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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

The effect of early-life PAT on microbiota maturity and dietary responses.(a) The OTUs that predict maturity and explained the greatest degree of variation in the model, ranked by contribution to reduction of mean square error (MSE). (b) Abundance of predictive OTUs over time. Dashed lines indicate introduction of HFD, time points 1–14 correspond to sequential samples (correlating with increasing day of life). (c) Average MAZ over time; z-score=0 indicates appropriate maturation; higher or lower z-scores indicate accelerated or delayed microbiota development, respectively. *** P<0.001 one-way ANOVA with Fisher's least significant difference adjusted for false-discovery rate.
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f4: The effect of early-life PAT on microbiota maturity and dietary responses.(a) The OTUs that predict maturity and explained the greatest degree of variation in the model, ranked by contribution to reduction of mean square error (MSE). (b) Abundance of predictive OTUs over time. Dashed lines indicate introduction of HFD, time points 1–14 correspond to sequential samples (correlating with increasing day of life). (c) Average MAZ over time; z-score=0 indicates appropriate maturation; higher or lower z-scores indicate accelerated or delayed microbiota development, respectively. *** P<0.001 one-way ANOVA with Fisher's least significant difference adjusted for false-discovery rate.

Mentions: Because of the importance of the developing microbiota, we compared the relative maturation rates of control and antibiotic-perturbed microbiota using a Random Forests17 regression model to predict day of life as a function of microbial composition18. Microbial maturity of control samples could be accurately predicted (Supplementary Fig. 5a) using 42 key operational taxonomical units (OTUs; Fig. 4a). Most of these 42 biomarkers showed marked population increases after HFD initiation, with delayed responses in the tylosin and mixture groups (Fig. 4b) accounting for their persistent microbial immaturity through day 142 (Fig. 4c). As the effects of diet and ageing cannot be separated, we constructed a second maturity model for the period of early life before HFD (Supplementary Fig. 5b). In the normally developing (control) mice, several OTUs predominated after weaning, diminished over time and were succeeded by other OTUs. Amoxicillin caused minimal disruption, whereas mixture and tylosin treatment substantially reduced OTUs associated with normal maturation (Supplementary Fig. 5c).


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)

The effect of early-life PAT on microbiota maturity and dietary responses.(a) The OTUs that predict maturity and explained the greatest degree of variation in the model, ranked by contribution to reduction of mean square error (MSE). (b) Abundance of predictive OTUs over time. Dashed lines indicate introduction of HFD, time points 1–14 correspond to sequential samples (correlating with increasing day of life). (c) Average MAZ over time; z-score=0 indicates appropriate maturation; higher or lower z-scores indicate accelerated or delayed microbiota development, respectively. *** P<0.001 one-way ANOVA with Fisher's least significant difference adjusted for false-discovery rate.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: The effect of early-life PAT on microbiota maturity and dietary responses.(a) The OTUs that predict maturity and explained the greatest degree of variation in the model, ranked by contribution to reduction of mean square error (MSE). (b) Abundance of predictive OTUs over time. Dashed lines indicate introduction of HFD, time points 1–14 correspond to sequential samples (correlating with increasing day of life). (c) Average MAZ over time; z-score=0 indicates appropriate maturation; higher or lower z-scores indicate accelerated or delayed microbiota development, respectively. *** P<0.001 one-way ANOVA with Fisher's least significant difference adjusted for false-discovery rate.
Mentions: Because of the importance of the developing microbiota, we compared the relative maturation rates of control and antibiotic-perturbed microbiota using a Random Forests17 regression model to predict day of life as a function of microbial composition18. Microbial maturity of control samples could be accurately predicted (Supplementary Fig. 5a) using 42 key operational taxonomical units (OTUs; Fig. 4a). Most of these 42 biomarkers showed marked population increases after HFD initiation, with delayed responses in the tylosin and mixture groups (Fig. 4b) accounting for their persistent microbial immaturity through day 142 (Fig. 4c). As the effects of diet and ageing cannot be separated, we constructed a second maturity model for the period of early life before HFD (Supplementary Fig. 5b). In the normally developing (control) mice, several OTUs predominated after weaning, diminished over time and were succeeded by other OTUs. Amoxicillin caused minimal disruption, whereas mixture and tylosin treatment substantially reduced OTUs associated with normal maturation (Supplementary Fig. 5c).

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