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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

Metagenomic alterations from early-life PAT.(a) Number of KEGG modules significantly upregulated in PAT and control mice (P<0.05, LEfSe). No modules were significantly different between control and amoxicillin in early life. (b–d) Median relative abundance of oxalate metabolism genes over time. (b) frc, formyl-CoA transferase, (c) oxc, oxalyl-CoA decarboxylase and (d) oxlT, oxalate/formate exchanger. (e) Faecal oxalate levels. (f) Hierarchical clustering of 73 host-associated microbial oxlT orthologs (rows) and the associated 60 shotgun sequencing samples (columns). NC, normal chow. (g) Relative abundance of 67 oxlt orthologs; each cluster group shows a unique presence pattern by condition, diet and time.
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f6: Metagenomic alterations from early-life PAT.(a) Number of KEGG modules significantly upregulated in PAT and control mice (P<0.05, LEfSe). No modules were significantly different between control and amoxicillin in early life. (b–d) Median relative abundance of oxalate metabolism genes over time. (b) frc, formyl-CoA transferase, (c) oxc, oxalyl-CoA decarboxylase and (d) oxlT, oxalate/formate exchanger. (e) Faecal oxalate levels. (f) Hierarchical clustering of 73 host-associated microbial oxlT orthologs (rows) and the associated 60 shotgun sequencing samples (columns). NC, normal chow. (g) Relative abundance of 67 oxlt orthologs; each cluster group shows a unique presence pattern by condition, diet and time.

Mentions: To further examine impact on microbiota function, control and PAT metabolic KEGG module abundance was compared using univariate analyses by LEfSe (ref. 21) (Fig. 6a). Compared with control, tylosin significantly affected several metabolic modules in both early-life (normal chow, pre-day 41; Supplementary Fig. 9b) and late-life (HFD, post-day 41; Supplementary Fig. 10b, Supplementary Table 1). Notably, tylosin shifted carbohydrate glycolytic metabolism, depleting the classic Embden–Meyerhoff pathway while increasing the alternate Entner–Doudoroff pathway. Importantly, the early-life tylosin-altered microbial functions related to energy yield from glucose were maintained after antibiotic exposure ceased and diet changed. Amoxicillin also significantly, but less extensively, altered late-life KEGG modules compared with control (Fig. 6a and Supplementary Fig. 10c). Both antibiotics depleted genes related to glycolysis, isoprenoid biosynthesis, tRNA biosynthesis and ribosomes, and enriched genes related to LPS synthesis, proline and vitamin biosynthesis, pyruvate oxidation and molecular transport (Supplementary Table 1). These data indicate metagenomic changes due to the early-life PAT, persisting well into adulthood. The conserved metabolic effects of both antibiotics indicate global, persistent responses to early-life perturbation.


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)

Metagenomic alterations from early-life PAT.(a) Number of KEGG modules significantly upregulated in PAT and control mice (P<0.05, LEfSe). No modules were significantly different between control and amoxicillin in early life. (b–d) Median relative abundance of oxalate metabolism genes over time. (b) frc, formyl-CoA transferase, (c) oxc, oxalyl-CoA decarboxylase and (d) oxlT, oxalate/formate exchanger. (e) Faecal oxalate levels. (f) Hierarchical clustering of 73 host-associated microbial oxlT orthologs (rows) and the associated 60 shotgun sequencing samples (columns). NC, normal chow. (g) Relative abundance of 67 oxlt orthologs; each cluster group shows a unique presence pattern by condition, diet and time.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Metagenomic alterations from early-life PAT.(a) Number of KEGG modules significantly upregulated in PAT and control mice (P<0.05, LEfSe). No modules were significantly different between control and amoxicillin in early life. (b–d) Median relative abundance of oxalate metabolism genes over time. (b) frc, formyl-CoA transferase, (c) oxc, oxalyl-CoA decarboxylase and (d) oxlT, oxalate/formate exchanger. (e) Faecal oxalate levels. (f) Hierarchical clustering of 73 host-associated microbial oxlT orthologs (rows) and the associated 60 shotgun sequencing samples (columns). NC, normal chow. (g) Relative abundance of 67 oxlt orthologs; each cluster group shows a unique presence pattern by condition, diet and time.
Mentions: To further examine impact on microbiota function, control and PAT metabolic KEGG module abundance was compared using univariate analyses by LEfSe (ref. 21) (Fig. 6a). Compared with control, tylosin significantly affected several metabolic modules in both early-life (normal chow, pre-day 41; Supplementary Fig. 9b) and late-life (HFD, post-day 41; Supplementary Fig. 10b, Supplementary Table 1). Notably, tylosin shifted carbohydrate glycolytic metabolism, depleting the classic Embden–Meyerhoff pathway while increasing the alternate Entner–Doudoroff pathway. Importantly, the early-life tylosin-altered microbial functions related to energy yield from glucose were maintained after antibiotic exposure ceased and diet changed. Amoxicillin also significantly, but less extensively, altered late-life KEGG modules compared with control (Fig. 6a and Supplementary Fig. 10c). Both antibiotics depleted genes related to glycolysis, isoprenoid biosynthesis, tRNA biosynthesis and ribosomes, and enriched genes related to LPS synthesis, proline and vitamin biosynthesis, pyruvate oxidation and molecular transport (Supplementary Table 1). These data indicate metagenomic changes due to the early-life PAT, persisting well into adulthood. The conserved metabolic effects of both antibiotics indicate global, persistent responses to early-life perturbation.

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