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Microbiota, Metabolites, and Colon Neoplasia

Award Number: R01CA252045
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Microbiota, Metabolites, and Colon Neoplasia - Project Summary The human diet can positively or negatively impact cancer incidence, with plant-derived compounds – such as polyphenols – often exhibiting antioxidant cancer-preventive properties. Walnuts are an exceptional source of polyphenolic ellagitannins (ETs) that are converted to ellagic acid and various urolithins by gut microbiota in the colon. Urolithin A (UroA) is of particular interest for its potent anti-cancer, anti-inflammatory, and prebiotic activities. However, UroA production in individuals can vary significantly, likely based on differences in gut microbiota. We will substantiate the anti-cancer benefits of a prebiotic/probiotic complex derived from consuming walnuts and determine the basis of human inter-individual variability in UroA formation. Our overall hypothesis is that walnut supplementation improves colonic health and lowers colorectal cancer (CRC) risk through UroA formation. This leads to several working hypotheses guiding our Aims: Working Hypothesis 1. UroA producers are at a lower risk of having an advanced colonic lesion; Working Hypothesis 2. Walnut supplementation will increase urinary UroA levels; and Working Hypothesis 3. CRC prevention by walnuts will be greater in UroA-producers than in non-producers. In Aim 1, we propose a randomized, controlled crossover trial in 69 patients (45-75 y) to examine walnut effects on CRC risk factors. We will associate an individual's ability to produce UroA with biomarkers of inflammation and CRC risk, and identify the bacterial species responsible for urolithin metabolism. In Aim 2, we will investigate prebiotic effects of ET-containing walnuts in two conditional mouse CRC models, focusing on important processes in CRC and inflammation, including bile acid metabolism, inflammation, and short chain fatty acid production. In Aim 3, we will test the probiotic effects of human UroA-producing microbiota in a mouse fecal microbiota transplant (MT) study and demonstrate a causal role for specific microbes in UroA formation. This will enable us to validate the concept that important protective effects of walnuts and other ET-rich foods occur through specific microbiota-derived metabolites. This will also define biomarkers and probiotics that highlight the benefits of these foods. Our approach incorporates personalized nutrition with a focus on UroA producers and non-producers in colonic health. Ultimately, our human and pre-clinical mouse studies may lead to prebiotics and probiotics that increase protective urolithins for CRC prevention. These highly significant studies will test the ability of the microbiota to generate colonic mucosa-protective agents (e.g., UroA). It is possible that high-risk patients can be efficiently converted to a protective state by taking probiotics to realize the full benefits of ET-rich foods.


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: 2025 ( Subtotal = $517,782 )
2025	2025	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Cancer Cause and Prevention Research	000	5	4/4/2025	NON-COMPETING CONTINUATION	$517,782
														Subtotal = $517,782

Issue Date FY: 2024 ( Subtotal = $557,628 )
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Cancer Cause and Prevention Research	000	4	5/24/2024	NON-COMPETING CONTINUATION	$557,628
														Subtotal = $557,628

Issue Date FY: 2023 ( Subtotal = $631,851 )
2023	2023	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Cancer Cause and Prevention Research	000	3	4/28/2023	NON-COMPETING CONTINUATION	$631,851
														Subtotal = $631,851

Issue Date FY: 2022 ( Subtotal = $649,547 )
2022	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Cancer Cause and Prevention Research	000	2	5/2/2022	NON-COMPETING CONTINUATION	$649,547
														Subtotal = $649,547

Issue Date FY: 2021 ( Subtotal = $710,422 )
2021	2021	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Cancer Cause and Prevention Research	000	1	4/26/2021	NEW	$710,422
														Subtotal = $710,422

Grand Total All Awards = $3,067,230

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Microbiota, Metabolites, and Colon Neoplasia

Award Number: R01CA252045

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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