Gut microbiota dysbiosis and metabolic dysfunction in infancy precedes childhood atopy and asthma development. Here we examined gut microbiota maturation over the first year of life in infants at high risk for asthma (HR), and whether it is modifiable by early-life Lactobacillus supplementation. We performed a longitudinal comparison of stool samples collected from HR infants randomized to daily oral Lactobacillus rhamnosus GG (HRLGG) or placebo (HRP) for 6 months, and healthy (HC) infants. Meconium microbiota of HRP participants is distinct, follows a delayed developmental trajectory, and is primarily glycolytic and depleted of a range of anti-inflammatory lipids at 6 months of age. These deficits are partly rescued in HRLGG infants, but this effect was lost at 12 months of age, 6 months after cessation of supplementation. Thus we show that early-life gut microbial development is distinct, but plastic, in HR infants. Our findings offer a novel strategy for early-life preventative interventions.

Author contributions S.R.L. designed the study, performed immune assays, animal models, metagenomic analysis, biochemical assays, mass spectrometry and statistical analyses, and developed the manuscript. K.A.S. assisted with animal models, performed all microscopy analysis and contributed to the manuscript. D.L.L. assisted with animal models and human immune assays. A.R.P. assisted with animal models and manuscript editing. K.E.F. and K.M. assisted with metagenomic and statistical analysis. E.F. assisted with microscopy. D.R.O., E.M.Z. and C.C.J. provided WHEALS cohort samples and data. M.M. and M.D.C. provided TIPS cohort samples and data. H.A.B. contributed to manuscript development. S.V.L. designed and supervised the study and developed the manuscript. Competing interests S.V.L. is co-founder of Siolta Therapeutics Inc., and serves as both a consultant and a member of its Board of Directors. Furthermore, the Regents of the University of California, UCSF have filed a provisional patent application (Application number 62/637,175) on behalf of S.V.L. and S.R.L. relating to the methods and compositions of EH genes.

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For high-risk infants, early LGG supplementation for the first 6 months of life does not appear to prevent the development of eczema or asthma at 2 years of age.

Colonization of the infant gut by microorganisms over the first year of life is crucial for development of a balanced immune response. Early alterations in the gastrointestinal microbiota of neonates has been linked with subsequent development of asthma and atopy in older children. Here we describe high-resolution culture-independent analysis of stool samples from 6-month old infants fed daily supplements of Lactobacillus casei subsp. Rhamnosus (LGG) or placebo in a double-blind, randomized Trial of Infant Probiotic Supplementation (TIPS). Bacterial community composition was examined using a high-density microarray, the 16S rRNA PhyloChip, and the microbial assemblages of infants with either high or low LGG abundance were compared. Communities with high abundance of LGG exhibited promotion of phylogenetically clustered taxa including a number of other known probiotic species, and were significantly more even in their distribution of community members. Ecologically, these aspects are characteristic of communities that are more resistant to perturbation and outgrowth of pathogens. PhyloChip analysis also permitted identification of taxa negatively correlated with LGG abundance that have previously been associated with atopy, as well as those positively correlated that may prove useful alternative targets for investigation as alternative probiotic species. From these findings we hypothesize that a key mechanism for the protective effect of LGG supplementation on subsequent development of allergic disease is through promotion of a stable, even, and functionally redundant infant gastrointestinal community.