{"title":"肠道细菌感染引发 3xTg-AD 转基因小鼠神经炎症和神经行为障碍","authors":"Gwoncheol Park,Saurabh Kadyan,Nathaniel Hochuli,Gloria Salazar,Orlando Laitano,Paramita Chakrabarty,Philip A Efron,M Ammar Zafar,Aaron Wilber,Ravinder Nagpal","doi":"10.1093/infdis/jiae165","DOIUrl":null,"url":null,"abstract":"BACKGROUND\r\nKlebsiella pneumoniae is infamous for hospital-acquired infections and sepsis, which have also been linked to Alzheimer disease (AD)-related neuroinflammatory and neurodegenerative impairment. However, its causative and mechanistic role in AD pathology remains unstudied.\r\n\r\nMETHODS\r\nA preclinical model of K. pneumoniae enteric infection and colonization is developed in an AD model (3xTg-AD mice) to investigate whether and how K. pneumoniae pathogenesis exacerbates neuropathogenesis via the gut-blood-brain axis.\r\n\r\nRESULTS\r\nK. pneumoniae, particularly under antibiotic-induced dysbiosis, was able to translocate from the gut to the bloodstream by penetrating the gut epithelial barrier. Subsequently, K. pneumoniae infiltrated the brain by breaching the blood-brain barrier. Significant neuroinflammatory phenotype was observed in mice with K. pneumoniae brain infection. K. pneumoniae-infected mice also exhibited impaired neurobehavioral function and elevated total tau levels in the brain. Metagenomic analyses revealed an inverse correlation of K. pneumoniae with gut biome diversity and commensal bacteria, highlighting how antibiotic-induced dysbiosis triggers an enteroseptic \"pathobiome\" signature implicated in gut-brain perturbations.\r\n\r\nCONCLUSIONS\r\nThe findings demonstrate how infectious agents following hospital-acquired infections and consequent antibiotic regimen may induce gut dysbiosis and pathobiome and increase the risk of sepsis, thereby increasing the predisposition to neuroinflammatory and neurobehavioral impairments via breaching the gut-blood-brain barrier.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"An Enteric Bacterial Infection Triggers Neuroinflammation and Neurobehavioral Impairment in 3xTg-AD Transgenic Mice.\",\"authors\":\"Gwoncheol Park,Saurabh Kadyan,Nathaniel Hochuli,Gloria Salazar,Orlando Laitano,Paramita Chakrabarty,Philip A Efron,M Ammar Zafar,Aaron Wilber,Ravinder Nagpal\",\"doi\":\"10.1093/infdis/jiae165\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"BACKGROUND\\r\\nKlebsiella pneumoniae is infamous for hospital-acquired infections and sepsis, which have also been linked to Alzheimer disease (AD)-related neuroinflammatory and neurodegenerative impairment. However, its causative and mechanistic role in AD pathology remains unstudied.\\r\\n\\r\\nMETHODS\\r\\nA preclinical model of K. pneumoniae enteric infection and colonization is developed in an AD model (3xTg-AD mice) to investigate whether and how K. pneumoniae pathogenesis exacerbates neuropathogenesis via the gut-blood-brain axis.\\r\\n\\r\\nRESULTS\\r\\nK. pneumoniae, particularly under antibiotic-induced dysbiosis, was able to translocate from the gut to the bloodstream by penetrating the gut epithelial barrier. Subsequently, K. pneumoniae infiltrated the brain by breaching the blood-brain barrier. Significant neuroinflammatory phenotype was observed in mice with K. pneumoniae brain infection. K. pneumoniae-infected mice also exhibited impaired neurobehavioral function and elevated total tau levels in the brain. Metagenomic analyses revealed an inverse correlation of K. pneumoniae with gut biome diversity and commensal bacteria, highlighting how antibiotic-induced dysbiosis triggers an enteroseptic \\\"pathobiome\\\" signature implicated in gut-brain perturbations.\\r\\n\\r\\nCONCLUSIONS\\r\\nThe findings demonstrate how infectious agents following hospital-acquired infections and consequent antibiotic regimen may induce gut dysbiosis and pathobiome and increase the risk of sepsis, thereby increasing the predisposition to neuroinflammatory and neurobehavioral impairments via breaching the gut-blood-brain barrier.\",\"PeriodicalId\":501010,\"journal\":{\"name\":\"The Journal of Infectious Diseases\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-09-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Infectious Diseases\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/infdis/jiae165\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Infectious Diseases","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/infdis/jiae165","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
背景肺炎克雷伯氏菌因医院获得性感染和败血症而臭名昭著,这也与阿尔茨海默病(AD)相关的神经炎症和神经退行性损伤有关。方法在 AD 模型(3xTg-AD 小鼠)中建立了肺炎链球菌肠道感染和定植的临床前模型,以研究肺炎链球菌的致病机制是否以及如何加重 AD 的病情。结果肺炎克雷伯菌,尤其是在抗生素诱导的菌群失调情况下,能够通过穿透肠道上皮屏障从肠道转运到血液中。随后,肺炎双球菌通过突破血脑屏障浸润大脑。在肺炎双球菌脑部感染的小鼠中观察到了明显的神经炎症表型。肺炎双球菌感染的小鼠还表现出神经行为功能受损和脑内总 tau 水平升高。元基因组分析表明,肺炎双球菌与肠道生物群多样性和共生菌呈反向相关,突出了抗生素诱导的菌群失调如何触发肠道 "病原生物群 "特征,从而导致肠道-大脑紊乱。结论:研究结果表明,医院获得性感染后的感染性病原体以及随之而来的抗生素治疗方案可能会诱发肠道菌群失调和病原生物群,并增加败血症的风险,从而通过突破肠道-血脑屏障增加神经炎症和神经行为障碍的易感性。
An Enteric Bacterial Infection Triggers Neuroinflammation and Neurobehavioral Impairment in 3xTg-AD Transgenic Mice.
BACKGROUND
Klebsiella pneumoniae is infamous for hospital-acquired infections and sepsis, which have also been linked to Alzheimer disease (AD)-related neuroinflammatory and neurodegenerative impairment. However, its causative and mechanistic role in AD pathology remains unstudied.
METHODS
A preclinical model of K. pneumoniae enteric infection and colonization is developed in an AD model (3xTg-AD mice) to investigate whether and how K. pneumoniae pathogenesis exacerbates neuropathogenesis via the gut-blood-brain axis.
RESULTS
K. pneumoniae, particularly under antibiotic-induced dysbiosis, was able to translocate from the gut to the bloodstream by penetrating the gut epithelial barrier. Subsequently, K. pneumoniae infiltrated the brain by breaching the blood-brain barrier. Significant neuroinflammatory phenotype was observed in mice with K. pneumoniae brain infection. K. pneumoniae-infected mice also exhibited impaired neurobehavioral function and elevated total tau levels in the brain. Metagenomic analyses revealed an inverse correlation of K. pneumoniae with gut biome diversity and commensal bacteria, highlighting how antibiotic-induced dysbiosis triggers an enteroseptic "pathobiome" signature implicated in gut-brain perturbations.
CONCLUSIONS
The findings demonstrate how infectious agents following hospital-acquired infections and consequent antibiotic regimen may induce gut dysbiosis and pathobiome and increase the risk of sepsis, thereby increasing the predisposition to neuroinflammatory and neurobehavioral impairments via breaching the gut-blood-brain barrier.