Interactions between host genetics and gut microbiota determine susceptibility to CNS autoimmunity

Area of Science:

• Neuroimmunology
• Microbiome Research
• Genetics of Autoimmunity

Background:

• Multiple sclerosis (MS) is a central nervous system autoimmune disease with complex etiology involving genetics and environmental factors.
• Gut microbiome dysbiosis is an emerging risk factor for immune-mediated diseases, but specific microbial associations and mechanisms in MS remain unclear.
• Understanding host genetics and gut microbiota interactions is crucial for deciphering MS pathogenesis.

Purpose of the Study:

• To identify specific gut microbes and their metabolic functions associated with susceptibility to experimental autoimmune encephalomyelitis (EAE), a model for MS.
• To investigate the interplay between host genetics and the gut microbiome in modulating central nervous system (CNS) autoimmunity.
• To explore microbiome-directed strategies for reducing autoimmune disease risk.

Main Methods:

• Utilized the EAE mouse model with 29 diverse host genotypes, employing microbiome sequencing and targeted manipulation.
• Performed microbiome transplantation and cohousing experiments to assess the impact of microbial transfer on EAE susceptibility.
• Employed bioinformatic analysis and bacterial isolation to identify and functionally confirm specific microbial contributions, including *Lactobacillus reuteri*.

Main Results:

• Identified specific gut bacteria and short-chain fatty acid metabolism as key factors influencing EAE susceptibility across multiple host genotypes.
• Demonstrated that microbiome transplantation into genetically identical hosts could modulate EAE susceptibility and systemic metabolite profiles.
• Found that *Lactobacillus reuteri* unexpectedly exacerbated EAE in genetically susceptible hosts, confirmed through functional studies.

Conclusions:

• Revealed complex interactions between host genetics and gut microbiota in modulating susceptibility to CNS autoimmunity.
• Highlighted the conserved role of short-chain fatty acid metabolism in EAE susceptibility across different genetic backgrounds.
• Underscored the importance of considering both host genetics and baseline gut microbiome composition for developing microbiome-targeted autoimmune disease prevention and treatment strategies.