Research
Our research focuses on precision nutrition and toxicology. We have two main research directions: (1) elucidate the specific lipid metabolic pathways, enzymes, and metabolites in the health effects of dietary polyunsaturated fatty acids, to develop personalized nutrition and individualized health strategies, and (2) determine the specific gut microbes and gut microbial enzymes in the metabolism and health effects of dietary or environmental compounds, to establish the gut microbes or gut microbial enzymes as potential predictive markers for precision nutrition or toxicology. Overall, our research seeks to elucidate the molecular mechanisms for the health effects of dietary and/or environmental compounds, in order to better understand their metabolic individualities, address inter-individual susceptibilities, and clarify their health effects.
Research Area 1: Elucidate the specific lipid metabolic pathways and metabolites in the health effects of dietary polyunsaturated fatty acids, to develop personalized nutrition and individualized health strategies
Background: Epidemiological and pre-clinical data support that ω-3 polyunsaturated fatty acids (PUFAs) reduce the risks of colonic inflammation and colorectal cancer; in contrast, ω-6 PUFAs are suggested to exacerbate colonic inflammation and colorectal cancer. This is important because the current Western diet has 30-50 times more ω-6 PUFAs than ω-3 PUFAs. Validation of the health effects of ω-3 and ω-6 PUFAs will significantly impact public health. However, after decades of research, the health effects of ω-3/ω-6 PUFAs remain inconclusive, making it difficult to make dietary recommendations. It is of critical importance to better understand the molecular mechanisms underlying the health effects of ω-3/ω-6 PUFAs, to optimize their use for disease prevention.
Our research: Our research focuses on the identification of the specific metabolic pathways and metabolites involved in the health effects ω-3/ω-6 PUFAs. We use liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics to identify the major pathway(s) involved in ω-3/ω-6 PUFA metabolism, then use cell culture- and animal-based disease models to determine the roles of the identified metabolic pathway(s) and metabolite(s) in the health effects of PUFAs. Using this strategy, our recent research showed that the cytochrome P450 (CYP) monooxygenase pathway is a major pathway to metabolize ω-3/ω-6 PUFAs in vivo and plays a critical role in mediating their effects on colonic inflammation and colon cancer.
Impact of our research on precision health: Previous studies have identified multiple single nucleotide polymorphisms in CYP monooxygenases, many of which have altered enzymatic activities and are associated with human diseases such as cardiovascular diseases. Based on our study, the polymorphisms in the genes encoding CYP monooxygenases could affect the metabolism and effects of ω-3/ω-6 PUFAs, contributing to inter-individual variations after the dietary intake of ω-3/ω-6 PUFAs. Overall, these research efforts could help us to better understand diet-gene interactions in the health effects of dietary PUFAs, facilitating the development of personalized nutrition and individualized health strategies.
Fig. 1. Our research focused on identification of the specific metabolic pathways and metabolites involved in the health effects of dietary PUFAs. The ω-6 and ω-3 PUFAs are metabolized by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes, leading to respective formation of ω-6-series metabolites that are predominately pro-inflammatory and pro-tumorigenic, and ω-3-series lipid metabolites which have less detrimental or even beneficial actions.
Representative publications:
Wang W., Yang J., Zhang J., Wang Y., Hwang S., Qi W., Wan D., Kim D., Sun J., Sanidad K.Z., Yang H., Park Y., Liu J., Liu Z., Hammock B.D., and Zhang G. (2018) Lipidomic profiling reveals soluble epoxide hydrolase as a therapeutic target of obesity-induced colonic inflammation. PNAS 115:5283-5288.
Wang W., Yang J., Edin M.L., Wang Y., Luo Y., Wan D., Yang H., Sanidad K.Z., Song M., Bisbee A.H., Bradbury J.A., Nan G., Zhang J., Shih B., Lee K.S.S., Minter L.M., Kim D., Xiao H., Liu J., Hammock B.D., Zeldin D.C., and Zhang G. (2019) Targeted metabolomics identifies the cytochrome P450 monooxygenase eicosanoid pathway as novel therapeutic target of colon tumorigenesis. Cancer Research 79:1822-1830.
Wang Y., Yang J., Wang W., Sanidad K.Z., Cinelli M.A., Wan D., Hwang S.H., Kim D., Lee K.S.S., Xiao H., Hammock B.D., and Zhang G. (2020) Soluble epoxide hydrolase is an endogenous regulator of obesity-induced intestinal barrier dysfunction and bacterial translocation. PNAS 117: 8431-8436.
Zhang J., Yang J., Duval C.N., Edin L.M., Williams A., Lei L., Tu M., Pourmand E., Song R., Graves J.P., DeGraff L.M., Wong J.L., Wang Y., Sun Q., Sanidad K.Z., Wong S., Han Y., Zhang Z., Lee K.S.S., Park Y., Xiao H., Liu Z., Decker E.A., Cui W., Zeldin D.C., and Zhang G. (2023) CYP eicosanoid pathway mediates colon cancer-promoting effects of dietary linoleic acid. FASEB J, in press.
Research Area 2: determine the specific gut microbes and gut microbial enzymes in the metabolism and health effects of dietary and/or environmental compounds, to establish the gut microbes or gut microbial enzymes as potential predictive markers for precision nutrition or toxicology
Background: Metabolic transformation plays a critical role in dietary and environmental compounds' bioavailability and health effects. While most previous research has focused on host tissues' metabolism, gut microbiota-mediated biotransformation is considerably understudied. It is important to better understand the roles of gut microbiota involved since the gastrointestinal tract is a major route of entry for the dietary/environmental compounds, which allows these compounds to interact with gut microbes. In addition, emerging research has shown that gut microbes can catalyze unique metabolic reactions that are distinct from, or even opposite to, those catalyzed by the host enzyme systems.
Our research: We have made substantial research progress in investigating how environmental/dietary compounds interact with the gut microbiota to modulate gut diseases. We showed that triclosan (TCS), which is a high-volume chemical used as an antimicrobial ingredient in more than 2,000 consumer products and a ubiquitous environmental contaminant, is a potential environmental risk factor for IBD and colon cancer via gut microbiota-dependent mechanisms.
Furthermore, we have made substantial research progress in elucidating the specific gut microbes or gut microbial enzymes involved in the metabolism and health effects of these compounds. Using a range of in vitro, ex vivo, and in vivo approaches, we determined the specific gut microbial enzymes, termed Loop-1 β-glucuronidase (GUS) enzymes, that are involved in the metabolic activation and gut toxicity of TCS. Through collaboration with Dr. Matthew Redinbo at UNC-Chapel Hill, we determined the crystal structures of the identified gut microbial enzymes and developed specific pharmacological inhibitors to target these enzymes.
Impact of our research on precision health: Based on our findings, human subjects with different abundances of Loop-1 GUS enzymes could have varied colonic metabolism of TCS, resulting in interindividual variations in responses to TCS exposure. Indeed, the Human Microbiota Project showed that ~40% of the tested human subjects did not have Loop-1 GUS enzymes in the fecal microbiota, and there was a wide range of abundance levels of Loop-1 GUS in those who have the Loop-1 GUS orthologs. Therefore, inter-individual differences in human microbiota could lead to varied responses after exposure to TCS. This finding could be applied to other environmental or dietary compounds. Overall, our research could help to clarify the individual health effects of the compounds in different populations.
Fig. 2. We study how exposure to certain environmental or dietary contaminants interacts with gut microbiota, resulting in increased risks of developing IBD and colon cancer. Our recent research showed that triclosan (TCS), a high-volume chemical that is used as an antimicrobial ingredient in consumer and industrial products, increases risks of IBD and colorectal cancer in mouse models (Sci Transl Med. 2018 10: eaan4116), supporting that it could be a novel risk factor of gut diseases. In addition, we showed that the presence of gut microbiota plays essential roles in TCS-driven gut pathology and we further identified the specific gut microbial enzymes involved in its metabolic activation and gut toxicity (Nat. Commun. 2022 13:136).
Representative publications:
Yang H., Wang W., Romano K.A., Gu M., Sanidad K., Kim D., Yang J., Schmidt B., Panigrahy D., Pei R., Martin D.A., Ozay E.I., Wang Y., Song M., Bolling B.W., Xiao H., Minter L.M., Yang G., Liu Z., Rey F.E., and Zhang G. (2018) A common antimicrobial additive increases colonic inflammation and colon tumorigenesis in mice. Science Translational Medicine 10:eaan4116. Doi: 10.1126/scitranslmed.aan4116.
Yang H., Sanidad K.Z., Wang W., Xie M., Gu M., Cao X., Xiao H., and Zhang G. (2019) Triclocarban exposure exaggerates colonic inflammation and colon tumorigenesis: roles of gut microbiota involved. Gut Microbes 24:1-12. Doi: 10.1080/19490976.2019.1690364.
Zhang J., Gibbs M.E., Sanidad K.Z., Zhang H., Liang Y., Zhao E., Chacon-Vargas K., Yeliseyev V., Parsonnet J., Haggerty T.D., Wang G., Simpson J.B., Jariwala P.B., Beaty V.V., Yang J., Yang H., Panigrahy A., Minter L.M., Kim D., Gibbons J.G., Liu L., Xiao H., Borlandelli V., Overkleeft H.S., Cloer E.W., Major M.B., Goldfarb D., Cai Z., Redinbo M.R., and Zhang G. (2022) Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract. Nature Communications, 13, https://doi.org/10.1038/s41467-021-27762-y.