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Impact of alcohol-induced intestinal microbiota dysbiosis in a rodent model of Alzheimer's disease.

ABSTRACT: Introduction: Alzheimer's disease (AD) is a devastating neurodegenerative disorder. While genetics are important in the development of AD, environment and lifestyle are also important factors influencing AD. One such lifestyle factor is alcohol consumption. Unhealthy and excessive chronic alcohol consumption is associated with a greater risk of all types of dementia, especially AD. Alcohol consumption has numerous effects on the body, including alterations to the intestinal microbiota (dysbiosis) and intestinal barrier dysfunction (leakiness and intestinal hyperpermeability), with evidence indicating that inflammation resulting from dysbiosis and barrier dysfunction can promote neuroinflammation impacting brain structure and function. Objective: This study sought to determine the impact of alcohol-induced dysbiosis and barrier dysfunction on AD-like behavior and brain pathology using a transgenic rodent model of AD (3xTg-AD). Methods: Alcohol (20%) was administered to 3xTg-AD mice in the drinking water for 20 weeks. Intestinal (stool) microbiota, intestinal barrier permeability, systemic inflammation (IL-6), behavior, and AD pathology (phosphorylated tau and β-amyloid), and microglia were examined. Results: Alcohol consumption changed the intestinal microbiota community (dysbiosis) and increased intestinal barrier permeability in both control and 3xTg-AD mice (oral/urine sugar test and lipopolysaccharide-binding protein (LBP)). However, alcohol consumption did not influence serum IL-6, behavior, or β-amyloid, phosphorylated tau, or microglia in 3xTg-AD mice. Important differences in genotype and sex were noted. Conclusion: Alcohol-induced microbiota dysbiosis and intestinal barrier dysfunction did not exacerbate behavior or AD-like brain pathology in the 3xTg-AD mouse model of AD which could, in part, be the result of a lack of systemic inflammation.

SUBMITTER: Frausto DM

PROVIDER: S-EPMC9421609 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Impact of alcohol-induced intestinal microbiota dysbiosis in a rodent model of Alzheimer's disease.

Frausto Dulce M DM Engen Phillip A PA Naqib Ankur A Jackson Aeja A Tran Laura L Green Stefan J SJ Shaikh Maliha M Forsyth Christopher B CB Keshavarzian Ali A Voigt Robin M RM

Frontiers in aging 20220815

<b>Introduction:</b> Alzheimer's disease (AD) is a devastating neurodegenerative disorder. While genetics are important in the development of AD, environment and lifestyle are also important factors influencing AD. One such lifestyle factor is alcohol consumption. Unhealthy and excessive chronic alcohol consumption is associated with a greater risk of all types of dementia, especially AD. Alcohol consumption has numerous effects on the body, including alterations to the intestinal microbiota (dy ...[more]

PMID: 36046496

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Project description:Alcohol intake causes many diseases including neuropsychiatric symptoms, nutritional deficiency, progressive pancreatitis, liver cirrhosis, and ischemic heart disease. The gut microbiota changes significantly after alcohol exposure. Alcohol consumption tends to increase in underage and young people, but the feature of the gut microbiota in puberty remains largely unexplored. In this study, we conducted alcohol-exposed pubertal and adult mice model to investigate the intestinal damage and gut microbiota change. Interestingly, the responses of pubertal mice and adult mice after alcohol exposure were different. We found that alcohol dehydrogenase decreased and aldehyde dehydrogenase increased in the liver of pubertal mice, thus reducing the accumulation of toxic acetaldehyde. Furthermore, alcohol exposure caused less intestinal injury in pubertal mice. Through the analysis of metagenome assembly genome, we obtained many unrecognized bacterial genomes. Limosillactobacillus reuteri (cluster_56) and Lactobacillus intestinalis (cluster_57) were assembled from the samples of pubertal mice, which were involved in the production of indole acetic acid and the transformation of bile acids in response to alcohol exposure. This study provided a new insight to investigate the gut microbiota change and explained the difference of the gut microbiota after alcohol exposure between pubertal mice and adult mice.ImportanceThis study elucidates the significant impact of alcohol exposure on the gut microbiota and metabolic pathways in mice, highlighting the differential responses between adolescent and adult stages. Alcohol exposure was found to damage the intestinal barrier, alter the microbial composition by decreasing beneficial bacteria like Lactobacillus, and increase harmful bacteria such as Alistipes. The study also discovered unique microbial changes and resilience in pubertal mice. Species-level metagenomic analysis revealed specific microbial taxa and metabolic functions affected by alcohol. Metagenome-assembled genomes (MAGs) found many species that could not be annotated by conventional methods including many members of Lachnospiraceae, greatly expanding our understanding of the gut microbiota composition. These findings underscore the need for further research on alcohol's effects on various organs and the implications of microbial metabolites on disease progression.

Project description:Background & aimsBile-acid metabolism and the intestinal microbiota are impaired in alcohol-related liver disease. Activation of the bile-acid receptor TGR5 (or GPBAR1) controls both biliary homeostasis and inflammatory processes. We examined the role of TGR5 in alcohol-induced liver injury in mice.MethodsWe used TGR5-deficient (TGR5-KO) and wild-type (WT) female mice, fed alcohol or not, to study the involvement of liver macrophages, the intestinal microbiota (16S sequencing), and bile-acid profiles (high-performance liquid chromatography coupled to tandem mass spectrometry). Hepatic triglyceride accumulation and inflammatory processes were assessed in parallel.ResultsTGR5 deficiency worsened liver injury, as shown by greater steatosis and inflammation than in WT mice. Isolation of liver macrophages from WT and TGR5-KO alcohol-fed mice showed that TGR5 deficiency did not increase the pro-inflammatory phenotype of liver macrophages but increased their recruitment to the liver. TGR5 deficiency induced dysbiosis, independently of alcohol intake, and transplantation of the TGR5-KO intestinal microbiota to WT mice was sufficient to worsen alcohol-induced liver inflammation. Secondary bile-acid levels were markedly lower in alcohol-fed TGR5-KO than normally fed WT and TGR5-KO mice. Consistent with these results, predictive analysis showed the abundance of bacterial genes involved in bile-acid transformation to be lower in alcohol-fed TGR5-KO than WT mice. This altered bile-acid profile may explain, in particular, why bile-acid synthesis was not repressed and inflammatory processes were exacerbated.ConclusionsA lack of TGR5 was associated with worsening of alcohol-induced liver injury, a phenotype mainly related to intestinal microbiota dysbiosis and an altered bile-acid profile, following the consumption of alcohol.Lay summaryExcessive chronic alcohol intake can induce liver disease. Bile acids are molecules produced by the liver and can modulate disease severity. We addressed the specific role of TGR5, a bile-acid receptor. We found that TGR5 deficiency worsened alcohol-induced liver injury and induced both intestinal microbiota dysbiosis and bile-acid pool remodelling. Our data suggest that both the intestinal microbiota and TGR5 may be targeted in the context of human alcohol-induced liver injury.

Dataset Information

Impact of alcohol-induced intestinal microbiota dysbiosis in a rodent model of Alzheimer's disease.

Publications

Impact of alcohol-induced intestinal microbiota dysbiosis in a rodent model of Alzheimer's disease.

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