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Specific changes in faecal microbiota are associated with familial Mediterranean fever
  1. Samuel Deshayes1,2,3,
  2. Soraya Fellahi4,5,
  3. Jean-Philippe Bastard4,5,
  4. Jean-Marie Launay6,
  5. Jacques Callebert6,
  6. Thibault Fraisse2,
  7. David Buob7,
  8. Jean-Jacques Boffa8,
  9. Irina Giurgea9,
  10. Charlotte Dupont10,
  11. Sarah Jegou3,
  12. Marjolène Straube3,
  13. Alexandre Karras11,
  14. Achille Aouba1,
  15. Gilles Grateau2,
  16. Harry Sokol3,12,13,
  17. Sophie Georgin-Lavialle2
  18. AA Amyloidosis Study Group
    1. 1 Service de Médecine Interne, Normandie Univ, UNICAEN, CHU de Caen Normandie, 14000 Caen, France
    2. 2 Service de Médecine Interne, Centre de référence des maladies auto-inflammatoires et des amyloses inflammatoires (CEREMAIA), Sorbonne Université, Assistance Publique des Hôpitaux de Paris, Hôpital Tenon, Paris, France
    3. 3 Service de Gastroentérologie, Centre de Recherche Saint-Antoine, CRSA, Sorbonne Université, Inserm, AP-HP, Hôpital Saint-Antoine, F-75012 Paris, France
    4. 4 UF Biomarqueurs Inflammatoires et Métaboliques, Service de Biochimie, Assistance Publique des Hôpitaux de Paris, Hôpital Tenon, Paris, France
    5. 5 Centre de Recherche Saint-Antoine, IHU ICAN, Sorbonne Universités, UPMC Université Paris 06, INSERM UMRS 938, Paris, France
    6. 6 Service de Biochimie, INSERM UMR S942, Assistance Publique des Hôpitaux de Paris, Hôpital Lariboisière, Paris, France
    7. 7 Service d'Anatomopathologie, Assistance Publique des Hôpitaux de Paris, Hôpital Tenon, Paris, France
    8. 8 INSERM 1155, Sorbonne Université, AP-HP, Hôpital Tenon, F-75020 Paris, France
    9. 9 Service de Génétique Médicale, Assistance Publique des Hôpitaux de Paris, Hôpital Trousseau, Paris, France
    10. 10 INSERM équipe Lipodystrophies génétiques et acquises. Service de biologiede la reproduction-CECOS, Sorbonne Université, Saint Antoine Research Center, AP-HP, Hôpital Tenon, F-75020 Paris, France
    11. 11 Service de Néphrologie, Assistance Publique des Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
    12. 12 MICALIS Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
    13. 13 Service de Gastroentérologie, Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
    1. Correspondence to Professor Harry Sokol, Gastroenterology Department, Hôpital Saint-Antoine, APHP, 75571 Paris CEDEX 12, France; harry.sokol{at}gmail.com; Dr Sophie Georgin-Lavialle, Internal Medicine Department, Hôpital Tenon, APHP, 75020 Paris, France; sophie.georgin-lavialle{at}aphp.fr

    Abstract

    Objectives Familial Mediterranean fever (FMF) can be complicated by AA amyloidosis (AAA), though it remains unclear why only some patients develop amyloidosis. We examined the gut microbiota composition and inflammatory markers in patients with FMF complicated or not by AAA.

    Methods We analysed the gut microbiota of 34 patients with FMF without AAA, 7 patients with FMF with AAA, 19 patients with AAA of another origin, and 26 controls using 16S ribosomal RNA gene sequencing with the Illumina MiSeq platform. Associations between bacterial taxa and clinical phenotypes were evaluated using multivariate association with linear models statistical method. Blood levels of interleukin (IL)−1β, IL-6, tumour necrosis factor-α and adipokines were assessed by ELISA; indoleamine 2,3-dioxygenase (IDO) activity was determined by high-performance liquid chromatography.

    Results Compared with healthy subjects, specific changes in faecal microbiota were observed in FMF and AAA groups. Several operational taxonomic units (OTUs) were associated with FMF. Moreover, two OTUs were over-represented in FMF-related AAA compared with FMF without AAA. Additionally, higher adiponectin levels and IDO activity were observed in FMF-related AAA compared with FMF without AAA (p<0.05).

    Conclusion The presence of specific changes in faecal microbiota in FMF and in FMF-related AAA suggests that intestinal microorganisms may play a role in the pathogenesis of these diseases. These findings may offer an opportunity to use techniques for gut microbiota manipulation.

    • familial Mediterranean fever
    • AA amyloidosis
    • microbiota
    • adipokines
    • indoleamine 2,3-dioxygenase
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    Footnotes

    • HS and SG-L are joint senior authors.

    • Handling editor Josef S Smolen

    • Presented at This work was previously presented at the 77th Congress of the French National Society of Internal Medicine 2018.

    • Collaborators The AA Amyloidosis Study Group includes Serge Amselem (Service de Génétique Médicale, Hôpital Trousseau, Assistance Publique des Hôpitaux de Paris, Paris, France), Camille Louvrier (Service de Génétique Médicale, Hôpital Trousseau, Assistance Publique des Hôpitaux de Paris, Paris, France), Léa Savey (Service de Médecine Interne, Hôpital Tenon, Assistance Publique des Hôpitaux de Paris, Paris, France), Joris Galland (Service de Néphrologie, Hôpital Tenon, Assistance Publique des Hôpitaux de Paris, Paris, France), Nicolas Martin Silva (Service de Médecine Interne, CHU de Caen, Caen, France), Antoine Hankard (Service de Médecine Interne, CHU de Caen, Caen, France), Alexandre Cez (Service de Néphrologie et Dialyse, Hôpital Tenon, Assistance Publique des Hôpitaux de Paris, Paris, France), Pierre-Antoine Michel (Service de Néphrologie et Dialyse, Hôpital Tenon, Assistance Publique des Hôpitaux de Paris, Paris, France), David Saadoun (Service de Médecine Interne et Immunologie Clinique, Groupe Hospitalier Pitié Salpétrière, Assistance Publique des Hôpitaux de Paris, Paris, France), Bertrand Knebelmann (Service de Néphrologie et de Transplantation, Hôpital Necker, Assistance Publique des Hôpitaux de Paris, Paris, France), Alexandre Hertig (Service de Néphrologie, Hôpital Tenon, Assistance Publique des Hôpitaux de Paris, Paris, France), Corinne Isnard Bagnis (Service de Néphrologie, Groupe Hospitalier Pitié Salpétrière, Assistance Publique des Hôpitaux de Paris, Paris, France), Tristan Legris (Service de Néphrologie, Hôpital de la Conception, Assistance Publique des Hôpitaux de Marseille, Marseille, France) and Xavier Belenfant (Service de Néphrologie, Centre Hospitalier Intercommunal André Grégoire, Montreuil, France).

    • Contributors SD, SG-L, HS, AA and GG designed the study, initiated this work and wrote the report. SD, SG-L and HS performed all statistical analyses. SD, SF, J-PB, J-ML, JC, SJ, MS, TF, SG-L and HS contributed to the sample preparation and carried out the experiments. SG-L, HS, AA, J-JB, AK and GG provided and cared for the study patients. All authors made substantial contributions to the acquisition of data, revised the article critically and gave the final approval of the manuscript to be submitted.

    • Funding This work was financed by a grant from Groupe Pasteur Mutualité and from the French Amyloidosis Association.

    • Competing interests None.

    • Patient consent for publication Not required.

    • Ethics approval The study was approved by the ethics committee (Comité de Protection des Personnes – Ile de France VI, n°DC-2015–2586) and was conducted in compliance with good clinical practices and the Declaration of Helsinki principles.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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