Pharmacomicrobiomics in inflammatory arthritis: gut microbiome as modulator of therapeutic response

Abstract

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.

Key points

  • 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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Fig. 1: Gut microorganisms in drug metabolism and physiology.
Fig. 2: Mechanisms of gut microbiome modulation of anti-rheumatic drug disposition and response.
Fig. 3: Translational implications of pharmacomicrobiomic studies in rheumatic diseases.

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Acknowledgements

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).

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All authors researched data for the article and substantially contributed to discussion of content, writing and review/editing of the manuscript before submission.

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Correspondence to Jose U. Scher.

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Competing interests

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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Glossary

Pharmacokinetics

The study of how an organism affects a drug, including absorption, distribution, bioavailability, metabolism and excretion.

Pharmacodynamics

The study of the biochemical, physiological and molecular effects of drugs on the body, including receptor binding, post-receptor effects and chemical interactions.

Xenobiotics

Chemical compounds (for example, drugs or pollutants) found within but not produced by living organisms.

Biotransformations

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.

Operons

Genetic regulatory systems found in bacteria and their viruses in which genes encoding functionally related proteins are clustered along the DNA.

Prebiotic

Non-digestible supplement that induces the growth (and/or activity) of commensal microorganisms.

Probiotic

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

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