Overview

This application is for renewal of a highly productive regional project that was started in 1971. The overall goal of W5122 researchers is to understand the impacts of bioactive dietary components and their metabolites on human health throughout the lifespan and to ensure safety of the food supply. Specific interests include the effects of phytochemicals, foodborne toxicants, endogenous microbial metabolites, and specific macro- and micronutrients on human health outcomes, as well as how food processing alters the chemistry and biological effects of dietary components.  Group members collectively utilize mechanistic, preclinical, clinical, and epidemiological research methods to provide a comprehensive translational approach for understanding how natural chemicals impact human health and food safety. 

Group members utilize cutting-edge research methodologies to address a broad range of research questions related to relevant topics including: 1) examining the effects of whole foods and specific dietary components on the intestinal microbiome, 2) understanding the molecular mechanisms by which specific dietary nutrients benefit and/or harm human health and modulate risk of diseases such as cancer, cardiovascular disease, and obesity/diabetes, 3) determining the effects of food processing on bioactivity and bioavailability of food-derived compounds, and 4) investigating trans-generational health effects of dietary and environmental exposures. The objectives of this renewal application represent our continued commitment to understanding the relationship between dietary components and human health while emphasizing emerging areas of scientific inquiry, such as the interplay between dietary chemicals and the gut microbiome, developmental programming, and chronic disease risk. W4122 was selected for the Western Region Award of Excellence in 2019, and has been highly successful over the past several reporting periods as measured by dozens of collaborative projects supported by substantial research funding (totals averaging ~$10M/year since 2017), extensive peer-reviewed scientific publications (>120 since 2019), graduate and undergraduate student training, and multiple outreach activities including presentation of lectures and development of websites and curriculum modules. We anticipate that this renewal project will be equally successful and will continue to have an impact on issues related to food safety and human health.

Stakeholders

Dietary bioactive chemicals are defined in this proposal as naturally occurring substances produced by plants, animals or microbes that exert beneficial or undesirable effects when they are consumed or metabolized by human or microbial enzymes in the body. How these chemicals influence human health, disease development, and food safety is important to everyone. Understanding how to enhance the benefits or minimize the risks of specific dietary compounds is particularly important for agricultural producers, food processors, healthcare professionals, and policy makers charged with determining optimal human nutrition requirements and maintaining the safety of the food supply.

Rationale

Natural chemicals consumed in foods and beverages have the ability to positively or negatively impact human health. Phytochemicals found in fruits in vegetables can reduce disease risk by acting as anti-oxidants, hormone mimics, signaling molecules, and modifiers of the host metabolism and gastrointestinal tract microbiota. Conversely, consumption of certain types of sugars and fats can increase inflammation, lead to reduced insulin sensitivity, and increase the risk of developing obesity/diabetes, cardiovascular disease, and other chronic disease conditions. Microbes and microbial metabolites found in food and the digestive tract can also exert positive, negative or neutral effects on human health. Beneficial microbial metabolites include short chain fatty acids, which act as cellular signals to modulate host metabolism and serve as energy for colonic epithelial cells, and products of phytochemical catabolism which may have increased bioactivity and bioavailability relative to their parent compounds. Probiotic microbes delivered to the digestive tract can persist and modify the intestinal environment through their metabolic end-products and synthesis of bioactive compounds to result in improved immune, metabolic, and neural function.  Microbial metabolites also include fungal and bacterial toxins, such as fumosin and aflatoxin, which are harmful to human health. Determining dietary exposure to these toxins and identifying their molecular targets in human hosts is critical to establishing acceptable exposure levels and ensuring a safe food supply. In general, in order to understand the particular benefits or risks of a given dietary chemical, it is necessary to understand dietary exposure levels, bioactive doses, factors influencing absorption and metabolism, molecular targets in the body, synergistic effects with other compounds and trans-generational effects. W5122 researchers are actively engaged in exploring these facets of dietary chemicals in the context of their consumption as whole foods, processed food products, food extracts and dietary supplements.

Dietary interactions with the gut microbiome. W5122 researchers have an established record of exploring mechanisms of action of beneficial and harmful dietary chemicals and for exploring ways to mitigate or enhance their effects through agricultural practices or food processing. However, the advent of new high-throughput (omics) technologies has allowed us to identify and examine how the trillions of microorganisms in our intestines contribute to host health and physiology. It has been established that these organisms are critical to digestion, pathogen protection, and immune modulation (1,2). An imbalance, or dysbiosis, of the microbiota has been associated with inflammatory diseases of the intestines but also with cardiometabolic dysfunction like Type 2 diabetes and heart disease (3) and with autoimmune conditions like rheumatoid arthritis (4) and Parkinson’s disease (5). Several mechanisms have linking microbiota, diet, and disease development or prevention are being established. One prevalent and well-supported hypothesis suggests that high fat diet induced microbial dysbiosis is associated with loss of integrity of the intestinal epithelial barrier and translocation of bacterial components such as lipopolysaccharides (ie. bacterial endotoxin), which results in a condition referred to as metabolic endotoxemia (6). Metabolic endotoxemia is associated with chronic low-grade inflammatory processes that contribute to various components of cardio-metabolic disease.

Specific microbial metabolites of dietary components are also key modulators of host disease processes. Dietary fiber serves as food for the colonic bacteria and is fermented to short chain fatty acids such as butyrate, proprionate, and acetate. These products can interact with free fatty acid receptors in the gut, liver, and adipose tissue to regulate intestinal transit time and glucose and lipid storage (7). Butyrate serves as the primary food source for colonic epithelial cells and is thought to have anti-tumorogenic effects by acting as a histone deacetylase inhibitor  (8). It has also been shown that butyrate is critical in maintaining hypoxic conditions at the epithelium-lumen interface and stabilizing the expression of Hypoxic Inducible Factor (HIF-1a), which regulates tight junctions between epithelial cells (9). Conversely, other metabolites produced by microbial processes can have detrimental effects on the host. Protein degradation by colonic bacteria is associated with production of pro-carcinogenic metabolites such as N-nitroso compounds and hydrogen sulfides (10). Choline and carnitine consumption are associated with microbial production of trimethylamine oxide (TMAO), which is actively being investigated as an important biomarker and potential modulator of cardiovascular disease risk (11). Therefore, understanding the influence of diet on the microbiota and microbial processes is emerging as an important aspect of understanding how dietary chemicals can influence or prevent certain diseases. W5122 researchers are making important contributions to this area, particularly with respect to understanding how dietary microbiota manipulation can be used to prevent colorectal cancer and cardiometabolic diseases.

Technical Feasibility of Studying Natural Dietary Chemicals. The research objective proposed herein exploits recent technical and conceptual advances in nutrient biochemistry and biomedicine. In particular, advances in next generation sequencing technologies, epigenetic arrays, and increased performance, throughput and sensitivity of chemistry platforms such as liquid and gas chromatography now allow us to explore dietary chemical interactions with hosts at a systems biology level that was previously impossible. Recent gains in in silico technologies, including bioinformatics pipelines, reference databases and integrative statistical models for examining multiple “omics” datasets is finally beginning to catch up with our ability to generate these datasets. These hypothesis-generating advances in big data analysis combined with our extensive expertise in a variety of model systems (human and animal cell culture, transgenic and knockout mice, mouse transplacental transport, rats, poultry, plant, rainbow trout, human subjects) will allow us to pursue this work. Advances in genetic engineering, such as CRISPR technology now permit the targeted manipulation of genetic material and can be used to increase beneficial and reduce harmful chemicals produced by plants and microorganisms that are in the US food supply.   Using a combination of approaches, W5122 members are establishing the benefits of nutrients such as omega-3 fatty acids, fiber, and iron as well as non-nutrient phytochemicals like indoles and polyphenols. They have also been used by W5122 investigators to identify adverse effects of mycotoxins, phytoestrogens and other hormone mimics in the food supply, as well as carcinogenic and inflammation-inducing microbial products resulting from catabolism of dietary components. Availability of current technologies and the diverse expertise of W5122 researchers allows us to embrace a “field to fork” approach for ensuring a safe and health benefitting food system. 

Impacts of Studying Dietary Bioactive Chemicals. There are a number of positive impacts that will result from this work. First, this research will continue to improve our understanding of the mechanisms responsible for the beneficial and detrimental effects of dietary bioactive chemicals and their endogenous metabolism. This knowledge is the foundation for determining recommendations of dietary intakes for optimal health and disease prevention, and advancing the field of personalized nutrition which strives to provide individualized dietary recommendations based on a person’s genetics, gut microbiome, and other factors. This is particularly timely given recent precision health initiatives supported by the NIH (Nutrition for Precision Health, All of Us) and the expansion of commercial offerings for personalized nutrition recommendations (Zoe, DayTwo, Viome).  Second, this research will improve the safety of the food supply by determining toxic exposure levels of adverse dietary bioactive compounds as well as identifying ways that food can be grown or processed to mitigate safety risks. Third, the discovery of novel bioactive compounds, beneficial human-associated bacteria and nutrient metabolites, or development of new crop varieties as a result of this research could provide new opportunities for disease prevention or treatment. Finally, research tools developed by W5122 researchers, such as reporter cell lines, new animal models, databases and biomarker identification can be widely implemented to improve the quality future research in this and related fields.

Influence of maternal nutrition on offspring health. Another area of research that is gaining increasing attention is the impact of maternal nutrition on offspring health and disease risk trajectory.  In particular, childhood obesity has reached epidemic proportions in developed countries worldwide, and is closely linked to the increasing prevalence of metabolic syndrome and type 2 diabetes in these populations (12-14).  Epidemiological studies have established that maternal overnutrition increases risk of obesity and diabetes in her offspring (15-17), but the mechanisms by which maternal diet or metabolic status “programs” the fetus in this manner are poorly understood.  Collaborative studies in the Chicco lab found that maternal obesity shifts fetal skeletal muscle to favor fatty acid uptake and oxidation at the expense of carbohydrate utilization in a non-human primate model, potentially favoring the development of glucose intolerance in developing offspring (18).  This is also seen in a novel ovine model recently developed by the Chicco lab in collaboration with other multi-state group members, which will be used to evaluate impacts of nutritional interventions to mitigate these effects.   Specifically, supplementing the maternal diet with polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) during pregnancy may reduce body mass index of infants at 1-2 years of age (19,20).  These fatty acids are selectively enriched in the fetal circulation compared to maternal circulation, play a key role in fetal brain and retinal development (21), and were recently found to play an important role in placental function by Dr. Natarajan and colleagues  (22).  This enrichment is impaired in preeclampsia and intrauterine growth restriction (IUGR), which may contribute to the associated cardiovascular, neural and metabolic complications seen in offspring from these pregnancies (23-25).  Dietary nutrient intake is also critical in neonates, where group members in California have found that intake of micronutrients such as iron and selenium and bioactive dietary supplements (e.g. probiotics, synbiotics) targeting the gut microbiome may improve early-life measures of metabolic disease risk and neurocognitive function.  Indeed, the interactions between maternal nutrition, gut health/microbiota and offspring health are being increasing appreciated (26), providing additional synergy among our group members and our proposed research objectives.

Advantages of Multi-state Study of Bioactive Dietary Chemicals. The collaborative nature of W5122 researchers provides the ideal approach to unraveling the complex role of dietary bioactive chemicals in development of cancer, metabolic diseases, and autoimmune disorders. The proposed work addresses complimentary and synergistic research objectives that require collaboration of scientists and experts from diverse backgrounds (toxicology, molecular biology, microbiology, genomics, nutrition, food science and risk assessment) and geographic diversity due to the wide range of food crops and dietary patterns involved. By approaching these nation-wide issues as a collective, we are able to bring together this diverse expertise to approach problems from various angles. Each participating research station also has unique facilities and research capabilities to ensure that we can fully address the complex issues involved in examining beneficial or detrimental effects of dietary chemicals. In addition to creating complementary approaches, W5122 collaborations have limited duplication of research efforts to facilitate progress. Past collaborative efforts have been important for completing research projects and publishing results in top scientific journals, leading to dozens of collaborative manuscripts with multiple W4122 members over the past five years (cited below and detailed in our annual accomplishments reports). This work has led to recommendations that have had far-reaching influence on dietary recommendations for disease prevention and in determining acceptable levels of exposure of specific dietary toxicants. They have also resulted in development of model systems and research tools that have been implemented both by other W5122 researchers as well as the broader research community. Continued interactions between the W5122 researchers are likely to result in further progress that will influence public policy, food production and processing systems, and facilitate future research efforts. In addition, the positions of W5122 members as faculty at major land-grant universities and USDA facilities ensure that data arising from collaborative activities will be disseminated to the greatest extent possible among stakeholders and will thus provide maximum benefits to the U.S. public. W5122's efforts and focus are not duplicated in any other regional project.