Bacteria - derived short chain fatty acids restore sympathoadrenal responsiveness to hypoglycemia after antibiotic-induced gut microbiota depletion

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Reviewed Marked as Reviewed by Svetlana up on 2025-2-11
study design
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
URI
Authors
LaGamma EF, Hu F, Pena Cruz F, Bouchev P, Nankova BB
Journal
Neurobiology of stress
Year
2021
Keywords:
Acute hypoglycemia, Epinephrine, Fecal whole genome sequencing, Microbiome, Oral antibiotics, Short chain fatty acids supplement
The microbiome co-evolved with their mammalian host over thousands of years. This commensal relationship serves a pivotal role in various metabolic, physiological, and immunological processes. Recently we discovered impaired adrenal catecholamine stress responses in germ-free mice suggesting developmental modification of the reflex arc or absence of an ongoing microbiome signal. To determine whether maturational arrest or an absent bacteria-derived metabolite was the cause, we tested whether depleting gut microbiome in young adult animals could also alter the peripheral stress responses to insulin-induced hypoglycemia. Groups of C57Bl6 male mice were given regular water (control) or a cocktail of non-absorbable broad-spectrum antibiotics (Abx) in the drinking water for two weeks before injection with insulin or saline. Abx mice displayed a profound decrease in microbial diversity and abundance of Bacteroidetes and Firmicutes, plus a markedly enlarged caecum and no detectable by-products of bacterial fermentation (sp. short chain fatty acids, SCFA). Tonic and stress-induced epinephrine levels were attenuated. Recolonization (Abx + R) restored bacterial diversity, but not the sympathoadrenal system responsiveness or caecal acetate, propionate and butyrate levels. In contrast, corticosterone (HPA) and glucagon (parasympathetic) resting values and responses to hypoglycemia remained similar across all conditions. Oral supplementation with SCFA improved epinephrine responses to hypoglycaemia. Whole genome shotgun sequence profiling of fecal samples from control, Abx and Abx + R cohorts identified nine microbes (SCFA producers) absent from both Abx and Abx + R groups. These results implicate gut microbiome depletion plus its attendant reduction in SCFA signalling in adversely affecting the release of epinephrine in response to hypoglycemia. We speculate that regardless of postnatal age, a mutable microbiome messaging system exists throughout life. Unravelling these mechanisms could lead to new therapeutic possibilities through controlled manipulation of the gut microbiota and its ability to alter systemic neurotransmitter responsiveness.

Experiment 1


Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): WikiWorks, Aleru Divine

Subjects

Location of subjects
United States of America
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 antibiotic Response to antibiotic,response to antibiotic
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Antibiotics (Abx) mice and Recolonized mice (Abx + R)
Group 1 name Corresponds to the case (exposed) group for case-control studies
Control mice
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Group of male mice given regular water.

Lab analysis

Sequencing type
WMS
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
Not specified
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
2.0


Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): Aleru Divine, WikiWorks

Source: Figure 4B

Description: Differentially abundant taxa (species level) that showed significant differences in relative abundance of bacterial communities in control (blue), Abx (red) and Abx + R (green) cohorts as identified by linear discriminant analysis (LDA) assessed by effect size analysis (LefSe) algorithm.

Abundance in Group 1: increased abundance in Control mice

NCBI Quality ControlLinks
Lachnospiraceae bacterium A4
Eubacteriales
Clostridioides difficile
Lachnospiraceae bacterium 28-4
Enterococcus faecalis
Anaerotruncus sp. G3(2012)
Oscillibacter sp. 1-3
Firmicutes bacterium ASF500
Lachnospiraceae bacterium 10-1
Christensenella
Eubacterium plexicaudatum
Enterocloster clostridioformis

Revision editor(s): Aleru Divine, WikiWorks

Experiment 2


Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): WikiWorks, Aleru Divine

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
Control mice and Antibiotics (Abx) mice
Group 1 name Corresponds to the case (exposed) group for case-control studies
Recolonized mice (Abx + R)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Group of male mice with antibiotics treatment followed by two weeks recolonization with co-housed age matched controls.

Lab analysis

Statistical Analysis

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): Aleru Divine, WikiWorks

Source: Figure 4B

Description: Differentially abundant taxa (species level) that showed significant differences in relative abundance of bacterial communities in control (blue), Abx (red) and Abx + R (green) cohorts as identified by linear discriminant analysis (LDA) assessed by effect size analysis (LefSe) algorithm.

Abundance in Group 1: increased abundance in Recolonized mice (Abx + R)

NCBI Quality ControlLinks
Adlercreutzia caecimuris
Agathobacter rectalis
Cupriavidus metallidurans
Lactiplantibacillus plantarum
Limosilactobacillus reuteri
Parabacteroides distasonis
Phocaeicola coprophilus
Lactobacillus casei group

Revision editor(s): Aleru Divine, WikiWorks

Experiment 3


Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): WikiWorks, Aleru Divine

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
Control mice and Recolonized mice (Abx + R)
Group 1 name Corresponds to the case (exposed) group for case-control studies
Antibiotics (Abx) mice
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Group of male mice given a cocktail of non-absorbable broad-spectrum antibiotics (Abx) in the drinking water for two weeks before injection with insulin or saline.

Lab analysis

Statistical Analysis

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): Aleru Divine, WikiWorks

Source: Figure 4B

Description: Differentially abundant taxa (species level) that showed significant differences in relative abundance of bacterial communities in control (blue), Abx (red) and Abx + R (green) cohorts as identified by linear discriminant analysis (LDA) assessed by effect size analysis (LefSe) algorithm.

Abundance in Group 1: increased abundance in Antibiotics (Abx) mice

NCBI Quality ControlLinks
Shigella boydii
Shigella flexneri
Shigella dysenteriae
Shigella sonnei
Escherichia

Revision editor(s): Aleru Divine, WikiWorks

Experiment 4


Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): Aleru Divine, WikiWorks

Differences from previous experiment shown

Subjects

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
Response to stress response to abiotic stress,response to biotic stress,Response to stress,response to stress
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Control mice
Group 1 name Corresponds to the case (exposed) group for case-control studies
Recolonized mice (Abx + R)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Group of male mice with antibiotics treatment followed by two weeks recolonization with co-housed age matched controls.

Lab analysis

Statistical Analysis

Alpha Diversity

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

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): Aleru Divine, WikiWorks

Source: Figure 5A

Description: Differentially abundant taxa associated with stress response (species level) that showed significance in relative abundance between control and Abx + R cohorts, as identified by LefSe.

Abundance in Group 1: increased abundance in Recolonized mice (Abx + R)

NCBI Quality ControlLinks
Adlercreutzia caecimuris
Agathobacter rectalis
Bacteroides acidifaciens
Cupriavidus metallidurans
Lactiplantibacillus plantarum
Parabacteroides distasonis
Phocaeicola coprophilus
Lactobacillus casei group

Revision editor(s): Aleru Divine, WikiWorks

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): Aleru Divine, WikiWorks

Source: Figure 5A

Description: Differentially abundant taxa associated with stress response (species level) that showed significance in relative abundance between control and Abx + R cohorts, as identified by LefSe.

Abundance in Group 1: decreased abundance in Recolonized mice (Abx + R)

NCBI Quality ControlLinks
Lachnospiraceae bacterium A4
Lachnospiraceae bacterium 28-4
Anaerotruncus sp. G3(2012)
Bacteroides xylanisolvens
Firmicutes bacterium ASF500
Lachnospiraceae bacterium 10-1
Christensenella
Bacteroides fragilis
Enterocloster clostridioformis

Revision editor(s): Aleru Divine, WikiWorks

Experiment 5


Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): Aleru Divine, WikiWorks

Differences from previous experiment shown

Subjects

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
Response to antibiotic Response to antibiotic,response to antibiotic
Group 1 name Corresponds to the case (exposed) group for case-control studies
Antibiotics (Abx) mice
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Group of male mice given a cocktail of non-absorbable broad-spectrum antibiotics (Abx) in the drinking water for two weeks before injection with insulin or saline.

Lab analysis

Statistical Analysis

Alpha Diversity

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

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): Aleru Divine, WikiWorks

Source: Supplementary Table S1

Description: Relative abundances of dominant species identified in the control, Abx and Abx+R cohorts

Abundance in Group 1: increased abundance in Antibiotics (Abx) mice

NCBI Quality ControlLinks
Escherichia coli
Shigella boydii
Shigella dysenteriae
Shigella flexneri
Shigella sonnei
Staphylococcus aureus

Revision editor(s): Aleru Divine, WikiWorks

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): Aleru Divine, WikiWorks

Source: Supplementary Table S1

Description: Relative abundances of dominant species identified in the control, Abx and Abx+R cohorts

Abundance in Group 1: decreased abundance in Antibiotics (Abx) mice

NCBI Quality ControlLinks
Anaerotruncus sp. G3(2012)
Dorea sp. 5-2
Firmicutes bacterium ASF500
Enterococcus faecalis
Christensenella
Oscillibacter sp. 1-3
Ligilactobacillus murinus
Enterocloster clostridioformis
Lachnospiraceae bacterium A4
Lachnospiraceae bacterium 10-1
Lachnospiraceae bacterium 3-1
Eubacteriales
Limosilactobacillus reuteri
Schaedlerella arabinosiphila
Eubacterium plexicaudatum
Lachnospiraceae bacterium A2
Eubacterium sp. 14-2

Revision editor(s): Aleru Divine, WikiWorks

Experiment 6


Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): Aleru Divine, WikiWorks

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Recolonized mice (Abx + R)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Group of male mice with antibiotics treatment followed by two weeks recolonization with co-housed age matched controls.

Lab analysis

Statistical Analysis

Alpha Diversity

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

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): Aleru Divine, WikiWorks

Source: Supplementary Table S1

Description: Relative abundances of dominant species identified in the control, Abx and Abx+R cohorts

Abundance in Group 1: increased abundance in Recolonized mice (Abx + R)

NCBI Quality ControlLinks
Cupriavidus metallidurans
Adlercreutzia caecimuris
Agathobacter rectalis

Revision editor(s): Aleru Divine, WikiWorks

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): Aleru Divine, WikiWorks

Source: Supplementary Table S1

Description: Relative abundances of dominant species identified in the control, Abx and Abx+R cohorts

Abundance in Group 1: decreased abundance in Recolonized mice (Abx + R)

NCBI Quality ControlLinks
Anaerotruncus sp. G3(2012)
Christensenella
Enterocloster clostridioformis
Lachnospiraceae bacterium A4
Lachnospiraceae bacterium 10-1
Bacteroides xylanisolvens

Revision editor(s): Aleru Divine, WikiWorks

Experiment 7


Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): WikiWorks, Aleru Divine

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies
Antibiotics (Abx) mice

Lab analysis

Statistical Analysis

Alpha Diversity

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

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): Aleru Divine, WikiWorks

Source: Supplementary Table S1

Description: Relative abundances of dominant species identified in the control, Abx and Abx+R cohorts

Abundance in Group 1: increased abundance in Recolonized mice (Abx + R)

NCBI Quality ControlLinks
Cupriavidus metallidurans
Ligilactobacillus animalis
Phocaeicola coprophilus
Christensenella
Lachnospiraceae bacterium MD335
Adlercreutzia caecimuris
Lachnospiraceae bacterium 10-1
Bacteroides uniformis
Limosilactobacillus reuteri
Eubacterium plexicaudatum
Lachnospiraceae bacterium 28-4
Parabacteroides goldsteinii
Parabacteroides distasonis
Enterococcus
Agathobacter rectalis

Revision editor(s): Aleru Divine, WikiWorks

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2025-2-11

Curated date: 2025/01/31

Curator: Aleru Divine

Revision editor(s): Aleru Divine, WikiWorks

Source: Supplementary Table S1

Description: Relative abundances of dominant species identified in the control, Abx and Abx+R cohorts

Abundance in Group 1: decreased abundance in Recolonized mice (Abx + R)

NCBI Quality ControlLinks
Shigella flexneri
Shigella sonnei
Shigella boydii
Shigella dysenteriae
Escherichia coli

Revision editor(s): Aleru Divine, WikiWorks