Gut microbiome may impact methotrexate response in RA
medwireNews: Treatment-naïve people with new-onset rheumatoid arthritis (RA) who respond to treatment with methotrexate have consistent differences in their gut microbiomes relative to non-responders, study findings indicate.
“We found that overall bacterial diversity is distinct between patients destined to respond to [methotrexate] compared to those that don’t,” write Jose Scher (New York University School of Medicine, USA) and co-authors in Arthritis & Rheumatology.
Their research suggested that “group(s) of microbes or bacterial functions, rather than dominant species, may be associated with or implicated in clinical response.”
Scher and team performed 16S ribosomal RNA gene and shotgun metagenomic sequencing on pretreatment fecal samples from 26 people with new-onset RA, of whom 39% were classed as methotrexate responders at 4 months according to an improvement in DAS28 score of at least 1.8 points with no requirement for a biologic.
They found that, overall, methotrexate non-responders had a significantly higher level of microbial diversity compared with responders.
At a microbial pathway level, non-responders had significantly increased MAP-kinase signaling, DNA replication, fatty acid degradation, and ABC transporters, along with significantly decreased lipopolysaccharide and folate biosynthesis.
The researchers note that folate has previously been implicated in methotrexate inadequate response.
Based on their sequencing findings, the team hypothesized that “the pretreatment [gut] microbiome could be used to predict clinical non-response” to methotrexate in RA.
They therefore built a microbiome-based model that incorporated 38 of the differential features they identified and tested it in a validation cohort of 21 people with new-onset RA.
Scher et al report that the model correctly classified 83.3% of methotrexate non-responders and 78.0% of responders, which they say “outperforms both a previous clinical pharmacogenetic-based approach in RA and the current clinical practice in early disease.”
The researchers also found that, following incubation of methotrexate with pretreatment fecal samples from people with RA, resulting methotrexate metabolite levels correlated with clinical response: samples that decreased methotrexate levels the fastest were typically derived from methotrexate non-responders.
“Taken together, these data provide a plausible mechanistic explanation for the association between the pre-treatment gut microbiome and drug response, where patients’ communities enriched for gut bacteria capable of efficiently metabolizing and/or depleting [methotrexate] are associated with worsened clinical outcomes,” Scher et al remark.
The researchers conclude that their findings “provide the first step towards predicting lack of response to oral [methotrexate] in [new-onset] RA patients and support the value of the gut microbiome as a possible prognostic tool and as a potential target in RA therapeutics.”
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