Following birth, neonates are rapidly colonized by microbes, which play important roles in health and disease. The gut contains the largest density of microorganisms, termed the gut microbiome, which plays fundamental roles in protection from pathogens, immune system training, and the breakdown of dietary compounds. Our research has shown that over the first year of life the infant gut microbiome is highly dynamic, providing a window of opportunity in which to seed a potentially beneficial microbiome to reduce the risk of early- and later-life disease risk. For instance, in a recent study of term infants, we showed that birth mode and breastfeeding are the most important variables for shaping the early life microbiome, which are directly correlated to an increased risk of obesity, allergy, asthma, and other disorders later in life. This, early life host-microbiome crosstalk and immune development is hypothesised to have important roles in long-term health. Our research has made important advances in the role of the preterm infant microbiome in health and disease. Unlike infants born at term, extremely preterm infants (<32 weeks gestation) have immature intestinal architecture and an underdeveloped immune system. They are also less likely to be vaginally delivered and breastfed, and they receive limited exposure to microbes during the first months of life, leading to a reduction in potentially beneficial bacteria. Because the preterm gut can become leaky, translocation of microbes into the bloodstream and/or intestinal cell death represent major problems in this vulnerable population. However, evidence from my group and others has shown that certain types of bacteria, such as Bifidobacterium, may increase gut and immune maturation. The latest work from my group further shows specific components of human milk are linked to colonisation by Bifidobacterium which together contribute toward the health or disease of an infant. While such associations provide insights, it is not possible to determine cause or effect. To advance this work, we have recently developed a novel model derived from primary human intestinal organoids that accurately recapitulates physiologically relevant oxygen conditions. This allows the co-culture of intestinal organoids with enteric anaerobic bacteria (i.e., oxygen sensitive bacteria that reside in the gut lumen). A better understanding of the interaction between bacteria and infant gut epithelial cells holds incredibly exciting possibilities to better predict, diagnose, and manipulate the microbiome of preterm infants at risk of disease.