Project Summary/Abstract
Traumatic brain injury (TBI) afflicts about three million Americans every year. The highest
incidence of TBI occurs in adults aged 75 and older who have higher mortality and worse long-
term functional outcomes than younger adults. This age-associated outcome difference has also
been reported in various animal studies. Yet, the molecular and cellular mechanisms have only
been partially elucidated, and age specific TBI treatments are notably lacking. Our published
microbiome analysis (16S RNA gene sequencing) data revealed that aged mice post-TBI
demonstrate a greater loss of beneficial commensal gut bacteria and a higher rise in opportunistic
deleterious species in the compared to young adult TBI mice. This increase in gut dysbiosis
correlated with worse neurodegeneration and neurocognitive deficits in aged TBI mice. Of note
preliminary data reveals a significant decrease in the size of the impact lesion and an attenuation
of neurocognitive deficits with transfer of a healthy microbiome into young adult TBI mice via fecal
microbiome transplantations (FMT) Hence, Dr. Davis hypothesizes that the post-TBI placement
of a young microbiome into an aged mouse will attenuate neurodegeneration and neurocognitive
deficits. For the K99 phase of the proposed research, Dr. Davis will validate the findings via single
cell RNA sequencing (scRNA-seq) to interrogate the transcriptional profiles of microglia over the
course of injury in aged mice FMT treated post-TBI. He will also compare microbiome scRNA-seq
data to anatomic, neurocognitive, and pathologic outcome measures with quantitative MRI,
behavioral phenotyping, and histopathology. For the R00 phase of the proposed research, Dr.
Davis will utilize aged (80-weeks-old) germ-free (GF) C57BL/6 mice reconstituted with the SCFA-
producing bacterium Butyrivibrio fibrosolvens (B. fib) before TBI or sham injury. Mutant B.fib that
produces 10-fold less SCFA will be used as a control. A separate cohort of aged wild type
C57BL/6 mice will receive water containing SCFAs (butyrate, acetate, and propionate) vs. vehicle
after TBI. scRNAseq will be used to determine if targeted microbial replacement or SCFA dietary
supplementation can attenuate microglia activation. Anatomic, neurocognitive, and pathologic
outcome measures will be determined with MRI, behavioral phenotyping, and histopathology.
Together, this proposal will fill current gaps in geriatric TBI research by providing new insights into
the molecular and cellular mechanisms leading to aging-associated differential TBI outcomes,
which can, in turn, pinpoint potential aging-specific TBI therapeutic targets, which are severely
lacking.