In the past three decades, extraordinary advances have been made in the understanding of the pathogenesis of, and treatment options for, inflammatory arthritides, including rheumatoid arthritis and spondyloarthritis. The use of methotrexate and subsequently biologic therapies (such as TNF inhibitors, among others) and oral small molecules have substantially improved clinical outcomes for many patients with inflammatory arthritis; for others, however, these agents do not substantially improve their symptoms. The emerging field of pharmacomicrobiomics, which investigates the effect of variations within the human gut microbiome on drugs, has already provided important insights into these therapeutics. Pharmacomicrobiomic studies have demonstrated that human gut microorganisms and their enzymatic products can affect the bioavailability, clinical efficacy and toxicity of a wide array of drugs through direct and indirect mechanisms. This discipline promises to facilitate the advent of microbiome-based precision medicine approaches in inflammatory arthritis, including strategies for predicting response to treatment and for modulating the microbiome to improve response to therapy or reduce drug toxicity.
Culture-independent, high-throughput DNA and RNA sequencing technologies —coupled with deeper insight into host mucosal immunology — have substantially advanced our understanding of the role of microorganisms in modulating health and disease.
Pharmacomicrobiomics, an emerging field that describes the complex interaction of drugs with the microbiome, is increasingly considered an important factor in the prediction of therapeutic responses in many medical subspecialties.
Multiple tools, including ex vivo cultures, metabolomics and gnotobiotic experiments, have enabled a deeper mechanistic understanding of host–microbial interactions in the pharmacokinetics of many available drugs.
Emerging evidence supports the notion that the bioavailability, clinical efficacy and toxicity of several drugs used to treat human inflammatory arthritis can be modulated by human gut microorganisms and their enzymatic products.
Pharmacomicrobiomics could potentially be incorporated into precision medicine approaches in rheumatology.
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McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).
Gladman, D. D., Antoni, C., Mease, P., Clegg, D. O. & Nash, P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann. Rheum. Dis. 64, ii14–ii17 (2005).
Barnas, J. L. & Ritchlin, C. T. Etiology and pathogenesis of psoriatic arthritis. Rheum. Dis. Clin. North Am. 41, 643–663 (2015).
Taurog, J. D., Chhabra, A. & Colbert, R. A. Ankylosing spondylitis and axial spondyloarthritis. N. Engl. J. Med. 374, 2563–2574 (2016).
Keffer, J. et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 10, 4025–4031 (1991).
McInnes, I. B. et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 386, 1137–1146 (2015).
Mease, P. J. et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 52, 3279–3289 (2005).
Emery, P. et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet 372, 375–382 (2008).
Liu, W. et al. Efficacy and safety of TNF-alpha inhibitors for active ankylosing spondylitis patients: multiple treatment comparisons in a network meta-analysis. Sci. Rep. 6, 32768 (2016).
Baeten, D. et al. Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N. Engl. J. Med. 373, 2534–2548 (2015).
Lee, E. B. et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N. Engl. J. Med. 370, 2377–2386 (2014).
Gladman, D. et al. Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors. N. Engl. J. Med. 377, 1525–1536 (2017).
Kavanaugh, A. et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann. Rheum. Dis. 73, 1020–1026 (2014).
Abdollahi-Roodsaz, S., Abramson, S. B. & Scher, J. U. The metabolic role of the gut microbiota in health and rheumatic disease: mechanisms and interventions. Nat. Rev. Rheumatol. 12, 446–455 (2016).
Curtis, J. R. et al. Use of a validated algorithm to estimate the annual cost of effective biologic treatment for rheumatoid arthritis. J. Med. Econ. 17, 555–566 (2014).
Scher, J. U. & Abramson, S. B. The microbiome and rheumatoid arthritis. Nat. Rev. Rheumatol. 7, 569–578 (2011).
Scher, J. U. et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2, e01202 (2013).
Scher, J. U. et al. Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol. 67, 128–139 (2015).
Koppel, N., Maini Rekdal V. & Balskus E. P. Chemical transformation of xenobiotics by the human gut microbiota. Science 356, eaag2770 (2017).
Saad, R., Rizkallah, M. R. & Aziz, R. K. Gut pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes. Gut Pathog. 4, 16 (2012).
Doestzada, M. et al. Pharmacomicrobiomics: a novel route towards personalized medicine? Protein Cell 9, 432–445 (2018).
Rizkallah M. S. R. & Aziz, R. K. The Human Microbiome Project, personalized medicine and the birth of pharmacomicrobiomics. Curr. Pharmacogenomics Person. Med. 8, 182–193 (2010).
JeT, Tréfouël, Nitti, F. & Bovet, D. Activité du p-aminophénylsulfamide surl’infection streptococcique expérimentar de la souris et du lapin. CR Soc. Biol. 120, 23 (1935).
Butler, V., Neu, H. & Lindenbaum, J. Digoxin-inactivating bacteria: identification in human gut flora. Science 220, 325–327 (1983).
Jobin, C. Precision medicine using microbiota. Science 359, 32–34 (2018).
Kuntz, T. M. & Gilbert, J. A. Introducing the microbiome into precision medicine. Trends Pharmacol. Sci. 38, 81–91 (2017).
Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).
Gensollen, T., Iyer, S. S., Kasper, D. L. & Blumberg, R. S. How colonization by microbiota in early life shapes the immune system. Science 352, 539–544 (2016).
Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).
Nicholson, J. K. et al. Host-gut microbiota metabolic interactions. Science 336, 1262–1267 (2012).
Honda, K. & Littman, D. R. The microbiome in infectious disease and inflammation. Annu. Rev. Immunol. 30, 759–795 (2012).
Sousa, T. et al. The gastrointestinal microbiota as a site for the biotransformation of drugs. Int. J. Pharm. 363, 1–25 (2008).
Birer, C. & Wright, E. S. Capturing the complex interplay between drugs and the intestinal microbiome. Clin. Pharmacol. Ther. 106, 501–504 (2019).
Maini Rekdal, V., Bess, E. N., Bisanz, J. E., Turnbaugh, P. J. & Balskus, E. P. Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism. Science 364, eaau6323 (2019).
Peppercorn, M. A. & Goldman, P. The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J. Pharmacol. Exp. Ther. 181, 555–562 (1972).
Nayak, R. R. & Turnbaugh, P. J. Mirror, mirror on the wall: which microbiomes will help heal them all? BMC Med. 14, 72 (2016).
Sharma, A. K., Jaiswal, S. K., Chaudhary, N. & Sharma, V. K. A novel approach for the prediction of species-specific biotransformation of xenobiotic/drug molecules by the human gut microbiota. Sci. Rep. 7, 9751 (2017).
Spanogiannopoulos, P., Bess, E. N., Carmody, R. N. & Turnbaugh, P. J. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat. Rev. Microbiol. 14, 273–287 (2016).
Gill, S. R. et al. Metagenomic analysis of the human distal gut microbiome. Science 312, 1355 (2006).
Human Microbiome Project. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).
Holmes, E. et al. Therapeutic modulation of microbiota-host metabolic interactions. Sci. Transl Med. 4, 137rv136 (2012).
Zimmermann, M., Zimmermann-Kogadeeva, M., Wegmann, R. & Goodman, A. L. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature 570, 462–467 (2019).
Couteau, D., McCartney, A. L., Gibson, G. R., Williamson, G. & Faulds, C. B. Isolation and characterization of human colonic bacteria able to hydrolyse chlorogenic acid. J. Appl. Microbiol. 90, 873–881 (2001).
Lindenbaum, J., Rund, D. G., Butler, V. P. Jr., Tse-Eng, D. & Saha, J. R. Inactivation of digoxin by the gut flora: reversal by antibiotic therapy. N. Engl. J. Med. 305, 789–794 (1981).
Haiser, H. J. et al. Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta. Science 341, 295–298 (2013).
Haiser, H. J., Seim, K. L., Balskus, E. P. & Turnbaugh, P. J. Mechanistic insight into digoxin inactivation by Eggerthella lenta augments our understanding of its pharmacokinetics. Gut Microbes 5, 233–238 (2014).
Koppel, N., Bisanz, J. E., Pandelia, M. E., Turnbaugh, P. J. & Balskus, E. P. Discovery and characterization of a prevalent human gut bacterial enzyme sufficient for the inactivation of a family of plant toxins. eLife 7, e33953 (2018).
Niehues, M. & Hensel, A. In-vitro interaction of L-dopa with bacterial adhesins of Helicobacter pylori: an explanation for clinicial differences in bioavailability? J. Pharm. Pharmacol. 61, 1303–1307 (2009).
LoGuidice, A., Wallace, B. D., Bendel, L., Redinbo, M. R. & Boelsterli, U. A. Pharmacologic targeting of bacterial beta-glucuronidase alleviates nonsteroidal anti-inflammatory drug-induced enteropathy in mice. J. Pharmacol. Exp. Ther. 341, 447–454 (2012).
Bjorkholm, B. et al. Intestinal microbiota regulate xenobiotic metabolism in the liver. PLoS One 4, e6958 (2009).
Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).
Tang, W. H. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. 368, 1575–1584 (2013).
Craciun, S. & Balskus, E. P. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc. Natl Acad. Sci. USA 109, 21307–21312 (2012).
Nakayama, H. et al. Intestinal anaerobic bacteria hydrolyse sorivudine, producing the high blood concentration of 5-(E)-(2-bromovinyl)uracil that increases the level and toxicity of 5-fluorouracil. Pharmacogenetics 7, 35–43 (1997).
Aziz, R. K., Hegazy, S. M., Yasser, R., Rizkallah, M. R. & ElRakaiby, M. T. Drug pharmacomicrobiomics and toxicomicrobiomics: from scattered reports to systematic studies of drug-microbiome interactions. Expert. Opin. Drug. Metab. Toxicol. 14, 1043–10553 (1918).
Wallace, B. D. et al. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science 330, 831–8353 (2010).
Saha, J. R., Butler, V. P. Jr., Neu, H. C. & Lindenbaum, J. Digoxin-inactivating bacteria: identification in human gut flora. Science 220, 325–3273 (1983).
Bisanz, J. E., Spanogiannopoulos, P., Pieper, L. M., Bustion, A. E. & Turnbaugh, P. J. How to determine the role of the microbiome in drug disposition. Drug. Metab. Dispos. 46, 1588–1595 (2018).
Nguyen, T. L., Vieira-Silva, S., Liston, A. & Raes, J. How informative is the mouse for human gut microbiota research? Dis. Model. Mech. 8, 1–16 (2015).
Faith, J. J. et al. Creating and characterizing communities of human gut microbes in gnotobiotic mice. ISME J. 4, 1094–1098 (2010).
Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).
Svartz, N. Treatment of rheumatoid arthritis with salicylazosulfapyridine. Acta Med. Scand. Suppl. 341, 247–254 (1958).
Svartz, N. The treatment of rheumatic polyarthritis with acid azo compounds. Rheumatism 4, 180–185 (1948).
Das, K. M. & Dubin, R. Clinical pharmacokinetics of sulphasalazine. Clin. Pharmacokinet. 1, 406–425 (1976).
Sousa, T. et al. On the colonic bacterial metabolism of azo-bonded prodrugs of 5-aminosalicylic acid. J. Pharm. Sci. 103, 3171–3175 (2014).
Valerino, D. M., Johns, D. G., Zaharko, D. S. & Oliverio, V. T. Studies of the metabolism of methotrexate by intestinal flora—I: Identification and study of biological properties of the metabolite 4-amino-4-deoxy-N 10-methylpteroic acid. Biochem. Pharmacol. 21, 821–831 (1972).
Zaharko, D. S., Bruckner, H. & Oliverio, V. T. Antibiotics alter methotrexate metabolism and excretion. Science 166, 887–888 (1969).
Viaud, S. et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342, 971–976 (2013).
Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967–970 (2013).
Dubin, K. et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat. Commun. 7, 10391 (2016).
Chaput, N. et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann. Oncol. 28, 1368–1379 (2017).
Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).
Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).
Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018).
Vetizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).
Wang, Y. et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat. Med. 24, 1804–1808 (2018).
Smith, M. H. & Bass A. R. Arthritis after cancer immunotherapy: symptom duration and treatment response. Arthritis Care Res. 71, 362–366 (2017).
Cappelli, L. C. et al. Clinical presentation of immune checkpoint inhibitor-induced inflammatory arthritis differs by immunotherapy regimen. Semin. Arthritis Rheum. 48, 553–557 (2018).
Paramsothy, S., Rosenstein, A. K., Mehandru, S. & Colombel, J. F. The current state of the art for biological therapies and new small molecules in inflammatory bowel disease. Mucosal Immunol. 11, 1558–1570 (2018).
Magnusson, M. K. et al. Anti-TNF therapy response in patients with ulcerative colitis is associated with colonic antimicrobial peptide expression and microbiota composition. J. Crohns Colitis 10, 943–952 (2016).
Ananthakrishnan, A. N. et al. Gut microbiome function predicts response to anti-integrin biologic therapy in inflammatory bowel diseases. Cell Host Microbe 21, 603–610 (2017).
Sandborn, W. J. et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N. Engl. J. Med. 367, 1519–1528 (2012).
Clayton, T. A., Baker, D., Lindon, J. C., Everett, J. R. & Nicholson, J. K. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc. Natl Acad. Sci. USA 106, 14728–14733 (2009).
Wilson, I. D. Drugs, bugs, and personalized medicine: pharmacometabonomics enters the ring. Proc. Natl Acad. Sci. USA 106, 14187–14188 (2009).
Haiser, H. J. & Turnbaugh, P. J. Developing a metagenomic view of xenobiotic metabolism. Pharmacol. Res. 69, 21–31 (2013).
Ryan, A. Azoreductases in drug metabolism. Br. J. Pharmacol. 174, 2161–2173 (2017).
Morrison, J. M., Wright, C. M. & John, G. H. Identification, isolation and characterization of a novel azoreductase from clostridium perfringens. Anaerobe 18, 229–234 (2012).
Chen, H., Wang, R. F. & Cerniglia, C. E. Molecular cloning, overexpression, purification, and characterization of an aerobic FMN-dependent azoreductase from Enterococcus faecalis. Protein Expr. Purif. 34, 302–310 (2004).
Delomenie, C. et al. Identification and functional characterization of arylamine N-acetyltransferases in eubacteria: evidence for highly selective acetylation of 5-aminosalicylic acid. J. Bacteriol. 183, 3417–3427 (2001).
Sim, E., Abuhammad, A. & Ryan, A. Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery. Br. J. Pharmacol. 171, 2705–2725 (2014).
Bazin, T. et al. Microbiota composition may predict anti-TNF alpha response in spondyloarthritis patients: an exploratory study. Sci. Rep. 8, 5446 (2018).
Kim, D. et al. Optimizing methods and dodging pitfalls in microbiome research. Microbiome 5, 52 (2017).
Rehaume, L. M. et al. IL-23 favours outgrowth of spondyloarthritis-associated pathobionts and suppresses host support for homeostatic microbiota. Ann. Rheum. Dis. 78, 494–503 (2019).
Manasson, J. et al. IL-17 inhibition in spondyloarthritis associates with subclinical gut microbiome perturbations and a distinctive IL-25-driven intestinal inflammation. Arthritis Rheumatol. https://doi.org/10.1002/art.41169 (2019).
Saunte, D. M., Mrowietz, U., Puig, L. & Zachariae, C. Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management. Br. J. Dermatol. 177, 47–62 (2017).
Gerard, R., Sendid, B., Colombel, J. F., Poulain, D. & Jouault, T. An immunological link between Candida albicans colonization and Crohn’s disease. Crit. Rev. Microbiol. 41, 135–139 (2015).
Colombel, J. F., Sendid, B., Jouault, T. & Poulain, D. Secukinumab failure in Crohn’s disease: the yeast connection? Gut 62, 800–801 (2013).
Favalli, E. G., Biggioggero, M. & Meroni, P. L. Methotrexate for the treatment of rheumatoid arthritis in the biologic era: still an “anchor” drug? Autoimmun. Rev. 13, 1102–1108 (2014).
Aletaha, D. & Smolen, J. S. Diagnosis and management of rheumatoid arthritis: a review. JAMA 320, 1360–1372 (2018).
Singh, J. A. et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 68, 1–26 (2016).
Smolen, J. S. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann. Rheum. Dis https://doi.org/10.1136/annrheumdis-2019-216655 (2020).
Detert, J. et al. Induction therapy with adalimumab plus methotrexate for 24 weeks followed by methotrexate monotherapy up to week 48 versus methotrexate therapy alone for DMARD-naive patients with early rheumatoid arthritis: HIT HARD, an investigator-initiated study. Ann. Rheum. Dis. 72, 844–850 (2013).
Hughes, C. D., Scott, D. L. & Ibrahim, F. Titrate Programme Investigators. Intensive therapy and remissions in rheumatoid arthritis: a systematic review. BMC Musculoskelet. Disord. 19, 389 (2018).
Smolen, J. S. et al. Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial. Lancet 383, 321–332 (2014).
Goodman, S. M., Cronstein, B. N. & Bykerk, V. P. Outcomes related to methotrexate dose and route of administration in patients with rheumatoid arthritis: a systematic literature review. Clin. Exp. Rheumatol. 33, 272–278 (2015).
Lebbe, C., Beyeler, C., Gerber, N. J. & Reichen, J. Intraindividual variability of the bioavailability of low dose methotrexate after oral administration in rheumatoid arthritis. Ann. Rheum. Dis. 53, 475–477 (1994).
van Roon, E. N. & van de Laar, M. A. Methotrexate bioavailability. Clin. Exp. Rheumatol. 28, S27–32 (2010).
Halilova, K. I. et al. Markers of treatment response to methotrexate in rheumatoid arthritis: where do we stand? Int. J. Rheumatol. 2012, 978396 (2012).
Angelis-Stoforidis, P., Vajda, F. J. & Christophidis, N. Methotrexate polyglutamate levels in circulating erythrocytes and polymorphs correlate with clinical efficacy in rheumatoid arthritis. Clin. Exp. Rheumatol. 17, 313–320 (1999).
Dervieux, T. et al. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum. 50, 2766–2774 (2004).
Danila, M. I. et al. Measurement of erythrocyte methotrexate polyglutamate levels: ready for clinical use in rheumatoid arthritis? Curr. Rheumatol. Rep. 12, 342–347 (2010).
Stamp, L. K. et al. Methotrexate polyglutamate concentrations are not associated with disease control in rheumatoid arthritis patients receiving long-term methotrexate therapy. Arthritis Rheum. 62, 359–368 (2010).
Hornung, N., Ellingsen, T., Attermann, J., Stengaard-Pedersen, K. & Poulsen, J. H. Patients with rheumatoid arthritis treated with methotrexate (methotrexate): concentrations of steady-state erythrocyte methotrexate correlate to plasma concentrations and clinical efficacy. J. Rheumatol. 35, 1709–1715 (2008).
Bluett, J. et al. Risk factors for oral methotrexate failure in patients with inflammatory polyarthritis: results from a UK prospective cohort study. Arthritis Res. Ther. 20, 50 (2018).
Dekkers, J. S. et al. Autoantibody status is not associated with early treatment response to first-line methotrexate in patients with early rheumatoid arthritis. Rheumatology 58, 149–153 (2019).
Hider, S. L. et al. Can clinical factors at presentation be used to predict outcome of treatment with methotrexate in patients with early inflammatory polyarthritis? Ann. Rheum. Dis. 68, 57–62 (2009).
Sergeant, J. C. et al. Prediction of primary non-response to methotrexate therapy using demographic, clinical and psychosocial variables: results from the UK Rheumatoid Arthritis Medication Study (RAMS). Arthritis Res. Ther. 20, 147 (2018).
Gupta, V., Katiyar, S., Singh, A., Misra, R. & Aggarwal, A. CD39 positive regulatory T cell frequency as a biomarker of treatment response to methotrexate in rheumatoid arthritis. Int. J. Rheum. Dis. 21, 1548–1556 (2018).
Lopez-Rodriguez, R. et al. Replication study of polymorphisms associated with response to methotrexate in patients with rheumatoid arthritis. Sci. Rep. 8, 7342 (2018).
de Rotte, M. et al. Development and validation of a prognostic multivariable model to predict insufficient clinical response to methotrexate in rheumatoid arthritis. PLoS One 13, e0208534 (2018).
Plant D. et al. Gene expression profiling identifies classifier of methotrexate non-response in patients with rheumatoid arthritis. Arthritis Rheum. https://doi.org/10.1002/art.40810 (2019).
Wessels, J. A. et al. A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Arthritis Rheum. 56, 1765–1775 (2007).
Eektimmerman, F. et al. Validation of a clinical pharmacogenetic model to predict methotrexate nonresponse in rheumatoid arthritis patients. Pharmacogenomics 20, 85–93 (2019).
Jenko, B. et al. Clinical pharmacogenetic models of treatment response to methotrexate monotherapy in Slovenian and Serbian rheumatoid arthritis patients: differences in patient’s management may preclude generalization of the models. Front. Pharmacol. 9, 20 (2018).
Lopez-Rodriguez, R. et al. Evaluation of a clinical pharmacogenetics model to predict methotrexate response in patients with rheumatoid arthritis. Pharmacogenomics J. 18, 539–545 (2018).
Zhang, X. et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat. Med. 21, 895–905 (2015).
Isaac, S. et al. Short- and long-term effects of oral vancomycin on the human intestinal microbiota. J. Antimicrob. Chemother. 72, 128–136 (2017).
Nayak, R. R. et al. Perturbation of the human gut microbiome by a non-antibiotic drug contributes to the resolution of autoimmune disease. bioRxiv https://doi.org/10.1101/600155 (2019).
Isaac, S. et al. The pre-treatment gut microbiome predicts early response to methotrexate in rheumatoid arthritis [abstract]. Arthritis Rheumatol. 71, 2769 (2019).
Costello, S. P. et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial. JAMA 321, 156–164 (2019).
Paramsothy, S. et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 389, 1218–1228 (2017).
Kragsnaes, M. S. et al. Efficacy and safety of faecal microbiota transplantation in patients with psoriatic arthritis: protocol for a 6-month, double-blind, randomised, placebo-controlled trial. BMJ Open 8, e019231 (2018).
Gjorevski, N., Ranga, A. & Lutolf, M. P. Bioengineering approaches to guide stem cell-based organogenesis. Development 141, 1794–1804 (2014).
Trietsch, S. J. et al. Membrane-free culture and real-time barrier integrity assessment of perfused intestinal epithelium tubes. Nat. Commun. 8, 262 (2017).
Bhatia, S. N. & Ingber, D. E. Microfluidic organs-on-chips. Nat. Biotechnol. 32, 760–772 (2014).
Lagier, J. C. et al. Culture of previously uncultured members of the human gut microbiota by culturomics. Nat. Microbiol. 1, 16203 (2016).
Maier, L. et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623–628 (2018).
The authors are supported by the NIH (grants R03AR072182 and R01AR074500 to J.U.S.; R01HL122593 and R01AR074500 to P.J.T.; K08AR073930 to R.N.). J.U.S. is further supported by The Riley Family Foundation, The Beatriz Snyder Foundation, the Rheumatology Research Foundation, the National Psoriasis Foundation and The Judith and Stewart Colton Center for Autoimmunity. P.J.T. is a Chan Zuckerberg Biohub investigator and a Nadia’s Gift Foundation Innovator supported, in part, by the Damon Runyon Cancer Research Foundation (DRR-42-16) and the Searle Scholars Program (SSP-2016-1352). C.U. is supported by MINECO (SAF2017-90083-R).
J.U.S. declares that he has served as a consultant for Amgen, BMS, Janssen, Novartis, Sanofi and UCB, and has received funds from Novartis to NYU School of Medicine to conduct investigator-initiated studies. J.U.S. and S.B.A. have been granted USPTO patent no. 10011883 (“Causative agents and diagnostic methods relating to rheumatoid arthritis”). P.J.T. declares he is on the scientific advisory boards for Kaleido, Seres, SNIPRbiome, uBiome, and WholeBiome; there is no direct overlap between the current article and these consulting duties. R.R.N. and C.U. declare no competing interests.
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The study of how an organism affects a drug, including absorption, distribution, bioavailability, metabolism and excretion.
The study of the biochemical, physiological and molecular effects of drugs on the body, including receptor binding, post-receptor effects and chemical interactions.
Chemical compounds (for example, drugs or pollutants) found within but not produced by living organisms.
The processes by which a compound (for example, a drug) is transformed from one form to another by a chemical reaction within the body.
- Microbial consortia
Two or more microbial groups living symbiotically.
- Random forest
A data construct classifier applied to machine learning that develops large numbers of random decision trees that analyse multiple sets of variables.
Genetic regulatory systems found in bacteria and their viruses in which genes encoding functionally related proteins are clustered along the DNA.
Non-digestible supplement that induces the growth (and/or activity) of commensal microorganisms.
Supplement containing live microorganisms that can alter the composition of microbiota and are supposed to provide health benefits to the host.
- Bacterial culturomics
A method that allows for the description of the microbial composition by high-throughput culture platforms.
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Scher, J.U., Nayak, R.R., Ubeda, C. et al. Pharmacomicrobiomics in inflammatory arthritis: gut microbiome as modulator of therapeutic response. Nat Rev Rheumatol 16, 282–292 (2020). https://doi.org/10.1038/s41584-020-0395-3