# GUT SPECIFIC AND TIME-LIMITED EVENTS IN EARLY LIFE PROMOTING TOLERANCE

> **NIH NIH U01** · WASHINGTON UNIVERSITY · 2021 · $406,057

## Abstract

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 naïve 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.

## Key facts

- **NIH application ID:** 10118081
- **Project number:** 5U01AI131342-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Rodney D Newberry
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $406,057
- **Award type:** 5
- **Project period:** 2017-03-15 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10118081

## Citation

> US National Institutes of Health, RePORTER application 10118081, GUT SPECIFIC AND TIME-LIMITED EVENTS IN EARLY LIFE PROMOTING TOLERANCE (5U01AI131342-05). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10118081. Licensed CC0.

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