Gut microbial interaction networks control autoimmunity to neuroretina

Area of Science:

• Immunology
• Microbiology
• Gastroenterology

Background:

• The gut microbiome plays a crucial role in immune-mediated inflammatory diseases.
• Autoimmune uveitis is a sight-threatening ocular inflammation driven by retina-specific T cells.
• Gut commensals can provide immune stimuli that trigger autoimmune diseases.

Purpose of the Study:

• To investigate the role of specific gut microbes in autoimmune uveitis.
• To understand the mechanisms by which gut microbes modulate immune responses in autoimmune diseases.
• To identify microbial biomarkers associated with autoimmune conditions.

Main Methods:

• Utilized a spontaneous autoimmune uveitis (sEAU) mouse model.
• Colonized germ-free (GF) mice with human gut commensals.
• Performed mechanistic gain-of-function experiments by enriching GF sEAU mice with Akkermansia.
• Analyzed microbiome composition, metabolite levels (SCFAs), and T-cell responses (Th1).

Main Results:

• Human gut flora contains uveitis-promoting microbes.
• Colonization with healthy donor commensals induced disease in GF mice.
• sEAU severity correlated with Akkermansia expansion, Firmicutes contraction, decreased SCFAs, and increased gut Th1 responses.
• Enrichment with Akkermansia exacerbated disease by outcompeting SCFA-producers and enhancing Th1 responses.
• An inverse correlation between Akkermansia and Firmicutes was observed in patients with uveitis, multiple sclerosis, and Crohn's disease.

Conclusions:

• Akkermansia promotes autoimmunity by disrupting the gut microbial ecosystem and enhancing pro-inflammatory Th1 responses.
• Gut microbial networks regulate systemic immune balance.
• These findings reveal a conserved mechanism for gut microbiome modulation of autoimmune and inflammatory diseases.