Early infancy microbial and metabolic alterations affect risk of childhood asthma

Abstract

Asthma is the most prevalent pediatric chronic disease and affects more than 300 million people worldwide. Recent evidence in mice has identified a "critical window" early in life where gut microbial changes (dysbiosis) are most influential in experimental asthma. However, current research has yet to establish whether these changes precede or are involved in human asthma. We compared the gut microbiota of 319 subjects enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study, and show that infants at risk of asthma exhibited transient gut microbial dysbiosis during the first 100 days of life. The relative abundance of the bacterial genera Lachnospira, Veillonella, Faecalibacterium, and Rothia was significantly decreased in children at risk of asthma. This reduction in bacterial taxa was accompanied by reduced levels of fecal acetate and dysregulation of enterohepatic metabolites. Inoculation of germ-free mice with these four bacterial taxa ameliorated airway inflammation in their adult progeny, demonstrating a causal role of these bacterial taxa in averting asthma development. These results enhance the potential for future microbe-based diagnostics and therapies, potentially in the form of probiotics, to prevent the development of asthma and other related allergic diseases in children.

A humanized microbiota mouse model of ovalbumin-induced lung inflammation

“…We have previously shown that mice inoculated with human feces with or without the 4 bacterial genera associated with asthma development in infants differed in lung inflammation based on production of IFNg, TNF and IL-6, supporting the latter hypothesis. 6 These findings confirm that, although lung inflammation is reduced in human microbiota colonized mice compared with mouse microbiota colonized mice, there remains measurable inflammation of mixed cellularity which is sufficient to identify changes after modification of the microbiota, enabling assessment of possible therapeutic interventions in this model. In addition, although asthma has historically been studied as an allergic Th2-type disease, recent transcriptomic studies of bronchial epithelial cells in humans indicated that a high Th2 phenotype is present in only 50% of asthmatics, 14,15 suggesting that an animal model exhibiting a mixed immune cell infiltrate will be useful to study an immune signature present in a large proportion of asthmatics that do not fit the classic asthma paradigm.…”

“…[3][4][5] We recently showed that reduction in 4 bacterial genera -Lachnospira, Veillonella, Faecalibacterium and Rothia -in the gut microbiota of infants at 3 months of age was associated with an increased risk of developing childhood asthma, and these differences were not observed at one year of age. 6 In addition to identifying this disparity in bacterial composition of the gut microbiota, we confirmed a functional difference with significantly lower levels of fecal acetate and higher levels of urine urobilinogen in children with an increased risk of developing asthma. Finally we demonstrated a causal relationship between these 4 genera and asthma development in a mouse model, leading to the exciting prospect of an early diagnostic tool for asthma in infants and the potential to intervene at this young age to prevent the later development of asthma.…”

“…The gut microbiota and development of asthma in school-aged children Identification of bacterial genera associated with the development of asthma 6 was based on stool samples from participants at 3 months and 1 y of age from the Canadian Healthy Infant Longitudinal Development (CHILD) Study, which includes children from birth to 5 y of age. The Asthma Predictive Index (API) 16 at 3 y of age was used to predict the presence of active asthma at school age, and while a positive API at 3 y is associated with a 77% chance of active asthma at school age, the children in the atopy + wheeze phenotype (used as the asthma 'extreme phenotype') were not followed to school age to confirm this, as this was beyond the scope of the original study (and the children had not reached school age).…”

Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes

“…Case-control studies have associated microbial traits in individuals with patterns of diseases, thereby implicating gastrointestinal microbial communities in a range of human disorders [6][7][8][9][10] . Metagenomics is able to resolve differences in the functional potential of microbial communities and has revealed a surprisingly stable set of core functions, even though gastrointestinal community structures display great inter-individual variation 2 .…”

Does the maternal vaginal microbiota play a role in seeding the microbiota of neonatal gut and nose?

“…Some of the clearest evidence concerns necrotizing enterocolitis (NEC) in premature infants, where gut microbiota composition is highly predictive of disease (Sim et al, 2015;Warner et al, 2016). Emerging evidence suggests that the differential acquisition and maturation of gut microbiota in healthy infants may have consequences for health later in life (Arrieta et al, 2015;Bisgaard et al, 2011;Dogra et al, 2015;Korpela et al, 2016). The microbiome of the upper respiratory tract, which contains the second most abundant bacterial population in the human body, has been less explored.…”