CE14 - Physiologie et physiopathologie

Mechanistic evaluation of the interaction between Enterobacteriaceae and fungi in the context of gut inflammation – Enterofun

Mechanistic evaluation of the interaction between Enterobacteriaceae and fungi in the context of gut inflammation

A previous study of the team allowed us to show that in vivo the presence of Enterobacteria in the intestinal microbiota drastically influenced the effects of fungi on intestinal inflammation. These observations led us to propose a project to study the mechanisms involved in these interactions in order to identify parameters regulating the positive or negative effects of fungi in the gut.

Objectives

The challenge of this project was twofold: (i) to broaden our in vivo understanding of the observed pheonomen of Enterobacteria-fungi interaction; (ii) to identify the effectors and mechanisms.<br />This collaborative project was initiated following the publication of an article by the coordinator and partner 2 reporting on the in vivo interaction between fungi and Enterobacteria. In this article it was shown that the positive or negative effects of different fungi on intestinal inflammation required the presence of Enterobacteria in vivo.<br />The project aimed to investigate the mechanisms underlying this interaction. This project was developed in 3 workpackages: (i) an essentially in vivo program where animal experiments were to specify the specificity of strains involved in these interactions, as well as the need for living or non-living strains; (ii) a second essentially in vitro program seeking to reproduce in vitro the interactions identified in vivo as well as to investigate whether the host was not a third partner essential to the identified effects; (iii) finally a purely mechanistic part where we will be interested in both the response of the host and the microbiota and in these interactions by transcriptomic and metabolomic analysis The use of mutant bacteria or mutant mice is also planned in order to verify the mechanisms involved once hypotheses are made thanks to the results of workpackage 2.<br /><br />Translated with www.DeepL.com/Translator (free version)

In vitro and in vivo approaches were conducted in this first part of the project.
- Model of colitis induced by dextran sodium sulfate with or without gavage of bacteria or fungi
- In vitro co-culture of E. coli and C. albicans or S. cerevisiae

The preliminary results of this study showed a very strong influence of the basal intestinal microbiota on the interaction phenotype observed in our preliminary study.
The analyses showed that a population of bacteria, the Muribaculaceae, could be at the origin of these changes in the behavior of enterobacteria and fungi.

Following these results, our work is to identify the main actors that explain this phenotype modification, to understand how they act but also to modify the microbiota accordingly in order to return to the initial objectives.
To study the impact of the Muribaculaceae population (Bacteroidetes bacteria, involved in the stimulation of mucus production by intestinal cells) on the lack of effect of yeast on DSS-induced colitis. Increasing the population of Muribaculaceae could increase the mucus layer covering the colonic epithelial cells, decreasing the implantation of yeasts and their effects on DSS-induced colitis. A high-fat diet decreases the proportion of Bacteroidetes bacteria and in particular the proportion of Muribaculaceae. We plan to perform experiments evaluating the importance of the direct and indirect consequences of a high-fat diet on the bacterial gut microbiota: impact on the mucus layer and thus on the implantation of fungal species and their potential effects on gut health.

Translated with www.DeepL.com/Translator (free version)

The results are for the moment too preliminary for any scientific production.

This project is part of a worldwide effort of the scientific community to determine the microbiota structure and its role in human health. Beside very advanced work today on the bacterial microbiota, we propose in this project to focus more specifically on the fungal subpopulation of the intestinal microbiota. This population is still poorly studied despite its strong potential in the ecological balance of the microbiota. It is considered that these microorganisms have an important role in the maintenance of a stable intestinal microbiota by interacting with the bacteria of this niche but also by interacting with the host and in particular its immune system. Among the diseases caused by an imbalance microbiota, the more clearly identified are inflammatory bowel diseases (IBD), which include Crohn's disease and ulcerative colitis. IBD affects in France today more than 200,000 patients and are constantly growing. It has dramatic and crippling consequences on the life of the patients (recurrent abdominal pain, chronic diarrhea, general weakness, etc.), and occurs among a young population of 20-30 years old, after long-term affection they often require surgery worsening the lifestyle of the patients and they can even lead to cancer.
The fungi, although in lower number, are components of the ecosystem and thus part of its equilibrium, and therefore became gradually a new area in microbiota investigation. While data is now increasing on the diversity of the fungal community in different animal and Human’s niches, very little is known on the specific role of the fungi within these ecosystems. In particular, fungal – bacterial interactions is poorly described, hence the aim of this project is by an integrative approach to decipher how Enterobacteriaceae and fungi interact in the gut microbiota, by which mechanism and with which consequences on the host health. Based on our recent results and since many results point to a potential link between fungal gut microbiota and inflammatory diseases the scope of our project will be focused on these particular settings.
The hypothesis of our integrative approach is that the fungal and the bacterial part of the microbiota have specific interactions driving the equilibrium of the gut microbiota, consequently influencing directly or indirectly the host homeostasis. Using the results published recently by the consortium partners the focus will be directed at the interplay between Enterobacteriaceae and fungi in particular during gut inflammation.
EnteroFun objectives are:
• To precisely dissect, using animal models, the Enterobacteriaceae – fungi interaction occurring in the gut, focusing in this first aim on the bacteria role, evaluating the strain specificities, the role of the physiological state of the bacteria as well as the effect of the quantity of bacteria;
• To explore direct interactions between bacterial and fungus using in vitro approaches miming the gut interaction in order to test modulation of the interaction using different treatments;
• Translate the findings gathered during the two previous studies to intervene in vivo on the microbiota in order to develop new therapeutic approaches in the treatment of IBD. To identify and test the potential of novel bacterial or fungal species implicated in the gut microbiota ecosystem equilibrium.
As such, Enterofun will allow huge progresses in the understanding of the microbiota ecosystem function, revealing a completely new area of research and potential new targets for microbiota modulation.

Project coordination

Mathias L Richard (MICrobiologie de l'ALImentation au service de la Santé)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CRSA CENTRE DE RECHERCHE SAINT-ANTOINE
INSERM UMRS 1151 INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
MICALIS MICrobiologie de l'ALImentation au service de la Santé

Help of the ANR 535,458 euros
Beginning and duration of the scientific project: January 2020 - 42 Months

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