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At the host-bacteria interface: Modulation of the intestinal microbiota and its metabolic activity by Card9 signalling in health and Inflammatory Bowel Diseases

Periodic Reporting for period 1 - MArylAND (At the host-bacteria interface: Modulation of the intestinal microbiota and its metabolic activity by Card9 signalling in health and Inflammatory Bowel Diseases)

Berichtszeitraum: 2017-11-01 bis 2019-10-31

The microbial community living in the human intestine is crucial to the health and nutrition of the host. Loss of the fragile balance within this complex ecosystem is involved in numerous pathologies, including inflammatory bowel disease (IBD).
IBD such as Crohn’s disease (CD) and ulcerative colitis (UC), are characterized by chronic and relapsing inflammation of the gastro-intestinal tract. Their incidence increased during the 20th century and continues to rise, affecting individuals in the most challenging and productive years of their lives 1 and thus representing major burdens of morbidity in western countries. Their incidence and prevalence are relatively high in industrialized countries (10-15 per 100 000 inhabitants/year and 100-150 per 100 000 respectively) and the lifelong risk to develop IBD is currently estimated to be over 1%. Unfortunately, no cure is currently possible for CD and UC. Most of the available treatments are immunosuppressants that are associated with potentially severe side effects such as infection and neoplasia. Moreover, despite recent progress, immunosuppressive treatments are not always effective and have, at best, suspensive effects. Finally, the course of these diseases remains poorly predictable leading to inappropriate treatment or delay in therapeutic adaptation.
There is thus a great unmet medical need both of new therapeutic approaches and biomarkers to predict clinical events. Although the exact pathogenesis of IBD is not fully understood, it is currently admitted that it develops as a result of a combination of genetic predisposition, dysbiosis of the gut microbiota, and environmental influences. Deciphering the host-bacteria crosstalk will improve our understanding of IBD and enable new preventive and therapeutic strategies.
Caspase recruitment domain 9 (Card9), one of the IBD susceptibility genes, codes for a protein involved in the response to fungi and bacteria. Sokol and colleagues showed that Card9-/- mice have an increased susceptibility to colitis, due to an altered gut microbiota that is not able to metabolise tryptophan into aryl hydrocarbon receptor (AhR) ligands. In humans, comparable mechanisms seem to be involved, as microbiota of IBD patients exhibit impaired production of AhR ligands, which mirrors the Card9-/- genotype.

The aim of the present project was to better understand how Card9 signalling modulates the susceptibility to intestinal inflammation. For this purpose, we took advantage of a strong collaborative environment and cutting-edge techniques, including gnotobiotic animals, cre-lox technology, transcriptomics, metabolomics and systems biology. Specifically, we planed to identify (i) cell types involved in Card9-dependent susceptibilty to colitis and (ii) dysregulated host pathways and microbiota changes in the absence of Card9.
Our scientific findings are still confidential but will soon be published in open-access scientific journals of high quality impact. Two research articles are in preparation, with one major article that should be submitted to an open-access high impact journal before October 2020.
We also plan to report the results to several national and international conferences, with the objective to ensure their wide dissemination.
"During this two years fellowship I have been able to follow two trainings, one in mice experimentation at the Ecole Vétérinaire Nationale d’Alfort (2018) and one in Data analysis with R, at the INRA Institute, Jouy-en-Josas (2018).
Moreover, I have participated to 2 international conferences: one poster presentation at the Keystone Symposium “Manipulation of the Gut Microbiota for Metabolic Health"", Banff, Canada (2018), and one oral presentation ‘Microbe-derived factors as regulators of the mucosal immune system’, at the Symposium 214 “IBD: From Pathophysiology to Personalized Medicine”, Oxford, UK (2019).
I also gave a talk at an international workshop: ‘Writing a successful Marie Curie Fellowship application’, UEG Week, Vienna, Austria (2018).

Concernig our project, innovative approaches are crucial to decipher mechanisms behind the exaggerated inflammation observed in IBD. Supported by Horizon2020, our work provides key information on cell types that mediate this chronic intestinal inflammation (that we cannot yet disclose). We plan to validate our mouse results using human samples, taking advantage of a biobank available at the Saint-Antoine Hospital (Paris). Indeed, my supervisor, the Pr. Harry Sokol decided to renew my contract for a supplemental year funded by the French ANR funding agency. This will be necessary to finish the experiments related to the MSCA funded project, to submit two manuscripts and to make the necessary revisions. Moreover, our scientific findings will be reported at national and international conferences during this additional year of funding to ensure their wide dissemination. We will also look for collaborations with industrial partners that are crucial to transfer the latest advancements from bench-to-bedside but also to disseminate knowledge and inventions in society for healthier diets and lifestyles. The overall objective of our work is to develop new preventive and therapeutic strategies for IBD patients.

This project enabled to synergise collaborative and creative research between scientists from different but complementary fields, especially from “wet” and computational sciences, in order to further dissect microbiota-driven human diseases. Personally, I have learned a lot in the fields of transcriptomics, proteomics and metabolomics. I have acquired new skills in mouse experimentation, and developed several functional assays in vitro. I have been able to lead my own project independently with the full support of my supervisor, the Pr. Harry Sokol, and the help of the technicians and engineers of my research team. I have supervised a student for an internship, which helped me to develop my management skills; and I am about to receive a new one when the covid crisis is over.

In addition, the extra year gave me the opportunity to write a review on a new project related to Fecal microbiota Transplantation (FMT). My future plan is to keep working on FMT, with the goal to obtain a permanent position of researcher in the team of my actual supervisor at the INSERM Institute in Paris, in 2021 or 2022."
Preliminary data on Card9 modulation of the microbiota