Gut microbiota regulate Alzheimer’s disease pathologies and cognitive disorders via PUFA-associated neuroinflammation

Abstract

ObjectiveThis study is to investigate the role of gut dysbiosis in triggering inflammation in the brain and its contribution to Alzheimer’s disease (AD) pathogenesis.DesignWe analysed the gut microbiota composition of 3×Tg mice in an age-dependent manner. We generated germ-free 3×Tg mice and recolonisation of germ-free 3×Tg mice with fecal samples from both patients with AD and age-matched healthy donors.ResultsMicrobial 16S rRNA sequencing revealed Bacteroides enrichment. We found a prominent reduction of cerebral amyloid-β plaques and neurofibrillary tangles pathology in germ-free 3×Tg mice as compared with specific-pathogen-free mice. And hippocampal RNAseq showed that inflammatory pathway and insulin/IGF-1 signalling in 3×Tg mice brain are aberrantly altered in the absence of gut microbiota. Poly-unsaturated fatty acid metabolites identified by metabolomic analysis, and their oxidative enzymes were selectively elevated, corresponding with microglia activation and inflammation. AD patients’ gut microbiome exacerbated AD pathologies in 3×Tg mice, associated with C/EBPβ/asparagine endopeptidase pathway activation and cognitive dysfunctions compared with healthy donors’ microbiota transplants.ConclusionsThese findings support that a complex gut microbiome is required for behavioural defects, microglia activation and AD pathologies, the gut microbiome contributes to pathologies in an AD mouse model and that dysbiosis of the human microbiome might be a risk factor for AD.

Parishin From Gastrodia Elata Ameliorates Aging Phenotype in Mice in a Gut Microbiota-Related Manner

“…Many studies have shown that the gut microbiota plays an important role in aging-related diseases and unhealthy aging. For example, gut dysbiosis contributes to Alzheimer’s disease pathologies by enhancing neuroinflammation and regulating microglia activation in the brain ( Chen et al, 2022 ); age-related changes in the gut microbiota influence systemic inflammation and stroke outcome ( Spychala et al, 2018 ). Transplantation of gut microbes from aged mice to adult mice induces an obese phenotype, promotes inflammatory responses, impairs spatial memory and learning ability, and causes an aging phenotype in adult mice, suggesting the possibility of adaptive changes in gut microbiota in response to the aging process and the possibility of life extension by modulating the gut microbiota ( Finlay et al, 2019 ).…”

The gut-immune-brain axis in neurodevelopment and neurological disorders

“…Although AD has traditionally only been studied from a neurological perspective, recent works implicate an immune and microbial basis in the development of the disorder. GF and ABX mouse models for AD are protected from Aβ plaque aggregation and neuroinflammation [93,94] . Furthermore, transgenic AD mice compose a distinct microbiome from their wildtype counterparts, with AD-associated microbiomes shifting with age and disease progression [2] .…”

“…In all of these individual studies, the microglia is the mechanism tying the microbiota with AD. Microglia of GF and ABX-treated AD mice have better recruitment and uptake of Aβ deposits, as well as reduced inflammatory phenotypes [2,94] . This may be attributed to microbial metabolite profiles in AD patients.…”

N-3 PUFA Ameliorates the Gut Microbiota, Bile Acid Profiles, and Neuropsychiatric Behaviours in a Rat Model of Geriatric Depression

“…N-3 polyunsaturated fatty acids (PUFAs) are essential dietary nutrients and play central roles in learning, memory, and the regulation of the nervous and cardiovascular systems [ 16 ]. Chen et al reported that gut dysbiosis might contribute to the pathogenesis of AD by inducing PUFA-associated neuroinflammation [ 17 ]. PUFAs slowed the short-term progression of illness in mice with abnormal neuropsychiatric behaviours by indirectly elevating the release of neurotransmitters [ 18 ] and modulated lipid disorders in humans by increasing levels of glycine-conjugated hyodeoxycholic acid (a secondary bile acid with hypolipidemic properties) [ 19 ].…”