use of multiple cutting edge technologies and translational analysis from mice to human. Beside scientific importance, it will have societal impact by identifying new therapeutic strategies in several human diseases with unmet needs.
The aims of the current proposal are (i) to identify the components of the gut microbiota, including both bacteria and fungi, involved in the control of the 3 Trp metabolism pathways in the gut, (ii) to decipher the reciprocal equilibrium between the pathways and to evaluate the potential of its modulation as a therapeutic target, and finally (iii) to assess the relevance of these phenomena in human patients.
This challenging project involves multi-disciplinary aspects, from microbiology to metabolism, inflammation and medicine, the use of multiple cutting edge technologies and translational analysis from mice to human. Beside scientific importance, it will have societal impact by identifying new therapeutic strategies in several human diseases with unmet needs.
We started to explore the role of tryptophan metabolism in several disease models and notably metabolic syndrome and intestinal inflammation. In two independent studies, we demonstrated that the metabolism of tryptophan by the gut microbiota is impaired in metabolic syndrome (both in human and in mice models). The indoles derivatives produced by the microbiota from the metabolism of tryptophan are able to activate the Aryl Hydrocarbon Receptor (AhR). In metabolic syndrome the lower production of these indoles worsens the disease severity. Interestingly, when we corrected this defect by a pharmacological approach or by bringing back some bacteria naturally able to produce AhR agonists, metabolic syndrome severity was improved.
As AhR activation seems beneficial in intestinal inflammation and metabolic syndrome, we used an in vitro screening system to identify intestinal bacteria with a strong capacity of AhR agonists production. Several candidates were selected and 2 of them were finally tested in colitis and metabolic syndrome models. The selection of these bacterial was also based on the ability to grow them. Among the two bacteria, one showed very strong therapeutic effects in both colitis and metabolic syndrome models. Importantly, these effects were abrogated in AhR KO mice, then demonstrating the AhR-based mechanism of action. We are currently trying to identify the metabolite responsible for this therapeutic effect and are preparing a manuscript to be submitted before the end of the year.
In the third task, we used human data, to identify candidates tryptophan metabolites with potential pro- or anti-inflammatory effects. We selected three metabolites with the strongest signal (2 with potential anti inflammatory effects and one with potential pro-inflammatory effects) and administered them to mice submitted to intestinal inflammation. Our hypothesis was verified in vivo. We elucidated the mechanisms of action, which is related to the modulation of energy metabolism in both epithelial cells and lymphocytes. Moreover, we designed a new therapeutic strategy based on the administration of a recombinant enzyme with the aim of rewiring the altered metabolism in IBD. The proof of concept experiments showed efficacy. The paper in currently in its final step of revision in “Gut” and it should be published soon.
As AhR activation seems beneficial in intestinal inflammation and metabolic syndrome, we used an in vitro screening system to identify intestinal bacteria with a strong capacity of AhR agonists production. Several candidates were selected and 2 of them were finally tested in colitis and metabolic syndrome models. The selection of these bacterial was also based on the ability to grow them. Among the two bacteria, one showed very strong therapeutic effects in both colitis and metabolic syndrome models. Importantly, these effects were abrogated in AhR KO mice, then demonstrating the AhR-based mechanism of action. We are currently trying to identify the metabolite responsible for this therapeutic effect and are preparing a manuscript to be submitted before the end of the year.
In the third task, we used human data, to identify candidates tryptophan metabolites with potential pro- or anti-inflammatory effects. We selected three metabolites with the strongest signal (2 with potential anti inflammatory effects and one with potential pro-inflammatory effects) and administered them to mice submitted to intestinal inflammation. Our hypothesis was verified in vivo. We elucidated the mechanisms of action, which is related to the modulation of energy metabolism in both epithelial cells and lymphocytes. Moreover, we designed a new therapeutic strategy based on the administration of a recombinant enzyme with the aim of rewiring the altered metabolism in IBD. The proof of concept experiments showed efficacy. The paper in currently in its final step of revision in “Gut” and it should be published soon.
Our results on the role of AhR in metabolic syndrome are novel and were published in high impact journals.
In the second part of the project, we aim at finalizing our analysis of the mechanisms of actions of the microorganisms and metabolites we identified. Based on the last results we acquired, we identified an innovative strategy to manipulate the tryptophan metabolism in a therapeutic perspective. These results have been patented.
In the second part of the project, we aim at finalizing our analysis of the mechanisms of actions of the microorganisms and metabolites we identified. Based on the last results we acquired, we identified an innovative strategy to manipulate the tryptophan metabolism in a therapeutic perspective. These results have been patented.