Death following traumatic brain injury in Drosophila is associated with intestinal barrier dysfunction

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.

DOI: http://dx.doi.org/10.7554/eLife.04790.001

eLife digest

Traumatic brain injury (TBI) caused by a violent blow to the head or body and the resultant collision of the brain against the skull is a major cause of disability and death in humans. Primary injury to the brain triggers secondary injuries that further damage the brain and other organs, generating many of the detrimental consequences of TBI. However, despite decades of study, the exact nature of these secondary injuries and their origin are poorly understood. A better understanding of secondary injuries should help to develop novel therapies to improve TBI outcomes in affected individuals.

To obtain this information, in 2013 researchers devised a method to inflict TBI in the common fruit fly, Drosophila melanogaster, an organism that is readily amenable to detailed genetic and molecular studies. This investigation demonstrated that flies subjected to TBI display many of the same symptoms observed in humans after a brain injury, including temporary loss of mobility and damage to the brain that becomes worse over time. In addition, many of the flies die within 24 hr after brain injury.

Now Katzenberger et al. use this experimental system to investigate the secondary injuries responsible for these deaths. First, genetic variants were identified that confer increased or decreased susceptibility to death after brain injury. Several of the identified genes affect the structural integrity of the intestinal barrier that isolates the contents of the gut—including nutrients and bacteria—from the circulatory system. Katzenberger et al. subsequently found that the breakdown of this barrier after brain injury permits bacteria and glucose to leak out of the intestine. Treating flies with antibiotics did not increase survival, whereas reducing glucose levels in the circulatory system after brain injury did. Thus, Katzenberger et al . conclude that high levels of glucose in the circulatory system, a condition known as hyperglycemia, is a key culprit in death following TBI.

Notably, these results parallel findings in humans, where hyperglycemia is highly predictive of death following TBI. Similarly, individuals with diabetes have a significantly increased risk of death after TBI. These results suggest that the secondary injuries leading to death are the same in flies and humans and that further studies in flies are likely to provide additional new information that will help us understand the complex consequences of TBI. Important challenges remain, including understanding precisely how the brain and intestine communicate, how injury to the brain leads to disruption of the intestinal barrier, and why elevated glucose levels increase mortality after brain injury. Answers to these questions could help pave the way to new therapies for TBI.

DOI: http://dx.doi.org/10.7554/eLife.04790.002