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Understanding the role of gut microbiome in trichloroethene-mediated autoimmunity

Award Number: R01ES037276
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Understanding the role of gut microbiome in trichloroethene-mediated autoimmunity - ABSTRACT Trichloroethene (trichloroethylene, TCE), an environmental and occupational agent, is known to cause autoimmune diseases (ADs), including SLE-like disease in humans. The etiology of SLE is multifactorial, which includes genetic, hormonal and environmental triggers. There is increasing evidence that environmental factors, including changes in microbiota contribute to ADs. Using female MRL+/+ (MRL/MpJ) mice, we have established that TCE exposure causes early induction of the disease. Our preliminary studies in these mice also show that TCE exposure leads to gut microbiome dysbiosis along with decreases in important bacterial metabolites [short-chain fatty acids (SCFAs)]. However, the contribution and mechanisms by which gut microbiota leads to TCE-mediated early induction of SLE are not known, and are the major focus of this proposal. We will test the central hypothesis that TCE exposure in genetically susceptible populations causes gut microbiome dysbiosis and impaired intestinal integrity together with mucosal immune dysregulation, which contribute to systemic autoimmune responses and eventually lead to SLE. To achieve our overarching goal of understanding the role of gut microbiome in TCE-mediated SLE, the following specific aims will be pursued. Aim 1 will establish that TCE exposure causes its SLE-promoting effects via dysbiosis of gut microbiota, and gut microbiota from TCE-treated MRL+/+ mice can transmit SLE phenotypes to control mice. Using fecal samples, 16S rRNA and metagenomic sequencing (WGS) will be performed to assess differential composition of the gut microbiome, and differences in the functional genes. Furthermore, using feces from TCE-treated mice, fecal microbiome transplant (FMT) studies will be performed in germ-free mice, which will firmly establish that altered microbiome plays a causative role in TCE-mediated autoimmunity. Aim 2 will determine if TCE- microbiome-host interactions contribute to disease outcome by affecting intestinal integrity and mucosal immunity. We will determine gut permeability in vivo, tight junction proteins and endotoxin levels in the circulation. Contribution of oxidative stress to epithelial integrity will also be assessed. We will also determine if TCE treatment skews the Treg-Th17 balance towards a Th17 phenotype, along with intestinal inflammasome activation and inflammatory cytokines. Adoptive transfer of Tregs will then be done to restore gut homeostasis. Aim 3 will determine if imbalances in SCFAs contribute to SLE pathogenesis by affecting mucosal immunity and barrier functions, and probiotic therapy can ameliorate TCE-mediated autoimmunity by restoring SCFAs. We will examine profiles of SCFAs and mucosal Tregs during initiation and progression of the disease, and conduct supplementation studies with SCFAs and probiotics to further establish the mechanisms by which microbiota contributes to TCE-mediated SLE. Successful completion of these aims will establish the causal role of gut microbiome dysbiosis in TCE-mediated SLE, delineate novel mechanisms contributing to disease pathogenesis, and help in designing novel therapeutic microbial targets for autoimmunity/SLE.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $718,775 )
2026	2026	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Environmental Health	000	1	3/31/2026	NEW	$718,775
														Subtotal = $718,775

Grand Total All Awards = $718,775

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Understanding the role of gut microbiome in trichloroethene-mediated autoimmunity

Award Number: R01ES037276

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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