Susceptibility to epilepsy after traumatic brain injury is associated with preexistent gut microbiome profile

Objective We examined whether posttraumatic epilepsy (PTE) is associated with measurable perturbations in gut microbiome. Methods Adult Sprague Dawley rats were subjected to lateral fluid percussion injury (LFPI). PTE was examined 7 months after LFPI, during 4-week continuous video-electroencephalographic monitoring. 16S ribosomal RNA gene sequencing was performed in fecal samples collected before LFPI/sham-LFPI and 1 week, 1 month, and 7 months thereafter. Longitudinal analyses of alpha diversity, beta diversity, and differential microbial abundance were performed. Short-chain fatty acids (SCFAs) were measured in fecal samples collected before LFPI by liquid chromatography with tandem mass spectrometry. Results Alpha diversity changed over time in both LFPI and sham-LFPI subjects; no association was observed between alpha diversity and LFPI, the severity of post-LFPI neuromotor impairments, and PTE. LFPI produced significant changes in beta diversity and selective changes in microbial abundances associated with the severity of neuromotor impairments. No association between LFPI-dependent microbial perturbations and PTE was detected. PTE was associated with beta diversity irrespective of timepoint vis-a-vis LFPI, including at baseline. Preexistent fecal microbial abundances of four amplicon sequence variants belonging to the Lachnospiraceae family (three enriched and one depleted) predicted the risk of PTE, with area under the curve (AUC) of .73. Global SCFA content was associated with the increased risk of PTE, with AUC of .722, and with 2-methylbutyric (depleted), valeric (depleted), isobutyric (enriched), and isovaleric (enriched) acids being the most important factors (AUC = .717). When the analyses of baseline microbial and SCFA compositions were combined, AUC to predict PTE increased to .78. Significance Whereas LFPI produces no perturbations in the gut microbiome that are associated with PTE, the risk of PTE can be stratified based on preexistent microbial abundances and SCFA content.

Automated summary

The objective of this study was to investigate the association between posttraumatic epilepsy (PTE) and changes in gut microbiome. The study found that there were changes in alpha diversity over time in both LFPI and sham-LFPI subjects, but no association was observed between alpha diversity and LFPI or the severity of post-LFPI neuromotor impairments and PTE. Beta diversity and selective changes in microbial abundances were associated with the severity of neuromotor impairments caused by LFPI. However, no association was found between LFPI-dependent microbial perturbations and PTE. Preexistent fecal microbial abundances and SCFA content were found to predict the risk of PTE, with certain microbial abundances and SCFAs being the most important factors. The study highlights the importance of preexisting microbial abundances and SCFA content in predicting the risk of PTE.