The Pretreatment Gut Microbiome Is Associated With Lack of Response to Methotrexate in New-Onset Rheumatoid Arthritis.
Administration, Oral
Adult
Antirheumatic Agents
/ metabolism
Arthritis, Rheumatoid
/ drug therapy
Bacteroidetes
/ genetics
Clostridiales
/ genetics
Cohort Studies
Escherichia
/ genetics
Euryarchaeota
/ genetics
Female
Firmicutes
/ genetics
Gastrointestinal Microbiome
/ genetics
Humans
Machine Learning
Male
Metabolomics
Metagenomics
Methotrexate
/ metabolism
Middle Aged
Prognosis
RNA, Ribosomal, 16S
Shigella
/ genetics
Treatment Outcome
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
revised:
15
11
2020
received:
03
07
2020
accepted:
02
12
2020
pubmed:
15
12
2020
medline:
13
8
2021
entrez:
14
12
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Substances chimiques
Antirheumatic Agents
0
RNA, Ribosomal, 16S
0
Methotrexate
YL5FZ2Y5U1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
931-942Subventions
Organisme : NIAID NIH HHS
ID : T32 AI060537
Pays : United States
Organisme : NIAMS NIH HHS
ID : K08AR073930
Pays : United States
Organisme : National Institute of Allergy and Infectious Diseases
ID : R01HL122593
Organisme : NIAMS NIH HHS
ID : R01AR074500
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020, American College of Rheumatology.
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