Effects of Mediterranean Diet on plasma metabolites and their relationship with insulin resistance and gut microbiota composition in a crossover randomized clinical trial

  • Serena Galié
    Affiliations
    Department of Biochemistry and Biotechnology, Faculty of Medicine and Health Sciences, University Rovira i Virgili (URV), Reus, Spain

    Institute of Health Pere Virgili, IISPV, University Hospital Sant Joan, Reus, Spain

    Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
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  • Jesús García-Gavilán
    Affiliations
    Department of Biochemistry and Biotechnology, Faculty of Medicine and Health Sciences, University Rovira i Virgili (URV), Reus, Spain

    Institute of Health Pere Virgili, IISPV, University Hospital Sant Joan, Reus, Spain

    Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
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  • Christopher Papandreou
    Correspondence
    Corresponding author. Institute of Health Pere Virgili, IISPV, University Hospital Sant Joan, Reus, Spain.
    Affiliations
    Department of Biochemistry and Biotechnology, Faculty of Medicine and Health Sciences, University Rovira i Virgili (URV), Reus, Spain

    Institute of Health Pere Virgili, IISPV, University Hospital Sant Joan, Reus, Spain

    Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
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  • Lucía Camacho-Barcía
    Affiliations
    Department of Biochemistry and Biotechnology, Faculty of Medicine and Health Sciences, University Rovira i Virgili (URV), Reus, Spain

    Institute of Health Pere Virgili, IISPV, University Hospital Sant Joan, Reus, Spain

    Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
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  • Pierre Arcelin
    Affiliations
    ABS Reus V. Centre d'Assistència Primària Marià Fortuny, SAGESSA, Reus, Spain
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  • Antoni Palau-Galindo
    Affiliations
    ABS Reus V. Centre d'Assistència Primària Marià Fortuny, SAGESSA, Reus, Spain
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  • Antoni Rabassa
    Affiliations
    Institute of Health Pere Virgili, IISPV, University Hospital Sant Joan, Reus, Spain
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  • Mònica Bulló
    Correspondence
    Corresponding author. Department of Biochemistry and Biotechnology, Faculty of Medicine and Health Sciences, Institute of Health Pere Virgili, IISPV, C/ Sant Llorenç 21 43201, Reus, Spain.
    Affiliations
    Department of Biochemistry and Biotechnology, Faculty of Medicine and Health Sciences, University Rovira i Virgili (URV), Reus, Spain

    Institute of Health Pere Virgili, IISPV, University Hospital Sant Joan, Reus, Spain

    Consorcio CIBER, M.P. Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
    Search for articles by this author
Published:April 26, 2021DOI:https://doi.org/10.1016/j.clnu.2021.04.028

      Summary

      Background & aims

      The Mediterranean Diet (MedDiet) may decrease the cardiometabolic risk through modulation of metabolic pathways. Furthermore, the interplay between MedDiet, metabolites and microbial metabolism may improve our understanding on the metabolic effects of this diet. We aimed to evaluate the effect of the MedDiet compared to nuts supplementation on circulating metabolites and their relationship with cardiometabolic health. We further examined whether changes in the metabolomic profiles were associated with changes in gut microbiota composition in a multi-omics integrative approach.

      Methods

      Forty-four adults with Metabolic Syndrome (MetS), (aged 37–65) participated in a randomized controlled, crossover 2-months dietary-intervention trial with a 1-month wash-out period, consuming a MedDiet or a non MedDiet plus nuts (50 g/day). Nutritional data were collected at the beginning and the end of each intervention period using 3-day dietary records, as well as fasting blood and fecal samples. Plasma metabolites (m = 378) were profiled using targeted metabolomics. Associations of these metabolites with the interventions were assessed with elastic net regression analyses. Gut microbiota composition was assessed by 16S rRNA sequencing. A sparse least regression analysis combined with a canonical correlation analysis was conducted between the plasma selected metabolites and genera in order to identify the relevant dual-omics signatures discriminating the dietary interventions.

      Results

      Changes in 65 circulating metabolites were significantly associated with the MedDiet (mainly lipids, acylcarnitines, amino acids, steroids and TCA intermediates). Importantly, these changes were associated with decreases in glucose, insulin and HOMA-IR. The network analysis identified two main clusters of genera with an opposite behaviour towards selected metabolites, mainly PC species, ChoE(20:5), TGs and medium/long-chain acylcarnitines.

      Conclusion

      Following a MedDiet, rather than consuming nuts in the context of a non-MedDiet was associated with a specific plasma metabolomic profile, which was also related to metabolic improvements in adults with MetS. The identified correlated network between specific bacteria and metabolites suggests interplay between diet, circulating metabolites and gut microbiota.
      The trial was registered in the ISRCTN with identifier ISRCTN88780852, https://doi.org/10.1186/ISRCTN88780852.

      Keywords

      Abbreviations:

      CVD (cardiovascular disease), GC-QTOF-MS (gas chromatography time-of-flight mass spectrometry), HOMA-IR (homeostasis model assessment of insulin resistance), LC-Q-TOF-MS (liquid chromatography quadrupole time-of-flight mass spectrometry), LC-QqQ-MS (liquid chromatography with triple-quadrupole mass spectrometry), LPC (lysophosphocholine), LPE (lysophosphoethanolamine), MedDiet (Mediterranean diet), MetS (metabolic syndrome), PC (phosphocholine), T2D (type-2 diabetes), TG (triglyceride), TMA (trimethylamine), TMAO (trimethylamine N-oxide), TCA (tricarboxylic acid)
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