Gut Microbiota Dysbiosis Induced by Decreasing Endogenous Melatonin Mediates the Pathogenesis of Alzheimer's Disease and Obesity

Study information

Reviewed Marked as Reviewed by Svetlana up on 2024-7-1

study design

laboratory experiment

Citation

PMID PubMed identifier for scientific articles.

35619714

DOI Digital object identifier for electronic documents.

10.3389/fimmu.2022.900132

URI

Authors

Zhang B, Chen T, Cao M, Yuan C, Reiter RJ, Zhao Z, Zhao Y, Chen L, Fan W, Wang X, Zhou X, Li C

Journal

Frontiers in immunology

Year

2022

Keywords:

alzheimer's disease, fecal microbiota transplantation, gut- brain axis, melatonin, microbiota dysbiosis, obesity, systemic inflammation

Lifestyle choices, external environment, aging, and other factors influence the synthesis of melatonin. Although the physiological functions of melatonin have been widely studied in relation to specific organs, the systemic effects of endogenous melatonin reduction has not been reported. This study evaluates the systemic changes and possible pathogenic risks in an endogenous melatonin reduction (EMR) mouse model deficient in the rate limiting enzyme in melatonin production, arylalkylamine N-acetyltransferase (Aanat) gene. Using this model, we identified a new relationship between melatonin, Alzheimer's disease (AD), and gut microbiota. Systematic changes were evaluated using multi-omics analysis. Fecal microbiota transplantation (FMT) was performed to examine the role of gut microbiota in the pathogenic risks of EMR. EMR mice exhibited a pan-metabolic disorder, with significant transcriptome changes in 11 organs, serum metabolome alterations as well as microbiota dysbiosis. Microbiota dysbiosis was accompanied by increased gut permeability along with gut and systemic inflammation. Correlation analysis revealed that systemic inflammation may be related to the increase of Ruminiclostridium_5 relative abundance. 8-month-old EMR mice had AD-like phenotypes, including Iba-1 activation, A β protein deposition and decreased spatial memory ability. Moreover, EMR mice showed decreased anti stress ability, under high-fat diet, EMR mice had greater body weight and more obvious hepatic steatosis compared with WT group. FMT improved gut permeability, systemic inflammation, and AD-related phenotypes, while reducing obesity in EMR mice. Our findings suggest EMR causes systemic changes mediated by gut microbiota dysbiosis, which may be a pathogenic factor for AD and obesity, we further proved the gut microbiota is a potential target for the prevention and treatment of AD and obesity.

Experiment 1

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Reviewed Marked as Reviewed by Svetlana up on 2024-7-1

Curated date: 2024/03/20

Curator: Shulamite

Revision editor(s): Shulamite, Deacme, Scholastica

Subjects

Location of subjects: China

Host species Species from which microbiome was sampled. Contact us to have more species added.: Mus musculus

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology: Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology: Alzheimer's disease biomarker measurement Alzheimer's disease biomarker measurement,alzheimer's disease biomarker measurement

Group 0 name Corresponds to the control (unexposed) group for case-control studies: Wild type (WT) mice

Group 1 name Corresponds to the case (exposed) group for case-control studies: Endogenous melatonin reduction (EMR) mice

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Mice that exhibited a pan-metabolic disorder, with significant transcriptome changes in 11 organs, serum metabolome alterations as well as microbiota dysbiosis.

Lab analysis

Sequencing type: 16S

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: V3-V4

Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance: Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).: relative abundances

Statistical test: LEfSe

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05

MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?: Yes

LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool: 2.0

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness: unchanged

Chao1 Abundance-based estimator of species richness: unchanged

Simpson Estimator of species richness and species evenness: more weight on species evenness: unchanged

Richness Number of species: unchanged

Signature 1

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Curated date: 2024/03/24

Curator: Shulamite

Revision editor(s): Shulamite, Deacme, Scholastica

Source: Figure 4C

Description: Distinct gut microbiota identified by LEfSe in endogenous melatonin reduction (EMR) versus wild type (WT) mice with biomarkers at all levels

Abundance in Group 1: increased abundance in Endogenous melatonin reduction (EMR) mice

NCBI	Quality Control	Links
Actinomycetota
Alphaproteobacteria
Amedibacterium
Bacilli
Candidatus Saccharimonadaceae
Candidatus Saccharimonadales
Candidatus Saccharimonadia
Candidatus Saccharimonas
Coriobacteriales
Coriobacteriia
Eggerthellaceae
Enterorhabdus
Lactobacillaceae
Lactobacillales
Lactobacillus
Micrococcaceae
Micrococcales
Paenarthrobacter
Papillibacter
Patescibacteria group
Ruminiclostridium
Lachnospiraceae_UCG_006Lachnospiraceae_UCG_006
GCA_900066225GCA_900066225

Revision editor(s): Shulamite, Deacme, Scholastica

Signature 2

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Curated date: 2024/03/25

Curator: Shulamite

Revision editor(s): Shulamite, Deacme, Scholastica

Source: Figure 4C

Description: Distinct gut microbiota identified by LEfSe in endogenous melatonin reduction (EMR) versus wild type (WT) mice with biomarkers at all levels

Abundance in Group 1: decreased abundance in Endogenous melatonin reduction (EMR) mice

NCBI	Quality Control	Links
Bacteroidales
Bacteroidia
Muribaculaceae
Ruminococcaceae bacterium UCG-005
unclassified Bacteroidales
unclassified Muribaculaceae
Bacteroidota

Revision editor(s): Shulamite, Deacme, Scholastica