Interleukin-17 Inhibition in Spondyloarthritis Is Associated With Subclinical Gut Microbiome Perturbations and a Distinctive Interleukin-25–Driven Intestinal Inflammation

Julia Manasson, David S. Wallach, Giuliana Guggino, Matthew Stapylton, Michelle H. Badri, Gary Solomon, Soumya M. Reddy, Roxana Coras, Alexander A. Aksenov, Drew R. Jones, Parvathy V. Girija, Andrea L. Neimann, Adriana Heguy, Leopoldo N. Segal, Pieter C. Dorrestein, Richard Bonneau, Monica Guma, Francesco Ciccia, Carles Ubeda, Jose C. ClementeJose U. Scher

Research output: Contribution to journalArticle

Abstract

Objective: To characterize the ecological effects of biologic therapies on the gut bacterial and fungal microbiome in psoriatic arthritis (PsA)/spondyloarthritis (SpA) patients. Methods: Fecal samples from PsA/SpA patients pre- and posttreatment with tumor necrosis factor inhibitors (TNFi; n = 15) or an anti–interleukin-17A monoclonal antibody inhibitor (IL-17i; n = 14) underwent sequencing (16S ribosomal RNA, internal transcribed spacer and shotgun metagenomics) and computational microbiome analysis. Fecal levels of fatty acid metabolites and cytokines/proteins implicated in PsA/SpA pathogenesis or intestinal inflammation were correlated with sequence data. Additionally, ileal biopsies obtained from SpA patients who developed clinically overt Crohn's disease (CD) after treatment with IL-17i (n = 5) were analyzed for expression of IL-23/Th17–related cytokines, IL-25/IL-17E–producing cells, and type 2 innate lymphoid cells (ILC2s). Results: There were significant shifts in abundance of specific taxa after treatment with IL-17i compared to TNFi, particularly Clostridiales (P = 0.016) and Candida albicans (P = 0.041). These subclinical alterations correlated with changes in bacterial community co-occurrence, metabolic pathways, IL-23/Th17–related cytokines, and various fatty acids. Ileal biopsies showed that clinically overt CD was associated with expansion of IL-25/IL-17E–producing tuft cells and ILC2s (P < 0.05), compared to pre–IL-17i treatment levels. Conclusion: In a subgroup of SpA patients, the initiation of IL-17A blockade correlated with features of subclinical gut inflammation and intestinal dysbiosis of certain bacterial and fungal taxa, most notably C albicans. Further, IL-17i–related CD was associated with overexpression of IL-25/IL-17E–producing tuft cells and ILC2s. These results may help to explain the potential link between inhibition of a specific IL-17 pathway and the (sub)clinical gut inflammation observed in SpA.

Original languageEnglish (US)
Pages (from-to)645-657
Number of pages13
JournalArthritis and Rheumatology
Volume72
Issue number4
DOIs
StatePublished - Apr 1 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

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