AryIMUNE

Aryl hydrocarbon receptor and immunity: Activation by diet, microbiota and probiotics

Project description

Background and aim

The aryl hydrocarbon receptor (AhR) is a transcription factor recently shown to be crucial for the maintenance of intestinal homeostasis, however its precise gut luminal activators and functional consequences are unknown. Activators originate from (i) the diet, such as indole-3-carbinol from cruciferous vegetables, (ii) the microbiota, (iii) lactic acid bacteria, used in food or as probiotics, that produce AhR agonists from catabolism of tryptophan. The overall aim of our project is to assess the effects of AhR activation by microbiota-derived components on intestinal immunity and physiology. We will specifically determine the dietary-microbiota interactions that lead to AhR activation and identify AhR-activating microorganisms, or their metabolites, with potential health benefits.

Achievements

Before starting the project, a consortium agreement has been signed between all the academic and industrial partners on november 2016. Three post docs have been hired for the project. The screening of probiotic strains for their ability to produce AhR agonists is completed and 3 candidates have been selected for in vivo studies in 3 pathological models. The clinical trial design has been approved by regulatory agencies in Canada. The study started on October 2017 and 10 participants have already been recruited.

Expected impact

We expect to better understand the host-microbiota crosstalk in health and disease and identify new dietary strategies to modulate AhR signalling to maintain gut health and alleviate intestinal inflammation.

Consortium

Partner Organization Partner Country
Farncombe Family Digestive Health Research Institute at McMaster University Canada
French National Institute for Agricultural Research (INRA) France
University Wageningen The Netherlands

Highlights

We identified an alteration in the gut microbiota function in Coeliac disease in human characterized by an impaired production of aryl hydrocarbon receptor (AhR) agonists. In Coeliac disease mouse models, correcting this alteration using a pharmacologic approach (adminstration of AhR agonists) or by using intestinal bacteria naturally producing AhR agonists alleviated the severity of the gluten immunopathology in the mouse model. 

Products

Title: Aryl hydrocarbon receptor and intestinal immunity
Author: Lamas B, Natividad J, Sokol H (first and last authors are Partners)
Link: https://doi.org/10.1038/s41385-018-0019-2
Title: Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease
Author: Agus A, Planchais J, Sokol H (Second and third authors are Partners)
Link: https://doi.org/10.1016/j.chom.2018.05.003

Reports


Endreport

Besides microbiota composition, gut microbiota functions are altered in many diseases. Focusing the research on gut microbiota function is very likely to be more relevant than composition. Our work shows that the metabolism of tryptophan by the gut microbiota is altered in Celiac disease with an impaired production of aryl hydrocarbon receptor (AhR) agonists. Preclinical data in mice show that correcting this alteration using a pharmacologic approach (adminstration of AhR agonists) or by using intestinal bacteria naturally producing AhR agonists could be a therapeutic strategy. Interestingly the therapeutic effects are modulated by dietary factors and particularly the amount of tryptophan in diet. 

We identified an alteration in the gut microbiota function in Coeliac disease in human characterized by an impaired production of aryl hydrocarbon receptor (AhR) agonists. In Coeliac disease mouse models, correcting this alteration using a pharmacologic approach (adminstration of AhR agonists) or by using intestinal bacteria naturally producing AhR agonists alleviated the severity of the gluten immunopathology in the mouse model. 

These results suggest the interest of preventive or therapeutic interventions restoring an impaired level of AhR agonist within the gut. This is particularly the case in Celiac disease. Recommendations favoring vegetables naturally enriched in AhR agonists might be advised as well as strategy modifying the microbiome to promote its natural production of AhR agonists. In this context, the use of bacteria naturally producing AhR agonist, alone or in combination with the above-mentionned strategy, is attractive.

Target group Authors Means of communication Hyperlink Pdf
Scientist sand physician Verdu E., Environmental factors: update on the role of gut microbiota in celiac disease, International Celiac disease symposium, Paris, 2019 oral presentation    
Scientists Verdu E., , Keystone symposia, Microbiome and Celiac disease Ireland, 2019 oral presentation    
  Verdu E., Gut microbiota in celiac disease, International Celiac disease symposium, New York, 2020 oral presentation    

Subjects

Features

Project number:
AryIMUNE
Duration: 100%
Duration: 100 %
2016
2019
Related subsidy round:
Project lead and secretary:
Harry Sokol