Perturbation of the human gut microbiome by a non-antibiotic drug contributes to the resolution of autoimmune disease

Abstract

15The trillions of microorganisms (microbiota) found within the human gut play a critical role in 16 shaping the immune system, yet these complex microbial communities are also highly sensitive 17 to numerous environmental factors. While much of the focus to date has been on dietary intake, 18 emerging data has begun to suggest that the use of pharmaceutical drugs, even those that are not 19 considered to be antibiotics, can alter the human gut microbiota with unknown consequences for 20 treatment outcomes. Here, we use a combination of in vitro, in vivo, and ex vivo methods to 21 demonstrate that the first-line therapy for rheumatoid arthritis (RA), methotrexate (MTX), has 22 off-target effects on the human gut microbiota, resulting in a significant growth advantage for 23 drug-resistant Firmicutes over the Bacteroidetes, which tend to be more sensitive. Longitudinal 24 analyses of the gut microbiotas of RA patients revealed that MTX-induced shifts in bacterial 25 relative abundance are associated with improved drug response and transplant experiments in 26 gnotobiotic mice show that these shifts lead to reduced inflammation. Together, these results 27 suggest that the mechanism-of-action of non-antibiotic drugs may be due in part to off-target 28 effects on the gut microbiota, while providing a critical first step towards explaining long-29 standing differences in drug response between patients. 30

A Two-Way Interaction between Methotrexate and the Gut Microbiota of Male Sprague–Dawley Rats

“…This was consistent with previous findings. 24 Such changes in bacterial populations were then reversed at the 100 mg/kg dose level potentially explaining the recently reported dose related antimicrobial effect of MTX. 24 …”

“…Low doses (i.e., at or below 15 mg/week) to patients increased the species richness and diversity of the microbiota and reversed the perturbation of the microbiota that is often associated with RA. 25 , 26 In a recent study, 24 MTX treatment (10 or 50 mg/kg) of gut microflora-humanized gnotobiotic mice decreased the relative abundance of Bacteroidetes and increased that of the Firmicutes. As the initial targeted human enzyme DHFR is conserved in all domains of life, such alterations were further demonstrated as an anti-inflammatory mechanism of MTX through potential interaction with off-target bacterial enzymes, such as DHFR in Escherichia coli or Lactobacillus casei .…”

“…MTX has recently been reported to inhibit the growth of 30% of 40 representative gut bacterial strains 23 and 84% of 43 bacterial isolates which had a combined relative abundance covering 43% of the human gut microbiota. 24 Studies exploring the effects of MTX on the gut microbiota have previously focused on the anti-inflammatory role of MTX in RA. Low doses (i.e., at or below 15 mg/week) to patients increased the species richness and diversity of the microbiota and reversed the perturbation of the microbiota that is often associated with RA.…”

Gut Microbiota-driven Drug Metabolism in Inflammatory Bowel Disease

“…However, parenterally administrated MTX can, just as with orally administrated MTX, come into contact with the intestinal microbiota due to biliary secretion and could also be prone to bacterial metabolism. 47 This interaction between parenterally administrated MTX and microbiota was confirmed in mice colonized with stool from an MTX-naïve RA patient. After either intraperitoneal injection of MTX or oral administration of MTX, the same effect was seen in the microbiota composition, namely a decrease in the phylum Bacteroidetes and an increase in two other phyla, Proteobacteria and Firmicutes.…”

The microbiome in rheumatology: Where are we and where should we go?

“…113 This appears to also hold true for methotrexate, which is known to be metabolised by the gut microbiome in mice 114 115 and humans, 116 and may have off-target, antibiotic effects. 117 In axial SpA, patients who respond to anti-TNF inhibitors exhibit a more resilient pretreatment gut microbiome, 118 while IL-17A inhibitors are associated with expansion of intestinal C. albicans in a subgroup of paients with SpA/PsA, 67 as well as an increased risk for the development of candidiasis. 119 120 Further progress in pharmacomicrobiomics will lead towards personalised therapeutic approaches that are based on patient microbiome features, allowing for improved selection of medications with the highest efficacy and lowest risk for toxicity.…”