The gut microbiota-induced kynurenic acid recruits GPR35-positive macrophages to promote experimental encephalitis

Area of Science:

• Immunology
• Microbiology
• Neuroscience

Background:

• The gut microbiome's role in neurological diseases like experimental autoimmune encephalomyelitis (EAE) is complex and not fully understood.
• Similarities exist between immune cells in the gut and the central nervous system, suggesting cross-talk.

Purpose of the Study:

• To investigate the link between gut microbiota, tryptophan metabolism, and the pathogenesis of EAE.
• To explore the role of kynurenic acid (KYNA) in modulating immune responses relevant to EAE.

Main Methods:

• Analysis of CD4+ T-cell populations in the spinal cord and small intestine.
• Investigation of microbial gene enrichment (EC:1.13.11.11) and its metabolic products.
• Assessment of kynurenic acid (KYNA) effects on GPR35-positive macrophage recruitment and T helper 17 (Th17) cell activation.
• Modulation of KYNA-GPR35 signaling in Cx3cr1+ macrophages to evaluate EAE amelioration.

Main Results:

• Identified similarities between CD4+ T cells in the spinal cord and small intestine.
• Demonstrated a synergistic relationship between microbiota (enriched with tryptophan metabolism gene EC:1.13.11.11) and intestinal cells for KYNA biosynthesis.
• KYNA was found to modulate GPR35-positive macrophage aggregation and activate Th17 immune responses, triggering EAE.
• Modulating KYNA-GPR35 signaling in macrophages significantly ameliorated EAE.

Conclusions:

• Microbial-derived tryptophan metabolites, specifically KYNA, play a critical role in regulating immune responses in EAE.
• The gut microbiota influences EAE pathogenesis through KYNA production, affecting immune cell behavior in the gut and potentially the central nervous system.
• Targeting the KYNA-mediated GPR35 pathway in macrophages presents a potential therapeutic strategy for EAE.