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Unraveling links between microbiome, food allergy and oral tolerance through meta-transcriptomic analysis of defined gut microbial communities

Grant number: 19/14245-1
Support type:Scholarships abroad - Research
Effective date (Start): February 01, 2020
Effective date (End): January 31, 2021
Field of knowledge:Agronomical Sciences - Food Science and Technology
Cooperation agreement: European Research Council
Principal Investigator:Christian Hoffmann
Grantee:Christian Hoffmann
Host: Caspar Ohnmacht
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Local de pesquisa : German Research Center for Environmental Health, Germany  
Associated research grant:13/07914-8 - FoRC - Food Research Center, AP.CEPID

Abstract

The gut microbiota living within the intestinal lumen composes one of the places with the highest microbial densities known: we harbor approximately 10^11 bacterial cells per cm3 within the colon. This unique microbial ecosystem has local and systemic effects, such as the digestion of food components, and the development of the immune system. Recent changes in human society affecting human health, such as our medical practices and dietary habits, have started to pressure this fine-tuned relationship. Breaks in this relationship can lead to undesirable states, dubbed dysbiosys, and such states have been linked to several diseases. For instance, changes in the microbiome occurring in early life e.g. through overuse of broad-spectrum antibiotics or other lifestyle habits are suspected to contribute to the onset of allergies. The intestinal lumen is constantly exposed to food and microbial antigens, and food allergies start when there is a failure in developing antigenic tolerance in the gut. The current understanding of food allergy implicates the microbiome as a key factor regulating food tolerance and allergy response, although the mechanisms controlling this relationship are not yet clear. Evidence that the gut microbiome and diet play a key role together in food allergy include the increase in frequency of regulatory T cells (Treg) in the colon of mice treated with butyrate, a microbiome metabolite originating from the fermentation of complex food carbohydrates. In recent years, independent research laboratories including the host laboratory have identified a subpopulation of Treg cells expressing the transcription factor RAR-related orphan receptor gamma t (ROR(³t)) that is exclusively induced upon microbial colonization of the intestinal tract. Furthermore, distinct microbial species are able to differentially promote the differentiation of these ROR(³t)+ Treg cells but underlying mechanisms remain unknown. ROR(³t)+ Treg cells have a suppressive role controlling intestinal Th2 cells, known to be the key cell type in allergic responses. It is however unknown why or how ROR(³t)+ Treg cells are induced only in response to certain members of the microbiota. We will use germ-free, gnotobiotic, and conventional mouse models to investigate the links between the antigenic or metabolite components being provided by the gut microbiome, through meta-transcriptomic studies and assessing Th2 and the ROR(³t)+ Treg cells in the gut, with ratio of both subsets expected to be central for immune tolerance in food allergy.