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

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2020-04, Vol.72 (4), p.645-657
• Main Authors: Manasson, Julia, Wallach, David S., Guggino, Giuliana, Stapylton, Matthew, Badri, Michelle H., Solomon, Gary, Reddy, Soumya M., Coras, Roxana, Aksenov, Alexander A., Jones, Drew R., Girija, Parvathy V., Neimann, Andrea L., Heguy, Adriana, Segal, Leopoldo N., Dorrestein, Pieter C., Bonneau, Richard, Guma, Monica, Ciccia, Francesco, Ubeda, Carles, Clemente, Jose C., Scher, Jose U.
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Arthritis; Arthritis, Psoriatic - drug therapy; Arthritis, Psoriatic - metabolism; Arthritis, Psoriatic - microbiology; Bacteria; Biological effects; Biopsy; Computer applications; Correlation; Crohn's disease; Cytokines; Digestive system; Dysbacteriosis; Ecological effects; Fatty acids; Female; Fungi; Gastrointestinal Microbiome - drug effects; Gastrointestinal tract; Gene sequencing; Helper cells; Humans; Inflammation; Inflammation - metabolism; Inflammatory diseases; Interleukin-17 - immunology; Interleukins; Intestinal microflora; Intestinal Mucosa - metabolism; Intestine; Intestines - drug effects; Intestines - microbiology; Lymphocytes T; Lymphoid cells; Male; Medical treatment; Metabolic pathways; Metabolites; Metagenomics; Microbiomes; Microbiota; Middle Aged; Monoclonal antibodies; Pathogenesis; Patients; Psoriatic arthritis; Rheumatic diseases; rRNA 16S; Spondylarthritis - drug therapy; Spondylarthritis - metabolism; Spondylarthritis - microbiology; Subgroups; Tumor Necrosis Factor Inhibitors - pharmacology; Tumor Necrosis Factor Inhibitors - therapeutic use
• ISSN: 2326-5191; 2326-5205
• DOI: 10.1002/art.41169

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.