Interleukin-17 Inhibition in Spondyloarthritis Is Associated With Subclinical Gut Microbiome Perturbations and a Distinctive Interleukin-25-Driven Intestinal Inflammation
Por:
Manasson J, Wallach DS, Guggino G, Stapylton M, Badri MH, Solomon G, Reddy SM, Coras R, Aksenov AA, Jones DR, Girija PV, Neimann AL, Heguy A, Segal LN, Dorrestein PC, Bonneau R, Guma M, Ciccia F, Ubeda C, Clemente JC and Scher JU
Publicada:
1 abr 2020
Ahead of Print:
12 mar 2020
Resumen:
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.
Filiaciones:
Manasson J:
Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY, USA
Wallach DS:
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Guggino G:
Dipartimento di Promozione della Salute, Materno-Infantile, Medicina Interna e Specialistica di Eccellenza "G. D'Alessandro" (PROMISE), University of Palermo, Palermo, Italy
Stapylton M:
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Badri MH:
Flatiron Institute, Center for Computational Biology, Simons Foundation, New York, NY, US
Solomon G:
Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY, USA
Reddy SM:
Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY, USA
Coras R:
Division of Rheumatology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
Aksenov AA:
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
Jones DR:
NYU Metabolomics Core Resource Laboratory, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA
Girija PV:
Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY, USA
Neimann AL:
Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA
Heguy A:
NYU Langone Health Genome Technology Center, Department of Pathology, New York University School of Medicine, New York, NY, USA
Segal LN:
Division of Pulmonary Critical Care, Department of Medicine, New York University School of Medicine, New York, NY, USA
Dorrestein PC:
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
Bonneau R:
Flatiron Institute, Center for Computational Biology, Simons Foundation, New York, NY, US
Richard Bonneau, PhD: Department of Biology, New York University, New York, NY, USA
Department of Computer Science, Courant Institute of Mathematical Sciences, New York, NY, USA
Guma M:
Division of Rheumatology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
Ciccia F:
Dipartimento di Medicina di Precisione, University of Naples, Naples, Italy
:
Centro Superior de Investigación en Salud Pública - FISABIO, Valencia, Spain
CIBER en Epidemiología y Salud Pública, Madrid, Spain
Clemente JC:
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Scher JU:
Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY, USA
Green Submitted, Green Accepted
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