Rationale:
Temporal lobe epilepsy is the most prevalent form of acquired epilepsy, and it is difficult to treat with current anti-seizure drugs. Developing new disease-modifying therapies is critical to treat/prevent seizures in high-risk groups. Although the precise mechanisms that lead to epilepsy remain unclear, evidence from experimental and clinical work suggests that brain inflammation is a significant contributor. Recent studies suggested a role for the gut microbiota in neuroinflammation and CNS function.
The gut microbiota consists of commensal microorganisms that co-exist in a symbiotic relationship with the host. Diet can alter the composition and diversity of the gut microbiota, promoting the growth or suppression of beneficial or harmful bacteria. Recently, the implication of the gut microbiota in epilepsy has gained attention. However, the effect of the gut microbiota in seizure/epilepsy following CNS viral infection remains unclear.
In our mouse model of infection-driven epilepsy, mice intra-cranially (IC) infected with Theiler’s murine encephalomyelitis virus (TMEV) develop behavioral seizures 3-10 days post-infection (dpi). Activation of the innate immune response and infiltration of macrophages into the CNS play a key role in seizure development. Studies found that people with epilepsy have altered microbiota composition. The ketogenic diet, used to treat refractory epilepsy, exert its effect by modulating the gut microbiota composition. Using our mouse model, we found that diet modulates seizure incidence, severity, and brain inflammation following CNS viral infection. Thus, we hypothesized that the presence of specific gut bacterial population(s) and derived metabolites could protect against seizures after CNS infection.
Methods:
C56BL/6J mice were maintained on the 2920X or the 8904 Teklad Rodent diet starting 10 days before the TMEV infection (day -10). At day 0, mice were IC infected with 2.4x10
4 PFU of TMEV. Handling-induced seizures were determined daily, from 3-7 dpi, and seizure severity was scored based on the Racine scale. At 7 dpi, mice were euthanized, cells were isolated from the brains, and cell populations and their inflammatory states were determined by flow cytometry. Fecal samples were collected at days 0 and 7dpi. Blood was obtained at 7dpi.
Results:
Mice fed the 8904-diet showed increased seizure incidence and a significant increase in seizure severity compared to mice fed the 2920X diet. Also, CNS-infiltrating macrophages were significantly higher, and MHC-II expression in microglia was increased in the 8904-fed mice. We are now performing 16S rRNA-seq (fecal) and metabolomics (fecal and blood) to determine gut composition and bacteria-derived metabolites, respectively.
Conclusions:
Our studies indicate a role for the gut microbiota in seizure development after viral encephalitis. Although our study is still ongoing, we are confident that this work has the potential to reveal the manipulation of the gut microbiota as a promising therapeutic approach to treat/cure seizures/epilepsy patients.
Funding: