In preliminary work, we identified a unique pre-weaning interval, we refer to as the post-neonatal phase, during which luminal antigens bypass the small intestine (SI) immune system and are assimilated by the colonic immune system. These events coincide with a bloom of tolerance-inducing colonic bacterial taxa, an influx of nave T cells, the translocation of live bacteria, and are followed by the expansion of a long-lived population of microbiota driven ROR?t+ inducible regulatory T-cells (iTregs), which have an enhanced capacity for tolerance, and control of Th2 responses. Our preliminary findings suggest that the timing and orchestration of events in the post-neonatal phase are under maternal control via chronological changes in breast milk, and altering maternal control, or altering of the gut microbiota during post-neonatal phase produce durable (life- long) deficits in tolerance induction, and persistent Th2 responses to antigens encountered throughout life. We hypothesize that during the post-neonatal phase luminal antigens and specific live gut bacteria are delivered to the colonic immune system and interact with specific cellular immune populations locally in the colon and in distant lymphoid tissues to establish a durable (life-long) and balanced immune system, and that disruption of these time-limited events during early life predisposes to allergic disorders. To explore this hypothesis and this unique period in early life we propose the following specific aims:
Aim 1 : Define the bacterial species that disseminate, their cellular and tissue localization, and the host pathways of translocation and antigen delivery during early life Aim 2: Define cellular populations acquiring antigen and carrying bacteria and the fate and function of effector T cells generated in the post-neonatal phase.
Aim 3 : Define the effects of disrupting events in the post-neonatal phase on the development of tolerance and in models of Th2 disease. The overarching premise for these studies is that understanding the biological processes imparting the benefits seen with current childhood feeding practices and antibiotic avoidance and understanding these benefits are restricted to a specific time in early life will provide insight into strategies to ?reset? an unbalanced immune response as a therapy for Th2 mediated diseases.

Public Health Relevance

Food allergy, asthma, and inflammatory bowel disease are rapidly increasing in children and young adults, and reduced risk for these diseases has been associated the introduction of dietary and microbial antigens via the gastrointestinal tract in early. However the factors conferring this benefit have remained enigmatic. These studies will identify when and why antigen introduction via the gastrointestinal tract in early life is beneficial and provide the basis for feeding and antibiotic use recommendations in early life.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAI1)
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Prabhudas, Mercy R
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Knoop, Kathryn A; Newberry, Rodney D (2018) Goblet cells: multifaceted players in immunity at mucosal surfaces. Mucosal Immunol 11:1551-1557
Kulkarni, Devesha H; McDonald, Keely G; Knoop, Kathryn A et al. (2018) Goblet cell associated antigen passages are inhibited during Salmonella typhimurium infection to prevent pathogen dissemination and limit responses to dietary antigens. Mucosal Immunol 11:1103-1113
Knoop, Kathryn A; Gustafsson, Jenny K; McDonald, Keely G et al. (2017) Microbial antigen encounter during a preweaning interval is critical for tolerance to gut bacteria. Sci Immunol 2:
McDonald, Keely G; Wheeler, Leroy W; McDole, Jeremiah R et al. (2017) CCR6 promotes steady-state mononuclear phagocyte association with the intestinal epithelium, imprinting and immune surveillance. Immunology 152:613-627