Methotrexate impacts conserved pathways in diverse human gut bacteria leading to decreased host immune activation

Nayak, Renuka R.; Alexander, Margaret; Deshpande, Ishani; Stapleton-Gray, Kye; Rimal, Bipin; Patterson, Andrew D.; Úbeda, Carles; Scher, Jose U.

doi:10.1016/j.chom.2020.12.008

Cited by 85 publications

(62 citation statements)

References 81 publications

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“…Indeed, several studies have shown that pharmaceutical drugs can be a modulator of gut microbiome composition and metabolic activity [ 74 – 76 ]. In this regard, a recently published study demonstrated that treatment with methotrexate (MTX) in RA patients induced compositional changes in members of the gut microbiota, such as Bacteroidetes, Lachnoclostridium, Collinsella aerofaciens , Dielma fastidiosa , and Prevotella copri , alongside the reduction in multiple immune cell types, which include activated T cells, IFN-γ+ T cells, myeloid cells, and B cells [ 77 ]. Along these lines, the use of csDMARDs (which includes methotrexate) was found to be significantly associated with gut microbiome composition in our PERMANOVA analysis.…”

Section: Discussionmentioning

confidence: 99%

Gut microbial determinants of clinically important improvement in patients with rheumatoid arthritis

et al. 2021

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Background Rapid advances in the past decade have shown that dysbiosis of the gut microbiome is a key hallmark of rheumatoid arthritis (RA). Yet, the relationship between the gut microbiome and clinical improvement in RA disease activity remains unclear. In this study, we explored the gut microbiome of patients with RA to identify features that are associated with, as well as predictive of, minimum clinically important improvement (MCII) in disease activity. Methods We conducted a retrospective, observational cohort study on patients diagnosed with RA between 1988 and 2014. Whole metagenome shotgun sequencing was performed on 64 stool samples, which were collected from 32 patients with RA at two separate time-points approximately 6–12 months apart. The Clinical Disease Activity Index (CDAI) of each patient was measured at both time-points to assess achievement of MCII; depending on this clinical status, patients were distinguished into two groups: MCII+ (who achieved MCII; n = 12) and MCII− (who did not achieve MCII; n = 20). Multiple linear regression models were used to identify microbial taxa and biochemical pathways associated with MCII while controlling for potentially confounding factors. Lastly, a deep-learning neural network was trained upon gut microbiome, clinical, and demographic data at baseline to classify patients according to MCII status, thereby enabling the prediction of whether a patient will achieve MCII at follow-up. Results We found age to be the largest determinant of the overall compositional variance in the gut microbiome (R2 = 7.7%, P = 0.001, PERMANOVA). Interestingly, the next factor identified to explain the most variance in the gut microbiome was MCII status (R2 = 3.8%, P = 0.005). Additionally, by looking at patients’ baseline gut microbiome profiles, we observed significantly different microbiome traits between patients who eventually showed MCII and those who did not. Taxonomic features include alpha- and beta-diversity measures, as well as several microbial taxa, such as Coprococcus, Bilophila sp. 4_1_30, and Eubacterium sp. 3_1_31. Notably, patients who achieved clinical improvement had higher alpha-diversity in their gut microbiomes at both baseline and follow-up visits. Functional profiling identified fifteen biochemical pathways, most of which were involved in the biosynthesis of L-arginine, L-methionine, and tetrahydrofolate, to be differentially abundant between the MCII patient groups. Moreover, MCII+ and MCII− groups showed significantly different fold-changes (from baseline to follow-up) in eight microbial taxa and in seven biochemical pathways. These results could suggest that, depending on the clinical course, gut microbiomes not only start at different ecological states, but also are on separate trajectories. Finally, the neural network proved to be highly effective in predicting which patients will achieve MCII (balanced accuracy = 90.0%, leave-one-out cross-validation), demonstrating potential clinical utility of gut microbiome profiles. Conclusions Our findings confirm the presence of taxonomic and functional signatures of the gut microbiome associated with MCII in RA patients. Ultimately, modifying the gut microbiome to enhance clinical outcome may hold promise as a future treatment for RA.

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Section: Discussionmentioning

confidence: 99%

Gut microbial determinants of clinically important improvement in patients with rheumatoid arthritis

et al. 2021

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“…MBI (mucositis) in the gastrointestinal tract is a major oncological obstacle because of its acute symptomology and systemic consequences. Although a strong body of data shows microbial injury after chemotherapy drugs, including MTX [26], it remains hotly debated if these Fig. 5.…”

Section: Discussionmentioning

confidence: 99%

Antibiotic-induced disruption of the microbiome exacerbates chemotherapy-induced diarrhoea and can be mitigated with autologous faecal microbiota transplantation

Wardill

Ferreira

et al. 2021

European Journal of Cancer

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Background: Chemotherapy is well documented to disrupt the gut microbiome, leading to poor treatment outcomes and a heightened risk of adverse toxicity. Although strong associations exist between its composition and gastrointestinal toxicity, its causal contribution remains unclear. Our inability to move beyond association has limited the development and implementation of microbial-based therapeutics in chemotherapy adjuncts with no clear rationale of how and when to deliver them. Methods/Results: Here, we investigate the impact of augmenting the gut microbiome on gastrointestinal toxicity caused by the chemotherapeutic agent, methotrexate (MTX). Faecal microbiome transplantation (FMT) delivered after MTX had no appreciable impact on gastrointestinal toxicity. In contrast, disruption of the microbiome with antibiotics administered before chemotherapy exacerbated gastrointestinal toxicity, impairing mucosal recovery

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“…These approximations indicate that our MSC estimates are relevant for patients receiving high dose MTX treatment (1-12 g/m 2 ) 26 . A recent study used a different approach estimating gut MTX concentrations following oral administration during treatment of rheumatoid arthritis 27 . Their data suggested MTX concentrations as high as 100 μg/mL are found in the gut, suggesting that our estimated MSC for plasmid-mediated antibiotic resistance determinants (25 μg/mL) is well within this concentration range.…”

Section: Resultsmentioning

confidence: 99%

The chemotherapeutic drug methotrexate selects for antibiotic resistance

Guðmundsdóttir

Fredheim

Koumans

et al. 2020

Preprint

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Many cytotoxic drugs used in cancer chemotherapy have antibacterial properties, but how bacterial populations are affected by these selective pressures is unknown. Here we test the hypothesis that the widely used cytotoxic drug methotrexate affects the evolution and selection of antibiotic resistance. We show that methotrexate can select for trimethoprim resistance determinants located on the chromosome or a plasmid. Additionally, methotrexate can co-select for virtually any antibiotic resistance determinant when present together with trimethoprim resistance on a multidrug-resistance clinical plasmid. These selective effects occur at concentrations 40- to >320-fold below the methotrexate minimal inhibitory concentration for Escherichia coli, suggesting a selective role of methotrexate chemotherapy for antibiotic resistance in patients that strongly depend on effective antibiotic treatment.One Sentence SummaryMethotrexate, a drug used in the treatments of cancers and inflammatory diseases, selects and co-selects antibiotic resistance determinants.

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Methotrexate impacts conserved pathways in diverse human gut bacteria leading to decreased host immune activation

Cited by 85 publications

References 81 publications

Gut microbial determinants of clinically important improvement in patients with rheumatoid arthritis

Gut microbial determinants of clinically important improvement in patients with rheumatoid arthritis

Antibiotic-induced disruption of the microbiome exacerbates chemotherapy-induced diarrhoea and can be mitigated with autologous faecal microbiota transplantation

The chemotherapeutic drug methotrexate selects for antibiotic resistance

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