Gut microbial interaction networks control autoimmunity to neuroretina

Zhang, A.; Horai, R.; Jittayasothorn, Y.; Badger, J. H.; Wu, Z.; Gupta, A.; Arunkumar, S.; Murphy, C. E.; Shi, G.; Nagarajan, V.; McCulloch, J. A.; Kodati, S.; Sen, H. N.; Lee, J. W.; Jacobs, J. P.; Xu, X.; Mattapallil, M. J.; Peng, Z.; Xu, B.; Palmer, R. J.; Majdalani, N.; Honda, K.; O'hUigin, C.; Caspi, R. R.

doi:10.64898/2025.12.04.691931

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bioRxiv · 10.64898/2025.12.04.691931

Gut microbial interaction networks control autoimmunity to neuroretina

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Abstract

The gut microbiome influences the development of immune-mediated inflammatory diseases, including autoimmune uveitis, a sight-threatening ocular inflammation driven by retina-specific T cells1. Using a model of spontaneous autoimmune uveitis (sEAU) we showed that gut commensals provide immune stimuli that trigger disease2. Here we report that uveitis-promoting microbes are present in human gut flora and that colonization of germ-free (GF) mice with commensals from healthy human donors was sufficient to provoke disease. Severity of sEAU correlated with expansion of Akkermansia and contraction of short-chain fatty acid (SCFA)-producing Firmicutes, followed by decreased SCFA levels and a dominant gut Th1 effector response. Mechanistic gain-of-function experiments, enriching GF sEAU mice with Akkermansia, reproduced these microbiome, metabolite and immune phenotype shifts, and exacerbated disease, suggesting that Akkermansia promotes autoimmunity by outcompeting SCFA-producers and enhancing Th1-type responses. An inverse correlation between Akkermansia (Verrucomicrobia) and Firmicutes was also present in patients with uveitis, multiple sclerosis and Crohns disease. These findings reveal a stereotypic gut microbial interaction network that regulates systemic immune balance, and may represent an ecologically conserved mechanism through which the gut microbiome modulates autoimmune and inflammatory diseases.

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Zhang, A., Horai, R., Jittayasothorn, Y., Badger, J. H., Wu, Z., Gupta, A., Arunkumar, S., Murphy, C. E., Shi, G., Nagarajan, V., McCulloch, J. A., Kodati, S., Sen, H. N., Lee, J. W., Jacobs, J. P., Xu, X., Mattapallil, M. J., Peng, Z., Xu, B., Palmer, R. J., Majdalani, N., Honda, K., O'hUigin, C., Caspi, R. R.. 2025-12-06. Gut microbial interaction networks control autoimmunity to neuroretina. https://doi.org/10.64898/2025.12.04.691931

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