Gut commensal Streptococcus parasanguinis-derived bacterial extracellular vesicles drive host neuroinflammatory activation in temporal lobe epilepsy

Gut microbial communities modulate host physiology through diverse bioactive functional outputs; however, how microbiome-derived signals shape neuroinflammatory states remains incompletely understood. Here, we identified Streptococcus parasanguinis (S. parasanguinis, G14) as a gut-enriched commensal associated with elevated neuroinflammatory activity in the context of temporal lobe epilepsy (TLE). In a lithium‒pilocarpine-induced mouse model, S. parasanguinis colonization exacerbated inflammatory signalling, accompanied by increased expression of Tnf-α, Il-1β, Il-6 and Ccl2.

Mechanistic analyses revealed that these effects were mediated by bacterial extracellular vesicles (BEVs). S. parasanguinis-derived BEVs (S. p BEVs) promoted peripheral and central inflammatory responses, potentially through peripheral immune-to-brain signalling. Notably, BEVs induced the expression of several ARM-associated genes in microglia, suggesting an ARM-associated activation pattern.

Together, these findings position BEVs as potential mediators of gut microbiome–host communication, linking microbial ecology to neuroinflammatory activation through a BEV–CCL2–microglial inflammatory axis. The authors acknowledge the financial support from National Natural Science Foundation of China (No.82160262), Scientific and Technological Innovation in Health Industry of Gansu Province in 2025 (China) (No. GSWSZD2025-12), Key Incubation Project Funds of the second hospital & clinical medical school, Lanzhou university (No. 2025-21-zdfy-011), and Gansu Provincial Key Talents Program in 2023 (China) (No. 2023RCXM43).

These authors contributed equally: Junqiang Li, Yan Wang, Weiwen Cai. Department of Neurology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, China Junqiang Li, Sirui Chen, Lan Zhang & Tiancheng Wang Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, China Junqiang Li, Yan Wang, Weiwen Cai, Wentao Zhang, Sirui Chen, Lan Zhang, Hui Sun & Long Qin Department of General Surgery, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, China Correspondence to Hui Sun, Long Qin or Tiancheng Wang. The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.