CE17 - Recherche translationnelle en santé

Repurposing Statins as Gut microbiota-dependent regulators of immune response – STRAT-MI-UP

Submission summary

Ten percent of the European population is on long-term statin therapy. Statins reduce major vascular events and vascular mortality in a large number of individuals. However, the efficacy and safety of this therapy is uncertain with elderly people, who often present co-morbidities and potential drug interactions. In addition, statin responses, both in terms of LDL cholesterol reduction and side effects, are patient-dependant and very variable, with good or poor responders to treatment and some being intolerant to it.

The therapeutic effects of statins include immunomodulatory and anticancer effects on host cells, suggesting their potential for broader applications. In particular, some statins exhibit bactericidal activities that influence the growth and virulence of bacterial strains in the intestinal microbiota. Given the growing evidence linking the gut microbiota to immunity and to the pharmacokinetics-pharmacodynamics of drugs, our project aims to determine the role of statins in the gut microbiota-mediated Tc1 (CD8+ interferon-g+ T cells) response in chronic inflammatory diseases and associated phenotypes in human and mouse models.

Our recent works directly related to the project revealed (i) the role of the intestinal microbiota in the regulation of host cholesterol homeostasis; the pleiotropic effect of statins on (ii) Human enterotypes and (iii) metabolotypes in human microbiome recipient mice ; (iv) the role of bile acids in the control of bacterial proliferation and hepatoprotection, and (v) alcoholic hepatitis; (vi) the metabolomic profiling as a tool for clustering patient subtypes. Our observations suggest that the heterogeneity of statins responses originate from their properties to remodel intestinal microbiota and this way impact immunity and associated chronic inflammatory diseases.

Our preliminary data revealed that microbiota composition modulates statin impact on disease progression in mouse models of chronic inflammatory diseases (atherosclerosis, grafted colorectal cancer). Pathophysiological responses (harmful or protective) to statins are associated with a significant alteration Tc1 cells response conditioned by functional remodeling of the basal intestinal microbiota.

Based on these data, our objectives are: - determination of the impact of statins on bacterial metabolites and taxa, associated with Tc1 responses, first in murine pathological models (task 1) and then in a cohort of dyslipidemic patients (task 2); - to transfer and validate in vivo “pathological phenotypes” in recipient models of atherosclerosis combined with spontaneous colorectal cancer on the basis of selection of good and poor human Tc1 cell responders, (task 3); - to identify biomarkers (metabolites and/or bacterial strains) that predict effects on the progression of both diseases (task 4). The research will include metabolomic/lipidomics analyses, metagenomics, and immune profiling of plasma, feces, immune and inflammatory tissues (blood cells, mesenteric and para-aortic nodes, lamina propria, aorta, and tumors).

In Task 1, we will complete our analysis on dyslipidemic mice (Ldlr-/-) and on a model of grafted colorectal lineage (MC38) with a particular interest in Tc1 cells in lesional and lymphoid tissues. In Task 2, we are halfway through the recruitment of 100 dyslipidemic patients as a basis for the selection of extreme phenotypes. In Task 3, we have already collected data demonstrating the feasibility of human fecal microbiota transfer in the Ldlr-/- recipient mouse model and in mice at risk to spontaneous colorectal cancer (APCmin/J). Omics data generated in this project and in the clinical project will be integrated to propose prognostic signatures of statin responses paving the way for personalized therapy.

Project coordination

Philippe LESNIK (Unité de recherche sur les maladies cardiovasculaires, du métabolisme et de la nutrition)

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

ICAN Institut de Cardiométabolisme et Nutrition (ICAN)
CDR SA CENTRE DE RECHERCHE SAINT-ANTOINE
CIC 1901 CIC PARIS-EST
UMRS 1166 Unité de recherche sur les maladies cardiovasculaires, du métabolisme et de la nutrition

Help of the ANR 592,041 euros
Beginning and duration of the scientific project: December 2020 - 36 Months

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