TY - JOUR
T1 - Interleukin-17 Inhibition in Spondyloarthritis Is Associated With Subclinical Gut Microbiome Perturbations and a Distinctive Interleukin-25–Driven Intestinal Inflammation
AU - Manasson, Julia
AU - Wallach, David S.
AU - Guggino, Giuliana
AU - Stapylton, Matthew
AU - Badri, Michelle H.
AU - Solomon, Gary
AU - Reddy, Soumya M.
AU - Coras, Roxana
AU - Aksenov, Alexander A.
AU - Jones, Drew R.
AU - Girija, Parvathy V.
AU - Neimann, Andrea L.
AU - Heguy, Adriana
AU - Segal, Leopoldo N.
AU - Dorrestein, Pieter C.
AU - Bonneau, Richard
AU - Guma, Monica
AU - Ciccia, Francesco
AU - Ubeda, Carles
AU - Clemente, Jose C.
AU - Scher, Jose U.
N1 - Funding Information:
We would like to acknowledge Michael Colin, Kristen Lee, Gary Zagon, and Pamela Rosenthal for recruiting patients to our study. We would also like to thank Rhina Medina and Luz Alvarado for coordinating and collecting patient samples, Yonghua Li for helping set up the 16S rRNA sequencing runs, and Benjamin Wu for his advice with preliminary data analysis. We would like to acknowledge the NYU Langone Genome Technology Center for 16S rRNA sequencing, María Jose Garzón and the Sequencing and Bioinformatics Service of FISABIO for ITS sequencing, as well as the University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences and the NYU Metabolomics Core Resource Laboratory for performing metabolomics. Although not included in this manuscript, we would like to thank Sergei Koralov and Lu Yang for the animal work related to this project.
Publisher Copyright:
© 2019, American College of Rheumatology
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
KW - Antibodies, Monoclonal, Humanized/pharmacology
KW - Arthritis, Psoriatic/drug therapy
KW - Female
KW - Gastrointestinal Microbiome/drug effects
KW - Humans
KW - Inflammation/metabolism
KW - Interleukin-17/immunology
KW - Intestinal Mucosa/metabolism
KW - Intestines/drug effects
KW - Male
KW - Middle Aged
KW - Spondylarthritis/drug therapy
KW - Tumor Necrosis Factor Inhibitors/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85081304661&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85081304661&partnerID=8YFLogxK
U2 - 10.1002/art.41169
DO - 10.1002/art.41169
M3 - Article
C2 - 31729183
AN - SCOPUS:85081304661
SN - 2326-5191
VL - 72
SP - 645
EP - 657
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
IS - 4
ER -