Gut microbial interaction networks control autoimmunity to neuroretina

The gut microbiome influences the development of immune-mediated inflammatory diseases. One such condition is autoimmune uveitis, a sight-threatening ocular inflammation driven by retina-specific T cells<sup>1</sup>. Using a model of spontaneous experimental autoimmune uveitis (sEAU) we showed that gut commensals provide innate and adaptive immune stimuli that trigger the disease<sup>2</sup>. Here we report that uveitis-promoting microbes are present in human gut flora and that colonization of germ-free (GF) mice with commensal flora 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, as well as 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. We propose that Akkermansia promotes autoimmunity by outcompeting SCFA-producers and enhancing Th1-type responses. Notably, an inverse correlation between Akkermansia (Verrucomicrobia) and Firmicutes was also present in fecal microbiome of patients with uveitis, multiple sclerosis and Crohn's 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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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2025-12-06
DOI
https://doi.org/10.64898/2025.12.04.691931
Primary Topic
Gut microbiota and health
Type
article
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article

Gut microbial interaction networks control autoimmunity to neuroretina

Nadim Majdalani, Rachel R Caspi, Caitlin E. Murphy, Colm Ó’hUigín et al.
bioRxiv (Cold Spring Harbor Laboratory)
Gut microbiota and health
article

Gut microbial interaction networks control autoimmunity to neuroretina

Nadim Majdalani, Rachel R Caspi, Caitlin E. Murphy, Colm Ó’hUigín, Zhichao Wu, Biying Xu, Shilpa Kodati, Zixuan Peng, Vijayaraj Nagarajan, John A. McCulloch, Jonathan P. Jacobs, Yingyos Jittayasothorn, Reiko Horai, Amy Zhang, Mary J. Mattapallil, Kenya Honda, Jonathan H. Badger, Guangpu Shi, Akriti Gupta, Xiaoyan Xu, H. Nida Sen, Robert Palmer, Jung Wha Lee, Samyuktha Arunkumar
article en

Abstract

The gut microbiome influences the development of immune-mediated inflammatory diseases. One such condition is autoimmune uveitis, a sight-threatening ocular inflammation driven by retina-specific T cells<sup>1</sup>. Using a model of spontaneous experimental autoimmune uveitis (sEAU) we showed that gut commensals provide innate and adaptive immune stimuli that trigger the disease<sup>2</sup>. Here we report that uveitis-promoting microbes are present in human gut flora and that colonization of germ-free (GF) mice with commensal flora 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, as well as 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. We propose that Akkermansia promotes autoimmunity by outcompeting SCFA-producers and enhancing Th1-type responses. Notably, an inverse correlation between Akkermansia (Verrucomicrobia) and Firmicutes was also present in fecal microbiome of patients with uveitis, multiple sclerosis and Crohn's 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.

bioRxiv (Cold Spring Harbor Laboratory)
National Institutes of Health (US), University of California, Los Angeles (US), Keio University (JP), National Institute of Dental and Craniofacial Research (US), National Eye Institute (US), National Cancer Institute (US), Center for Cancer Research (US)
Openalex Percentile: Top 65%
Gut microbiota and health
DOIOpen Access PDFOpenAlex
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