Traumatic Brain Injury, Perturbations in Gut Microbiome and Posttraumatic Epilepsy
Abstract number :
1.399
Submission category :
1. Basic Mechanisms / 1A. Epileptogenesis of acquired epilepsies
Year :
2021
Submission ID :
1886441
Source :
www.aesnet.org
Presentation date :
12/4/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:56 AM
Authors :
Andrey Mazarati, PhD - David Geffen School of Medicine, University of California, Los Angeles; Jesus-Servando Medel-Matus, PhD - David Geffen School of Medicine, University of California, Los Angeles; Venu Lagishetty, PhD - David Geffen School of Medicine, University of California, Los Angeles; Cesar Santana-Gomez, PhD - David Geffen School of Medicine, University of California, Los Angeles; Don Shin, B.Sci. - David Geffen School of Medicine, University of California, Los Angeles; Jonathan Jacobs, MD, PhD - David Geffen School of Medicine, University of California, Los Angeles; Richard Staba, MD - David Geffen School of Medicine, University of California, Los Angeles; Raman Sankar, MD, PhD - David Geffen School of Medicine, University of California, Los Angeles
Rationale: Gut dysbiosis has been reported after traumatic brain injury (TBI), and in epilepsies of several etiologies. Using a rat model of TBI-posttraumatic epilepsy (PTE) continuum, lateral fluid percussion injury (LFPI), we studied whether TBI altered gut microbiota, whether such alterations were associated with PTE, and whether fecal microbiome transfer (FMT) from post-LFPI rats altered the recipients’ susceptibility to epilepsy.
Methods: LFPI (target 2 atm) and sham-LFPI were induced in 50-day-old Sprague Dawley rats. Neuromotor score was assessed 1 day after surgery. Fecal samples were collected before, 1 week, 1 and 6 months after LFPI. 6 months after LFPI, rats underwent 8 weeks of video-EEG monitoring for spontaneous seizures. Afterwards, 30 rats were kindled from basolateral amygdala. Fecal microbiota was analyzed by 16S ribosomal RNA gene sequencing in 60 LFPI and 21 sham-LFPI rats. Microbial diversity was assessed by the Shannon index of richness and evenness. Beta analysis of microbial composition was performed using Bray-Curtis dissimilarity and visualized by principal coordinates analysis. Microbes were analyzed at the level of amplicon sequence variants. For FMT, the following donors were used (n=4 per type): naïve; 1 week after LFPI, which subsequently would develop PTE; 7 months after LFPI with PTE and without PTE. Fecal samples were combined for the same donor type and given to recipients via oral gavage (7 per group) 3 weeks after LFPI, including 2 weeks of antibiotic treatment to suppress commensal microbiota. PTE was studied 7-9 months later.
Results: Microbial diversity was reduced 1 week after surgery both in LFPI and in sham-LFPI rats. No changes were found at other time points. Before LFPI, microbial composition was similar between LFPI and sham-LFPI rats (p=0.08). Significant differences between LFPI and sham-LFPI subjects were detected at 1 week (p=0.04), 1 month (p=0.006) and 6 months (p=0.01; PERMANOVA). Most notable changes were for microbes of Ruminococcaceae and Lachnospiraceae families.
Spontaneous seizures were detected in 18 out of 60 LFPI rats. 13 rats kindled faster, 10- slower and 7- similar to sham-LFPI rats. No connection was detected between microbial composition at any of the time points, and neuromotor score, spontaneous seizures, and kindling.
FMT had no effects on spontaneous seizures, for any of the donor type. FMT significantly delayed kindling in LFPI rats notwithstanding the donor type (Kruskal Wallis + Dunn’s). Antibiotics alone had no effects.
Conclusions: LFPI in rats rapidly and persistently altered gut microbial composition, with only transient reduction in microbial diversity, the latter likely due to surgery rather than TBI proper. No association was detected between LFPI-induced dysbiosis and PTE. FMT had modest antiepileptic effect notwithstanding the donor type. This effect was likely due to components of microbiome that had not been not altered by TBI, and that remain to be further identified.
Funding: Please list any funding that was received in support of this abstract.: DoD grant W81XWH-19-1-0430; S.Neelakantan and V.Harinarayan Endowment to Epilepsy Research Laboratories.
Basic Mechanisms