[Paper Review] Microbiome-derived bile acids contribute to elevated antigenic response and bone erosion in rheumatoid arthritis

Xiuli Su, Xiaona Li+16 more|arXiv (Cornell University)|Jul 14, 2023

Mycobacterium research and diagnosisMedicine3 citations

TL;DR

This study identifies a gut microbiome-bile acid axis as a key driver of autoimmune responses and bone destruction in rheumatoid arthritis (RA). Using multi-omics profiling in RA patients, it shows that Bacteroides-dominated dysbiosis increases secondary bile acid production via bile salt hydrolase (BSH) and 7α-hydroxysteroid dehydrogenase (7α-HSDH) enzymes, which correlates with anti-citrullinated protein antibody (ACPA) levels and radiographic bone erosion, implicating microbial bile acids as potential mediators of RA pathogenesis and therapeutic targets.

ABSTRACT

Rheumatoid arthritis (RA) is a chronic, disabling and incurable autoimmune disease. It has been widely recognized that gut microbial dysbiosis is an important contributor to the pathogenesis of RA, although distinct alterations in microbiota have been associated with this disease. Yet, the metabolites that mediate the impacts of the gut microbiome on RA are less well understood. Here, with microbial profiling and non-targeted metabolomics, we revealed profound yet diverse perturbation of the gut microbiome and metabolome in RA patients in a discovery set. In the Bacteroides-dominated RA patients, differentiation of gut microbiome resulted in distinct bile acid profiles compared to healthy subjects. Predominated Bacteroides species expressing BSH and 7a-HSDH increased, leading to elevated secondary bile acid production in this subgroup of RA patients. Reduced serum fibroblast growth factor-19 and dysregulated bile acids were evidence of impaired farnesoid X receptor-mediated signaling in the patients. This gut microbiota-bile acid axis was correlated to ACPA. The patients from the validation sets demonstrated that ACPA-positive patients have more abundant bacteria expressing BSH and 7a-HSDH but less Clostridium scindens expressing 7a-dehydroxylation enzymes, together with dysregulated microbial bile acid metabolism and more severe bone erosion than ACPA-negative ones. Mediation analyses revealed putative causal relationships between the gut microbiome, bile acids, and ACPA-positive RA, supporting a potential causal effect of Bacteroides species in increasing levels of ACPA and bone erosion mediated via disturbing bile acid metabolism. These results provide insights into the role of gut dysbiosis in RA in a manifestation-specific manner, as well as the functions of bile acids in this gut-joint axis, which may be a potential intervention target for precisely controlling RA conditions.

Motivation & Objective

• To investigate the role of gut microbiome-derived metabolites in rheumatoid arthritis (RA) pathogenesis.
• To determine whether bile acid metabolism is altered in RA patients and linked to autoimmunity and joint damage.
• To identify specific microbial taxa and enzymes involved in bile acid transformation in RA.
• To evaluate the causal relationship between gut microbiota, bile acids, and ACPA-positive RA.
• To explore the potential of targeting the gut-joint axis via bile acid metabolism for RA intervention.

Proposed method

• Non-targeted metabolomics and 16S rRNA gene sequencing were used to profile gut microbiota and metabolomes in RA patients and healthy controls.
• Microbial functional potential was assessed by quantifying genes encoding bile salt hydrolase (BSH) and 7α-hydroxysteroid dehydrogenase (7α-HSDH).
• Serum fibroblast growth factor-19 (FGF-19) levels were measured as a marker of farnesoid X receptor (FXR) signaling activity.
• Statistical mediation analysis was applied to test causal pathways from microbiota to ACPA and bone erosion via bile acid metabolism.
• Findings were validated in independent patient cohorts to confirm associations with ACPA status and radiographic damage.
• Subgroup analysis focused on Bacteroides-dominated microbiota to identify specific microbial drivers of bile acid dysregulation.

Experimental results

Research questions

• RQ1 How does gut microbial dysbiosis in RA patients alter bile acid metabolism?
• RQ2 Which microbial enzymes (e.g., BSH, 7α-HSDH) are enriched in RA patients and linked to secondary bile acid production?
• RQ3 Is there a correlation between serum FGF-19 levels and bile acid signaling in RA patients?
• RQ4 To what extent do microbiome-derived bile acids mediate ACPA production and bone erosion in RA?
• RQ5 Can a causal pathway be established from gut microbiota to ACPA-positive RA through bile acid metabolism?

Key findings

• RA patients with Bacteroides-dominated microbiota exhibited significantly elevated levels of secondary bile acids due to increased expression of bile salt hydrolase (BSH) and 7α-hydroxysteroid dehydrogenase (7α-HSDH).
• Serum fibroblast growth factor-19 (FGF-19) was reduced in RA patients, indicating impaired farnesoid X receptor (FXR)-mediated bile acid signaling.
• ACPA-positive RA patients had higher abundance of bacteria expressing BSH and 7α-HSDH, and lower levels of Clostridium scindens, which produces 7α-dehydroxylation enzymes.
• Dysregulated microbial bile acid metabolism was significantly correlated with increased radiographic bone erosion in ACPA-positive patients.
• Mediation analysis revealed a putative causal pathway from Bacteroides species to elevated ACPA and bone erosion via altered bile acid metabolism.
• The gut microbiome-bile acid axis was specifically linked to ACPA-positive RA, suggesting a manifestation-specific mechanism in RA pathogenesis.