The bacteria that live in our gut are important for many processes in our body. When this collection of microbes (known as the microbiome) gets out of balance, it is often associated with a wide array of inflammatory, autoimmune, neuronal and metabolic disorders. This is especially evident in preterm infants (11% of births worldwide), where immaturity of both the gut tissue and its bacteria may lead to detrimental consequences (preterm birth accounts for 35% of all newborns deaths).
One of the important factors of a healthy gut microbiome is the gut barrier, namely the cells that line the inside of the gut. Gut barrier integrity is crucial at all ages, and plays an important role in diseases such as irritable bowel syndrome and inflammatory bowel diseases. In healthy term infants, the gut barrier is strengthened and reinforced in the first 1-2 weeks of life, resulting in a significant decrease in gut permeability and in microbiome composition remodeling. However, in preterm infants, an immature barrier interrupts with the assembly of the infant gut microbiome and is associated with severe preterm-related morbidities including necrotizing enterocolitis (NEC) and neonatal sepsis.
Despite recent advances, deep longitudinal studies of preterm microbiome development and functions, coupled with mechanistic understanding of host-microbiome communications within the preterm gut, are mostly missing. Here, we propose to investigate the ‘epithelial barrier hypothesis’ in the context of the preterm gut bacteria and its impact on preterm infants’ survival, development and overall health.
Specifically, we propose to: (1) Establish a new Israeli preterm biobank, enrolling 300 infants, with daily sampling throughout their hospital admission, and to profile the microbiome trajectories of probiotic-free premature infants; (2) Examine intestinal responses to complex microbial communities using a novel 3D gut organ culture system. This unique system preserves the physiologic tissue structure and cellular complexity, yet allows tight experimental control, and thus facilitates experiments that cannot be easily performed otherwise; (3) Identify bacterial strains that are associated with gut barrier integrity and overall preterm infant health.
This comprehensive and ambitious research harnesses clinical, experimental and computational expertise to provide in-depth characterization of the molecular mechanisms that mediate gut barrier modulation by preterm gut microbiome, and to identify barrier-modulating microbial strains within the preterm microbiome. We expect that this interdisciplinary study will lay the foundations for the development of improved, microbiome-based, personalized neonatal care. Moreover, insights gained from this research may be harnessed towards identification of new microbiome-modulating therapeutic targets in a range of barrier-related disorders.