The incidence of infectious diseases has declined in the past 100 years due to the widespread use of vaccines and antimicrobials, improved hygiene practices and advances in healthcare approaches. Concurrently, inflammatory disorders such as asthma, type 1 diabetes and inflammatory bowel disease have increased. However, recent global pandemics and steadily growing antimicrobial resistance show that infectious diseases remain a serious threat to human health. Exposure to microorganisms in early life is a critical process that helps to train the human immune system to recognise and respond to invading pathogens later in life. However, emerging evidence indicates that humans harbour a highly diverse community of intestinal microorganisms (gut microbiota), much of which remains uncharacterised. Therefore, microbiota-immune interactions in early life are highly complex and may influence immune responses to both infection and inflammatory disease in adulthood. The gut microbiota is limited in diversity during the first months of life. Upon the introduction of solid foods (weaning), it diversifies rapidly. This programmed diversification of the gut microbiota exposes the immune system to a vast array of microbes, antigens and metabolites. In animal models, this early-life gut microbiota ‘imprints’ tolerance in the immune system to particular inflammatory stimuli, thereby protecting mice against inflammatory disorders such as allergy and colitis. However, the mechanisms of immune imprinting remain largely unknown. Current evidence in humans is only observational. However, this evidence indicates that antibiotics and other exposures that impair the maturation of the early-life gut microbiota, such as C-section birth and formula feeding, are associated with increased risk of later immune-mediated disorders such as asthma, inflammatory bowel disease and type 1 diabetes. Similarly, early-life antibiotic exposure is associated with increased susceptibility to later infections. Therefore, the early-life gut microbiota may influence immune system responses later in life. However, the influence of the early-life gut microbiota on later life immune response to infection is poorly characterised. Understanding how the gut microbiota trains the immune system to respond to later life infection would have major implications on medical approaches to tackle infectious diseases. With ever-present threats of global pandemics and expanding antimicrobial resistance, it is essential to identify new strategies to target infectious diseases. This project has the potential to uncover novel mechanisms by which the early-life gut microbiota trains immune responses to later life infection and therefore may help to uncover novel preventative therapies or therapeutic targets for infectious diseases. The overall objectives of the project were:
1. To evaluate the impact of the gut microbiota on the susceptibility to intestinal infection in adulthood
2. To establish whether microbiota-induced immune cells in the intestine influence susceptibility and immune response to intestinal infection in adulthood
3. To identify specific gut microbes and/or microbial metabolites during weaning that promote induction of intestinal immune cells and modulate subsequent susceptibility to intestinal infection in adulthood
This project found that exposure to antibiotics during early-life reduced early colonization of an intestinal pathogen (Citrobacter rodentium) in male mice during adulthood in addition to a reduced inflammatory response in the intestine. This may be due, in part, to changes induced by the early-life gut microbiota on intestinal epithelial cells. Collectively, the project found a role of the early-life gut microbiota on the immune response to infection in adulthood.
