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Microbiome Dysbiosis and Postoperative Delirium Pathogenesis

微生物群失调与术后谵妄发病机制

基本信息

批准号：
10055132
负责人：
Shiqian Shen
金额：
$ 45.91万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10055132
关键词：
16S ribosomal RNA sequencing Abdomen Acute Adult Age Aging Alzheimer&apos s disease related dementia Amyloid beta-Protein Anesthesia procedures Animal Model Antibiotics Attenuated Behavior Behavioral Biochemical Biological Biosensing Techniques Blood Brain Butyrates Caring Cefazolin Cognition Communities Confusion Data Delirium Development Disease Elements Endocrine Feces General Anesthesia Genus Hippocampus Germ-Free Goals Hour Human Immune Impaired cognition Inflammation Interleukin-6 Intervention Isoflurane Label Lead Measurement Measures Methods Microglia Mitochondria Modeling Morbidity - disease rate Mus Neuraxis Neuropathogenesis Operative Surgical Procedures Outcome Pathogenesis Patients Postoperative Complications Postoperative Period Precipitating Factors Predisposing Factor Probiotics Research Risk Risk Factors Role Structure System Technology Testing United States National Institutes of Health age related aged base behavior test care costs cognitive function confusion assessment method dysbiosis extracellular gut microbiota high risk innovation insight microbiome microbiota mitochondrial dysfunction mortality nano neuroinflammation new technology novel post-operative cognitive dysfunction postoperative delirium prevent tool

项目摘要

Abstract Postoperative delirium (POD), a condition characterized by a state of confusion, is one of the most common postoperative complications among senior patients and is associated with substantially increased rates of morbidity and mortality, increased cost of care, and risk of developing Alzheimer’s disease and related dementias (ADRD). However, even with ongoing POD studies, the pathogenesis of POD is still mostly unknown, which impedes further studies of POD, including the targeted interventions. Thus, there is no treatment for POD at present. Consistent with the notion that gut microbiota dysbiosis (e.g., gut microbiota community structure changes), neuroinflammation and mitochondrial dysfunction are part of ADRD neuropathogenesis and are also associated with cognitive impairments, our preliminary studies showed that the open abdominal surgery under general anesthesia (anesthesia/surgery) induced an age-dependent gut microbiota dysbiosis, neuroinflammation, mitochondrial dysfunction and POD-like behavior in the mice. Thus, we will extend these studies to further define a potential multifactorial model of POD pathogenesis by testing the following hypothesis: anesthesia/surgery-induced neuroinflammation (the precipitating factor and the contributor) is promoted by age-associated microbiota dysbiosis (the predisposing factor and the modulator), leading to mitochondrial dysfunction and POD-like behavior in mice. We will employ biochemical and behavioral tools to accomplish two Specific Aims: (1) we will assess the effects of anesthesia/surgery on gut microbiota and fecal b-amyloid, blood and brain level of IL-6, microglia activation, brain Ab and mitochondrial function, and POD-like behavior in aged mice (18 month-old mice or 3 month-old germ-free mice fed with feces of the 18 months old mice) as compared to those in adult mice (9 months old mice or 3 month- old germ-free mice fed with feces of the 9 months old mice); (2) we will assess whether treatment with butyrate, antibiotic (e.g., cefazolin) and probiotic can mitigate the POD-like behavior and their associated changes in feces, blood, and brain in the mice. We will employ an innovative label-free nano-biosensing system for biomolecular analysis (nanobeam technology) in the proposed studies. This proposal aims to investigate an understudied topic in innovative systems through testing novel hypotheses. These studies could ultimately help to develop the targeted interventions of POD by targeting microbiota dysbiosis. These efforts would ultimately promote safer anesthesia and surgical care, leading to better postoperative outcomes for senior patients and, consequently, the development of strategies towards preventing ADRD.

摘要