Colonization by Akkermansia muciniphila modulates central nervous system autoimmunity in an ecological context-dependent manner

Daniel Peipert¹Theresa L Montgomery¹Lucinda C Toppen²Margaret Frances J Lee³Matthew J Scarborough²Dimitry N Krementsov^1*

• ¹Department of Biomedical and Health Sciences, University of Vermont, Burlington, United States
• ²Department of Civil and Environmental Engineering, University of Vermont, Burlington, United States
• ³Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, United States

Multiple sclerosis is autoimmune disease of the central nervous system (CNS) in which myelin-reactive immune attack drives demyelination and subsequent disability. Various studies have documented elevated abundance of the commensal gut bacterium Akkermansia muciniphila (A. muciniphila) in people with multiple sclerosis compared to healthy control subjects, suggesting that its elevated abundance may be a risk factor for the development of CNS autoimmunity. However, A. muciniphila is considered beneficial in various other pathological contexts, and recent studies suggest that A. muciniphila may be paradoxically associated with reduced disability and progression in multiple sclerosis. Moreover, experimental modulation of A. muciniphila levels in experimental autoimmune encephalomyelitis (EAE), an autoimmune model of multiple sclerosis, has generated conflicting results, suggesting that the effects of this microbe on CNS autoimmunity could be context-dependent. To address this possibility, we generated two distinct microbiome models in C57BL/6J mice, each stably colonized by A. muciniphila or A. muciniphila-free, providing divergent ecological contexts in which A. muciniphila may exert a differential impact. We found that A. muciniphila colonization increased EAE severity only in a specific microbiome context, in conjunction with increased Th17 responses and CNS-infiltrating immune cells. Using full-length 16S DNA sequencing to profile gut microbiome composition, we found that A. muciniphila colonization drove a reduction of Clostridia, key producers of short-chain fatty acids (SCFAs), specifically in the microbiome model in which A. muciniphila exacerbates EAE. Inferred metagenomic analyses suggested reduced SCFA production in the presence of A. muciniphila, which was confirmed by mass spectrometry. Consistently, provision of high dietary fiber as a substrate for SCFA production suppressed EAE only in the context of the Clostridia-rich microbiome responsive to A. muciniphila colonization. Taken together, our data suggest that the effect of A. muciniphila on CNS autoimmunity is highly dependent on the overall composition of the gut microbiome and suggest that this microbe may contribute to decreased gut SCFA metabolism in multiple sclerosis.