Artacho A, Isaac S, Nayak R, et al. - In view of the observations that a clinically adequate outcome is not achieved in up to 50% of patients with RA despite oral methotrexate (MTX) being the anchor drug for RA, researchers sought to determine if MTX efficacy in new‐onset RA (NORA) can be predicted by assessing inter‐individual differences in the human gut microbiome. They performed 16S rRNA gene and shotgun metagenomic sequencing on the baseline gut microbiomes of drug‐naïve, NORA patients (n = 26). Validation of results was done in an additional independent cohort (n = 21). They performed ex vivo experiments coupled with metabolomics analysis evaluating the correlation between microbiome‐driven MTX depletion and clinical response to attain insight into potential microbial mechanisms. Significant relationships were identified between the abundance of gut bacterial taxa and their genes with future clinical response, including orthologs related to purine and methotrexate metabolism. A microbiome‐based model was developed that predicted lack of response to MTX in an independent group of patients via applying machine learning techniques to the metagenomic data. Finally, MTX levels remaining after ex vivo incubation with distal gut samples from pre‐treatment RA patients significantly linked with the magnitude of future clinical response, indicating that the gut microbiome possibly have direct influence on MTX metabolism and treatment outcomes.