Antibiotics in early life associate with specific gut microbiota signatures in a prospective longitudinal infant cohort

Korpela, Katri; Salonen, Anne; Saxén, Harri; Nikkonen, Anne; Peltola, Ville; Jaakkola, Tytti; Vos, Willem M. de; Kolho, Kaija Leena

doi:10.1038/s41390-020-0761-5

Cited by 69 publications

(61 citation statements)

References 37 publications

(39 reference statements)

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“…Resistomic and taxonomic composition are intrinsically intertwined, but the extent to which early-life factors shape the resistome via infant gut microbial composition has not been established. Variation to ecological successional patterns of microbiome assembly has been observed by our group and others in association with gestational age [13], delivery mode [15,20,23], feeding mode [23,24], intrapartum antibiotic exposure [13,19,20,[25][26][27][28], geographic diversity [29,30], and antibiotic usage [11,12,29,31]. As ARGs can be passed horizontally between bacteria through mobile genetic elements or vertically within the infant gut [11,12,19] and differential infant characteristics impact the trajectory of microbial composition [12,15,32], taxonomic composition is an important factor to consider in context to resistome development.…”

Section: Introductionsupporting

confidence: 72%

The Infant Gut Resistome is Associated with E. coli and Early-life Exposures

Lebeaux

Coker

Dade

et al. 2020

Preprint

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Background: Antibiotic resistance is an increasing threat to human health. The human gut microbiome harbors a collection of bacterial antimicrobial resistance genes (ARGs) known as the resistome. The factors associated with establishment of the resistome in early life are not well understood and clarifying these factors would inform strategies to decrease antibiotic resistance. We investigated the early-life exposures and taxonomic signatures associated with resistome development over the first year of life in a large, prospective cohort in the United States. Shotgun metagenomic sequencing was used to profile both microbial composition and ARGs in stool samples collected at 6 weeks and 1 year of age from infants enrolled in the New Hampshire Birth Cohort Study. Negative binomial regression and statistical modeling was used to examine infant factors such as sex, delivery mode, feeding method, gestational age, antibiotic exposure, and infant gut microbiome composition in relation to the diversity and relative abundance of ARGs.Results: Metagenomic sequencing was performed on paired samples from 195 full term (at least 37 weeks’ gestation) and 15 late preterm (33-36 weeks’ gestation) infants. 6-week samples compared to 1-year samples had 4.37 times (95% CI: 3.54-5.39) the rate of harboring ARGs. The majority of ARGs that were at a greater relative abundance at 6 weeks (chi-squared p < 0.01) worked through the mechanism of antibiotic efflux (i.e., by pumping antibiotics out of the cell). The overall relative abundance of the resistome was strongly correlated with Proteobacteria (Spearman correlation = 78.9%) and specifically E. coli (62.2%) relative abundance in the gut microbiome. Among infant characteristics, delivery mode was most strongly associated with the diversity and relative abundance of ARGs. Infants born via cesarean delivery had a higher risk of harboring unique ARGs [relative risk = 1.12 (95% CI: 0.97 – 1.29)] as well as a having an increased risk for overall ARG relative abundance [relative risk = 1.43 (95% CI: 1.12 – 1.84)] at 1 year compared to infants born vaginally. Additionally, 6 specific ARGs were at a greater relative abundance in infants delivered by cesarean section compared to vaginally delivered infants across both time points. Conclusions: Our findings suggest that the developing infant gut resistome may be alterable by early-life exposures. Establishing the extent to which infant characteristics and early-life exposures impact the resistome can ultimately lead to interventions that decrease the transmission of ARGs and thus the possibility of antibiotic resistant life threatening infections.

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Section: Introductionsupporting

confidence: 72%

The Infant Gut Resistome is Associated with E. coli and Early-life Exposures

Lebeaux

Coker

Dade

et al. 2020

Preprint

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“…Contradictory findings exist in the literature with humans, laboratory animals and in vitro studies reporting high interindividual effects [68], no effects [69,70], only shortterm effects [62,65], or both short-and long-term effects on microbial composition [60,71,72] after administration of amoxicillin with or without clavulanic acid. In a study in rats, a 7-day course of amoxicillin during the weaning period caused transient alterations in microbial composition that resolved by 20 days after its discontinuation [61].…”

Section: Discussionmentioning

confidence: 99%

“…In a study in rats, a 7-day course of amoxicillin during the weaning period caused transient alterations in microbial composition that resolved by 20 days after its discontinuation [61]. In another study in infants, a 5-to 8-day course of amoxicillin caused long-term changes in microbial composition that persisted for 6 months after treatment withdrawal [72].…”

Section: Discussionmentioning

confidence: 99%

Short- and long-term effects of amoxicillin/clavulanic acid or doxycycline on the gastrointestinal microbiome of growing cats

Pilla

et al. 2021

Preprint

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Antibiotic treatment in early life influences gastrointestinal (GI) microbial composition and function. In humans, the resultant intestinal dysbiosis is associated with an increased risk for certain diseases later in life. The objective of this study was to determine the temporal effects of antibiotic treatment on the GI microbiome of young cats. Fecal samples were collected from cats randomly allocated to receive either amoxicillin/clavulanic acid (20 mg/kg q12h) for 20 days (AMC group; 15 cats) or doxycycline (10 mg/kg q24h) for 28 days (DOX group;15 cats) as part of the standard treatment of upper respiratory tract infection. In addition, feces were collected from healthy control cats (CON group;15 cats). All cats were approximately two months of age at enrolment. Samples were collected on days 0 (baseline), 20 or 28 (AMC and DOX, respectively; last day of treatment), 60, 120, and 300. DNA was extracted and sequencing of the 16S rRNA gene and qPCR assays were performed. Fecal microbial composition was different on the last day of treatment for AMC cats, and 1 month after the end of antibiotic treatment for DOX cats, compared to CON cats. Species richness was significantly greater in DOX cats compared to CON cats on the last day of treatment. Abundance of Enterobacteriales was increased, and that of Erysipelotrichi was decreased in cats of the AMC group on the last day of treatment compared to CON cats. The abundance of the phylum Proteobacteria was increased in cats of the DOX group on days 60 and 120 compared to cats of the CON group. Only minor differences in abundances between the treatment groups and the control group were present on day 300. Both antibiotics appear to delay the developmental progression of the microbiome, and this effect is more profound during treatment with amoxicillin/clavulanic acid and one month after treatment with doxycycline. Future studies are required to determine if these changes influence microbiome function and whether they have possible effects on disease susceptibility in cats.

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“…All epidemiological studies, both prospective and retrospective, remain mainly observational; with the exceptions being Korpela et al . [ 31 , 33 ]. This is unsurprising given the limitations for causation studies in humans, but we should lean on and expand studies in animals, where strong evidence linking microbiota composition to, e.g.…”

Section: Discussionmentioning

confidence: 99%

The impact of early life antibiotic use on atopic and metabolic disorders

Bejaoui

Poulsen

2020

Evolution, Medicine, and Public Health

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Background and objectives The impact of antibiotics use early in life on later-in-life morbidities has received substantial attention as explanations for atopic and metabolic disorders with a surge as modern lifestyle diseases. The objective of this study was to perform meta-analyses to determine if antibiotics administration during the first two years of infant life is associated with increased risks of atopic or metabolic disorders later in life. Methodology We screened more than 100 English-language prospective and retrospective studies published between January 2002 and March 2020 and assessed study quality using the Newcastle–Ottawa scale. We performed overall and subgroup meta-analyses on 31 high-quality comparable studies on atopic and 23 on metabolic disorders, involving more than 3.5 million children. Results Antibiotic exposure prenatally and during the first two years of life significantly impacts the risk of developing atopic and metabolic disorders. Exposure during the first six months of life appears most critical, consistent with this being the time when the microbiome is most susceptible to irreversible perturbations. The presence of dose-response associations and stronger impacts of broad- than narrow-spectrum antibiotics further point to effects being mediated by microbiota-induced changes. Conclusions and implications Our findings support that antibiotics use is a mismatch to modernity that can negatively affect the symbiotic associations we rely on for proper immune function and metabolism. Improving our understanding of these associations, the underlying proximate mechanisms, and the impact of antibiotics use on future human-symbiont evolution will be important to improve human health. Abstract The use of antibiotics in infancy has been suggested to increase the risks of atopic and metabolic disorders later in life. Through meta-analyses of more than 100 studies (>3.5mio children), we confirm these risks, and the observed patterns are consistent with this being due to microbiota-driven changes.

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Antibiotics in early life associate with specific gut microbiota signatures in a prospective longitudinal infant cohort

Cited by 69 publications

References 37 publications

The Infant Gut Resistome is Associated with E. coli and Early-life Exposures

The Infant Gut Resistome is Associated with E. coli and Early-life Exposures

Short- and long-term effects of amoxicillin/clavulanic acid or doxycycline on the gastrointestinal microbiome of growing cats

The impact of early life antibiotic use on atopic and metabolic disorders

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