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

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. The etiology of MS is multifactorial, with disease risk determined by genetics and environmental factors. An emerging risk factor for immune-mediated diseases is an imbalance in the gut microbiome. However, the identity of gut microbes associated with disease risk, their mechanisms of action, and the interactions with host genetics remain obscure. To address these questions, we utilized the principal autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE), together with a genetically diverse mouse model representing 29 unique host genotypes, interrogated by microbiome sequencing and targeted microbiome manipulation. We identified specific gut bacteria and their metabolic functions associated with EAE susceptibility, implicating short-chain fatty acid metabolism as a key element conserved across multiple host genotypes. In parallel, we used a reductionist approach focused on two of the most disparate phenotypes identified in our screen. Manipulation of the gut microbiome by transplantation and cohousing demonstrated that transfer of these microbiomes into genetically identical hosts was sufficient to modulate EAE susceptibility and systemic metabolite profiles. Parallel bioinformatic approaches identified Lactobacillus reuteri as a commensal species unexpectedly associated with exacerbation of EAE in a genetically susceptible host, which was functionally confirmed by bacterial isolation and commensal colonization studies. These results reveal complex interactions between host genetics and gut microbiota modulating susceptibility to CNS autoimmunity, providing insights into microbiome-directed strategies aimed at lowering the risk for autoimmune disease and underscoring the need to consider host genetics and baseline gut microbiome composition.

The microbiome requires a genetically susceptible host to induce central nervous system autoimmunity

“…However, it is critical to understand disease-specific probiotics. This paper, as well as well as another recently published paper, has identified L. reuteri as a detrimental organism that can contribute to CNS autoimmunity (1,18). L. reuteri can be found in several over-the-counter probiotics, raising the question of whether probiotics with L. reuteri are safe for MS patients.…”

“…The microbiome has recently been recognized as an environmental factor that contributes to MS. In Montgomery et al (1), the authors harnessed the natural genetic diversity between B6 mice, PWD/ PhJ (PWD) wild-derived mice, and a panel of 27 B6.Chr PWD consomic mice to investigate gene plus microbiome interactions. They identified chromosomes that affected disease susceptibility and also identified microbes that increased disease severity in disease-susceptible hosts.…”

“…The SJL mouse immunized with proteolipid protein results in a relapsing remitting disease. Finally, the wild-derived inbred strain PWD is resistant to EAE when immunized with MOG and effect linked to the altered transcription of MS-associated genes (1).…”

“…Critically, this formulation did not have L. reuteri. There is currently little guidance on which probiotics could be beneficial or detrimental to patients with MS; however, these recent findings in EAE (1,18) suggest that patients and physicians should exercise caution when using modifying the microbiota to treat MS.…”

Exploring the Gut-Brain Axis for the Control of CNS Inflammatory Demyelination: Immunomodulation by Bacteroides fragilis’ Polysaccharide A

“…It has been shown that Prevotella histicola suppresses EAE through Tregs ( 96 ), while Lactobacillus reuteri exacerbates the disease through pathogenic CD4 + and CD8 + T cell responses ( 97 ). The prophylactic administration of individual lactobacilli strains reduces EAE severity through diminished myelin oligodendrocyte glycoprotein (MOG)- T cell reactivity ( 98 ).…”