# Gut region-specific mechanisms that limit dissemination of microbial signals from the intestine

> **NIH NIH U01** · WASHINGTON UNIVERSITY · 2024 · $441,000

## Abstract

ABSTRACT
A major concern of the intestinal mucosa is to execute its role in absorption of nutrients while minimizing
inflammatory or adverse immune interactions with the microbiome. Managing absorption entails not only
sorting of nutrients by intestinal epithelial cells but also delivery of those nutrients to specialized blood and
lymphatic vessels present in each villus of the small intestine. In turn, the blood and lymphatic vessels that
collectively manage outflow from the gut may need to rely on specialized mechanisms that operate to limit
dissemination of microbial signals to distal sites like the lung or the liver to avoid downstream organ injury. It is
now appreciated, for instance, that alcoholic and nonalcoholic liver damage is driven substantially by microbial
transit from the gut to the liver via the portal vein. Likewise, pulmonary damage can ensue in response to
injurious cargo in lymph that gains access to blood via the thoracic duct and quickly next flows to the lungs. Yet
mechanisms protecting against dissemination of microbial signals from the intestinal mucosa remain
incompletely understood, possibly making planned manipulations of the mucosal barrier, as in vaccination or
disease therapy, riskier than needed or resulting in surprises. For instance, our preliminary data suggest that
the documented and seemingly counterintuitive liver damage that can result from anti-TNF neutralizing
antibody therapy to treat inflammatory disease of the bowel may be due, at least in part, to disruption of
leukocyte-mediated surveillance of the draining venous vasculature that removes microbes that escape the
intestinal mucosal before they arrive to the liver. To fill in these basic knowledge gaps, we propose herein to
delineate how different regions of the intestine program leukocyte-dependent and leukocyte-independent
strategies to protect downstream cells and tissues against dissemination of microbial signals. In aim 1, we
focus on mechanisms operative in phagocytic removal from gut-draining venous blood of whole microbes that
escape the intestinal mucosal barrier and otherwise deliver the microbes to deeper tissues or distal locations.
In aim 2, we will compare how the small bowel and colon may differentially transport and neutralize soluble
microbial signals, like LPS, that can inadvertently escape the epithelial barrier to promote inflammation. This
effort will include comprehensive proteomic and lipidomic evaluation of lymph and blood draining different
regions of the gut mucosa, working with expert collaborators and taking advantage of our laboratory’s expertise
in lymphatic biology and recent studies in the transport of intestinal cargo into gut-draining venous blood.

## Key facts

- **NIH application ID:** 10868455
- **Project number:** 5U01AI163064-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Gwendalyn J Randolph
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $441,000
- **Award type:** 5
- **Project period:** 2021-09-08 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868455

## Citation

> US National Institutes of Health, RePORTER application 10868455, Gut region-specific mechanisms that limit dissemination of microbial signals from the intestine (5U01AI163064-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10868455. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*