Gut microbiota-based biomarkers of Alzheimer's disease and its modulation by a ketogenic diet

基于肠道微生物群的阿尔茨海默病生物标志物及其生酮饮食的调节

• 批准号: 10461652
• 负责人: Hariom Yadav
• 金额: $ 60.42万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461652
• 关键词: AD transgenic mice; APP-PS1; Address; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; American; American Heart Association; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Amyloid deposition; Bacteria; Biological Assay; Biological Markers; Brain; Caregivers; Cerebrospinal Fluid; Characteristics; Clinical Research; Clinical Trials; Cognition; Cognitive; Consensus; Data; Dementia; Deposition; Diagnosis; Diet; Dietary Intervention; Disease; Disease Marker; Elderly; Family; Fatty acid glycerol esters; Feces; Goals; Health; Human; Impaired cognition; Individual; Intervention; Measures; Mediating; Morbidity - disease rate; Mus; Nerve Degeneration; Older Population; Participant; Pathology; Patients; Persons; Pharmacologic Substance; Pilot Projects; Play; Prevention; Prognosis; Research; Role; Senile Plaques; Societies; Source; Symptoms; Testing; Time; Validation; base; candidate marker; cohort; design; dietary supplements; disorder prevention; dysbiosis; early detection biomarkers; effective therapy; fecal transplantation; feeding; forest; gut bacteria; gut microbiota; gut-brain axis; improved; individual patient; ketogenic diet; microbial; microbial signature; microbiota; microbiota profiles; microbiota transplantation; mild cognitive impairment; mortality; neuroinflammation; normal aging; personalized predictions; prevent; prognostic; recruit; responders and non-responders; response; translational study

Project Summary Cognitive decline and Alzheimer's disease (AD) are major causes of morbidity and mortality worldwide and are substantially burdensome to those affected, their caregivers, and society in general. There remain important and formidable challenges in diagnosis, prognosis and prevention of this disease. Mild cognition impairment (MCI) is characteristic of early stage AD, and interventions targeting MCI can prevent progression of AD. Currently, no effective treatments are available and highly reliable consensus-based prognostic criteria for mild cognitive impairment (MCI) are lacking. Moreover, there is insufficient evidence to support the use of pharmaceutical agents or dietary supplements to prevent/treat MCI/AD. However, emerging research demonstrates that gut microbiota influences gut-brain communication and pathology of AD. Others and our preliminary data show that AD and MCI patient's gut harbors a perturbed and unique microbiota (dysbiosis) compared to cognitively normal individuals, suggesting that the gut microbiota could be a source of new biomarkers for MCI/AD. Diet is the single most significant modulator of the gut microbiota. A ketogenic diet (KD) is a powerful modulator of brain function and improves AD pathology, along with modulating the gut microbiota. However, currently it is unknown whether a modified Mediterranean KD (MMKD) primarily acts on the brain or the gut microbiota to ameliorate AD. Our preliminary data show that in participants with MCI, MMKD improved the gut microbiota signature and markers of AD in cerebrospinal fluid (CSF). In addition, gut microbiota signatures were significantly different in individuals with and without MCI, with certain bacteria associated with MCI status. Overall, MMKD was effective to improve AD markers in CSF and microbiota. However, certain people responded better (responders) than others (non- responders) in improving markers of AD and changing unique microbiota signature. We thus hypothesize that (a) gut microbiota-based biomarkers can predict MCI and MMKD response, and (b) MMKD acts through the microbiota to reduce AD pathology. To test our hypotheses, we propose to use a cohort of participants with and without MCI already being recruited for ongoing studies at Wake Forest Alzheimer's Disease Research Center (ADRC) led by Dr. Craft. We will examine whether our new microbiota-based markers could strengthen MCI prognosis and predict MMKD response, and test whether a MMKD modulates gut microbiota and thereby improves AD pathology. Three specific aims are designed to: 1) establish if the gut microbiota signature can predict MCI in humans, 2) determine whether gut microbiota signature can predict MMKD responders and non- responders to ameliorate AD markers, and 3) assess whether gut microbiota mediates MMKD's beneficial effects to ameliorate AD pathology. Completion of these state-of-the-art studies by a highly interdisciplinary team will establish proof-of-concept that gut microbiota-based markers can strengthen prognosis of MCI and will open translational opportunities to explore the use of MMKD as a non-pharmacological approach to ameliorate AD pathology.

项目总结