TY - JOUR
T1 - Susceptibility to epilepsy after traumatic brain injury is associated with preexistent gut microbiome profile
AU - Medel-Matus, Jesus Servando
AU - Lagishetty, Venu
AU - Santana-Gomez, Cesar
AU - Shin, Don
AU - Mowrey, Wenzhu
AU - Staba, Richard J.
AU - Galanopoulou, Aristea S.
AU - Sankar, Raman
AU - Jacobs, Jonathan P.
AU - Mazarati, Andrey M.
N1 - Funding Information:
The work was supported by Department of Defense Epilepsy Research Program grant W81XWH‐19‐1‐0430 to A.M.M., Sudha Neelakantan and Venky Harinarayan Charitable Fund endowment to Epilepsy Research Laboratories to Raman Sankar and A.M.M., Veterans Administration grant CDA2 IK2CX001717 to J.P.J., National Institutes of Health grant U54NS100064 to A.S.G. and R.J.S., and Department of Defense Epilepsy Research Program grant W81XWH‐18‐1‐0612 to A.S.G. and A.M.M.
Publisher Copyright:
© 2022 International League Against Epilepsy.
PY - 2022/7
Y1 - 2022/7
N2 - 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-à-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.
AB - 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-à-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.
KW - fluid percussion injury
KW - microbiota
KW - posttraumatic epilepsy
KW - random forest classifier
KW - short-chain fatty acids
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U2 - 10.1111/epi.17248
DO - 10.1111/epi.17248
M3 - Article
C2 - 35366338
AN - SCOPUS:85128218571
SN - 0013-9580
VL - 63
SP - 1835
EP - 1848
JO - Epilepsia
JF - Epilepsia
IS - 7
ER -