Temporal dynamics in early-life regulation of non-communicable disease trajectories

Non-communicable immune-mediated disorders have dramatically increased in prevalence since the mid 20th century, particularly in countries characterized by macro-societal changes like progressive urbanization, widespread use of antibiotics, high consumption of ultra-processed foods, extreme hygiene, and loss of biodiversity. The etiology of autoimmune diseases is poorly understood, and whether these diseases still increase in prevalence is not clearly defined. However, allergy prevalence is still on the rise, especially in children, and constitutes an epidemic in Europe and North America, threatening to become a pandemic as the above listed macro-societal changes are becoming more frequent in countries around the world. Many studies have linked a low gut microbial diversity and the presence or absence of specific gut bacterial species in infancy with increased risk of developing asthma and allergies in later life, but specific mechanisms responsible for these associations have remained elusive.

In the present thesis studies, we therefore aimed to identify gut microbial changes during infancy linking to later disease development and uncover mechanisms explaining how such changes may affect disease development. We used a systems immunology-based approach, combining multiple omics technologies with functional studies and absolute quantifications in a human longitudinal birth cohort and examined the responses to identified bacterial-derived metabolites in primary human immune cells. In the cohort, we found that a group of aromatic lactic acid-producing bifidobacteria were the most abundant species in the infant gut in the first six months of life, and that their abundance in this period associated with a reduced incidence of circulating food allergen-specific IgE during the first 5 years of life. We additionally found that they are the species contributing the most to a high gut bacterial load in the first six months, and that a high load associated with reduced incidence of circulating food allergen-specific IgE during the first 5 years of life, atopic dermatitis at 2 years, and drug prescriptions for both asthma and hay fever medication during the first 14 years of life. Mechanistically linking these findings to disease development, we discovered that high fecal levels of one of the aromatic lactic acids produced by these bifidobacteria, 4-hydroxyphenyllactate, also associated with reduced incidence of the outcomes, and further demonstrated that it possesses a direct inhibitory effect on IgE production at physiological relevant levels ex vivo. Moreover, we showed that many lifestyle choices are influential, since high abundance of the aromatic lactic acid-producing bifidobacteria and a high gut bacterial load in early life was promoted by vaginal birth, exclusive breastfeeding in the first two months of life, having older siblings, an anthroposophic lifestyle, organic/biodynamic diet during pregnancy, and a high degree of gut bacterial coating with maternal antibodies in the first week of life.

Upon transition to solid food, the gut microbial metabolite butyrate plays an important role in ensuring homeostasis and tolerance in a gut environment rich in lipopolysaccharide (LPS)-producing bacteria. We therefore examined the effect of butyrate in LPS-responsive dendritic cells to also expand the understanding of signaling pathways activated by butyrate. We discovered mechanistic effects by which butyrate prevents pro-inflammatory Type 1 immune priming and promotes homeostasis at epigenetic, transcript, and protein level, and uncovered butyrateinduced transcription factor binding at transcriptionally upregulated G-protein coupled receptors that may contribute to immune and metabolic homeostasis.

Collectively, our studies uncover early life changes in the gut microbiota linking to disease development, mechanistic effects by which bacteria-derived metabolites may confer tolerance and homeostasis, and lifestyle choices affecting the abundance of specific beneficial bacteria during infancy, which may help pave the way for improved disease prevention and treatment in the future.