Antibiotics and the developing intestinal microbiome, metabolome and inflammatory environment: a randomized trial of preterm infants

Abstract

15Antibiotic use in neonates can have detrimental effects on the developing gut microbiome, 16increasing the risk of morbidity. A majority of preterm neonates receive antibiotics after birth 17 without clear evidence to guide this practice. Increasing evidence suggests associations between 18 early-life antibiotic use, intestinal dysbiosis, and morbidity that challenge the efficacy of this 19 common neonatal practice. Here we present microbiome and metabolomic results from the 20 Routine Early Antibiotic use in Symptomatic preterm Neonates (REASON) study, which is the 21 first trial to randomize symptomatic preterm neonates to receive or not receive antibiotics in the 22 first 48 hours after birth. Using 16S rRNA sequencing of stool samples collected longitudinally 23for 91 neonates, we show that antibiotics alter trends in microbiome diversity and development 24 between randomized neonates and illustrate that type of nutrition helps shape the early infant gut 25 microbiome. Integrating multi-omic data for the gut microbiome, stool immune markers, stool 26 metabolites, and inferred metabolic pathways, we identified an association between Veillonella 27 and the neurotransmitter gamma-aminobutyric acid (GABA). Our results suggest early antibiotic 28 use may impact the gut-brain axis with the potential for consequences in early life development. 29 Main 30Premature infants are particularly susceptible to infections secondary to increased need for 31 invasive procedures and immaturity of the immune system, skin, and gastrointestinal tract1-3. 32Increasingly, there is growing concern that risk factors for mortality may originate from 33underlying pathologies that could also be responsible for premature birth4. Symptoms of 34 prematurity are difficult to discern from symptoms of infection which, compounded by the 35 3 increased risk of infection, have led to most premature infants being exposed to antibiotics early 36 in life5-7. Despite high mortality rates, the incidence of culture positive early onset sepsis (EOS) 37 is relatively low, between 0.2-0.6%8. In the absence of a positive culture, a majority of preterm 38 infants receive antibiotics immediately after birth based on maternal risk factors (e.g. intra-39 amniotic infection) or laboratory abnormalities (e.g. elevated serum C-reactive protein (CRP) 40 because of the risk of mortality8. Given the low incidence of culture positive EOS in this 41 population, it is possible that such high rates of antibiotic use are unnecessary and may increase 42 morbidity in these infants9. Other morbidities in the neonatal intensive care unit (NICU) such as 43 necrotizing enterocolitis (NEC) also have high mortality rates and have been associated with 44 prolonged antibiotic exposure.10,11. Nevertheless, antibiotics remain the most commonly 45 prescribed medication in the NICU12,13. 46The gut microbiome comprises a highly volatile community structure early in life14. Microbial 47Randomized clinical trials have the advantage of controlling for the numerous covariates that 58 cou...

Antibiotics Effects on the Fecal Metabolome in Preterm Infants

“…Analysis using a volcano plot ( Figure 2) demonstrates a few metabolites that are more significantly isolated between the groups, specifically gamma aminobutanoate (GABA). This neurotransmitter correlated with certain microbial taxa, as described previously [20]. Analysis using a volcano plot ( Figure 2) demonstrates a few metabolites that are more significantly isolated between the groups, specifically gamma aminobutanoate (GABA).…”

“…In the metabolomics sub analysis within the REASON trial, relative abundance of Veillonella and Bifidobacterium in the stool were both significantly affected by the administration of antibiotics. Veillonella showed a positive association with GABA, suggesting an antibiotic-mediated perturbation of a metabolite known to affect the gut-brain axis [20]. These variances could be significant for the lifetime health of the individual since they are occurring during a very sensitive window for development [9].…”

“…Weekly stool samples and extensive clinical meta-data were collected longitudinally during the hospitalization. Preliminary results showed that antibiotic use alters the microbiome and metabolome, including metabolites related to the gut-brain axis [20]. Of particular interest, gamma aminobutanoate (GABA), which is a major neurotransmitter, was found to be affected by antibiotic use.…”

Plasmids shape the diverse accessory resistomes of Escherichia coli ST131

“…ST131 spreads between mother-infant pairs [28] likely via an oro-faecal transmission route [29], and such colonisation of infants can last for long periods [30]. Consequently, AMR gene screening can inform on treatment strategies [31] and the effect of antibiotics on microbiomes [32].…”

Plasmids shape the diverse accessory resistomes ofEscherichia coliST131

“…ST131 spreads between mother-infant pairs [28] likely via an oro-faecal transmission route [29], and such colonisation of infants can last for long periods [30]. Consequently, AMR gene screening can inform on treatment strategies [31] and the effect of antibiotics on microbiomes [32]. The ST131 resistome (the set of AMR genes) includes ESBL genes [33][34] allowing third-generation cephalosporin-resistance [35] and are associated with three main cefotaximase (CTX-M) resistance alleles: blaCTX-M-14/15/27 [36].…”