Gut microbiota-derived metabolites mediate the neuroprotective effect of melatonin in cognitive impairment induced by sleep deprivation

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Reviewed Marked as Reviewed by Folakunmi on 2024-2-12
study design
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
URI
Authors
Wang X, Wang Z, Cao J, Dong Y, Chen Y
Journal
Microbiome
Year
2023
Keywords:
Cognitive impairment, Hippocampus, Melatonin, Microbial–gut–brain axis, Sleep deprivation
Sleep loss is a serious global health concern. Consequences include memory deficits and gastrointestinal dysfunction. Our previous research showed that melatonin can effectively improve cognitive impairment and intestinal microbiota disturbances caused by sleep deprivation (SD). The present study further explored the mechanism by which exogenous melatonin prevents SD-induced cognitive impairments. Here, we established fecal microbiota transplantation, Aeromonas colonization and LPS or butyrate supplementation tests to evaluate the role of the intestinal microbiota and its metabolites in melatonin in alleviating SD-induced memory impairment.  RESULTS: Transplantation of the SD-gut microbiota into normal mice induced microglia overactivation and neuronal apoptosis in the hippocampus, cognitive decline, and colonic microbiota disorder, manifesting as increased levels of Aeromonas and LPS and decreased levels of Lachnospiraceae_NK4A136 and butyrate. All these events were reversed with the transplantation of SD + melatonin-gut microbiota. Colonization with Aeromonas and the addition of LPS produced an inflammatory response in the hippocampus and spatial memory impairment in mice. These changes were reversed by supplementation with melatonin, accompanied by decreased levels of Aeromonas and LPS. Butyrate administration to sleep-deprived mice restored inflammatory responses and memory impairment. In vitro, LPS supplementation caused an inflammatory response in BV2 cells, which was improved by butyrate supplementation. This ameliorative effect of butyrate was blocked by pretreatment with MCT1 inhibitor and HDAC3 agonist but was mimicked by TLR4 and p-P65 antagonists.  CONCLUSIONS: Gut microbes and their metabolites mediate the ameliorative effects of melatonin on SD-induced cognitive impairment. A feasible mechanism is that melatonin downregulates the levels of Aeromonas and constituent LPS and upregulates the levels of Lachnospiraceae_NK4A136 and butyrate in the colon. These changes lessen the inflammatory response and neuronal apoptosis in the hippocampus through crosstalk between the TLR4/NF-κB and MCT1/ HDAC3 signaling pathways. Video Abstract.

Experiment 1


Reviewed Marked as Reviewed by Folakunmi on 2024-2-12

Curated date: 2023/10/09

Curator: Davvve

Revision editor(s): Davvve, Folakunmi

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
Response to transplant Response to transplant,response to transplant
Group 0 name Corresponds to the control (unexposed) group for case-control studies
SD-FMT AND SD+MEL-FMT
Group 1 name Corresponds to the case (exposed) group for case-control studies
CON-FMT: receiving control microbiota FMT mice
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
FMT administered mice without sleep deprivation.
Group 0 sample size Number of subjects in the control (unexposed) group
7
Group 1 sample size Number of subjects in the case (exposed) group
7
Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
There were no antibiotic exclusions

Lab analysis

Sequencing type
16S
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
V1-V9
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
PacBio RS

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)?
No
LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool
3.0

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

Reviewed Marked as Reviewed by Folakunmi on 2024-2-12

Curated date: 2023/10/13

Curator: Davvve

Revision editor(s): Peace Sandy, Davvve, Folakunmi, Chinelsy

Source: fig 4

Description: Difference between the gut microbiome of the CON- FNT and the SD-FMT groups by LEFse

Abundance in Group 1: increased abundance in CON-FMT: receiving control microbiota FMT mice

NCBI Quality ControlLinks
Clostridium sp.
Deferribacteraceae
Deferribacterales
Deferribacteres
Deferribacterota
Lachnospiraceae bacterium NK4A136
Mucispirillum
Mucispirillum schaedleri
Ruminiclostridium
Turicimonas
uncultured Lachnospiraceae bacterium
uncultured bacterium A2_10

Revision editor(s): Peace Sandy, Davvve, Folakunmi, Chinelsy

Experiment 2


Reviewed Marked as Reviewed by Folakunmi on 2024-2-12

Curated date: 2023/10/30

Curator: Davvve

Revision editor(s): Davvve, Folakunmi

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
CON-FMT:( receiving control microbiota FMT mice) and SD+Mel-FMT:( receiving SD+Mel (20 mg/kg) microbiota FMT mice)
Group 1 name Corresponds to the case (exposed) group for case-control studies
SD-FMT: receiving Sleep deprivation FMT mice
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
This are sleep deprived mice that are also subjected to FMT .
Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
There were no antibiotic

Lab analysis

Statistical Analysis

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

Reviewed Marked as Reviewed by Folakunmi on 2024-2-12

Curated date: 2023/11/06

Curator: Davvve

Revision editor(s): Davvve, Folakunmi

Source: Fig 4C, 4F, 4D

Description: C Linear discriminant analysis efect size (LEfSe) was performed to identify the bacteria that are differentially represented between the different groups

Abundance in Group 1: increased abundance in SD-FMT: receiving Sleep deprivation FMT mice

NCBI Quality ControlLinks
Alloprevotella
Bacteroidales
Bacteroidota
Betaproteobacteria
Burkholderiaceae
Burkholderiales
Erysipelotrichales
Gammaproteobacteria
Methylophilaceae
Parasutterella
Prevotellaceae
Pseudomonadota
Sutterellaceae
Turicimonas
Turicimonas muris
unclassified Bacteroidia
uncultured Alloprevotella sp.
uncultured Parasutterella sp.

Revision editor(s): Davvve, Folakunmi

Signature 2

Reviewed Marked as Reviewed by Folakunmi on 2024-2-12

Curated date: 2024/02/12

Curator: Folakunmi

Revision editor(s): Folakunmi

Source: Fig 4G-J

Description: Linear discriminant analysis effect size (LEfSe) performed to identify the bacteria that are differentially represented between the different groups

Abundance in Group 1: decreased abundance in SD-FMT: receiving Sleep deprivation FMT mice

NCBI Quality ControlLinks
Eubacterium xylanophilum
Lachnospiraceae bacterium NK4A136
Ruminococcus
Lachnospiraceae bacterium A2

Revision editor(s): Folakunmi

Experiment 3


Reviewed Marked as Reviewed by Folakunmi on 2024-2-12

Curated date: 2023/11/06

Curator: Davvve

Revision editor(s): Davvve, Folakunmi

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
CON-FMT and SD-FMT
Group 1 name Corresponds to the case (exposed) group for case-control studies
SD+Mel-FMT:( receiving SD+Mel (20 mg/kg) microbiota FMT mice)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Sleep deprived mice receiving Mel and FMT
Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
There were no antibiotics exclusions from this study

Lab analysis

Statistical Analysis

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

Reviewed Marked as Reviewed by Folakunmi on 2024-2-12

Curated date: 2023/11/06

Curator: Davvve

Revision editor(s): Davvve

Source: fig 4c

Description: Linear discriminant analysis efect size (LEfSe) was performed to identify the bacteria that are differentially represented between the different groups

Abundance in Group 1: increased abundance in SD+Mel-FMT:( receiving SD+Mel (20 mg/kg) microbiota FMT mice)

NCBI Quality ControlLinks
Clostridiales bacterium CIEAF 020
Mollicutes
Mycoplasmatota
Rikenellaceae
Alistipes
uncultured Alistipes sp.
Patescibacteria group
Candidatus Saccharimonadales
Candidatus Saccharimonadaceae
uncultured Candidatus Saccharimonas sp.
Candidatus Saccharimonas
Candidatus Saccharimonadia
Ruminococcus
uncultured Ruminococcus sp.
Anaeroplasma
Anaeroplasmatales
uncultured Anaeroplasma sp.
Anaeroplasmataceae
Candidatus Gastranaerophilales
uncultured Gastranaerophilales bacterium
Cyanobacteriota
Candidatus Melainabacteria
Eubacterium ventriosum
Eubacterium
Eubacterium xylanophilum
uncultured Mollicutes bacterium
Alistipes ihumii

Revision editor(s): Davvve