Immune interactions with commensal microbes in early life

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Project Summary/Abstract Events in early life, particularly those altering the gut microbiota and immune development, can have an important role in determining future risk of immune related disorders. For example, it has been reported that the how substances are encountered by the immune system, the timing of feeding practices, hygiene, and the use of antibiotics, in early life can modify the risk of immune driven disorders later in life. A common theme amongst many of these studies is that these risk factors likely affect the developing microbiota. However, the biologic basis for how early life microbial changes can affect the risk of immune disorders later in life is incompletely understood. Previous data from our laboratories have suggested that during this preweaning period, specific live gut bacteria are selectively delivered to the immune system and that interaction of these live bacteria with cellular immune populations locally in the colonic lamina propria or in distant lymphoid tissues establishes a durable (life- long) and balanced immune system. In preliminary studies, we observed substantial variance in the amount of bacterial translocation in this preweaning period, which was corroborated with studies of antigen-specific T cell responses to a translocating bacterial spp. We therefore hypothesize that the magnitude and quality of the immune response to these translocating bacteria species during the preweaning period is a stochastic event during normal ontogeny which represents an important variable in determining whether an individual establishes a balanced immune system and prevents immune mediated pathologies in later life. However, the nature of these translocating bacteria and methods to quantify the antigen-specific responses to these bacteria remain a gap in our knowledge. We will address this question by identifying and characterizing how the translocating bacteria are encountered by the immune system (Aim 1) and generate reagents to track bacterial antigen presentation via T cell responses in vivo (Aim 2). We will use these reagents to integrate the immune response over the preweaning period to translocating bacterial spp. during physiologic development and correlate it with intestinal immune challenges including infection and experimental colitis in later life (Aim 3). If successful, this project may reveal that preweaning translocation is an important stochastic developmental variable involved in generating intestinal immune health and homeostasis.