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Metabolic and metagenomic outcomes from early-life pulsed antibiotic treatment.

Nobel YR, Cox LM, Kirigin FF, Bokulich NA, Yamanishi S, Teitler I, Chung J, Sohn J, Barber CM, Goldfarb DS, Raju K, Abubucker S, Zhou Y, Ruiz VE, Li H, Mitreva M, Alekseyenko AV, Weinstock GM, Sodergren E, Blaser MJ - Nat Commun (2015)

Bottom Line: Here we use a mouse model mimicking paediatric antibiotic use and find that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide alters both host and microbiota development.Early-life PAT accelerates total mass and bone growth, and causes progressive changes in gut microbiome diversity, population structure and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic.This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.

ABSTRACT
Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Here we use a mouse model mimicking paediatric antibiotic use and find that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide alters both host and microbiota development. Early-life PAT accelerates total mass and bone growth, and causes progressive changes in gut microbiome diversity, population structure and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. Whereas control microbiota rapidly adapts to a change in diet, PAT slows the ecological progression, with delays lasting several months with previous macrolide exposure. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment.

No MeSH data available.


Related in: MedlinePlus

PAT alters hepatic gene expression.(a) Number of differentially expressed genes (P<0.01 and /log2fold change/>0.5) that are up- or down-regulated in the underlined group with respect to the comparator group. (b,c) Venn diagrams showing numbers of upregulated or downregulated genes, respectively, that are shared or unique. (d) Principal component analysis plot of hepatic gene expression data, representing 30.2% of total variation. (e) Expression of hepatic genes significantly altered by amoxicillin or tylosin with respect to control. (f) Predicted biological functions that are differentially represented (P<0.05, z-score /2/) based on Ingenuity Pathway Analysis of hepatic expression. Amox., amoxicillin; Ctrl, control; Tylo., tylosin.
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f2: PAT alters hepatic gene expression.(a) Number of differentially expressed genes (P<0.01 and /log2fold change/>0.5) that are up- or down-regulated in the underlined group with respect to the comparator group. (b,c) Venn diagrams showing numbers of upregulated or downregulated genes, respectively, that are shared or unique. (d) Principal component analysis plot of hepatic gene expression data, representing 30.2% of total variation. (e) Expression of hepatic genes significantly altered by amoxicillin or tylosin with respect to control. (f) Predicted biological functions that are differentially represented (P<0.05, z-score /2/) based on Ingenuity Pathway Analysis of hepatic expression. Amox., amoxicillin; Ctrl, control; Tylo., tylosin.

Mentions: As hepatic metabolism can be altered with early-life antibiotic exposure13, potentially as a result of altered growth, direct effect of antibiotics or influence of the microbiota through the enterohepatic circulation, we examined whether we could detect PAT effects on the liver long after antibiotic cessation. Early-life tylosin significantly elevated micro- and overall hepatic steatosis in later life (Supplementary Fig. 2a–e), while amoxicillin significantly reduced microsteatosis. All groups had similar liver mass (Supplementary Fig. 2f). PAT induced changes in hepatic gene expression, with more upregulated than downregulated genes with respect to controls (Fig. 2a). While few genes had been significantly modulated by both the early-life tylosin and amoxicillin exposures (Fig. 2b–d), hierarchical clustering of genes significant in either group (Fig. 2e) indicates similar trends in both antibiotic groups.


Metabolic and metagenomic outcomes from early-life pulsed antibiotic treatment.

Nobel YR, Cox LM, Kirigin FF, Bokulich NA, Yamanishi S, Teitler I, Chung J, Sohn J, Barber CM, Goldfarb DS, Raju K, Abubucker S, Zhou Y, Ruiz VE, Li H, Mitreva M, Alekseyenko AV, Weinstock GM, Sodergren E, Blaser MJ - Nat Commun (2015)

PAT alters hepatic gene expression.(a) Number of differentially expressed genes (P<0.01 and /log2fold change/>0.5) that are up- or down-regulated in the underlined group with respect to the comparator group. (b,c) Venn diagrams showing numbers of upregulated or downregulated genes, respectively, that are shared or unique. (d) Principal component analysis plot of hepatic gene expression data, representing 30.2% of total variation. (e) Expression of hepatic genes significantly altered by amoxicillin or tylosin with respect to control. (f) Predicted biological functions that are differentially represented (P<0.05, z-score /2/) based on Ingenuity Pathway Analysis of hepatic expression. Amox., amoxicillin; Ctrl, control; Tylo., tylosin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4491183&req=5

f2: PAT alters hepatic gene expression.(a) Number of differentially expressed genes (P<0.01 and /log2fold change/>0.5) that are up- or down-regulated in the underlined group with respect to the comparator group. (b,c) Venn diagrams showing numbers of upregulated or downregulated genes, respectively, that are shared or unique. (d) Principal component analysis plot of hepatic gene expression data, representing 30.2% of total variation. (e) Expression of hepatic genes significantly altered by amoxicillin or tylosin with respect to control. (f) Predicted biological functions that are differentially represented (P<0.05, z-score /2/) based on Ingenuity Pathway Analysis of hepatic expression. Amox., amoxicillin; Ctrl, control; Tylo., tylosin.
Mentions: As hepatic metabolism can be altered with early-life antibiotic exposure13, potentially as a result of altered growth, direct effect of antibiotics or influence of the microbiota through the enterohepatic circulation, we examined whether we could detect PAT effects on the liver long after antibiotic cessation. Early-life tylosin significantly elevated micro- and overall hepatic steatosis in later life (Supplementary Fig. 2a–e), while amoxicillin significantly reduced microsteatosis. All groups had similar liver mass (Supplementary Fig. 2f). PAT induced changes in hepatic gene expression, with more upregulated than downregulated genes with respect to controls (Fig. 2a). While few genes had been significantly modulated by both the early-life tylosin and amoxicillin exposures (Fig. 2b–d), hierarchical clustering of genes significant in either group (Fig. 2e) indicates similar trends in both antibiotic groups.

Bottom Line: Here we use a mouse model mimicking paediatric antibiotic use and find that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide alters both host and microbiota development.Early-life PAT accelerates total mass and bone growth, and causes progressive changes in gut microbiome diversity, population structure and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic.This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.

ABSTRACT
Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Here we use a mouse model mimicking paediatric antibiotic use and find that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide alters both host and microbiota development. Early-life PAT accelerates total mass and bone growth, and causes progressive changes in gut microbiome diversity, population structure and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. Whereas control microbiota rapidly adapts to a change in diet, PAT slows the ecological progression, with delays lasting several months with previous macrolide exposure. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment.

No MeSH data available.


Related in: MedlinePlus