# Contribution of phytochemicals to gut symbiont colonization and synthesis of immunomodulatory sphingolipids

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $402,750

## Abstract

Project summary
Recent findings in studies of the human microbiome have added a layer of complexity to research on the impact
of the diet on health. While the health benefits of certain classes of diet-derived molecules are well appreciated,
the molecular mechanisms underlying these benefits have been only partially elucidated. The diet provides
nutrients not only to the host but also to the microorganisms that make up the gut microbiota. The commensal
metagenome, which numerically exceeds the host genome by >100-fold, contributes enormous chemical
diversity to nutrient metabolism. Dietary metabolites attributable to specific gut commensals, have been identified
as key effector molecules of host health and disease in several studies.
At the tripartite juncture of host, diet, and microbiota, we have been investigating a unique class of sphingolipids
of the gut commensal Bacteroides fragilis (BfaGCs) and their host immunomodulatory functions. BfaGCs
regulate the proliferation of invariant natural killer T (NKT) cells in the host's colon, which determines disease
susceptibility in the NKT cell–mediated murine model of inflammatory bowel disease. This colonic NKT-cell
regulation by B. fragilis occurs only when colonization takes place during the first few days of life in mice. This
observation indicates that early postnatal exposure of the gut immune system to the microbiota is crucial in
establishing the number of gut NKT cells throughout life. Further studies have shown that terminal branching in
the glycosphingolipid structure is crucial in directing either agonism or antagonism of NKT cells functions. It is of
considerable interest that dietary branched-chain amino acids (BCAAs) can dictate the lipid structure of BfaGCs.
This observation suggests a novel concept in symbiotic mediator synthesis: direct incorporation of dietary factors
into bacterial biochemical pathways, where they are further converted into bioactive mediators.
BCAAs are essential amino acids for humans and are primarily produced by plants. Many BCAA-rich diets of
plant origin are also rich in plant oligosaccharides (POs), some of which are metabolized exclusively by B. fragilis
and confer this a survival advantage to this organism in the competitive environment of the gut. We hypothesize
that these phytochemicals (BCAAs and POs) act synergistically to help induce colonization by B. fragilis and
promote the production of NKT cell–regulatory BfaGCs that protect the host from NKT cell–mediated colitis.
Using multi-pronged approaches (bacterial genetics, gnotobiotic mouse models, and high-sensitivity analytical
platforms), we propose (1) to characterize critical genes in the BCAA-derived sphingolipid biosynthetic pathway
in B. fragilis and investigate their colonic NKT cell modulatory functions and (2) to determine the impact of
phytochemicals on immunomodulatory BfaGC production, postnatal NKT cell development, and colitis resistance
in adulthood. We expect to acquire molecular-lev...

## Key facts

- **NIH application ID:** 10339335
- **Project number:** 5R01AT010268-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Sungwhan F Oh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,750
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339335

## Citation

> US National Institutes of Health, RePORTER application 10339335, Contribution of phytochemicals to gut symbiont colonization and synthesis of immunomodulatory sphingolipids (5R01AT010268-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10339335. Licensed CC0.

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