Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population Original paper
Researched by:
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Kimberly Eyer
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Kimberly Eyer
Kimberly Eyer, a Registered Nurse with 30 years of nursing experience across diverse settings, including Home Health, ICU, Operating Room Nursing, and Research. Her roles have encompassed Operating Room Nurse, RN First Assistant, and Acting Director of a Same Day Surgery Center. Her specialty areas include Adult Cardiac Surgery, Congenital Cardiac Surgery, Vascular Surgery, and Neurosurgery.
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Rheumatoid Arthritis
Rheumatoid Arthritis
OverviewRheumatoid arthritis (RA) is a systemic autoimmune disease marked by chronic joint inflammation, synovitis, and bone erosion, driven by Treg/Th17 imbalance, excessive IL-17, TNF-α, and IL-1 production, and macrophage activation. Emerging evidence links microbial dysbiosis and heavy metal exposure to RA, [1][2] with gut microbiota influencing autoimmune activation via Toll-like receptor (TLR) signaling, inflammasome activation, […]
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Kimberly Eyer
Researched by:
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Kimberly Eyer
ID
Kimberly Eyer
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Kimberly Eyer
What was studied?
This study conducted a metagenome-wide association study (MWAS) using deep shotgun sequencing to explore the gut microbiome’s role in rheumatoid arthritis (RA) in a Japanese cohort. It aimed to identify specific taxa, functional genes, and pathways that differentiate RA patients from healthy controls and to investigate how these microbial features may align with host genomic susceptibility to RA.
Who was studied?
A total of 124 individuals were included: 82 patients with RA and 42 healthy controls. All participants were Japanese, which allowed the study to explore population-specific host-microbiome interactions. Fecal samples were subjected to whole-genome shotgun sequencing with an average depth of 13 Gb per sample, allowing for species-level taxonomic resolution and robust functional inference.
What were the most important findings?
The study revealed a significant enrichment of multiple Prevotella species—P. denticola, P. marshii, P. disiens, P. corporis, and P. amnii—in the RA gut microbiome. These taxa were associated with RA independent of previously reported P. copri. Notably, many of the enriched Prevotella species are typically found in the oral cavity, supporting the concept of oral-gut translocation in RA. Using a non-linear machine learning approach (UMAP with DBSCAN clustering), a specific taxa cluster was identified that distinguished RA patients based on microbial composition. Functionally, the abundance of a redox-related gene (R6FCZ7), attributed to various Bacteroides species, was significantly decreased in RA. This gene is implicated in reactive oxygen species management, linking redox stress to RA pathophysiology. Pathway analysis highlighted enrichment in fatty acid biosynthesis, glycosaminoglycan degradation, and adipocytokine signaling—processes central to joint inflammation and immune regulation. A key novel insight was the significant overlap between microbial and host genomic pathways, particularly Th17 cell differentiation and IL-17 signaling, underscoring a population-specific gut-host immunogenetic axis. Importantly, microbial diversity measures (alpha and beta) showed no significant differences between RA and control groups, suggesting that compositional and functional shifts, not diversity per se, underlie RA-associated dysbiosis.
| Feature or Function | Finding in RA Patients | Implications for RA Pathogenesis |
|---|---|---|
| Prevotella spp. (e.g., P. denticola) | Significantly enriched | Major microbial associations; potential immune activators |
| R6FCZ7 gene (redox function) | Decreased abundance in Bacteroides species | Redox imbalance; linked to oxidative stress and joint inflammation |
| Functional Pathways | Enriched: fatty acid biosynthesis, GAG degradation | Supports metabolic reprogramming and joint tissue remodeling |
| Adipocytokine signaling | Significantly enriched | Links gut microbiota to systemic inflammation and metabolic dysfunction |
| Th17 cell and IL-17 signaling | Pathway overlap in microbiome and host genome | Suggests shared immunogenetic and microbial drivers of RA |
| Taxa cluster (identified via UMAP-DBSCAN) | Distinct cluster enriched in RA | Offers machine learning-derived biomarker grouping |
| Microbial Diversity | No significant alpha or beta diversity differences | Indicates dysbiosis in RA is compositional/functional rather than richness-based |
What are the greatest implications of this study?
This study represents a major advancement in understanding the gut microbiome’s contribution to RA by leveraging high-resolution metagenomics and integrating microbial data with host GWAS results. The identification of multiple Prevotella species beyond P. copri, the depletion of redox-active genes in Bacteroides, and the alignment of microbial and genetic immune signaling pathways provide a mechanistic basis for how gut dysbiosis may drive RA onset and progression. These findings establish Major Microbial Associations (MMAs) for RA and offer direction for developing microbiome-targeted interventions such as probiotics or fecal microbial transplants. Moreover, the observed population-specific microbiome-genome linkage highlights the need for ethnicity-aware microbiome research in precision medicine. For the Microbiome Signatures Database, this study substantiates Prevotella spp. as dominant MMAs in RA and supports functional biomarkers involving metal ion binding and redox homeostasis as potential microbial targets in disease modulation.