Immune-gut-metabolite Interactions in Multiple Sclerosis: A Mendelian Randomization and Mediation Study

Area of Science:

• Immunology
• Microbiology
• Metabolomics
• Neuroscience

Background:

• Multiple sclerosis (MS) is a complex autoimmune disease involving inflammation and neurodegeneration.
• The roles of immune dysregulation, gut microbiota, and metabolic alterations in MS are suspected but not fully understood.
• Causal relationships between these factors and MS pathogenesis require further investigation.

Purpose of the Study:

• To investigate the causal effects of immune cell phenotypes, inflammatory proteins, gut microbiota, and plasma metabolites on MS using genetic data.
• To explore potential reverse causality and mediating pathways in MS pathogenesis.
• To identify novel therapeutic targets by elucidating the immune-microbiota-metabolite axis in MS.

Main Methods:

• Two-sample Mendelian randomization (MR) analyses were conducted using publicly available genetic data.
• Investigated 731 immune cell phenotypes, 91 inflammatory proteins, 473 gut microbiota taxa, and 1,400 plasma metabolites.
• Sensitivity analyses, bidirectional MR, and two-step mediation analyses were employed to ensure robustness and explore complex relationships.

Main Results:

• Identified significant causal associations between 13 immune cell phenotypes, 3 inflammatory proteins, 16 gut microbiota, and 14 plasma metabolites with MS.
• Bidirectional MR indicated reverse causality for certain gut microbiota.
• Mediation analyses revealed complex pathways, including specific T cell subsets, microbial genera, and metabolites influencing MS risk and protection.

Conclusions:

• Provided robust genetic evidence for the causal roles of immune factors, gut microbiota, and metabolites in MS.
• Highlighted intricate interaction networks within the immune-microbiota-metabolite axis.
• Offered novel insights into MS pathogenesis and potential avenues for therapeutic intervention.