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Fecal miRNAs, new mediators of host-microbiota interaction in Inflammatory Bowel Disease

Periodic Reporting for period 1 - miR-IBD (Fecal miRNAs, new mediators of host-microbiota interaction in Inflammatory Bowel Disease)

Okres sprawozdawczy: 2019-10-01 do 2021-09-30

Inflammatory bowel disease (IBD) is associated with a disturbance of the gut microbiota (dysbiosis). The maintenance of an adequate dialogue between the host intestine and the microbiota is crucial for preserving intestinal healthiness and prevent inflammation. Our proposed study relied on the observation that small entities, microRNAs (miRNAs) were abundantly accumulating in stool thus suggesting that they may be important players in the host-microbiota dialogue. At the origin of the project, our preliminary data indicated that miRNA were modified in mouse model that spontaneously develop intestinal inflammation (IL10 knock-out mice). Although the causal links between alterations in these different parameters (miRNAs, microbiota and inflammation) were not fully elucidated, our preliminary data in mice suggested that some miRNAs found in stool could impact microbiota and gut inflammation. Our research project thus aimed to understand the role played by fecal miRNAs in host-microbiota dialogue and how player could impact intestinal inflammation.
Various approaches were used to achieve our project, including the use of mouse models, exploitation of human stool samples, and the use of in vivo and in vitro/ex vivo systems to study either the host or the microbiota independently.
Overall, this project allowed to identify a crosstalk between gut miRNAs, the microbiota and intestinal inflammation. This improved understanding of the interactions between the microbiota and miRNAs could suggest new approaches for manipulating microbiota toward being inherently less harmful when the host-microbiota relationship is perturbed such as in IBD and could clearly benefit future efforts to treat IBD.
Work was conducted according to three scientific objectives and 15 work packages (WPs). The three objectives were as follow:
Objective 1: Determine the role played by the intestinal microbiota in miRNA-mediated modulation of intestinal inflammation.
Objective 2: Investigate the ability of specific miRNAs / anti-miRNAs to modulate intestinal inflammation.
Objective 3: Identify whether fecal miRNAs are indicators of microbiota and intestinal healthiness in IBD patients.

WP1 comprised ethical considerations that we have complied with. WP2-4 involved setting up the tools for completion of the first objective, performing the experiment, collecting and analyzing data. The experiments were in part performed by two Master 2 students and a post-doctoral fellow that I supervise(d). WP5-6 consisted in the investigation of the therapeutic potential of targeting miRNA in IBD. In WP7-10, miRNA and microbiota were together analyzed in stool samples from IBD patients. WP11-15 involved management of the project, impact on the career of the fellow including securing a tenure position, dissemination and communication.

Overall, the objectives were reached and we have demonstrated direct interaction of miRNA on the microbiota, and the therapeutic potential of targeting miRNA. The relevance of our finding was validated in IBD patients.

Here is a summary of the work completed during the award period: Animal ethics authorization, Collection of stool samples from patients, Funding applications completed or in progress, Student and postdoctoral supervision (Master, postdoctoral supervision), Experiments completed and follow-up experiments initiated, Poster and oral communication at local seminars, national and international conferences, Publication: review and original research articles published or in writing, editorial.

Overall, results obtained during the award period will be i) directly exploited, compiled and published as an original research article, ii) exploited as the basis of follow-up studies iii) used as the foundations of a line of research from which further research project will be built.
The incidence of IBD is rising in developed countries, with currently 3 Million Europeans. The overall goal of this proposal was to investigate the crosstalk among gut miRNAs, the microbiota and intestinal inflammation. The results obtained during the time course of the award period, supported the promise of our hypothesis, and therefore further mechanistic follow-up studies are now warranted. Ultimately, we must establish whether a modified microbiota is a cause or consequence of the altered gut miRNA content, as this will help us define appropriate therapeutic targets for manipulating the microbiota and/or host. Determining whether fecal miRNAs can modulate the microbiota, understanding how that modulation operates, and determining whether fecal miRNAs actively shape the microbiota will provide a new and unique opportunity to manipulate this complex community in a way that could benefit the host and, ultimately, patients with dysbiosis-associated inflammation. Testing the potential therapeutic effects of exogenous miRNAs will also be a future direction of the project. Indeed, findings have shown that ginger exosomes exert anti-inflammatory effects in vitro and in vivo. The fact that these exosomes were found to be highly loaded with miRNAs supports the hypothesis that exogenous miRNAs could also affect the microbiota in a manner that benefits the host. Understanding this particular aspect will be relevant to the development of alternative therapeutic strategies for shaping the microbiota of patients with intestinal inflammation and alleviating their symptoms. Depending on the origin, either dietary changes or supplementation with synthetic miRNAs could be used as a type of probiotic. In many cases, strategies used to alleviate symptoms in IBD patients through dietary recommendations have failed. One possible explanation for this failure is that most such recommendations are based on macronutrients. Focusing on micronutrients or small entities in the diet could prove to be more beneficial. Hence, this project could have impact on public health and provide new bases for dietary interventions.
Objective of the study