Clonal hematopoiesis are not associated with an increased systemic inflammation, ATHerosclerosis nor incidence of atherothrombosis: Results from the 3-city study (CHIP-3C)

International audienceBackground and Aims : Clonal hematopoiesis of indeterminate Potential (CHIP) is defined by the detection of leukemia-associated mutations in the absence of hematological malignancy. This condition is associated with an increased mortality mainly driven by athero-thrombotic complications. Previous studies in mouse models demonstrated that CHIP increase atherosclerosis development. However the association between CHIP, atherosclerosis and athero-thrombosis remains poorly evaluated in patients. Methods: The 3-city study is a population-based longitudinal study that enrolled individuals aged ≥65 years. In this cohort, we selected 322 persons who had no cardiovascular event before inclusion. Eighty five of them suffered from a myocardial infarction or stroke during the 12-year follow-up. We searched for CHIP by a targeted NGS strategy on DNA collected at inclusion. Anthropomorphic, cardiovascular (risk factors, diet, atherosclerosis) and biological (CRP level) data at inclusion as well as incidence of athero-thrombotic events were compared between patients with or without CHIP. Results: A CHIP was detected in 41% of patients. As described, most patients presented mutations in DNMT3A (46%) and TET2 (30%). Patients with CHIP were slightly older than patients without CHIP (74.2 years VS 73 years, p=0.03). Neither the cardiovascular risk profile, nor the CRP levels (1.66 VS 1.75), nor the number of atheromatous plaques nor the intima-media thickness (0.67 VS 0.68) were different between patients with and without CHIP. The incidence of athero-thrombotic complications (myocardial infarction or stroke) was similar between patients with a CHIP and patients without. Conclusions: In conclusion, CHIP, in particular involving DNMT3A mutations, are not strongly associated with systemic inflammation, atherosclerosis or athero-thrombotic events

Mucosal microbial load in Crohn's disease: A potential predictor of response to faecal microbiota transplantation

BACKGROUND: The remission of Crohn's disease (CD) can be accomplished by faecal microbiota transplantation (FMT). However, this procedure has a low success rate, which could be attributed to mis-communication between recipient intestinal mucosa and donor microbiota. METHODS: Here we used a human explant tissue model and an in vivo mouse model to examine changes in recipient intestinal mucosa upon contact with a faecal suspension (FS) obtained from a healthy donor. CD patients provided resected inflamed and non-inflamed mucosal tissues, whereas control colonic mucosa samples were collected from colorectal cancer patients. For the models, mucosal microbiome composition and tissue response were evaluated. FINDINGS: We show that cytokine release and tissue damage were significantly greater in inflamed compared to non-inflamed CD tissues. Moreover, mucosal samples harbouring an initial low microbial load presented a shift in composition towards that of the FS, an increase in the relative count of Faecalibacterium prausnitzii, and a higher secretion of anti-inflammatory cytokine IL-10 compared to those with a high microbial load. INTERPRETATION: Our results indicate that FMT during active inflammatory disease can compromise treatment outcome. We recommend the stratification of FMT recipients on the basis of tissue microbial load as a strategy to ensure successful colonization. FUNDING: This study was supported by grants from the Instituto de Salud Carlos III/FEDER (PI17/00614), the European Commission: (INCOMED-267128) and PERIS (SLT002/16). K.M. is a postdoctoral fellow and S.V. a senior clinical investigator of the Fund for Scientific Research Flanders, Belgium (FWO-Vlaanderen).status: publishe