Death following traumatic brain injury in Drosophila is associated with intestinal barrier dysfunction.
Death following traumatic brain injury in Drosophila is associated with intestinal barrier dysfunction.
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DOI：
10.7554/elife.04790
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发表时间：
2015-03-05
期刊：
影响因子：
7.7
通讯作者：
Wassarman DA
中科院分区：
文献类型：
--
作者：
Katzenberger RJ;Chtarbanova S;Rimkus SA;Fischer JA;Kaur G;Seppala JM;Swanson LC;Zajac JE;Ganetzky B;Wassarman DA
创伤性脑损伤（TBI）是世界范围内死亡和残疾的主要原因。不利的TBI结果是由对大脑的原发性机械损伤和随后的不限于大脑的继发性非机械损伤引起的。我们对黑腹果蝇的全基因组关联研究表明，TBI后死亡的概率与组织屏障功能和葡萄糖稳态相关基因的单核苷酸多态性有关。我们发现TBI导致肠和血脑屏障功能障碍，并且肠屏障功能障碍与死亡概率高度相关。此外，我们还发现，原发性损伤后摄入葡萄糖会通过继发性损伤机制增加死亡概率，从而加剧肠道屏障功能障碍。我们的研究结果表明，TBI后死亡概率的自然变化部分是由于影响肠道屏障功能障碍的遗传差异。DOI：www.example.com创伤性脑损伤（TBI）是由头部或身体受到猛烈打击以及大脑与头骨的碰撞造成的，是人类残疾和死亡的主要原因。对大脑的原发性损伤引发继发性损伤，进一步损害大脑和其他器官，产生TBI的许多有害后果。然而，尽管经过数十年的研究，这些继发性损伤的确切性质及其起源仍然知之甚少。更好地了解继发性损伤应该有助于开发新的治疗方法，以改善受影响个体的TBI结果。为了获得这一信息，2013年，研究人员设计了一种方法，在普通果蝇Drosophila melanogaster中施加TBI，这种生物很容易进行详细的遗传和分子研究。这项研究表明，遭受TBI的苍蝇显示出许多与人类脑损伤后观察到的症状相同的症状，包括暂时丧失活动能力和随着时间的推移变得更糟的大脑损伤。此外，许多苍蝇在脑损伤后24小时内死亡。现在Katzenberger等人使用这个实验系统来调查造成这些死亡的继发性伤害。首先，确定了遗传变异，赋予脑损伤后死亡的易感性增加或减少。几个已确定的基因影响肠屏障的结构完整性，肠屏障将肠道内容物（包括营养物质和细菌）与循环系统隔离开来。Katzenberger等人随后发现，脑损伤后这一屏障的破坏允许细菌和葡萄糖泄漏出肠道。用抗生素治疗苍蝇并没有增加存活率，而降低脑损伤后循环系统中的葡萄糖水平却有效果。因此，Katzenberger等人得出结论，循环系统中的高水平葡萄糖，一种称为高血糖症的病症，是TBI后死亡的关键罪魁祸首。值得注意的是，这些结果与人类中的发现相似，其中高血糖症高度预测TBI后的死亡。同样，糖尿病患者在TBI后死亡的风险显著增加。这些结果表明，导致死亡的继发性损伤在苍蝇和人类中是相同的，对苍蝇的进一步研究可能会提供更多的新信息，帮助我们了解TBI的复杂后果。重要的挑战仍然存在，包括准确理解大脑和肠道如何沟通，大脑损伤如何导致肠道屏障破坏，以及为什么葡萄糖水平升高会增加脑损伤后的死亡率。这些问题的答案可能有助于为TBI的新疗法铺平道路。DOI：www.example.com网站
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 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