DMARDs–Gut Microbiota Feedback: Comparison
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Evidence suggests that the increase or decrease of microorganism communities has an effect on the production of metabolites that are related with immunomodulatory functions. This review suggests that there is feedback between DMARDs and gut microbiota, based on the evidence that supports that DMARDs favor intestinal dysbiosis, as well as on the evidence that some bacterial genera participate in DMARDs-type xenobiotics’ metabolism and in the production of metabolites with an immunomodulatory effect. This document sets a precedent in which DMARDs-promoted dysbiosis could cause, in time, variability of response to different therapeutic schemes. 

  • DMARDs
  • Gut microbiota
  • Response to therapy

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1. Introduction

The clinical practice guides for the treatment of rheumatoid arthritis (RA) establish different therapeutic schemes to diminish the clinical activity, limit the articular radiological damage progression, and the functional incapacity. However, response to treatment is variable and this effect can be attributed to genetic factors as well as clinical or serologyc factors, and presence of comorbidities, among others [1,2][1][2].

Technological evolution has opened up the possibility of studying gut microbiota and also allows for the potential role in clinical characteristics and the response variability to RA treatment to be established. Originally, the microorganism recount in fecal culture allowed for the identification of big bacterial groups in the gut microbiota of RA patients [3,4,5,6][3][4][5][6]. The use of gas–liquid chromatography facilitated the identification of metabolites from bacteria[7][8] [7,8] and real-time polymerase chain reaction (qPCR) analysis to quantitatively identify bacterial species [9,10,11,12,13][9][10][11][12][13]. Similarly, the analysis of bacterial 16s ribosomal ribonucleic acid sequencing (rRNA) [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] revolutionized the study of microbial diversity and the bacterial metagenome in RA [17,19,25,26,33,34,35,36,37,38][17][19][25][26][33][34][35][36][37][38]. In humans, the gut microbiome plays an important role in immunologic mechanisms and the inflammatory process. Changes in microbiota, influenced also by lifestyle and diet, may promote intestinal increased permeability and local inflammation, causing a spread of inflammation to the joints. Several nutrients such as polyunsaturated fatty acids, vitamin D, antioxidant, flavonoids, and probiotics present anti-inflammatory properties, featuring a protective role for RA development, while others such as red meat, high sugary drinks, and salt have a harmful effect [39][39]. Furthermore, the combination of probiotics and methotrexate (MTX) have been proven to contribute with the efficiency of the response to treatment[40][41] [40,41] as well as in the specific variability of clinically relevant microbial species in the inflammatory process associated with RA [33].

Particularly, a great variability of bacterial species is shown in RA patients throughout the different clinical stages of the analyzed studies. However, cohort studies[6][25][33][37] [6,25,33,37] allowed for an association between gut microbiota and pharmacological response variability in RA to be established. It is important then, to know the mechanisms that DMARDs put gut microbiota through and gut dysbiosis implications in the modulation of response to treatment as well as the strategies that should be followed to restore microbial symbiosis in RA.

2. Disease-Modifying Antirheumatic Drugs (DMARDs) Usage in RA

International guides of clinical practice recommend the use of DMARDs as a pharmacological treatment in RA. These could have a conventional synthetic origin (csDMARDs) such as methotrexate (MTX), sulfasalazine (SSZ), or leflunomide (LEF) and could be administered in monotherapy or a combined therapy. They could also be administered along with the gradual and temporal use of corticosteroids (Cs) [42]. Hydroxychloroquine (HCQ) and chloroquine (CLQ) are also recommended drugs [43,44][43][44]. Recently, treat to target therapy (T2T), which includes the combined use of MTX + SSZ + HCQ [45][45], has been suggested as the best therapy because of its efficiency at accomplishing clinical remission in RA patients through the rational use of drugs and because it is economically feasible [46][46]. The use of biological DMARDs (boDMARDs)[42][47][48][49][50] [42,47,48,49,50] or biosimilar DMARDs (bsDMARDs) is also included in treatment schemes when faced with a poor response to conventional drugs [51][51]. Nonetheless, the use of csDMARDs is still the principal strategy in RA treatment globally.

3. Gut Microbiota and csDMARDs’ Metabolism

In vivo and in vitro studies revealed that gut microbiota has a role in the metabolism of approximately 50 drugs [52]. Zimmermann et al. [53][53] evaluated in an in vitro study 76 bacterial strains in gut microbiota and the metabolism of 271 drugs. They demonstrated that each bacterial strain metabolized from 11 to 95 drugs and that 176 drugs presented substantial metabolic change through the reduction of the drugs’ active molecules by some bacterial strain, which would allow the suggestion that the bioavailability of DMARDs is subjected to bacterial metabolism.

MTX is the key drug in the T2T scheme. It is used orally or parenterally in RA treatment [54][54]. MTX’s metabolism occurs through three different pathways. (1) Metabolized by gut bacteria in 2,4-diamino-N(10)-methylpteroic acid (DAMPA); a metabolite that represents less than 5% of MTX administered doses [55][55]. It has been proven that carboxypeptidase-G2 (CPDG2), a bacterial enzyme, induces the hydrolysis of MTX and non-toxic metabolite production such as DAMPA and glutamate [56,57,58,59][56][57][58][59]. In an in vitro study, it was proven that the species Pseudomonas catalyzed the synthesis of glutamate thorough CPDG2 from MTX [60][60], by which gut bacteria, which already modulates the drugs’ active metabolite availability, can also possibly modulate its effects. (2) The second metabolic pathway occurs in the liver, where MTX bio-transforms into 7-OH-MTX [61][61]. This metabolite is considered an inhibitor of human dihydrofolate reductase enzyme (DHFR). Gut microbiota also includes the DHFR enzyme, so it can modulate the drug’s metabolism, and at the same time, the drug can modulate microbial metabolism, thus creating a strong relationship. (3) The third pathway happens through the intracellular conversion of MTX into polyglutamates. This pathway is considered the most important one given that it contains the principal mechanism of immunomodulation [62][62]. The principal cells and tissue where MTX is metabolized into polyglutamate derivates are: fibroblasts, myeloid precursors, keratinocytes, cortical and trabecular bone, and enterocytes [63][63], so homeostasis and intestinal barrier integrity are essential for the principal active form of MTX synthesis.

Gut microbiota is a key element in intestinal mucus’ homeostasis and, aside from the fact that it has a direct participation in MTX’s metabolism, it can indirectly regulate pharmacological metabolism through the maintenance of intestinal barrier integrity. It is known that microbial dysbiosis has an impact on mechanisms of translocation, immunomodulation, metabolism, and enzymatic degradation on a gut level and it compromises microbial diversity [64][64]. It was reported that administering high doses of MTX produces antibacterial activity, thus in vivo diminishing Bacteroidetes abundancy and the increase of Firmicutes [25,65][25][65]. Similarly, it was observed in murine models that treatment with MTX diminishes the abundance of Bacteroides fragilis [66], but not the one from the order Lactobacillales [67][67].

On the other hand, it was also proven that SSZ has effects over gut microbiota when it is administered in monotherapy or in combination with MTX [42,68][42][68]. SSZ is metabolized by gut microbiota through chemical reactions that are mediated by azoreductases, which reduce SSZ into sulfapyridine and 5-aminosalicylic acid (5-ASA/mesalazine). This last one is considered an anti-inflammatory component [52]. Most of 5-ASA is held in the colon and experiences enterohepatic re-circulation and finally is excreted in the feces [69]. At the same time, 5-ASA could be inactivated by microbial arylamine of N-acetyltransferases (NATs) [70][70], inhibiting the anti-inflammatory effects of the drug. Sulfapyridine, on the other hand, has anti-microbial effects [71][71] and is also metabolized in the liver through the acetylation by the arylamine NAT-2, hydroxylation, and glucuronidation [72,73][72][73]. Due to all of the above, the abundance of bacteria that produces azoreductases—Bifidobacterium, Lactobacillus, Enterococcus, Clostridium, Eubacterium, and Bacteroides genus [74[74][75][76],75,76], and bacteria that produces NATs could have a relevant impact on the markers that define the response to RA treatment.

Regarding the use of LEF, it was established that its mechanism of immunomodulatory action happens through its active metabolite A 77 1726, which participates in the inhibition of pyrimidine’s synthesis de novo by inhibiting dihydroorotate dehydrogenase and as a consequence, the lymphocyte proliferation [77,78][77][78]. To date, there is no direct evidence between LEF treatment and gut microbiota modulation, however, it is known that Eggerthella lenta uses ornithine as a substrate to generate energy, thus producing citrulline and carbamoyl-phosphate synthase. This last one is involved in the pyrimidine pathway, so its production by microbial species could be related to the active metabolism of LEF [78][78], and the production of citrulline along with the presence of citrullinated antigens of bacterial origin. Nonetheless, in the study of Chen et al. [19][19] the elevated abundance was not related to the citrulline serum levels.

CLQ and HCQ are drugs that are included in the treatment scheme for RA[43] [43] because of their effects in the inhibition of the processing and presentation of antigens[79] [79] and because they limit the activation and proliferation of T-lymphocytes and the synthesis of pro-inflammatory cytokines[80] [80] such as TNF-α, IL-1β, IL-6 [81][81], IL-17, and IL-22 [82][82]. In a model of arthritic rats’ K/BxN, it was shown that the consumption of HCQ increased the intestinal abundance of Akkermansia and Parabacteroides while diminishing Clostridium sensu stricto-1 [83][83]. In RA patients, Chen et. al. [19] [19] reported that the intake of HCQ increased the bacterial diversity. Recently, it was described that the T2T scheme modulated the presence of bloodstream bacteria in RA patients by promoting the abundance of the genera Haemophilus, Alloprevotella, Eremococcus, and Lachnospiraceae_UCG001, possibly translocated from classic niches of the human microbiome [31][31].

The effect of boDMARDs on gut microbiota has also been shown in an arthritic rat model DBA/IJ, treated with etanercept (ETN). It was reported that there was a decrease in the relative abundance of bacterial genus Escherichia/Shigella and the genera Lactobacillus, Clostridium XVIa, and Tannerella [84][84]. This only strengthens the evidence of the intimate relationship between gut microbiota and the immune system, given that boDMARDs can have a direct immunomodulatory effect, local or systemic, over their cellular targets as well as the indirect way through gut microbiota modulation.

Therefore, DMARDs-promoted dysbiosis could cause, in time, variability of response to different therapeutic schemes.

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