Gut microbial dysbiosis exacerbates long-term cognitive impairments by promoting intestinal dysfunction and neuroinflammation following neonatal hypoxia-ischemia

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Reviewed Marked as Reviewed by Svetlana up on 2025-4-22
study design
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
URI Uniform resource identifier for web resources.
Authors
Chen A, Teng C, Wei J, Wu X, Zhang H, Chen P, Cai D, Qian H, Zhu H, Zheng X, Chen X
Journal
Gut microbes
Year
2025
Keywords:
Neonatal hypoxic-ischemic brain damage, cognitive impairments, fecal microbiota transplantation, microbiota-gut-brain axis, neuroinflammation
Neonatal hypoxic-ischemic brain damage (HIBD) is considered as a major cause of long-term cognitive impairments in newborns. It has been demonstrated that gut microbiota is closely associated with the prognosis of various neurological disorders. However, the role of microbiota-gut-brain axis on cognitive function following neonatal HIBD remains elusive. In this experiment, the correlation analysis supported the involvement of gut microbial changes following hypoxic-ischemic (HI) insult in the development of long-term cognitive impairments. Subsequent experiment revealed the involvement of the intestinal dysfunction in the hippocampal neuroinflammation and synaptic injury. In causal relationship validation experiments, fecal microbiota transplantation (FMT) from cognitively normal rats could restore gut microbial composition, improve intestinal dysfunction, reduce the serum levels of lipopolysaccharides (LPS) and inflammatory mediators, and alleviate neuroinflammation, synaptic damage and cognitive impairments in neonatal HIBD recipient rats. Conversely, the FMT from neonatal HIBD rats could induce above adverse pathological changes in the normal recipient rats. Moreover, oral administration of anti-inflammatory agent dexamethasone (DEX) exhibited the potential to alleviate these detrimental effects in neonatal HIBD rats, with the efficacy being partly reliant on gut microbiota. Further experiment on the potential molecular mechanisms using RNA sequencing indicated a significant increase in the toll-like receptor 4 (TLR4) gene in the intestinal tissues of neonatal HIBD rats. Additionally, the interventions such as TLR4 inhibitor TLR4-IN-C34 administration, FMT, and oral DEX were demonstrated to modulate intestinal function by inhibiting the LPS/TLR4 signaling pathway, thereby exerting neuroprotective effects. Collectively, these findings underscore the contribution of gut microbial dysbiosis post HI insult in activating the LPS/TLR4 signaling pathway, triggering intestinal inflammation and dysfunction, exacerbating systemic inflammation, and consequently worsening synaptic and cognitive impairments in neonatal HIBD rats. Hence, rectifying gut microbial dysbiosis or regulating intestinal function may represent a promising strategy for alleviating long-term cognitive impairments in neonates affected by HIBD.

Experiment 1


Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/03/20

Curator: IsaacImitini

Revision editor(s): IsaacImitini, Tosin

Subjects

Location of subjects
China
Host species Species from which microbiome was sampled. Contact us to have more species added.
Rattus norvegicus
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
Brain hypoxia-Ischemia Hypoxia-Ischemia, Brain,Brain hypoxia-Ischemia,brain hypoxia-Ischemia
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Sham Group
Group 1 name Corresponds to the case (exposed) group for case-control studies
HI (hypoxic-ischemic) Group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Neonatal rats that underwent hypoxia-ischema (HI) to induce brain injury
Group 0 sample size Number of subjects in the control (unexposed) group
8
Group 1 sample size Number of subjects in the case (exposed) group
8

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)?
No
LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool
2

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

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/03/26

Curator: IsaacImitini

Revision editor(s): IsaacImitini, Tosin

Source: Figure 2I and 2J

Description: Taxonomic significant differences in gut microbiota between rats in sham group and HI (hypoxic-ischemic) group using Lefse analysis

Abundance in Group 1: increased abundance in HI (hypoxic-ischemic) Group

NCBI Quality ControlLinks
Deferribacteraceae
Deferribacterales
Deferribacteres
Enterobacterales
Enterobacteriaceae
Fusobacteriaceae
Fusobacteriales
Fusobacteriia
Gammaproteobacteria
Lactobacillaceae
Prevotellaceae
Streptococcaceae
Vibrionaceae

Revision editor(s): IsaacImitini, Tosin

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/03/27

Curator: IsaacImitini

Revision editor(s): IsaacImitini, Tosin

Source: Figure 2I and 2J

Description: Taxonomic significant differences in gut microbiota between rats in sham group and HI (hypoxic-ischemic) group using LeFse analysis

Abundance in Group 1: decreased abundance in HI (hypoxic-ischemic) Group

NCBI Quality ControlLinks
Akkermansiaceae
Bacteroidaceae
Enterococcaceae
Terriglobia
Verrucomicrobiales
Verrucomicrobiia
Victivallaceae
Helicobacteraceae
Caryophanaceae

Revision editor(s): IsaacImitini, Tosin

Experiment 2


Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/03/27

Curator: IsaacImitini

Revision editor(s): IsaacImitini, Tosin

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
Sham group
Group 1 name Corresponds to the case (exposed) group for case-control studies
HI (hypoxic-ischemic) group

Lab analysis

Statistical Analysis

Statistical test
T-Test
LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool
Not specified

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

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/03/27

Curator: IsaacImitini

Revision editor(s): IsaacImitini, Tosin

Source: Figure 2G and Figure 2K-O

Description: Relative abundance of significant differential taxa between Sham and HI (hypoxic ischemia) groups

Abundance in Group 1: increased abundance in HI (hypoxic-ischemic) group

NCBI Quality ControlLinks
Pseudomonadota
Fusobacteriaceae
Enterobacteriaceae
Prevotellaceae

Revision editor(s): IsaacImitini, Tosin

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/03/27

Curator: IsaacImitini

Revision editor(s): IsaacImitini, Tosin

Source: Figure 2G and Figure 2K-O

Description: Relative abundance of significant differential taxa between Sham and HI (hypoxic ischemia) groups

Abundance in Group 1: decreased abundance in HI (hypoxic-ischemic) group

NCBI Quality ControlLinks
Enterococcaceae
Akkermansiaceae

Revision editor(s): IsaacImitini, Tosin

Experiment 3


Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Differences from previous experiment shown

Subjects

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
Sham + Sham FMT (fecal microbiota transplantation) group
Group 1 name Corresponds to the case (exposed) group for case-control studies
Sham + HI (hypoxic-ischemic) FMT (fecal microbiota transplantation) group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Sham group and HI (hypoxic-ischemic) donor rats who transferred fecal microbiota to sham group.
Group 0 sample size Number of subjects in the control (unexposed) group
Not specified
Group 1 sample size Number of subjects in the case (exposed) group
Not specified

Lab analysis

Sequencing type
PCR
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
Not specified

Statistical Analysis

Matched on Factors on which subjects have been matched on in a case-control study
age


Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Source: Figure 7B

Description: Quantification of f_Enterobacteriaceae and f_Akkermansiaceae in fecal samples between [Sham + Sham FMT (fecal microbiota transplantation) group and Sham + HI (hypoxic-ischemic) FMT (fecal microbiota transplantation) group]

Abundance in Group 1: increased abundance in Sham + HI (hypoxic-ischemic) FMT (fecal microbiota transplantation) group

NCBI Quality ControlLinks
Enterobacteriaceae

Revision editor(s): Tosin

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Source: Figure 7C

Description: Quantification of f_Enterobacteriaceae and f_Akkermansiaceae in fecal samples between [Sham + Sham FMT (fecal microbiota transplantation) group and Sham + HI (hypoxic-ischemic) FMT (fecal microbiota transplantation) group]

Abundance in Group 1: decreased abundance in Sham + HI (hypoxic-ischemic) FMT (fecal microbiota transplantation) group

NCBI Quality ControlLinks
Akkermansiaceae

Revision editor(s): Tosin

Experiment 4


Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
HI (hypoxic-ischemic) + Sham FMT (fecal microbiota transplantation) group
Group 1 name Corresponds to the case (exposed) group for case-control studies
HI (hypoxic-ischemic) + HI (hypoxic-ischemic) FMT (fecal microbiota transplantation) group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
HI (hypoxic-ischemic) group recipient rats who received fecal microbiota from HI group and sham group donor rats.

Lab analysis

Statistical Analysis

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Source: Figure 7B

Description: Quantification of f_Enterobacteriaceae and f_Akkermansiaceae in fecal samples between [HI (hypoxic-ischemic) + Sham FMT (fecal microbiota transplantation) and HI (hypoxic-ischemic) + HI (hypoxic-ischemic) FMT (fecal microbiota transplantation) groups].

Abundance in Group 1: increased abundance in HI (hypoxic-ischemic) + HI (hypoxic-ischemic) FMT (fecal microbiota transplantation) group

NCBI Quality ControlLinks
Enterobacteriaceae

Revision editor(s): Tosin

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Source: Figure 7C

Description: Quantification of f_Enterobacteriaceae and f_Akkermansiaceae in fecal samples between [HI (hypoxic-ischemic) + Sham FMT (fecal microbiota transplantation) and HI (hypoxic-ischemic) + HI (hypoxic-ischemic) FMT (fecal microbiota transplantation) groups].

Abundance in Group 1: decreased abundance in HI (hypoxic-ischemic) + HI (hypoxic-ischemic) FMT (fecal microbiota transplantation) group

NCBI Quality ControlLinks
Akkermansiaceae

Revision editor(s): Tosin

Experiment 5


Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
HI (hypoxic-ischemic) + HI (hypoxic-ischemic) FMT (fecal microbiota transplantation) group
Group 1 name Corresponds to the case (exposed) group for case-control studies
HI (hypoxic-ischemic) + DEX (dexamethasone) FMT (fecal microbiota transplantation) group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
The rats in the HI+DEX (hypoxic-ischemic + dexamethasone) group were administered (dexamethasone) DEX (ST1254, beyotime, China) orally at a dosage of 1 mg/kg daily from the 7th postnatal day to the 3rd day after HI insult.

Lab analysis

Statistical Analysis

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Source: Figure 10C

Description: Quantification of f_Enterobacteriaceae and f_Akkermansiaceae in fecal samples between [HI (hypoxic-ischemic) + HI (hypoxic-ischemic) FMT (fecal microbiota transplantation and HI (hypoxic-ischemic) + DEX (dexamethasone) FMT (fecal microbiota transplantation) groups].

Abundance in Group 1: increased abundance in HI (hypoxic-ischemic) + DEX (dexamethasone) FMT (fecal microbiota transplantation) group

NCBI Quality ControlLinks
Akkermansiaceae

Revision editor(s): Tosin

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Source: Figure 10B

Description: Quantification of f_Enterobacteriaceae and f_Akkermansiaceae in fecal samples between [HI (hypoxic-ischemic) + HI (hypoxic-ischemic) FMT (fecal microbiota transplantation and HI (hypoxic-ischemic) + DEX (dexamethasone) FMT (fecal microbiota transplantation) groups].

Abundance in Group 1: decreased abundance in HI (hypoxic-ischemic) + DEX (dexamethasone) FMT (fecal microbiota transplantation) group

NCBI Quality ControlLinks
Enterobacteriaceae

Revision editor(s): Tosin

Experiment 6


Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Differences from previous experiment shown

Subjects

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
Treatment outcome measurement Treatment outcome measurement,treatment outcome measurement
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Sham Group
Group 1 name Corresponds to the case (exposed) group for case-control studies
HI (hypoxic-ischemic) Group
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Neonatal rats that underwent hypoxia-ischema (HI) to induce brain injury
Group 0 sample size Number of subjects in the control (unexposed) group
8
Group 1 sample size Number of subjects in the case (exposed) group
8

Lab analysis

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

Statistical Analysis

Matched on Factors on which subjects have been matched on in a case-control study
Not specified

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

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Source: Figure S3a

Description: The effects of oral DEX (dexamethasone) treatment on the gut microbiota in the neonatal HIBD rats. Quantification of f_Enterobacteriaceae and f_Akkermansiaceae in the fecal samples between Sham and HI (hypoxic-ischemic) Groups.

Abundance in Group 1: increased abundance in HI (hypoxic-ischemic) Group

NCBI Quality ControlLinks
Enterobacteriaceae

Revision editor(s): Tosin

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Source: Figure S3b

Description: The effects of oral DEX treatment on the gut microbiota in the neonatal HIBD rats. Quantification of f_Enterobacteriaceae and f_Akkermansiaceae in the fecal samples between Sham and HI (hypoxic-ischemic) Groups.

Abundance in Group 1: decreased abundance in HI (hypoxic-ischemic) Group

NCBI Quality ControlLinks
Akkermansiaceae

Revision editor(s): Tosin

Experiment 7


Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
HI (hypoxic-ischemic) group
Group 1 name Corresponds to the case (exposed) group for case-control studies
HI (hypoxic-ischemic) + DEX (dexamethasone) groups
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
The rats in the HI+DEX (hypoxic-ischemic + dexamethasone) group were administered (dexamethasone) DEX (ST1254, beyotime, China) orally at a dosage of 1 mg/kg daily from the 7th postnatal day to the 3rd day after HI insult.

Lab analysis

Statistical Analysis

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Source: Figure S3b

Description: The effects of oral DEX treatment on the gut microbiota in the neonatal HIBD rats. Quantification of f_Enterobacteriaceae and f_Akkermansiaceae in the fecal samples between HI (hypoxic-ischemic) and HI + DEX (hypoxic-ischemic + dexamethasone) groups.

Abundance in Group 1: increased abundance in HI (hypoxic-ischemic) + DEX (dexamethasone) groups

NCBI Quality ControlLinks
Akkermansiaceae

Revision editor(s): Tosin

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2025-4-22

Curated date: 2025/04/17

Curator: Tosin

Revision editor(s): Tosin

Source: Figure S3a

Description: The effects of oral DEX treatment on the gut microbiota in the neonatal HIBD rats. Quantification of f_Enterobacteriaceae and f_Akkermansiaceae in the fecal samples between HI (hypoxic-ischemic) and HI + DEX (hypoxic-ischemic + HI (Groups.

Abundance in Group 1: decreased abundance in HI (hypoxic-ischemic) + DEX (dexamethasone) groups

NCBI Quality ControlLinks
Enterobacteriaceae

Revision editor(s): Tosin