# Mucosal modulation by LGG and R. gnavus specific tryptophan metabolites

> **NIH NIH R01** · RUTGERS THE STATE UNIV OF NJ NEWARK · 2020 · $387,500

## Abstract

PROJECT SUMMARY:
The dietary benefits of tryptophan have been classically linked to its property as an essential amino acid required
by mammals for protein synthesis, but recent work in the past decade has revealed its equally essential role as
an important source of metabolites for the microbial community to generate signals, mainly via the Aryl
Hydrocarbon Receptor (AHR), to affect a plethora of cellular functions. AHR signaling pathway is highly
promiscuous not only responding to diverse ligands with resembling structures, but also crosstalk with and is
modulated by numerous cellular signaling pathways. Distinct agonists can result in ligand selective differences
in AHR structure and function, ultimately leading to agonist-selective gene expression and biological effects. In
the gut, AHR activation by bacterial tryptophan catabolites influences mucosal homeostasis and microbiota
composition. Although bacterial tryptophan metabolites and AHR axis may contribute to microbial sensing and
tolerance, it is unclear if probiotics and pathobionts produce distinct tryptophan metabolites thereby eliciting
bacterial species- and agonist-specific host mucosal modulating effects. Both Lactobacillus and Ruminoccocus
spp catabolize tryptophan to a variety of tryptamine and indolic products that bind at low to high affinities to the
AHR. The identities and specific biological effects of tryptophan metabolites produced by the probiotic
Lactobacillus rhamnosus GG (LGG) and the pathobiont R. gnavus are currently unknown. Preliminary RNA-Seq
analysis of mouse intestinal mucosa perfused with live LGG revealed a robust induction of AHR signaling activity
as well as anti-inflammatory cytokines. Bacterial 16s rRNA sequencing and untargeted fecal metabolomics
screening of a newly engineered Lyz1 knockout mouse model revealed a dysbiosis featured by expansion of
mucolytic bacterial species (e.g., R. gnavus), accompanied by a pronounced elevation of tryptophan metabolites
and a changed epithelial cell composition. The hypothesis is that the probiotic LGG and the pathobiont R. gnavus
metabolize dietary tryptophan into distinct agonists that elicit differential mucosal modulating effects via the host
AHR signaling. Aim I will use mono-colonization of germ-free mice, dietary tryptophan depletion, unbiased
metabolomics profiling, and isogenic mutant bacteria deficient in tryptophan-metabolizing to identify LGG and R.
gnavus specific tryptophan metabolites and their differential mucosal modulating effects. Aim 2 will employ
organoid culture, intraluminal perfusion of AHR agonists, and genetic ablation of host AHR signaling to determine
the direct effects of bacterial species-specific tryptophan metabolites and AHR signaling on Lyz1-deficient mouse
mucosal homeostasis and colitis susceptibility. This MPI project uses rigorous approaches, including
gnotobiotics, bacterial genetics, dietary manipulation, and unbiased metabolomics, etc. to address an important
mechanism involvin...

## Key facts

- **NIH application ID:** 9994821
- **Project number:** 5R01AT010243-03
- **Recipient organization:** RUTGERS THE STATE UNIV OF NJ NEWARK
- **Principal Investigator:** RONALDO PARAOAN FERRARIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2018-09-20 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994821

## Citation

> US National Institutes of Health, RePORTER application 9994821, Mucosal modulation by LGG and R. gnavus specific tryptophan metabolites (5R01AT010243-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9994821. Licensed CC0.

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