# Gut dysbiosis and tryptophan metabolism in lupus

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2021 · $441,220

## Abstract

Project Summary/Abstract
Tryptophan (Trp) is an essential amino acid that is used for the biosynthesis of key compounds such as serotonin
(5HT), NAD, kynurenine (Kyn), and AhR ligands. The gut microbiome is a critical participant in Trp metabolism
through which it modulates immune activation. High Kyn and low 5HT levels have been found in lupus patients,
which has been proposed to be the consequence of increased oxidation or interferon levels associated with this
disease. Imbalance of gut microbial populations has been associated with lupus in patients and mouse models.
Based on published studies as well as our unpublished results presented here, the premise of this proposal is
that gut dysbiosis is an essential player in Trp metabolite imbalance in lupus, and that the interplay between the
gut microbiota, Trp metabolism, and genetic susceptibility modulates systemic autoimmunity.
Using a congenic model in which lupus-prone mice (B6.Sle1.Sle2.Sle3, or TC for short) share over 95% of their
genome with control B6 mice, we showed that transfers of TC fecal microbiota induce a transient autoimmunity
in gnotobiotic (GF) B6 mice. As in lupus patients, the serum and feces of TC mice present high Kyn and low 5HT
levels, and this metabolite imbalance was eliminated by a broad-spectrum antibiotic treatment. Furthermore, a
low Trp diet prevented autoimmunity while a high Trp diet accelerated disease progression. In a NYU cohort of
well-characterized lupus patients, disease severity was positively correlated with a reduction of fecal bacterial
diversity and negatively correlated with Trp serum levels. A preliminary analysis predicted that SLE patients had
a greater abundance of bacteria with an enhanced catabolism of Trp into Kyn. We postulate that clinical lupus
disease activity is in part driven by specific gut dysbiosis resulting in greater Trp catabolism and/or increased
Trp catabolic products that enhance genetically driven pro-inflammatory pathways. To test this hypothesis, we
propose three specific aims: 1. To elucidate the effect of Trp on the immunoregulatory properties of the fecal
microbiota of lupus mice. 2. To evaluate the mitigation of gut dysbiosis by dietary Trp in lupus-prone mice. 3. To
determine whether altered Trp metabolism in SLE patients is associated with an enrichment for Trp-catabolizing
fecal microbiota.
With a multidisciplinary approach, we propose to dissect the mechanisms by which genetically-prone (mouse or
human) individuals develop autoimmune activation that leads to gut dysbiosis, which feeds back to autoimmune
activation. A consequence of this gut dysbiosis is a disruption of Trp metabolism with the generation of
metabolites that activate pro-inflammatory pathways such as mTOR and AhR. Lupus genetic susceptibility may
also alter the expression of genes in the endogenous Trp pathway. Establishing causal relationships between
these variables and the identification of gut taxa responsible for Trp degradation would represent a ...

## Key facts

- **NIH application ID:** 10079461
- **Project number:** 5R01AI143313-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Laurence Morel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $441,220
- **Award type:** 5
- **Project period:** 2019-01-11 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10079461

## Citation

> US National Institutes of Health, RePORTER application 10079461, Gut dysbiosis and tryptophan metabolism in lupus (5R01AI143313-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10079461. Licensed CC0.

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