Intestinal microbiota development in childhood : implications for health and disease

This thesis characterises the development of the intestinal microbiota in healthy children. The influence of four common factors potentially modulating the microbiota prenatal stress, breastfeeding duration, antibiotic use, and probiotic use were investigated, as well as the association between early-life microbiota composition and the development of BMI. In addition, the microbiota in healthy children was contrasted with that that of children with inflammatory bowel disease, characterising the association between treatment response and microbiota. The bacterial composition was analysed from faecal samples using two DNA-based methods, a phylogenetic microarray, as well as sequencing of the 16S rRNA gene amplicons. In addition, real-time qPCR was conducted to measure bile-salt hydrolase genes and antibiotic resistance genes. Bacteria were cultured anaerobically for antibiotic susceptibility testing. The results showed that the microbiota in childhood are sensitive to modulating factors, and are predictive of later-life health. Maternal stress during pregnancy was associated with altered microbiota development over the first months of life. Long duration of breastfeeding was associated with slow microbiota maturation, normal BMI, and low antibiotic use in preschool age, if the microbiota were not disrupted by antibiotic use before weaning. The results indicate that some of the benefits of breastfeeding are microbiota-dependent. Early microbiota maturation was associated with fast growth in infancy and increased BMI in preschool age. Antibiotic use emerged as a central regulator of the microbiome, with potential effects on the metabolic development of the child. Lactobacillus rhamnosus GG supplementation prevented some of the penicillin-associated changes, but failed to prevent the macrolide-associated loss of bifidobacteria. The probiotic supplementation also reduced antibiotic use for at least 3 years after the intervention. In IBD patients, the microbiota composition varied along a gradient of intestinal inflammation and resembled the microbiota composition of antibiotic-treated healthy children. High microbiota similarity to non-antibiotic treated healthy controls predicted positive response to anti-TNF-α treatment in IBD patients. This work suggests that maternal wellbeing is the first step towards healthy microbiota in the child. Promoting a natural microbiota development in childhood by breastfeeding, avoiding unnecessary antibiotics, careful selection of the antibiotic when it is needed, and possibly the use of specific probiotic strains, may have long-term health benefits, particularly in terms of weight development and immune health.