Dragos Ciocan, MD, PhD; Anne-Marie Cassard, PhD; Laurent Becquemont, MD; Céline Verstuyft, MD; Cosmin Sebastian Voican, MD, PhD; Khalil El Asmar, PhD; Romain Colle, MD, PhD; Denis David, PhD; Séverine Trabado, PhD; Bruno Feve, MD; Philippe Chanson, MD; Gabriel Perlemuter*, MD, PhD; Emmanuelle Corruble*, MD
Background: The microbiota interacts with the brain through the gut–brain axis, and a distinct dysbiosis may lead to major depressive episodes. Bacteria can pass through the gut barrier and be found in the blood. Using a multiomic approach, we investigated whether a distinct blood microbiome and metabolome was associated with major depressive episodes, and how it was modulated by treatment.
Methods: In this case–control multiomic study, we analyzed the blood microbiome composition, inferred bacterial functions and metabolomic profile of 56 patients experiencing a current major depressive episode and 56 matched healthy controls, before and after treatment, using 16S rDNA sequencing and liquid chromatography coupled to tandem mass spectrometry.
Results: The baseline blood microbiome in patients with a major depressive episode was distinct from that of healthy controls (patients with a major depressive episode had a higher proportion of Janthinobacterium and lower levels of Neisseria) and changed after antidepressant treatment. Predicted microbiome functions confirmed by metabolomic profiling showed that patients who were experiencing a major depressive episode had alterations in the cyanoamino acid pathway at baseline. High baseline levels of Firmicutes and low proportions of Bosea and Tetrasphaera were associated with response to antidepressant treatment. Based on inferred baseline metagenomic profiles, bacterial pathways that were significantly associated with treatment response were related to xenobiotics, amino acids, and lipid and carbohydrate metabolism, including tryptophan and drug metabolism. Metabolomic analyses showed that plasma tryptophan levels are independently associated with response to antidepressant treatment.
Limitations: Our study has some limitations, including a lack of information on blood microbiome origin and the lack of a validation cohort to confirm our results.
Conclusion: Patients with depression have a distinct blood microbiome and metabolomic signature that changes after treatment. Dysbiosis could be a new therapeutic target and prognostic tool for the treatment of patients who are experiencing a major depressive episode.
Submitted Aug. 12, 2020; Revised Jan. 7, 2021, Accepted Jan. 26, 2021
Acknowledgments: This study was funded by the Programme Hospitalier de Recherche Clinique National of the French Ministry of Health (AOM06022 for the METADAP study and AOM09122 for the VARIETE study) and sponsored by the Assistance Publique-Hôpitaux de Paris (NCT01831648). The biobank METADAP is stored in CRB Paris South (BRIF: BB-0033-00089).
Affiliations: From the INSERM UMRS 996 — Intestinal Microbiota, Macrophages and Liver Inflammation, DHU Hepatinov, Clamart, France (Ciocan, Cassard, Voican, Perlemuter); the University Paris-Saclay, University Paris-Sud, Faculty of Medicine, Le Kremlin-Bicêtre, France (Ciocan, Cassard, Becquemont, Verstuyft, Voican, El Asmar, Colle, Trabado, Chanson, Perlemuter, Corruble); the APHP, Hepato-Gastroenterology and Nutrition, Antoine-Béclère Hospital, Clamart, France (Ciocan, Voican, Perlemuter); the Centre for Clinical Research (CRC), Kremlin-Bicêtre Hospital, AP-HP, Le Kremlin-Bicêtre, France (Becquemont); the INSERM UMR-1178, CESP, “MOODS” Team, Le Kremlin-Bicêtre, France (Becquemont, Verstuyft, El Asmar, David, Corruble); the Department of Molecular Genetics, Pharmacogenetics and Hormones, Kremlin-Bicêtre Hospital, AP-HP, Le Kremlin-Bicêtre, 94275, France (Becquemont, Verstuyft, Trabado); the Psychiatry Department, Kremlin-Bicêtre Hospital, AP-HP, Le Kremlin-Bicêtre, 94275, France (Colle, Corruble); the University Paris-Saclay, University Paris-Sud, Faculty of Pharmacy, Chatenay-Malabry, 92 296, France (David); the INSERM 1185, University Paris-Saclay, University Paris-Sud, Faculty of Medicine, Le Kremlin-Bicêtre, 94276, France (Trabado, Chanson); the Department of Endocrinology, Saint-Antoine Hospital, AP-HP, Sorbonne University, University Paris 6, Paris, France (Feve); the INSERM UMR S_938, Saint-Antoine Research Centre, Paris, France (Feve); and the Department of Endocrinology and Reproductive Diseases, Kremlin-Bicêtre Hospital, AP-HP, Le Kremlin-Bicêtre, 94275, France (Chanson).
Competing interests: D. David serves as a consultant for and receives compensation from Lundbeck. G. Perlemuter reports grants and personal fees from Servier (IRIS); personal fees and non-financial support from Gilead; personal fees from Bicodex, Pileje, Elsevier Masson, Flammarion and Solar; and non-financial support from Abbvie, all outside the submitted work. No other competing interests declared.
Contributors: D. Ciocan, A.-M. Cassard, L. Becquemont, C. Verstuyft, S. Trabado, G. Perlemuter and E. Corruble designed the study. D. Ciocan, C. Verstuyft, C. Voican, P. Chanson and E. Corruble acquired the data, which D. Ciocan, A.-M. Cassard, K. El Asmar, R. Colle, D. David, B. Feve, G. Perlemuter and E. Corruble analyzed. D. Ciocan, L. Becquemont, D. David and E. Corruble wrote the article, which A.-M. Cassard, C. Verstuyft, C. Voican, K. El Asmar, R. Colle, S. Trabado, B. Feve, P. Chanson, G. Perlemuter and E. Corruble reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.
Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BYNC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/
Correspondence to: E. Corruble, Service de Psychiatrie, Hôpital de Bicêtre, 78 Rue du Général Leclerc, Le Kremlin Bicêtre, F-94275, France, email@example.com; G. Perlemuter, Service d’Hépato-Gastroentérologie et Nutrition, Hôpital Antoine-Béclère, 157 rue de la Porte de Trivaux, Clamart, F-92141, France, firstname.lastname@example.org