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

Russell, Jordan T.; Ruoss, J. Lauren; Cruz, Diomel de la; Li, Nan; Bazacliu, Catalina; Patton, Laura; McKinley, Kelley Lobean; Garrett, Timothy J.; Polin, Richard A.; Triplett, Eric W.; Neu, Josef

doi:10.1038/s41598-021-80982-6

Cited by 44 publications

(48 citation statements)

References 84 publications

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“…Our results expand upon previous reports that antibiotic use leads to alterations in the developmental pattern of goblet and Paneth cells [ 55 ]. Both cell types are key components of the mucosal barrier and play important roles in intestinal stem cell homeostasis, development of the microbiome, and host defense against intestinal pathogens.…”

Section: Discussionsupporting

confidence: 90%

Early Antibiotic Exposure Alters Intestinal Development and Increases Susceptibility to Necrotizing Enterocolitis: A Mechanistic Study

et al. 2022

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Increasing evidence suggests that prolonged antibiotic therapy in preterm infants is associated with increased mortality and morbidities, such as necrotizing enterocolitis (NEC), a devastating gastrointestinal pathology characterized by intestinal inflammation and necrosis. While a clinical correlation exists between antibiotic use and the development of NEC, the potential causality of antibiotics in NEC development has not yet been demonstrated. Here, we tested the effects of systemic standard-of-care antibiotic therapy for ten days on intestinal development in neonatal mice. Systemic antibiotic treatment impaired the intestinal development by reducing intestinal cell proliferation, villi height, crypt depth, and goblet and Paneth cell numbers. Oral bacterial challenge in pups who received antibiotics resulted in NEC-like intestinal injury in more than half the pups, likely due to a reduction in mucous-producing cells affecting microbial–epithelial interactions. These data support a novel mechanism that could explain why preterm infants exposed to prolonged antibiotics after birth have a higher incidence of NEC and other gastrointestinal disorders.

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Section: Discussionsupporting

confidence: 90%

Early Antibiotic Exposure Alters Intestinal Development and Increases Susceptibility to Necrotizing Enterocolitis: A Mechanistic Study

et al. 2022

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“…In addition, stool microbial patterns showed signi cant change over three timepoints, similar to prior studies 14,19 . When we quanti ed the impact of NICU exposures on the stool-associated bacterial community richness and composition, as well as the metabolome, there were differences associated with an infant's exposure to antibiotics at all timepoints, which is also consistent with previous studies [29][30][31] .…”

Section: Discussionsupporting

confidence: 86%

The Impact of Maternal Asthma on the Preterm Infants' Gut Metabolome and Microbiome - The Microbiome, Atopic Disease, and Prematurity (MAP) Study

Bai-Tong

Thoemmes

Weldon

et al. 2021

Preprint

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Preterm infants are at a greater risk for the development of asthma and atopic disease, which can lead to lifelong negative health consequences. This may, in part, be due to alterations that occur in the gut microbiome and metabolome during their stay in the Neonatal Intensive Care Unit (NICU). To explore the differential roles of family history (i.e., predisposition due to maternal asthma diagnosis) and hospital-related environmental and clinical factors that alter microbial exposures early in life, we looked at a unique cohort of preterm infants born £ 34 weeks gestational age from two local level III NICUs, as part of the MAP (Microbiome, Atopic disease, and Prematurity) Study. Weekly stool, milk feeds, and saliva were collected until hospital discharge, and monthly stool and milk samples were collected at home until one year of age. We also chose a sub-cohort of infants whose mothers had a history of asthma and matched gestational age and sex to infants of mothers without a history of asthma (control). We performed a prospective, paired metagenomic and metabolomic analysis of stool and milk feed samples collected at birth, 2 weeks, and 6 weeks postnatal age. Although there were clinical factors associated with shifts in the diversity and composition of stool-associated bacterial communities, maternal asthma diagnosis did not play an observable role in shaping the infant gut microbiome in the study period. There were significant differences, however, in the metabolite profile between the maternal asthma and control groups at 6 weeks postnatal age. The most notable changes occurred in the linoleic acid spectral network, which plays a role in inflammatory and immune pathways, suggesting early metabolomic changes in the gut of preterm infants born to mothers with a history of asthma. Our pilot analysis suggests that a history of maternal asthma alters a preterm infants’ metabolomic pathways in the gut as early as the first 6 weeks of life.

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“…DNA extraction, 16S rRNA barcoded PCR, and V3-V4 16S rRNA Illumina sequencing were performed as previously described ( Russell et al., 2019 ). Bacterial quantification through universal 16s rRNA primers was performed as described previously ( Russell et al., 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Gut microbiome markers in subgroups of HLA class II genotyped infants signal future celiac disease in the general population: ABIS study

Milletich

Ahrens²,

Russell³

et al. 2022

Front. Cell. Infect. Microbiol.

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Although gut microbiome dysbiosis has been illustrated in celiac disease (CD), there are disagreements about what constitutes these microbial signatures and the timeline by which they precede diagnosis is largely unknown. The study of high-genetic-risk patients or those already with CD limits our knowledge of dysbiosis that may occur early in life in a generalized population. To explore early gut microbial imbalances correlated with future celiac disease (fCD), we analyzed the stool of 1478 infants aged one year, 26 of whom later acquired CD, with a mean age of diagnosis of 10.96 ± 5.6 years. With a novel iterative control-matching algorithm using the prospective general population cohort, All Babies In Southeast Sweden, we found nine core microbes with prevalence differences and seven differentially abundant bacteria between fCD infants and controls. The differences were validated using 100 separate, iterative permutations of matched controls, which suggests the bacterial signatures are significant in fCD even when accounting for the inherent variability in a general population. This work is the first to our knowledge to demonstrate that gut microbial differences in prevalence and abundance exist in infants aged one year up to 19 years before a diagnosis of CD in a general population.

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

Cited by 44 publications

References 84 publications

Early Antibiotic Exposure Alters Intestinal Development and Increases Susceptibility to Necrotizing Enterocolitis: A Mechanistic Study

Early Antibiotic Exposure Alters Intestinal Development and Increases Susceptibility to Necrotizing Enterocolitis: A Mechanistic Study

The Impact of Maternal Asthma on the Preterm Infants' Gut Metabolome and Microbiome - The Microbiome, Atopic Disease, and Prematurity (MAP) Study

Gut microbiome markers in subgroups of HLA class II genotyped infants signal future celiac disease in the general population: ABIS study

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