# Developmental flame retardant exposure, gut microbiome, and obesity

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $679,987

## Abstract

PROJECT SUMMARY
Obesity and type-II diabetes are a pandemic, causing grave social and economic burdens in the United States.
Epidemiological and animal studies showed that the flame retardants polybrominated diphenyl ethers (PBDEs)
and a most widely used current PBDE-alternative – tetrabromobisphenol A (TBBPA) are linked to obesity and
diabetes. However, mechanisms governing early life exposure to flame retardants and obesity/diabetes remains
unknown; no studies have compared the effect of PBDEs vs. TBBPA, and little is known regarding how early life
flame retardant plus additional risk factors (e.g. dietary factors) later in life modulate obesity. The liver- and
intestine-enriched pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are novel regulators
for obesity. Intestinal inflammation, as triggered by dysbiosis of the gut microbiota, is an early mediator of obesity
and type-II diabetes. In the previous grant cycle, we have demonstrated that: 1) early life exposure to the PBDEs
and TBBPA produces a pro-inflammatory/pro-obese microbial signature later in life; 2) PXR and CAR are
necessary in maintaining the basal healthy gut flora to prevent the blooming of pro-inflammatory microbes; 3)
the presence of gut microbiome promotes immunotolerance in the liver, whereas early life exposure to PBDEs
produced gut dysbiosis associated with enhanced immune cell hepatic mobilization, reduced PXR/CAR signaling,
and predicted liver injuries in adulthood; Early life exposure to an industrial PBDE mixture persistently disrupted
the microbial tryptophan metabolism. We also showed that the microbial tryptophan metabolite indole-3-
propionic acid (IPA) mimicry FKK6 compound protected against intestinal inflammation associated with
increased anti-inflammatory short-chain fatty acids (SCFAs) and the SCFA-producing microbes. Building on our
findings, the objective of the renewal is to determine how the host nuclear receptors, gut microbiome, and early
life flame retardant exposure interact to modulate the adult onset of obesity and type-II diabetes. Our central
hypothesis is: early life flame retardant exposures upset the physiological functions of PXR/CAR, leading to pro-
inflammation and pro-obesity microbial metabolites and elevated AhR signaling, which augmented obesity
following a 2nd hit (e.g. a high fat diet [HFD]) later in life; whereas the microbial mimicry is a novel remediation
strategy. We will test this hypothesis in 3 Aims: Aim 1 will determine to what extent PXR and CAR modulate the
inflammation- and obesity-related host and microbial signatures following early life exposure to PBDEs and
TBBPA. Aim 2 will determine how early life flame retardant exposure and PXR/CAR interact to modulate the
high fat diet-induced obesity later in life. Aim 3 will determine how gut microbiome mechanistically contributes
to the divergent roles of PXR and CAR in obesity following the “two-hit” exposure paradigm. The overall impact
of this research is tha...

## Key facts

- **NIH application ID:** 10879401
- **Project number:** 2R01ES030197-06A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Julia Yue Cui
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $679,987
- **Award type:** 2
- **Project period:** 2019-01-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879401

## Citation

> US National Institutes of Health, RePORTER application 10879401, Developmental flame retardant exposure, gut microbiome, and obesity (2R01ES030197-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10879401. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*