# Dietary and Microbial Reprogramming of Intestinal Microbiota-Produced Metabolites

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $625,691

## Abstract

PROJECT SUMMARY
The human colon houses a complex community of microbes, known as the gut microbiota, which possesses unmapped
metabolic capabilities. Bacterial metabolic pathways process components of diet, like amino acids, and produce an array
of ill-defined metabolites. Many of the metabolites produced by this microbial ecosystem are absorbed by the human host,
modified by host enzymes, and ultimately excreted by the kidneys. When the kidneys fail, these solutes accumulate and
comprise a significant portion of the "uremic" solutes found at very high levels in the plasma of patients maintained on
dialysis. These compounds can vary widely between individual patients, yet are relatively stable over time within an
individual, potentially reflecting inter-individual differences in gut microbiota composition. A few of these molecules
have been investigated and linked to poor health outcomes in renal patients. For most of these compounds, however,
neither the biochemical pathways responsible for their formation nor their biological effects on the host have been
elucidated. This application is focused on the prevalent high concentration uremic solutes derived from tyrosine, 4-
ethylphenylsulfate (4-EPS) and p-cresolsulfate (PCS), as well as 4-hydroxyphenylpropionic acid sulfate, a tyrosine
metabolite not associated with uremia but important in understanding the tyrosine-utilization niche within the gut
ecosystem. The goals of the research are to (i) determine the genes and species within the gut microbiota responsible for
production of the microbial metabolites 4-ethylphenol and p-cresol that serve as precursors to 4-EPS and PCS; (ii)
elucidate the effects of these molecules on aspects of host biology relevant to uremic illness; and (iii) investigate two
distinct strategies for microbiota reprogramming with a goal of lowering uremic solute levels in a host. Aim 1 employs
two approaches to predict microbial metabolic pathways, one using a computational/machine learning approach and a
second method using comparative genomics combined with bacterial metabolomic phenotyping. Gene predictions will be
genetically validated using gene deletion or heterologous expression. In Aim 2, gnotobiotic mice are used as a platform to
investigate the conversion of microbial metabolites into circulating solutes, and how solute levels are affected by diet and
other members of the microbiota. Isotopically labeled amino acids are used to trace dietary substrates to uremic solute
products. Aim 3 leverages gnotobiotic mice colonized by WT versus mutant bacteria, which differ in the presence or
absence of 4-EPS or PCS, to examine the effect of the metabolite on host biology. Changes in arterial thrombosis and
cognitive function relevant to uremic illness will be assessed. The focus of Aim 4 is to reprogram the microbiota to reduce
production of harmful uremic solutes. Single strain targeted reprogramming or complex consortium-based microbiota
reconstitution using a diverse arr...

## Key facts

- **NIH application ID:** 10598485
- **Project number:** 5R01DK101674-09
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** MICHAEL ANDREW FISCHBACH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $625,691
- **Award type:** 5
- **Project period:** 2014-09-18 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10598485

## Citation

> US National Institutes of Health, RePORTER application 10598485, Dietary and Microbial Reprogramming of Intestinal Microbiota-Produced Metabolites (5R01DK101674-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10598485. Licensed CC0.

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