Alejandro Artacho1, Sandrine Isaac1, Renuka Nayak2, Alejandra Flor-Duro1, Margaret Alexander2, Imhoi Koo3, Julia Manasson4, Philip B Smith3, Pamela Rosenthal4, Yamen Homsi5, Percio Gulko6, Javier Pons1, Leonor Puchades-Carrasco7, Peter Izmirly4, Andrew Patterson3, Steven B Abramson4, Antonio Pineda-Lucena8, Peter J Turnbaugh9, Carles Ubeda10, Jose U Scher4. 1. Center for Public Health Research, FISABIO, Valencia, Spain. 2. University of California, San Francisco. 3. Pennsylvania State University, University Park. 4. New York University School of Medicine and NYU Langone Orthopedic Hospital, New York. 5. NYU Langone Hospital, Brooklyn, New York. 6. Mount Sinai School of Medicine, New York, New York. 7. Centro de Investigación Príncipe Felipe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain. 8. Centro de Investigación Príncipe Felipe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain, and Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain. 9. University of California and Chan Zuckerberg Biohub, San Francisco, California. 10. Centro Superior de Investigación en Salud Pública, La Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, Valencia, Spain, and CIBERESP, Madrid, Spain.
Abstract
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.
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.
Authors: Georg Schett; Proton Rahman; Christopher Ritchlin; Iain B McInnes; Dirk Elewaut; Jose U Scher Journal: Nat Rev Rheumatol Date: 2022-05-05 Impact factor: 20.543
Authors: Peter Spanogiannopoulos; Than S Kyaw; Ben G H Guthrie; Patrick H Bradley; Joyce V Lee; Jonathan Melamed; Ysabella Noelle Amora Malig; Kathy N Lam; Daryll Gempis; Moriah Sandy; Wesley Kidder; Erin L Van Blarigan; Chloe E Atreya; Alan Venook; Roy R Gerona; Andrei Goga; Katherine S Pollard; Peter J Turnbaugh Journal: Nat Microbiol Date: 2022-09-22 Impact factor: 30.964
Authors: Mihnea R Mangalea; David Paez-Espino; Kristopher Kieft; Anushila Chatterjee; Meagan E Chriswell; Jennifer A Seifert; Marie L Feser; M Kristen Demoruelle; Alexandra Sakatos; Karthik Anantharaman; Kevin D Deane; Kristine A Kuhn; V Michael Holers; Breck A Duerkop Journal: Cell Host Microbe Date: 2021-05-05 Impact factor: 21.023
Authors: Renuka R Nayak; Margaret Alexander; Ishani Deshpande; Kye Stapleton-Gray; Bipin Rimal; Andrew D Patterson; Carles Ubeda; Jose U Scher; Peter J Turnbaugh Journal: Cell Host Microbe Date: 2021-01-12 Impact factor: 21.023