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.
Keywords:
D. melanogaster; blood–brain barrier; chromosomes; genes; glucose homeostasis; grainyhead; hexosamine biosynthesis pathway; innate immune response; neuroscience; septate junction.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Bacterial Load
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Blood-Aqueous Barrier / metabolism
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Blood-Aqueous Barrier / physiopathology
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Blood-Brain Barrier / metabolism
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Blood-Brain Barrier / physiopathology
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Blood-Retinal Barrier / metabolism
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Blood-Retinal Barrier / physiopathology
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Brain Injuries / genetics*
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Brain Injuries / metabolism
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Brain Injuries / mortality
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Disease Models, Animal
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Drosophila Proteins / genetics*
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Drosophila Proteins / metabolism
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Drosophila melanogaster / genetics
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Drosophila melanogaster / metabolism
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Gene Expression
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Glucose / administration & dosage
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Glucose / metabolism
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Glucose / pharmacology
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Hemolymph / metabolism
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Hemolymph / microbiology
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Humans
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Intestinal Mucosa / metabolism*
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Intestines / drug effects
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Intestines / physiopathology
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Polymorphism, Single Nucleotide*
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Reverse Transcriptase Polymerase Chain Reaction
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Risk Factors
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Survival Rate
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Time Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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DNA-Binding Proteins
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Drosophila Proteins
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Transcription Factors
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grh protein, Drosophila
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Glucose