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.

Public Health Relevance

Postoperative delirium, the most common postoperative complication among senior patients, is an acute condition characterized by a state of confusion and is associated with substantially increased rates of morbidity and mortality, cost of care, and risk of developing Alzheimer?s disease and related dementias. However, the pathogenesis of postoperative delirium remains largely unknown. The proposed research will determine whether the interaction of age-associated gut microbiota with anesthesia/surgery-induced neuroinflammation can contribute to the brain mitochondrial dysfunction and delirium-like behavior in mice, which will ultimately lead to targeted interventions (e.g., treatment with probiotics) for the postoperative delirium.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Aging Systems and Geriatrics Study Section (ASG)
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Roberts, Luci
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Massachusetts General Hospital
United States
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