# Immune Regulation by Bacteroides Polysaccharide Capsules

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2020 · $224,459

## Abstract

Abstract
Symbiotic human gut bacteria perform a number of beneficial physiological processes, including fermentation
of dietary fiber polysaccharides and instruction of mucosal immune development. During homeostasis, the
immune system utilizes several mechanisms to tolerate gut microbes; however, the same symbionts can cause
inflammation when certain defects in the immune system exist. Gut symbionts have also evolved mechanisms
to protect themselves from the host immune response, including the propensity to synthesize a variety of
different surface capsular polysaccharides (CPS). Bacteroides thetaiotaomicron (B. theta) is a model gut
symbiont that degrades a wide variety of dietary, host, and microbial glycans and dedicates hundreds of genes
to CPS production. The ability to express multiple different capsules, along with their complex, phase-variable
regulation, is a common feature of gut Bacteroidales species, including B. fragilis and B. theta. One of the
many B. fragilis CPS, termed PSA, is zwitterionic, and has been shown to modulate host cytokine levels and
induce anti-inflammatory responses that limit intestinal disease. Recently, several other diverse intestinal
bacteria, besides B. fragilis, have been shown to produce zwitterionic CPS that also exhibit anti-inflammatory
properties. Thus, it has emerged that several CPS, among just a small set studied, have evolved bioactive
properties. In parallel, genome sequencing has revealed a bewildering diversification of genetic loci involved in
CPS by human gut bacteria. The central hypothesis of this proposal is that other gut bacterial CPS (especially
non-zwitterionic forms) have evolved and been selected under immune pressure to possess a variety of
immunomodulatory functions. To test this premise, we have created a novel experimental system: a defined
CD4+ TCRtg mouse line in which T cells are specific for a B. theta outer membrane protein, combined with a
set of B. theta strains that each either express a single CPS or none at all. Our hypothesis is supported by two
major findings that set the basis for this proposal. First, when eight individual strains that each express a
different B. theta CPS were tested for their ability to be processed and presented by macrophages to stimulate
T cells in vitro, there is a broad range of activities, from weak to strong. Second, analysis of just 14 other
sequenced B. theta strains, revealed extensive CPS diversification. Strikingly, we identified a total of 49 unique
cps loci among just these 14 strains, suggesting that the “universe” of Bacteroides CPS is large. We propose
to test our hypothesis through two aims: 1) Determine the mechanisms by which 4 individual B. theta capsules
exert their range of immunomodulatory activities, and 2) Isolate and express novel CPS genes from
Bacteroides species and measure their immunomodulatory activity in vivo and in vitro. Polysaccharides are the
most diverse class of biomolecules in nature and have the potential to...

## Key facts

- **NIH application ID:** 9823859
- **Project number:** 5R21AI142257-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** PAUL M ALLEN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $224,459
- **Award type:** 5
- **Project period:** 2018-11-15 → 2020-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9823859

## Citation

> US National Institutes of Health, RePORTER application 9823859, Immune Regulation by Bacteroides Polysaccharide Capsules (5R21AI142257-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9823859. Licensed CC0.

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