HLA-B27-associated gut microbiota and amino acid perturbations promote ankylosing spondylitis through M1 macrophage activation.

HLA-B27 positivity, particularly in AS, was associated with marked alterations in gut microbial composition and metabolic profiles.

• Study integrated fecal gut microbiota analysis, untargeted metabolomics, and clinical phenotyping in 88 participants.
• Cohort included HLA-B27-positive AS patients (n=28), HLA-B27-positive healthy controls (n=30), and HLA-B27-negative healthy controls (n=30).
• Forty bacterial species showed progressive disease-related shifts across cohorts.
• Microbial and metabolic signatures robustly distinguished AS from both control groups.

Three amino acid-related metabolic pathways were consistently disrupted in ankylosing spondylitis.

• The three disrupted pathways identified were tryptophan metabolism, cysteine metabolism, and pyruvate-centered biosynthesis of branched-chain amino acids, ornithine, and lysine.
• These pathways were identified through integrated pathway and metabolomic analyses.
• Correlation network analyses linked differential taxa, metabolites, and clinical indices to reveal previously unrecognized microbial and metabolic signatures.

Fecal microbiota transplantation from AS clinical donors into antibiotic-treated mice recapitulated key disease-relevant features.

• FMT from clinical donors into antibiotic-treated mice was used to explore causality.
• Disease-relevant features recapitulated included impaired intestinal barrier function, systemic inflammation, trabecular bone loss, and polarization of macrophages toward a proinflammatory M1 phenotype.
• The FMT model served as the primary in vivo mechanistic platform for validating microbial contributions to AS pathogenesis.

Cinnabarinic acid was identified as a critical microbial-derived metabolite that suppresses M1 macrophage polarization via activation of the aryl hydrocarbon receptor pathway.

• Cinnabarinic acid was identified through mechanistic validation experiments.
• Its mechanism of action involves activation of the aryl hydrocarbon receptor (AhR) pathway.
• Cinnabarinic acid conferred protection in the FMT mouse model.
• This finding positioned cinnabarinic acid as a downstream mediator linking gut microbial metabolic activity to macrophage-mediated inflammation.

HLA-B27-associated gut dysbiosis and metabolic reprogramming promote AS pathogenesis through macrophage-mediated inflammation and osteocatabolic signaling.

• Findings support a model in which microbial-metabolic pathways act as potential therapeutic targets.
• M1 macrophage polarization was identified as a key mechanistic link between gut dysbiosis and systemic disease features.
• Trabecular bone loss was among the disease features reproduced in the FMT mouse model, implicating osteocatabolic signaling downstream of macrophage activation.