# Using diet to alter immune manipulation by Eggerthella lenta metabolites: eating away at autoimmunity

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $65,310

## Abstract

Project Summary/Abstract
The identification of environmental factors such as commensal bacterial metabolites that modulate immune
responses could provide therapeutic targets for immune-driven diseases. Indeed T helper 17 (Th17) cells, a
major immune cell type involved in autoimmunity, are regulated by the microbiota. Our long-term goal is to
identify immune-modulatory members of the microbiota and understand the mechanisms whereby
they influence the immune system in diverse environmental contexts. Here, we propose a distinct
mechanism of microbial-driven Th17 induction where resident gut bacteria produce metabolites that traverse
the gut barrier resulting in Th17 activation. Moreover, we hypothesize that this immune manipulation is altered
by the diet. These hypotheses stem from our preliminary studies on the prevalent gut bacteria, Eggerthella
lenta, whose levels are increased in patients with the Th17 driven disease, rheumatoid arthritis (RA). We found
that E. lenta colonization induces Th17 cells and contributes to more severe colitis in a gnotobiotic mouse
model. Critically, high arginine conditions lead to decreased activity of an E. lenta-metabolizing enzyme, Cgr2,
and our initial studies indicate that high Arg decreases E. lenta-mediated Th17 induction in a Cgr2 dependent
manner. Based on these preliminary findings we propose to 1) Identify the mechanism by which E. lenta
induces Th17 cells 2) Determine the influence of E. lenta colonization on mouse models of RA and
inflammatory bowel disease (IBD) and 3) Assess the effect of dietary Arg on E. lenta’s induction of Th17 cells
and autoimmunity. By manipulating Cgr2 though heterologous expression and natural E. lenta strain variants
that possess or lack Cgr2, we will investigate the role of this bacterial protein in Th17 induction. To identify the
bacterial product produced by E. lenta responsible for Th17 induction we will perform mass spectrometry on
HPLC fractionated E. lenta conditioned media, which we have shown to have Th17 inducing capabilities
compared to a media control. Further, we will examine if E. lenta’s induction of autoimmunity is altered by
dietary conditions using mouse models of RA and IBD and high and low Arg diets. These studies will provide
insight into unique mechanisms of Th17 induction and examine how dietary alteration and bacterial metabolites
affect autoimmunity. Our novel approach of investigating immune regulation with a microbial-centric
perspective will aid in uncovering new mechanisms of immune regulation where the dietary alterations of
immune-active microbial metabolites could provide effective therapy. These proposed studies will provide a
rich training experience where our multidisciplinary approach will supply exceptional opportunities to expand
skills in microbiology, microbiota studies, immunology, and biochemistry. We believe the outstanding research
climate at UCSF of collaboration and expertise in these fields will steer this project and training to...

## Key facts

- **NIH application ID:** 9956588
- **Project number:** 5F32AI147456-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Margaret Rose Alexander
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9956588

## Citation

> US National Institutes of Health, RePORTER application 9956588, Using diet to alter immune manipulation by Eggerthella lenta metabolites: eating away at autoimmunity (5F32AI147456-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9956588. Licensed CC0.

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