Role of early life gut microbiota in colonisation resistance development (360G-Wellcome-100974_B_13_Z)

We are born completely sterile, but soon become colonised by complex microbial communities that shapes our immune defense for life. Disturbances in early colonisation events, such as antibiotic exposure, can lead to increased susceptibility to enteric pathogens in later life. Knowledge on the composition and diversity of a healthy gastrointestinal tract microbiota, and on how changes in the microbiota increase susceptibility to enteric infection, is incomplete. These gaps in our knowledge are du e, in large part, to a lack of mechanistic data on initial development of the microbiota during the critical early life window. Hypothesis: Early life exposure to intestinal Bifidobacteria species protects from enteric infections later in life. This timely New Investigator proposal seeks to uncover how the dominant early life microbiota genus, Bifidobacterium, colonise the host gastrointestinal tract and subsequently modulate critical resistance to enteric infection, through microbial colo nisation (termed colonisation resistance). I aim to understand how antibiotic-induced early life perturbations may alter this microbial community, ultimately leading to a breakdown in pathogen protection. Finally, I will seek to identify bifidobacterial strains and communities that can restore an early life microbiota ecosystem able to control enteric pathogen infection. We will exploit state-of-the-art genomic and culturing technologies, in combination with unique in vitro and in vivo murine mo dels, to study these early life microbiota-host interactions. Gaining further knowledge about the colonisation of pioneer bacteria, and their associated products, may provide a powerful opportunity for manipulating community restructuring after perturbations in the microbiota, which is crucial in infectious disease settings.