Source: UNIV OF MASSACHUSETTS submitted to NRP
INTERACTIONS OF OXIDIZED PUFAS WITH GUT MICROBIOTA TO PROMOTE COLONIC INFLAMMATION
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
COMPLETE
Funding Source
AFRI COMPETITIVE GRANT
Reporting Frequency
Annual
Accession No.
1021990
Grant No.
2020-67017-30844
Cumulative Award Amt.
$499,826.00
Proposal No.
2019-08016
Multistate No.
(N/A)
Project Start Date
Apr 15, 2020
Project End Date
Apr 14, 2025
Grant Year
2020
Program Code
[A1343]- Food and Human Health
Recipient Organization
UNIV OF MASSACHUSETTS
(N/A)
AMHERST,MA 01003
Performing Department
Dept: Food Sciences
Non Technical Summary
Polyunsaturated fatty acids (PUFAs) are substantial part of our diet and are consumed by the whole population almost every day: the ω-6 PUFA linoleic acid (LA, 18:2ω-6) is a major component of vegetable oil, and the ω-3 PUFAs eicosapentaenoic acid (EPA, 20:5ω-3) and docosahexaenoic acid (DHA, 20:6ω-3) are major components of fish oil. Rich in polyunsaturated fats, both ω-6 and ω-3 PUFAs are highly prone to oxidation. Our preliminary data supports that oxidized ω-3/ω-6 PUFAs, even at low oxidative status, could cause adverse effects on gut microbiota and gut health. In this application, we will test our hypothesis that dietary intake of oxidized ω-3/ω-6 PUFAs, even at low oxidative status (within the current industry limit for oxidative status of vegetable or fish oil), perturbs gut microbiota, resulting in increased colonic inflammation and associated diseases. Using genetically engineered mouse model, 16S rRNA sequencing, fecal transplant in germ-free mice, we will mechanistically study the effects of oxidized PUFAs on gut microbiota and gut health.
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
70170101010100%
Knowledge Area
701 - Nutrient Composition of Food;

Subject Of Investigation
7010 - Biological Cell Systems;

Field Of Science
1010 - Nutrition and metabolism;
Goals / Objectives
Polyunsaturated fatty acids (PUFAs) are substantial part of our diet and are consumed by the whole population almost every day: the ω-6 PUFA linoleic acid (LA, 18:2ω-6) is a major component of vegetable oil, and the ω-3 PUFAs eicosapentaenoic acid (EPA, 20:5ω-3) and docosahexaenoic acid (DHA, 20:6ω-3) are major components of fish oil. Rich in polyunsaturated fats, both ω-6 and ω-3 PUFAs are highly prone to oxidation: notably, recent studies showed that ~83% ω-3 PUFA products on the market are overly oxidized. To date, the effects of oxidized ω-3/ω-6 PUFAs on human health are under-studied. Our preliminary study showed that dietary administration of oxidized ω-3/ω-6 PUFAs, even at a low oxidative status (within the current industry limit for oxidative status of vegetable or fish oil), exaggerated dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced colon tumorigenesis in mice, via gut microbiota-dependent mechanisms. Therefore, in this project we will test the hypothesis that dietary intake of oxidized ω-3/ω-6 PUFAs, even at low oxidative status (within the current industry limit for oxidative status of vegetable or fish oil), perturbs gut microbiota, resulting in increased colonic inflammation and associated diseases. Through this project, we propose to, for the first time, study the effects of oxidized ω-3/ω-6 PUFAs on gut microbiota and gut health, which could lead to significant and positive impact for the food industry, regulatory policy, and public health.
Project Methods
We propose three specific aims and the methods for each aim are discussed below:Aim 1: further validate the effects of oxidized ω-3/ω-6 PUFAs on colonic inflammation. Our preliminary data showed that dietary administration of oxidized ω-3/ω-6 PUFAs exaggerated DSS-induced colitis and AOM/DSS-induced colon tumorigenesis in mice. However, these chemically induced models (DSS and AOM/DSS) are highly acute and have some limitations to study the pathogenesis of colonic inflammation and colon cancer in humans. To better understand the effects of oxidized ω-3/ω-6 PUFAs, here we will study their actions on colitis using another colitis model, the Il-10-/- mice. We will test the hypothesis that dietary administration of oxidized ω-3/ω-6 PUFAs, even at low oxidative status, exaggerates colonic inflammation in the Il-10-/- mice.Aim 2: determine the effects of oxidized ω-3/ω-6 PUFAs on gut bacteria in vivo and in vitro. Our preliminary data supports that oxidized PUFAs alter gut microbiota, resulting in exaggerated colonic inflammation. Here we will further determine the effects of ω-3/ω-6 PUFAs on gut microbiota, and elucidate the underlying mechanisms. Using 16S rRNA sequencing and in vitro gut bacteria culture, we will test the hypothesis that dietary administration of oxidized ω-3/ω-6 PUFAs alters the composition of gut microbiota, in part via inducing redox stress to suppress the growth of beneficial anaerobic bacteria and enhance the growth of pathologic bacteria.Aim 3: determine the extent to which oxidized ω-3/ω-6 PUFAs-induced alterations in gut microbiota promotes colonic inflammation. Our preliminary data supports that gut microbiota is essentially required for the pro-colitis effects of oxidized PUFAs, however, the functional roles of the microbiota involved are unknown. Using fecal transplant in germ-free mice, we will test the hypothesis that oxidized ω-3/ω-6 PUFAs-induced alterations in gut microbiota promotes colonic inflammation. Successful accomplishment of this aim will elucidate the functional roles of the microbiota in the pro-colitis effects of oxidized PUFAs, and lay the foundation to perform in-depth mechanism studies to better understand how diet-microbiota interactions affect human health.

Progress 04/15/20 to 04/14/25

Outputs
Target Audience:In this study, we will study the effects of oxidized PUFAs on gut microbiota and gut health. The target audience includes: (i)the general population (since the general public widely consumes oxidized PUFAs), (ii) the food industry (since oxidation of PUFAs is a common and serious problem for many food products), and (iii) food and nutrition researchers Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?This project has provided extensive research training for multiple graduate students. How have the results been disseminated to communities of interest?By publications in peer-reviewed journals and presentations at conferences What do you plan to do during the next reporting period to accomplish the goals?Publications in peer-reviewed journals and presentations at conferences.

Impacts
What was accomplished under these goals? We have made satisfactory progress during this period by publishing 13 peer-reviewed journal articles in high-qualityjournals. See the specific published articles for the details of experimental results achieved in this period.

Publications

  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2024 Citation: Yi, L., Han, Y., Shen, P., Du, H., Guo, X., Zhou, Z., & Xiao, H. (2024). Dietary Porphyra tenera ameliorated dextran sodium sulfate-induced colitis in mice via modulating gut microbiota dysbiosis. Food chemistry, 461, 140832.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2025 Citation: Yi, L., Du, H., Shen, P., Guo, X., Han, Y., Thanuphol, P., & Xiao, H. (2025). Dietary intake of Laminaria japonica suppresses intestinal inflammation in Dextran-sulfate-sodium-treated mice by modulating gut microbiota dysbiosis. Food Bioscience, 106914.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2024 Citation: Luo, M., Han, Y., Chen, Y., Du, H., Chen, B., Gao, Z., ... & Xiao, H. (2024). Unveiling the role of gut microbiota in curcumin metabolism using antibiotic-treated mice. Food Chemistry, 460, 140706.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2024 Citation: Ma, G., Tao, Q., Li, X., Han, Y., Du, H., Hu, Q., & Xiao, H. (2024). Metabolomics study of dietary Pleurotus eryngii ?-type glycosidic polysaccharide on colitis induced by dextran sodium sulfate in miceExploration for the potential metabolic indicators in urine and serum. Food Chemistry, 458, 140195.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2024 Citation: Du, H., Han, Y., Ma, G., Tan, C., Hu, Q., & Xiao, H. (2024). Dietary intake of whole king oyster mushroom (Pleurotus eryngii) attenuated obesity via ameliorating lipid metabolism and alleviating gut microbiota dysbiosis. Food Research International, 184, 114228.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2021 Citation: Lei, L., Yang, J., Zhang, J., & Zhang, G. (2021). The lipid peroxidation product EKODE exacerbates colonic inflammation and colon tumorigenesis. Redox biology, 42, 101880.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2021 Citation: Lei, L., Zhang, J., Decker, E. A., & Zhang, G. (2021). Roles of lipid peroxidation-derived electrophiles in pathogenesis of colonic inflammation and colon cancer. Frontiers in Cell and Developmental Biology, 9, 665591.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2024 Citation: Sun, Y., Zhou, J., Du, H., Zhou, Z., Han, Y., Luo, M., ... & Xiao, H. (2024). The anti-inflammatory potential of a strain of probiotic Bifidobacterium pseudocatenulatum G7: in vitro and in vivo evidence. Journal of Agricultural and Food Chemistry, 72(18), 10355-10365.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2021 Citation: Wang, G., Zhang, H., Zhang, J., Sanidad, K. Z., Yeliseyev, V., Parsonnet, J., ... & Zhang, G. (2021). Metabolic fate of environmental chemical triclocarban in colon tissues: roles of gut microbiota involved. Science of The Total Environment, 787, 147677.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2021 Citation: Zhang, H., Sanidad, K. Z., Zhu, L., Parsonnet, J., Haggerty, T. D., Zhang, G., & Cai, Z. (2021). Frequent occurrence of triclosan hydroxylation in mammals: A combined theoretical and experimental investigation. Journal of Hazardous Materials, 407, 124803.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2020 Citation: Tu, M., Wang, W., Zhang, G., & Hammock, B. D. (2020). ?-3 Polyunsaturated fatty acids on colonic inflammation and colon cancer: Roles of lipid-metabolizing enzymes involved. Nutrients, 12(11), 3301.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2024 Citation: Luo, M., Wong, S., Thanuphol, P., Du, H., Han, Y., Lin, M., ... & Xiao, H. (2024). Isolation and Identification of Human Gut Bacteria Capable of Converting Curcumin to Its Hydrogenated Metabolites. Journal of Agricultural and Food Chemistry, 72(37), 20410-20418.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2022 Citation: Zhang, J., Walker, M. E., Sanidad, K. Z., Zhang, H., Liang, Y., Zhao, E., ... & Zhang, G. (2022). Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract. Nature communications, 13(1), 136.


Progress 04/15/24 to 04/14/25

Outputs
Target Audience:In this study, we will study the effects of oxidized PUFAs on gut microbiota and gut health. The target audience includes: (i)the general population (since oxidized PUFAs are widely consumed by the general public), (ii) the food industry (since oxidation of PUFAs is a common and serious problem for many food products), and (iii) food and nutrition researchers Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?This project has provided extensive research training for multiple graduate students. How have the results been disseminated to communities of interest?By publications in peer-reviewed journals and presentations at conferences What do you plan to do during the next reporting period to accomplish the goals?Publications in peer-reviewed journals and presentations at conferences.

Impacts
What was accomplished under these goals? We have made satisfactory progress during this period by publishing six peer-reviewed journal articles in high-quality journals, one conference abstract, and one PhDthesis. See the specific published articles for the details of experimental results achieved in this period.

Publications

  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2024 Citation: Yi, L., Han, Y., Shen, P., Du, H., Guo, X., Zhou, Z., & Xiao, H. (2024). Dietary Porphyra tenera ameliorated dextran sodium sulfate-induced colitis in mice via modulating gut microbiota dysbiosis. Food chemistry, 461, 140832.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2025 Citation: Yi, L., Du, H., Shen, P., Guo, X., Han, Y., Thanuphol, P., & Xiao, H. (2025). Dietary intake of Laminaria japonica suppresses intestinal inflammation in Dextran-sulfate-sodium-treated mice by modulating gut microbiota dysbiosis. Food Bioscience, 106914.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2024 Citation: Luo, M., Han, Y., Chen, Y., Du, H., Chen, B., Gao, Z., ... & Xiao, H. (2024). Unveiling the role of gut microbiota in curcumin metabolism using antibiotic-treated mice. Food Chemistry, 460, 140706.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2024 Citation: Ma, G., Tao, Q., Li, X., Han, Y., Du, H., Hu, Q., & Xiao, H. (2024). Metabolomics study of dietary Pleurotus eryngii ?-type glycosidic polysaccharide on colitis induced by dextran sodium sulfate in miceExploration for the potential metabolic indicators in urine and serum. Food Chemistry, 458, 140195.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2024 Citation: Du, H., Han, Y., Ma, G., Tan, C., Hu, Q., & Xiao, H. (2024). Dietary intake of whole king oyster mushroom (Pleurotus eryngii) attenuated obesity via ameliorating lipid metabolism and alleviating gut microbiota dysbiosis. Food Research International, 184, 114228.
  • Type: Peer Reviewed Journal Articles Status: Published Year Published: 2024 Citation: Sun, Y., Zhou, J., Du, H., Zhou, Z., Han, Y., Luo, M., ... & Xiao, H. (2024). The anti-inflammatory potential of a strain of probiotic Bifidobacterium pseudocatenulatum G7: in vitro and in vivo evidence. Journal of Agricultural and Food Chemistry, 72(18), 10355-10365.
  • Type: Conference Papers and Presentations Status: Published Year Published: 2025 Citation: UNRAVELING THE ROLE OF LIPID PEROXIDATION PRODUCTS IN INFLAMMATORY BOWEL DISEASE. Siu Wong, Hang Xiao, NUTRITION 2025, Orlando, Florida, May 31  June 3.
  • Type: Theses/Dissertations Status: Accepted Year Published: 2025 Citation: UNRAVELING THE ROLE OF LIPID PEROXIDATION PRODUCTS IN INFLAMMATORY BOWEL DISEASE. Siu Wong, Molecular and Cellular Biology Program, Department of Food Science, UMass Amherst.


Progress 04/15/23 to 04/14/24

Outputs
Target Audience:In this study, we will study the effects of oxidized PUFAs on gut microbiota and gut health. The target audience include: (i) general population (since oxidized PUFAs are widely consumed by the general public), (ii) food industry (since oxidation of PUFA is a common and serious problem for many food products), and (iii) food and nutrition researchers Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?This project has provided extensive research training for multiple graduate students. How have the results been disseminated to communities of interest?By publications in the peer-reviewed journal publications and presentations in the conferences What do you plan to do during the next reporting period to accomplish the goals?Publications in the peer-reviewed journal publications and presentations in the conferences.

Impacts
What was accomplished under these goals? We have made satisfactory progress in this period by publishing 4peer-reviewed journal publications in quality journals. See the specific published articles for the details of experimental results achieved in this period.

Publications

  • Type: Journal Articles Status: Published Year Published: 2023 Citation: Zhang, Jianan, et al. "CYP eicosanoid pathway mediates colon cancer?promoting effects of dietary linoleic acid." The FASEB Journal 37.7 (2023): e23009.
  • Type: Journal Articles Status: Published Year Published: 2024 Citation: Du, Hengjun, et al. "Dietary intake of whole king oyster mushroom (Pleurotus eryngii) attenuated obesity via ameliorating lipid metabolism and alleviating gut microbiota dysbiosis." Food Research International 184 (2024): 114228.
  • Type: Journal Articles Status: Published Year Published: 2024 Citation: Sun, Yukun, et al. "The Anti-inflammatory Potential of a Strain of Probiotic Bifidobacterium pseudocatenulatum G7: In Vitro and In Vivo Evidence." Journal of Agricultural and Food Chemistry (2024).
  • Type: Journal Articles Status: Published Year Published: 2023 Citation: Zhang, Hongna, et al. "Microbiota-mediated reactivation of triclosan oxidative metabolites in colon tissues." Journal of Hazardous Materials 445 (2023): 130509.


Progress 04/15/22 to 04/14/23

Outputs
Target Audience:In this study, we will study the effects of oxidized PUFAs on gut microbiota and gut health. The target audience include: (i) general population (since oxidized PUFAs are widely consumed by the general public), (ii) food industry (since oxidation of PUFA is a common and serious problem for many food products), and (iii) food and nutrition researchers. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?This project has provided extensive research training for multiple graduate students. How have the results been disseminated to communities of interest?By publications in the peer-reviewed journal publications and presentations in the conferences. What do you plan to do during the next reporting period to accomplish the goals?Publications in the peer-reviewed journal publications and presentations in the conferences.

Impacts
What was accomplished under these goals? We have made satisfactory progress in this period by publishing 3 peer-reviewed journal publications in quality journals. See the specific published articles for the details of experimental results achieved in this period.

Publications

  • Type: Journal Articles Status: Published Year Published: 2023 Citation: Zhang, Hongna, et al. "Microbiota-mediated reactivation of triclosan oxidative metabolites in colon tissues." Journal of Hazardous Materials 445 (2023): 130509.
  • Type: Journal Articles Status: Published Year Published: 2022 Citation: Sanidad, Katherine Z., et al. "Triclosan and triclocarban as potential risk factors of colitis and colon cancer: roles of gut microbiota involved." Science of The Total Environment (2022): 156776.
  • Type: Journal Articles Status: Published Year Published: 2022 Citation: Zhang, Jianan, et al. "Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract." Nature communications 13.1 (2022): 136.


Progress 04/15/21 to 04/14/22

Outputs
Target Audience:In this study, we will study the effects of oxidized PUFAs on gut microbiota and gut health. The target audience include: (i) general population (since oxidized PUFAs are widely consumed by the general public), (ii) food industry (since oxidation of PUFA is a common and serious problem for many food products), and (iii) food and nutrition researchers. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?This project has provided extensive research training for multiple graduate students. How have the results been disseminated to communities of interest?By publications in the peer-reviewed journal publications and presentations in the conferences. What do you plan to do during the next reporting period to accomplish the goals?Publications in the peer-reviewed journal publications and presentations in the conferences.

Impacts
What was accomplished under these goals? We have made satisfactory progress in this period by publishing 6 peer-reviewed journal publications in quality journals and 1 Ph.D. dissertation thesises. See the specific published articles for the details of experimental results achieved in this period.

Publications

  • Type: Journal Articles Status: Published Year Published: 2021 Citation: Wang, Guangqiang, et al. "Metabolic fate of environmental chemical triclocarban in colon tissues: roles of gut microbiota involved." Science of The Total Environment 787 (2021): 147677.
  • Type: Journal Articles Status: Published Year Published: 2021 Citation: Lei, Lei, et al. "The lipid peroxidation product EKODE exacerbates colonic inflammation and colon tumorigenesis." Redox biology 42 (2021): 101880.
  • Type: Journal Articles Status: Published Year Published: 2021 Citation: Lei, Lei, et al. "Roles of lipid peroxidation-derived electrophiles in pathogenesis of colonic inflammation and colon cancer." Frontiers in Cell and Developmental Biology 9 (2021): 665591.
  • Type: Journal Articles Status: Published Year Published: 2021 Citation: Zhang, Hongna, et al. "Frequent occurrence of triclosan hydroxylation in mammals: A combined theoretical and experimental investigation." Journal of Hazardous Materials 407 (2021): 124803.


Progress 04/15/20 to 04/14/21

Outputs
Target Audience:In this study, we will study the effects of oxidized PUFAs on gut microbiota and gut health. The target audience include: (i) general population (since oxidized PUFAs are widely consumed by the general public), (ii) food industry (since oxidation of PUFA is a common and serious problem for many food products), and (iii) food and nutrition researchers. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?This project supports the study and research of graduate students in the department. Notably, with the support of this research, we are able to perform some advanced mouse models, such as Il-10-/- mouse model and fecal transplant in germ-free mice, which helps the training and research experience of the students. Due to the pandemic, we did not have travel to attend conference in the year of 2020. How have the results been disseminated to communities of interest?We are in the process to finish the animal experiments, and prepare for submission of manuscripts. Due to the pandemic, we did not have travel to attend conference in the year of 2020. What do you plan to do during the next reporting period to accomplish the goals?Our major future work will be aim 2 (16S rRNA sequencing to better understand how oxidized PUFAs affect gut microbiota) and aim 3 (fecal transplant in germ-free mice to determine the functional roles of gut microbiota in mediating the colitis-enhancing effects of oxidized PUFAs). We are currently running these two experiments now, and will try to finish in the next round of progress report.

Impacts
What was accomplished under these goals? We have made substantial research progress on the effects of oxidized vs. un-oxidized corn oil (rich in n-6 PUFAs) on gut health. Our preliminary data showed that dietary administration of oxidized corn oil exaggerated DSS-induced colitis and AOM/DSS-induced colon tumorigenesis in mice. However, these chemically induced models (DSS and AOM/DSS) are highly acute and have some limitations to study the pathogenesis of colonic inflammation and colon cancer in humans. To better understand the effects of oxidized PUFAs, in this project we studied their actions on colitis using another colitis model, the Il-10-/- mice. Progress report: We treated C57BL/6 Il-10-/- mice with a completely defined isocaloric diet containing 10 wt/wt% total fat from either un-oxidized or oxidized corn oil for 15 weeks, and found that treatment with oxidized corn oil reduced colon length, increased CD45+ cells into the colon and small intestine, enhanced expression of pro-inflammatory cytokines (Tnf-α, Mcp-1 and Ifn-γ) in the colon, increased plasma concentrations of TNF-α and IFN-γ and exaggerated crypt damage in the colon. Overall, these experiments support that the oxidized PUFAs increased colitis in Il-10-/- mice (Aim 1 of our proposal). We are currently performing 16S rRNA sequencing analysis (Aim 2), in order to better understand how oxidized PUFAs affect gut microbiota. In addition, we have performed fecal transplant in germ-free mice (Aim 3) and are in the process of biochemical analysis of the receipt mice.

Publications

  • Type: Journal Articles Status: Published Year Published: 2020 Citation: Tu M., Wang W., Zhang G., and Hammock B.D. (2020) n-3 polyunsaturated fatty acids on co-lonic inflammation and colon cancer: roles of lipid metabolizing enzymes involved. Nutrients, 12:3301.
  • Type: Journal Articles Status: Published Year Published: 2020 Citation: Zhang J., Tu M., Liu Z., and Zhang G. (2020) Soluble epoxide hydrolase as a therapeutic target for obesity-induced disorders: roles of gut barrier function involved. Prostaglandins, Leukotri-enes and Essential Fatty Acids, Doi: 10.1016/j.plefa.2020.102180