Neonates at high risk for asthma exhibit meconium microbiota dysbiosis that may be temporarily modifiable by oral Lactobacillus rhamnosus GG supplementation

Recent observational data in infants (here; here) suggest a developmental origin for childhood atopy and subsequent asthma involving the gut microbiome perturbation and associated metabolic dysfunction in early life. However, little is known regarding gut microbiota maturation over the first year of life in infants at high risk for asthma and whether targeting the gut microbiome may modify disease risk.

A new study, led by Prof. Susan V. Lynch from the Division of Gastroenterology, Department of Medicine at University of California San Francisco (San Francisco, USA), has found that Lactobacillus rhamnosus GG supplementation may partly modify meconium microbiota dysbiosis in neonates at high risk for asthma.

The researchers compared stool samples collected from newborns at high risk for asthma, born to at least one biological parent with asthma and enrolled in the trial of infant probiotic supplementation study, that were randomized to daily oral Lactobacillus rhamnosus GG strain ATCC 53103 (LGG, at 1 x 10¹⁰ colony forming units; n = 10) or placebo (n = 15) for the first 6 months of life. Healthy infants at low risk for asthma with no family history of atopy were included as controls (n = 29). Stool samples were collected from all infants at birth, 1, 3, 6, 9, and 12 months of age and subjected to parallel 16S ribosomal ribonucleic acid-based gut microbiota profiling. Besides this, liquid chromatography-mass spectrometry metabolomics analyses were performed in a subset of 6 and 12 month samples.

Infants at high risk for asthma exhibited delayed gut microbiota diversification over the first year of life, due to reduced rates of gain in both community richness (the number of species in the faecal samples communities) and evenness (the number of individuals from each species in the community). In contrast, infants that received LGG exhibited a rate of bacterial gut diversification comparable to that of the healthy controls. However, although LGG supplementation rescued the microbiota evenness deficit observed in the placebo group, it did not mitigate the delay in bacterial species accumulation observed in these infants.

LGG only rescued defects in community evenness by influencing a relatively small subset of bacterial taxa.

The greatest degree of variation in infants at high risk for asthma and healthy controls community composition was detected in meconium samples. Compared to healthy controls, the meconium of infants at high risk for asthma was enriched for Enterobacteriaceae and Bacteroidaceae, and depleted of Akkermansia, Faecalibacterium, and Rothia, the latter being involved in a high risk of atopy, recurrent wheeze, and asthma latter in childhood (here; here). Besides this, persistent founder microbial communities differed between infants at high risk for asthma and healthy controls. For instance, infants at high risk for asthma were more likely to be persistently colonized by specific taxa within Blautia and Ruminococcus, while healthy controls exhibited specific Peptostreptococcaceae, Staphylococcus, Anaerococcus, Rhodobacter, Akkermansia, and Faecalibacterium members during the first year of life. These data support the fact that the time of arrival of specific bacteria is a relevant determinant of microbial developmental trajectories in early life.

Finally, LGG supplementation enriched specific faecal taxa and metabolites. Specifically, the faecal microbiota of infants at high risk for asthma that received LGG shared a greater degree of taxonomic overlap with healthy controls, and indeed, LGG had an impact on gut microbial metabolites in a subset of samples at both 6 and 12 months. At 6 months of age, healthy control infants and infants at high risk for asthma that received oral LGG exhibited an enrichment of omega-3 anti-inflammatory fatty acids known to promote immune tolerance in early infancy. Besides this, an enrichment of the precursor for alternative microbial short chain fatty acids biosynthesis 4-acetamidobutanoate was also detected in healthy controls and infants at high risk for asthma that received LGG, compared with the placebo group. In contrast, the placebo group followed a delayed developmental trajectory characterized by an enrichment of inflammatory mediators in the gut and glycolytic metabolic pathways and a depletion of a range of anti-inflammatory lipids at 6 months of age. LGG-associated faecal products were also able to promote regulatory T cell expansion and interleukin-10 production ex vivo at 6 months of age. These results support the ‘plastic’ nature of the gut microbiota following probiotic administration during the first year of life.

In conclusion, neonates at high risk for asthma exhibit meconium microbiota dysbiosis and a reduced rate of gut bacterial diversification over the first year of life that may be temporarily modifiable by oral LGG supplementation. On the whole, these results enhance the potential for future gut microbiota-based diagnostics and therapies to prevent the development of asthma and other related allergic diseases in children.

Reference:

Durack J, Kimes NE, Lin DL, et al. Delayed gut microbiota development in high-risk for asthma infants is temprarily modifiable by Lactobacillus supplementation. Nat Commun. 2018; 9(1):707. doi: 10.1038/s41467-018-03157-4.