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.

Fig. 1 ∣. Gut microorganisms in drug metabolism and physiology.

a ∣ Bacteria and other microorganisms that inhabit the human gut can directly alter the chemical structures of many dietary components, environmental chemicals and pharmaceuticals. These biotransformations have the potential to affect drug bioavailability, pharmacokinetics, clinical efficacy and the development of adverse events. An accumulating body of evidence is clarifying the molecular mechanisms responsible for many of these biological changes in anti-inflammatory medications. b ∣ Microorganisms can directly alter a drug through inactivation, activation or direct physical interactions that alter the drug’s bioavailability. c ∣ Indirect mechanisms of drug biotransformation include the production of intermediate bioactive metabolites by gut microorganisms and the alteration of host gene regulation and expression in response to microbial interactions.

Fig. 2 ∣. Mechanisms of gut microbiome modulation of anti-rheumatic drug disposition and response.

The microbial metabolism of anti-rheumatic drugs can lead to their activation or inactivation, or result in the production of toxic compounds. a ∣ Activation is the conversion of a prodrug into its bioactive form, thus contributing to therapeutic concentrations. For example, biotransformation of sulfasalazine produces 5-aminosalicylic acid (5-ASA) and sulfapyridine (the active form of the prodrug in rheumatoid arthritis), b ∣ Inactivation is the conversion of an active metabolite into a less bioactive metabolite. For example, methotrexate is converted into 2,4-diamino-N¹⁰-methylpteroic acid (DAMPA) through the action of an (as yet uncharacterized) microbial enzyme. c ∣ Toxicity results from the production of bacterial metabolites that are deleterious to the host, for example, through the hydrolysis of glucuronidated NSAIDs.

Fig. 3 ∣. Translational implications of pharmacomicrobiomic studies in rheumatic diseases.

In clinical studies with deeply phenotyped patient populations and known outcomes of synthetic (sDMARDs) or biologic DMARDs (bDMARDs) (such as efficacy and adverse events) (left panel), microbial features can be integrated with established biomarkers of response (for example, host genetics or immune cell profiles) via machine learning and network analyses to develop predictive tools. Mechanistic studies applying in vivo methods (middle panel) and in vitro or ex vivo methods (right panel) can complement and expand the understanding of drug biotransformation by the human gut microbiome, including activation, inactivation, conversion into toxic metabolites and bioavailability. FMT, faecal microbiota transplantation.