The evolution of human health is a continuum of transitions, involving multifaceted processes at multiple levels, and there is an urgent need for integrative biomarkers that can characterize and predict progression toward disease development. The objective of this work was to perform a systems metabolomics approach to predict metabolic syndrome (MetS) development. A case-control design was used within the French occupational GAZEL cohort (n = 112 males: discovery study; n = 94: replication/validation study). Our integrative strategy was to combine untargeted metabolomics with clinical, sociodemographic, and food habit parameters to describe early phenotypes and build multidimensional predictive models. Different models were built from the discriminant variables, and prediction performances were optimized either when reducing the number of metabolites used or when keeping the associated signature. We illustrated that a selected reduced metabolic profile was able to reveal subtle phenotypic differences 5 years before MetS occurrence. Moreover, resulting metabolomic markers, when combined with clinical characteristics, allowed improving the disease development prediction. The validation study showed that this predictive performance was specific to the MetS component. This work also demonstrates the interest of such an approach to discover subphenotypes that will need further characterization to be able to shift to molecular reclassification and targeting of MetS.

Epidemiological studies have associated red meat intake with risk of colorectal cancer. Experimental studies explain this positive association by the oxidative properties of heme iron released in the colon. This latter is a potent catalyst for lipid peroxidation, resulting in the neoformation of deleterious aldehydes in the fecal water of heme-fed rats. The toxicity of fecal water of heme-fed rats was associated to such lipid peroxidation. This study demonstrated that fecal water of hemoglobin- and beef-fed rats preferentially induced apoptosis in mouse normal colon epithelial cells than in those carrying mutation on Apc (Adenomatous polyposis coli) gene, considered as preneoplastic. Highlighting the importance of lipid peroxidation and neoformation of secondary aldehydes like 4-hydroxy-2-nonenal (HNE), we optimized the depletion of carbonyl compounds in the fecal water which turned out to abolish the differential apoptosis in both cell lines. To explain the resistance of preneoplastic cells towards fecal water toxicity, we focused on Nrf2, known to be activated by aldehydes, including HNE. Fecal water activated Nrf2 in both cell lines, associated with the induction of Nrf2-target genes related to aldehydes detoxification. However, the antioxidant defense appeared to be higher in preneoplastic cells, favoring their survival, as evidenced by Nrf2 inactivation. Taken together, our results suggest that Nrf2-dependent antioxidant response was involved in the resistance of preneoplastic cells upon exposure to fecal water of hemoglobin- and beef-fed rats. This difference could explain the promoting effect of red meat and heme-enriched diet on colorectal cancer, by initiating positive selection of preneoplastic cells.

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