Abstract
Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Unfavorable TBI outcomes result from primary mechanical injuries to the brain and ensuing secondary non-mechanical injuries that are not limited to the brain. Our genome-wide association study of Drosophila melanogaster revealed that the probability of death following TBI is associated with single nucleotide polymorphisms in genes involved in tissue barrier function and glucose homeostasis. We found that TBI causes intestinal and blood-brain barrier dysfunction and that intestinal barrier dysfunction is highly correlated with the probability of death. Furthermore, we found that ingestion of glucose after a primary injury increases the probability of death through a secondary injury mechanism that exacerbates intestinal barrier dysfunction. Our results indicate that natural variation in the probability of death following TBI is due in part to genetic differences that affect intestinal barrier dysfunction.
Highlights
Traumatic brain injury (TBI) is the leading cause of death for people under the age of 44 in the United States (Harrison-Felix et al, 2009; Coronado et al, 2011)
The probability of death following traumatic injury is a quantitative trait To investigate the role of genotype in determining the mortality index at 24 hr (MI24), we analyzed the D. melanogaster Genetic Reference Panel (DGRP), a collection of wild-type, fully sequenced, isogenic fly lines (Mackay et al, 2012)
We found that the MI24 had a continuous distribution among the RAL lines, over a wide range from 6.7 ± 0.8 to 57.5 ± 1.7 (Figure 1A and Supplementary file 1)
Summary
Traumatic brain injury (TBI) is the leading cause of death for people under the age of 44 in the United States (Harrison-Felix et al, 2009; Coronado et al, 2011). Because secondary injuries are non-mechanical and are delayed relative to primary injuries they may be sensitive to therapeutic interventions. We have used a Drosophila melanogaster model to investigate the mechanisms underlying secondary injuries that cause death following traumatic injury. Our fly model uses the high-impact trauma (HIT) device, consisting of a metal spring with a stationary end attached to a board and a free end positioned over a polyurethane pad, to inflict traumatic injury (Katzenberger et al, 2013).
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