The Potential of Gut Microbiota Metabolic Capability to Detect Drug Response in Rheumatoid Arthritis Patients

Abstract

Gut microbiota plays an essential role in the development of rheumatoid arthritis (RA) and affects drug responses. However, the underlying mechanism remains elusive and urgent to elucidate to explore the pathology and clinical treatment of RA. Therefore, we selected methotrexate (MTX) as an example of RA drugs to explore the interactions between the gut microbiota and drug responses and obtain an in-depth understanding of their correlation from the perspective of the metabolic capability of gut microbiota on drug metabolism. We identified 2,654 proteins and the corresponding genes involved in MTX metabolism and then profiled their abundances in the gut microbiome datasets of four cohorts. We found that the gut microbiota harbored various genes involved in MTX metabolism in healthy individuals and RA patients. Interestingly, the number of genes involved in MTX metabolism was not significantly different between response (R) and non-response (NR) groups to MTX, but the gene composition in the microbial communities significantly differed between these two groups. Particularly, several models were built based on clinical information, as well as data on the gene, taxonomical, and functional biomarkers by using the random forest algorithm and then validated. Our findings provide bases for clinical management not only of RA but also other gut microbiome-related diseases. First, it suggests that the potential metabolic capability of gut microbiota on drug metabolism is important because they affect drug efficiency; as such, clinical treatment strategies should incorporate the gene compositions of gut microbial communities, in particular genes involved in drug metabolism. Second, a suitable model can be developed to determine hosts' responses to drugs before clinical treatment.

Keywords: clinical medication; drug metabolism; gut microbiota; methotrexate; rheumatoid arthritis.

FIGURE 1

Construction of protein databases for clinical drugs in rheumatoid arthritis (RA) treatment and the human gut metagenome datasets used in the present study. (A) Construction of databases for detection of proteins and the corresponding genes involved in drug metabolism in the gut microbial communities of RA patients. (B) Gut metagenome datasets used in this study were collected from four cohorts, namely, BioProject PRJNA682730, PRJEB6997, PRJNA356102, and PRJEB13870 (only the dataset of healthy individuals was used).

FIGURE 2

Significant differences in the composition of genes involved in methotrexate (MTX) metabolism between the R and NR groups. (A) Gut microbiota harbors various genes involved in MTX metabolism in healthy individuals and RA patients. (B) Distribution of genes involved in MTX metabolism in the gut microbiota in the R and NR groups based on the training data of the BioProject PRJNA682730. A significant difference existed between the R and NR groups based on (C) Bray–Curtis dissimilarity and (D) Principal component analysis (PCA) analysis. (E) Linear discriminant analysis (LDA) analysis of the sample distribution showed a distinct separation between the R and NR groups.

FIGURE 3

Analysis of biomarkers and the construction of models for distinguishing the samples of the R and NR groups. (A) Gene biomarkers involved in methotrexate (MTX) metabolism, (B) taxonomical biomarkers at the species level, and (C) functional biomarkers identified between the R and NR groups. (D) Models were built using the random forest algorithm and verified; the profile of genes involved in MTX metabolism is an important feature that should be used to predict host response to MTX.

FIGURE 4

Host-tracking, functional annotation, and physical distribution of genes involved in methotrexate (MTX) metabolism were explored to obtain an in-depth understanding of the interactions between drug response and gut microbiota. (A) Taxonomical distribution of genes involved in MTX metabolism. The results suggest that Firmicutes and Bacteroidetes were the dominant hosts of the genes involved in MTX metabolism and had the potential to metabolize MTX in the intestinal tract. (B) Distribution of functional traits for genes involved in MTX metabolism. (C) Occurrences of the thymidylate synthase gene and dihydrofolate reductase gene in different assembled contigs were used as an example to reveal the complex and diverse distributions of genes involved in MTX metabolism.