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The Pretreatment Gut Microbiome Is Associated With Lack of Response to Methotrexate in New‐Onset Rheumatoid Arthritis
Author(s) -
Artacho Alejandro,
Isaac Sandrine,
Nayak Renuka,
FlorDuro Alejandra,
Alexander Margaret,
Koo Imhoi,
Manasson Julia,
Smith Philip B.,
Rosenthal Pamela,
Homsi Yamen,
Gulko Percio,
Pons Javier,
PuchadesCarrasco Leonor,
Izmirly Peter,
Patterson Andrew,
Abramson Steven B.,
PinedaLucena Antonio,
Turnbaugh Peter J.,
Ubeda Carles,
Scher Jose U.
Publication year - 2021
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41622
Subject(s) - microbiome , metagenomics , methotrexate , rheumatoid arthritis , ex vivo , gut microbiome , medicine , biology , immunology , bioinformatics , in vivo , gene , genetics
Objective Although oral methotrexate (MTX) remains the anchor drug for rheumatoid arthritis (RA), up to 50% of patients do not achieve a clinically adequate outcome. In addition, there is a lack of prognostic tools for treatment response prior to drug initiation. This study was undertaken to investigate whether interindividual differences in the human gut microbiome can aid in the prediction of MTX efficacy in new‐onset RA. Methods We performed 16S ribosomal RNA gene and shotgun metagenomic sequencing on the baseline gut microbiomes of drug‐naive patients with new‐onset RA (n = 26). Results were validated in an additional independent cohort (n = 21). To gain insight into potential microbial mechanisms, we conducted ex vivo experiments coupled with metabolomics analysis to evaluate the association between microbiome‐driven MTX depletion and clinical response. Results Our analysis revealed significant associations of the abundance of gut bacterial taxa and their genes with future clinical response (q < 0.05), including orthologs related to purine and MTX metabolism. Machine learning techniques were applied to the metagenomic data, resulting in a microbiome‐based model that predicted lack of response to MTX in an independent group of patients. Finally, MTX levels remaining after ex vivo incubation with distal gut samples from pretreatment RA patients significantly correlated with the magnitude of future clinical response, suggesting a possible direct effect of the gut microbiome on MTX metabolism and treatment outcomes. Conclusion Taken together, these findings are the first step toward predicting lack of response to oral MTX in patients with new‐onset RA and support the value of the gut microbiome as a possible prognostic tool and as a potential target in RA therapeutics.