Female-enriched Eggerthella lenta drives neuroinflammation and IFN-γ via host receptor TLR2

Rock, R. R.; Alexander, M.; Noecker, C.; Trepka, K.; Upadhyay, V.; Ortega, E.; Ramirez, L.; Siewart, L.; Olson, C.; Halsey, T.; Probstel, A.-K.; Baranzini, S.; Turnbaugh, P. J.

doi:10.64898/2026.03.16.711194

bioRxiv · 10.64898/2026.03.16.711194

Female-enriched Eggerthella lenta drives neuroinflammation and IFN-γ via host receptor TLR2

Rock, R. R.·Alexander, M.·Noecker, C.·Trepka, K.·Upadhyay, V.·Ortega, E.·Ramirez, L.·Siewart, L.·Olson, C.·Halsey, T.·Probstel, A.-K.·Baranzini, S.·Turnbaugh, P. J.

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Abstract

Women are at increased risk of autoimmune diseases, including multiple sclerosis (MS); however, the degree to which sex differences in the gut microbiota impact autoimmunity remains largely unexplored. Our 27-cohort meta-analysis revealed 60 sex-associated gut bacterial species. Leveraging an independent clinical cohort, we demonstrate that female-enriched species significantly associate with MS status and clinical disability (EDSS). Top female-enriched species Eggerthella lenta drove disease in the experimental autoimmune encephalomyelitis (EAE) MS model, consistent with brain and gut lamina propria T cell infiltration and MS-associated T helper (Th) signatures. E. lenta induced intestinal Th1 and Th17 in healthy mice, independent of bacterial viability. Mechanistically, we demonstrate that TLR2 directly drives E. lenta-induced IFN-{gamma} production in Th cells and is necessary for exacerbation of EAE. Together, we identify a causal host-microbe axis contributing to sex differences in autoimmunity and provide a framework for evaluating sex as a biological variable in human microbiome research. HIGHLIGHTSO_LI27-cohort meta-analysis identifies a robust sex-signature in human gut microbiota. C_LIO_LIFemale-enriched species are associated with MS risk and severity. C_LIO_LIFemale-enriched Eggerthella lenta exacerbates the EAE model. C_LIO_LIE. lenta impacts neuroinflammation via toll-like receptor 2. C_LI

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Rock, R. R., Alexander, M., Noecker, C., Trepka, K., Upadhyay, V., Ortega, E., Ramirez, L., Siewart, L., Olson, C., Halsey, T., Probstel, A.-K., Baranzini, S., Turnbaugh, P. J.. 2026-03-19. Female-enriched Eggerthella lenta drives neuroinflammation and IFN-γ via host receptor TLR2. https://doi.org/10.64898/2026.03.16.711194

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