Source: BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOP submitted to NRP
ENHANCING NK CELL FUNCTIONS BY BERRY METABOLITES FOR COLON CANCER CHEMOPREVENTION
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
COMPLETE
Funding Source
AFRI COMPETITIVE GRANT
Reporting Frequency
Annual
Accession No.
1031781
Grant No.
2024-67017-41792
Cumulative Award Amt.
$111,406.75
Proposal No.
2023-07345
Multistate No.
(N/A)
Project Start Date
May 1, 2023
Project End Date
Apr 30, 2024
Grant Year
2024
Program Code
[A1343]- Food and Human Health
Recipient Organization
BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOP
1500 EAST DUARTE ROAD
DUARTE,CA 91010
Performing Department
(N/A)
Non Technical Summary
Black raspberries contain compounds like polyphenols and anthocyanins, showing promise in strengthening natural killer (NK) cells vital in fighting cancer. By specifically targeting NK cells, these black raspberry compounds might amplify their function, aiding in spotting and eradicating early colon cancer cells. This interaction opens a potential path for dietary strategies to enhance the body's immune response against colon cancer. Employing black raspberries to bolster NK cell-led surveillance against this cancer presents an intriguing avenue in preventive measures, potentially reinforcing the body's inherent defense mechanisms. Moreover,we aim to explore whether Smad4 impacts in NK cells collaborate or add to its role in colonic epithelial cells during colorectal cancer advancement. Then, we willascertain whether BRB-derived gut bacterial metabolites can target Smad4 in both colonic epithelial cells and NK cells.
Animal Health Component
(N/A)
Research Effort Categories
Basic
100%
Applied
(N/A)
Developmental
(N/A)
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
72438401010100%
Knowledge Area
724 - Healthy Lifestyle;

Subject Of Investigation
3840 - Laboratory animals;

Field Of Science
1010 - Nutrition and metabolism;
Goals / Objectives
In colorectal cancer (CRC), higher levels of tumor-infiltrating natural killer (NK) cells have shown a correlation with extended survival. However, the specific mechanisms utilized by NK cells to regulate CRC development remain unclear. Our research revealed that NK cell depletion accelerated colon tumor progression in mouse CRC models. Additionally, we observed suppressed Smad4 expression in circulating NK cells of untreated metastatic CRC patients. Notably, NK cell-specific deletion of Smad4 led to increased colon tumor development in two mouse CRC models. Mechanistically, this deletion significantly reduced NK cell cytotoxicity, notably granzyme B (Gzmb) expression, a crucial factor in cytolytic cells. Unveiling Smad4's role in NK cells offers a promising avenue for targeting the NK immune cell lineage in cancer. We investigated a black raspberry (BRB) intervention, demonstrating enhanced NK cell infiltration in tumors and increased levels of gut bacteria metabolites in CRC patients. These metabolites upregulated Smad4 and Gzmb expression and amplified the cytotoxicity of primary human NK cells. We propose that BRB-derived gut bacteria metabolites may suppress CRC by enhancing Smad4 expression in NK cells. We aim to dissect Smad4's role in NK cells (Aim 1) and identify BRB fractions that produce gut bacteria metabolites stimulating Smad4 signaling in NK cells to halt CRC progression (Aim 2). Our findings underscore the potential of these metabolites in elevating Smad4 levels within NK cells to impede CRC advancement. Expanding on Aim 1, we found reduced Smad4 expression in circulating NK cells of untreated metastatic CRC patients. Furthermore, NK cell-specific Smad4 deletion promoted colon adenomas in DSS-treated ApcMin/+ mice and adenocarcinomas in AOM/DSS-treated mice. Research has linked Smad4 loss in colonic epithelium with poor CRC patient survival. Thus, targeting Smad4 in both colonic epithelium and NK cells might offer a robust approach to manage CRC. Dietary intervention with black raspberries (BRBs) increased Smad4 expression in colonic epithelium in FAP or CRC patients and the two CRC mouse models. Additionally, BRB benzoate metabolites, like hippurate, potentially boosted Smad4 and Gzmb expression, heightening primary human NK cell cytotoxicity. Notably, increased hippurate levels are indicative of a healthy gut microbiota in humans and possess antitumor effects. Our study suggests a novel mechanism involving benzoate metabolites from plant-based foods that could clinically elevate Smad4 in colonic epithelium and NK cells, potentially delaying CRC progression. Concerning Aim 2, we observed that protocatechuic acid (PCA), a gut bacterial metabolite of BRB-derived anthocyanins, inhibited adenoma development and altered gut microbiome profiles in ApcMin/+ mice. Mechanistically, anti-inflammatory bacterial profiles replaced pro-inflammatory ones across all treatments, notably with the 5% BRB and 500 ppm PCA-supplemented diets, accompanied by reduced COX-2 and prostaglandin E2 levels in colonic mucosa. Additionally, 500 ppm PCA increased IFN-γ and SMAD4 levels in primary cultured human NK cells, suggesting potential benefits of BRBs and lower-dose PCA in CRC by inhibiting adenoma growth, modifying gut microbiome conditions, and promoting a favorable environment for CRC patients.As highlighted above, substantial strides have been achieved during the duration of our project. We are enthusiastic about finalizing the project during the initial carryover phase. Our primary focus will revolve around breeding the Cdx2pCre/+NKp46iCre/+Smad4fl/flApcMin/+ mice, enabling us to investigate whether Smad4 effects in NK cells interact synergistically or additively with Smad4 effects in colonic epithelial cells throughout colorectal cancer progression. Subsequently, our aim is to ascertain whether BRB-derived gut bacterial metabolites possess the ability to target Smad4 in both colonic epithelial cells and NK cells.
Project Methods
We will use the Cdx2pCre/+NKp46iCre/+Smad4fl/flApcMin/+ mice and study whether the effects of Smad4 in NK cells are synergistic or additive with the effects of Smad4 in colonic epithelial cells during colorectal cancer progression. Subsequently, we willascertain whether BRB-derived gut bacterial metabolites can target Smad4 in both colonic epithelial cells and NK cells.

Progress 05/01/23 to 04/30/24

Outputs
Target Audience:Our publications on nutrition and chronic human diseases could benefit healthcare providers, patients, caregivers, and the general population in preventing and managing these conditions. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?Dr. Athena Dong, a medical school graduate as of May 2024 from the Medical College of Wisconsin, has been trained under this NIFA-funded project. Dr. Dong is now continuing her residency training at the University of Southern California. The professional training provided by the NIFA-funded project has given her solid scientific evidence of how foods can benefit people's health. How have the results been disseminated to communities of interest?The results have been published or are under review in peer-reviewed food-related journals, with specific DOIs assigned. Audiences can easily access these open-access articles at no cost through search engines like Google. What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? In the final report of the no-cost extension period, we continued to pursue our goal of using nutrition to prevent chronic human diseases. Below, we have listed our accomplishments in published articles related to this effort. Huang YW, Chen HZ, Niu B, Wu W, Gao H, Yu J, Wang LS. Black raspberry-mediated metabolic changes in patients with familial adenomatous polyposis associated with rectal polyp regression. Food Frontiers. 2024;5:259-266. doi.org/10.1002/fft2.323. Accepted. NIFA Support Acknowledged. Dr. Yu, the PD, is a co-corresponding author. Dong A, Huang YW, Chen H, Liu R, Wu W, Gao H, Wang CK, Yu J, Wang LS. The potential use of natural killer cells to treat Alzheimer's disease: Can nutrition play a role? eFood. 2024;5:e145. doi.org/10.1002/efd2.145. Accepted. NIFA Support Acknowledged. Dr. Yu, the PD, is a co-corresponding author. Dong A, Huang YW, Zong Z, Xiao S, Wu W, Gao H, Yu J, Wang LS. The nutritional impact on CAR therapy. eFood. 2024;5:e136. doi.org/10.1002/efd2.136. Accepted. NIFA Support Acknowledged. Dr. Yu, the PD, is a co-corresponding author. Wang CK, Tandoro Y, Chiu HF, Tan CL, Hsieh MH, Huang YW, Yu J, Wang LS, Chan CH. Dietary Black Raspberry Supplementation as Natural Polyphenol Source Against Mild Dementia Patients with Overweight and Helicobacter pylori Infection. npj Science of Food. doi.org/10.21203/rs.3.rs-3899398/v1. Under review. NIFA Support Acknowledged.

Publications

  • Type: Journal Articles Status: Accepted Year Published: 2024 Citation: Huang YW, Chen HZ, Niu B, Wu W, Gao H, Yu J, Wang LS. Black raspberrymediated metabolic changes in patients with familial adenomatous polyposis associated with rectal polyp regression. Food Frontiers. 2024;5:259-266. doi.org/10.1002/fft2.323. Accepted. NIFA Support Acknowledged. Dr. Yu, the PD, is a co-corresponding author.
  • Type: Journal Articles Status: Accepted Year Published: 2024 Citation: Dong A, Huang YW, Chen H, Liu R, Wu W, Gao H, Wang CK, Yu J, Wang LS. The potential use of natural killer cells to treat Alzheimer's disease: Can nutrition play a role? eFood. 2024;5:e145. doi.org/10.1002/efd2.145. Accepted. NIFA Support Acknowledged. Dr. Yu, the PD, is a co-corresponding author.
  • Type: Journal Articles Status: Accepted Year Published: 2024 Citation: Dong A, Huang YW, Zong Z, Xiao S, Wu W, Gao H, Yu J, Wang LS. The nutritional impact on CAR therapy. eFood. 2024;5:e136. doi.org/10.1002/efd2.136. Accepted. NIFA Support Acknowledged. Dr. Yu, the PD, is a co-corresponding author.
  • Type: Journal Articles Status: Under Review Year Published: 2024 Citation: Wang CK, Tandoro Y, Chiu HF, Tan CL, Hsieh MH, Huang YW, Yu J, Wang LS, Chan CH. Dietary Black Raspberry Supplementation as Natural Polyphenol Source Against Mild Dementia Patients with Overweight and Helicobacter pylori Infection. npj Science of Food. doi.org/10.21203/rs.3.rs-3899398/v1. Under review. NIFA Support Acknowledged.