Diet, including nutrients and bioactive components, plays a vital role to improve health and reduce the burden of chronic diseases. This research project includes a team of trans-disciplinary scientists with expertise in biomolecular, clinical, community, and international nutrition. This scientific team will continue to engage in collaborative research at the intersection of basic science and research translation. Of specific focus, the team is addressing critical issues concerning the bioavailability of and mechanisms by which bioactive food components mediate human health, and by extension, evidence-based dietary recommendations that can increase a healthy lifespan. The team will accomplish project goals by testing a myriad of complementary sub-hypotheses that employ various experimental and clinical models to yield expected long-range outcomes that can enhance the health of individuals, communities, and the global population by reducing the risk of malnutrition-associated morbidity and mortality. Indeed, there are numerous chronic diseases and developmental disorders for which risk may be modified by bioactive compounds in our diet. Together, team members define interactions among essential nutrients and non-essential health-promoting nutrients in relation to human health outcomes. This effort requires transdisciplinary approaches to advance knowledge that will lead to effective preventative and therapeutic dietary strategies, especially in vulnerable groups and with consideration of inter-individual responses to dietary factors. Factors determining the absorption/bioavailability and targeted mechanism of actions will be addressed through preclinical and translational approaches in this multi-state effort. A major outcome of this approach is to establish the foundation for evidence-based dietary recommendations for communities and individuals.

Nutrition is a central scientific premise for the promotion of optimal health, including the prevention, treatment and management of disease. The relationship between food, nutrition and health, however, is complex, dynamic, multi-faceted across the entire biopsychosocial framework, and highly affected by biological as well as environmental, socioeconomic, cultural and behavioral factors (US Dietary Guidelines 2020-2025). Global population growth, cultural, and economic factors also mediate access to healthy foods. The complex network of factors contributes to malnutrition, which not only considers deficient intakes of bioactive food components but also consequences of overnutrition or excess intakes. Malnutrition, in all its forms, includes undernutrition (wasting, stunting, and underweight), inadequate vitamins or minerals, and overweightness/obesity (overnutrition) that result in diet-related non-communicable diseases. Importantly, susceptibility to environmental factors, as well as age, gender, race and disease-state may influence bioavailability and absorption of micronutrients.

Both developed and emerging economies experience rising levels of chronic diseases such as obesity, type 2 diabetes, and cardiovascular diseases (Anderson et al., 2019). The etiology of each of these diseases is complex and varied, but a unifying concept is that bioactive food components, and by extension dietary patterns, play a fundamental role to regulate disease risk. Epidemiological evidence suggests phytochemical intake is associated with reduced risk of developing chronic diseases (Xiao & Bai, 2019), however we remain limited in our ability to establish evidence-based nutrition recommendations to achieve optimal health because of their limited bioavailability, complex structure, specificity to influence biomarkers and/or health outcomes, and they often have broad biological targets that influence multiple biomolecular and/or physiological responses (Manach et al., 2009).

Members of this group are expected to advance nutrition knowledge through the application of well-established approaches and experimental techniques, but also through the implementation of novel and innovative tools. These collective approaches are critical to account for the bioavailability and diversity of dietary phytochemicals and their biological activities that often occur with wide inter-individual variability. For addressing bioavailability, examples of novel approaches include: (i) the use of exosomes as carriers of nutrients/phytochemicals that are regulated in their release of these compounds; (ii) the application of nanoparticles and prebiotic fibers to enhance the bioavailability and absorptive efficiency across the intestinal barrier; (iii) the development of transgenic mouse and cell culture systems to assess the bioavailability of exosomes and their cargo in milk; and (iv) the use of site-specific intestinal viral knockdown approaches to determine localized receptor effects. Our team is actively examining a broad number of dietary constituents including, but not limited to, folate, exosomes present in milk and their RNA cargos, phospholipids, zinc, fat-soluble nutrients (vitamins A, D, E, K), various carotenoids, isothiocyanates, polyphenols, and citrus monoterpenes; all of which have important roles in human health and protection against chronic disease.

Alterations in energy metabolism such as obesity, diabetes, and atherosclerosis contribute to the development of cardiovascular disease, the leading cause of death in the United States. Our transdisciplinary approach tackles these conditions with diverse strategies including dietary and behavioral interventions, discovery and characterization of novel bioactive constituents of foods, and the evaluation of the molecular mechanisms behind the effects of (phyto)nutrients in health. Efforts to mitigate the clinical consequences of cardiometabolic disorders are not only warranted, but provide significant promise to achieve healthspan. Outcomes of these studies will help to control the undesirable biological changes including inflammation, fat accumulation, and oxidative distress responses – that can promote alterations in energy metabolism. Others enlisted on this multi-disciplinary team focus their scientific attention on cancer chemoprevention because it is the second leading cause of death in the United States, and ~40% of Americans are estimated to receive a cancer diagnosis in their lifetime (American Cancer Society, 2022). Goals of these investigators are not only to identify and characterize health-promoting dietary constituents and their metabolites, but also their anti-inflammatory and anti-neoplastic functions that can improve intestinal health and alleviate cancer risk or serve as adjuvant therapy for standard-of-care treatments. Chronic inflammation, aging, specific morbidities, dietary patterns, and specific bioactive food components have been associated with improved or decreased brain health. There are more than 600 diseases of the nervous system, such as brain tumors, epilepsy, Parkinson's disease and neural tube defects (NTD) as well as less familiar ones such as frontotemporal dementia (Essa et al., 2016). There is also evidence supporting an interrelationship of poor cognitive health and other disorders. For example, cognitive dysfunction has been recognized as a complication of obesity-associated nonalcoholic fatty liver disease, probably caused by neuroinflammation (Kjærgaard et al., 2021). Proper diet can also play an important role in building and maintaining bone mass throughout life, primarily by providing bone-building nutrients and by influencing absorption and retention of these nutrients. Our team will continue long-standing scientific inquiry on calcium and isoflavones and will expand into other nutrients and bioactive compounds including vitamin D, vitamin K, milk exosomes, and fermentable carbohydrates (i.e., fructooligosaccharides). Application of new and novel techniques and approaches to assess the impact of dietary interventions on bone outcomes through the collaborative and complementary expertise within the research group will afford an unprecedented opportunity for research in this area.

The overarching goal of our Multi-state efforts is to achieve research translation for broad-based nutrition recommendations that can help achieve healthspan for Americans and persons worldwide. However, our team also recognizes that conventional ‘one-size-fits-all’ recommendations have substantial limitations for achieving this goal. Precision nutrition is the conceptual framework that addresses the constellation of integrated factors to influence healthspan and well-being throughout life. Members of this interdisciplinary team are leaders in the application of multi-omics technologies (e.g., (meta)genomics, transcriptomics, metabolomics) towards the study of (phyto)nutrients, including the regulation of their bioavailability and their bioactive functions that thwart disease. For example, the metabolites generated by bacterial populations of the gut microbiota are increasingly recognized for the favorable or unfavorable influences on the pathogenesis of disease and the success of therapeutic intervention. Our team members integrate approaches to study the complex connections of thousands of data points generated through the assessment of metagenomic, metabolomic, and/or transcriptomic signatures of gut bacteria and the human host in disease and with relation to precision nutrition benefits of phytonutrients. These approaches are critical for understanding why different individuals and persons of different races or ethnic groups respond differently to intervention, have different health risks despite similar diets, and will ultimately permit an understanding of the unique biological factors that can predict successful treatment or reduction of risk for chronic diseases.

Importance of Work: There is a need to further understand the independent and interactive role of nutrients and bioactive food constituents in promoting optimal health. Our goal is to provide a clear understanding of the factors that determine their bioavailability and mechanisms of action. This will establish the foundation for evidence-based dietary recommendations to stakeholders that ultimately affect the health of our nation and the world. The opportunity for our experts to share knowledge, techniques and resources is central to achieving our collective goal in a timely, resource-efficient, and strategic manner. Our transdisciplinary approach thereby rapidly advances our understanding of health-promoting dietary approaches having the potential for broader impact on human health, which will be made possible through this multi-state collaboration.

Technical Feasibility of Studying Bioavailability and Bioactivity of Food Components: This W4002 Multi-state group is an extremely diverse group of nutrition scientists across the continental US and Hawaii who have complementary expertise and access to specialized resources. These characteristics uniquely position our Multi-state group to identify the mechanisms and bioavailability of (phyto)nutrients and other bioactive food components. All of the proposed projects involve established methodologies in the respective investigators’ laboratories and through this collaborative effort, are feasible (see related work from W4002 and our previous groups). W4002 researchers have established a national and international prominence to study the mechanisms and bioavailability of nutrients and dietary bioactive components important in chronic disease prevention. We have extensive experience in pharmacokinetic modeling of nutrients, bioavailability studies in preclinical models and humans, integrative multi-omics studies, as well as significant expertise in the study of chronic diseases in relation to malnutrition and metabolic disorders in translational models. Our approaches span novel “bench-to-bedside” and “clinic-to-community” innovations to favorably impact the health and welfare of our end-users. Many of the proposed methodologies were pioneered by previous W4002 members and will be leveraged in this multi-state effort.

Advantages of a Multi-State Effort for the Study of Bioavailability and Bioactivity of Dietary Bioactive Components: This multi-state effort will provide the vehicle for collaborative efforts towards the investigation of mechanisms at the molecular/cellular level and directly translate these benefits to susceptible populations. The effort and scope of our research would not be possible without the collaborative expertise of each multi-state station. Indeed, defining the bioavailability and bioactivity of dietary bioactive components requires a transdisciplinary approach to achieve research translation. The input of each station enlisted on this project will promote synergy to address knowledge gaps of importance to human health by combining efforts and expertise, and sharing resources unique to each individual station that will support the expected successful completion of this multistate effort. The issues to be addressed and benefits gained are expected to exceed those achieved by any single station, thus potentiating national and global impact. Researchers in this group collaborate routinely, either formally through shared submission of competitive proposals, sharing authorship on peer-reviewed publications, and presenting invited seminars at each other’s academic institute, or less formally by sharing research protocols and/or resources that can benefit other team members. Since the health issues of this project are addressed through complementary, multi-disciplinary approaches, there is little to no concern of scientific duplication among members’ respective institutes. Our members will also produce innovative, state of the art methodologies for understanding the metabolism and roles for dietary bioactive constituents that can promote human health. The breadth and depth of expertise (from basic science to human population studies to outreach/extension) among faculty at major land-grant universities facilitates translational studies. Knowledge gained from W5002 collaborative activities will be disseminated to the scientific community and relevant end-users maximal impact and benefit to public health. Importantly, efforts and focus specific to W5002 are not duplicated in any other multi-state project. Some examples of co-authored publications include joint publications with NE and CA-D (Zhou et al., 2022) or OH and CT (Hirahatake et al., 2019; Bruno, et al., 2020). The W4002 group has also facilitated intra-state collaborations, such as projects within NE (Khanam et al., 2021; Liu et al., 2020) and CA-D (Kim et al., 2022). Aside from multistate collaborations amongst group members, the W4002 group has facilitated collaborations with other institutions/members outside of the group. Examples of these collaborations are: IL, HI, and CA-D (Jinno et al., 2018; Liu et al., 2018a,b), HI and the FDA in IL (Ho & Redan, 2021), IL and OR (Joyce et al., 2022; Cam et al., 2019; Song et al., 2020), FL and AZ (Smith et al., 2021), IL and MD (Coronel et al., 2022), IN and PA (Wu et al., 2021), IN and WA (Li et al., 2021).

University of Arizona is a Hispanic-serving institution (HSI), the University of Hawaii is a Native Hawaiian-serving institution, and University of California Davis is an Asian American and Native American Pacific Islander-serving institution (AANAPISI). The investigators at these institutions and within the W4002 group conduct research, teaching and outreach activities directly benefit underserved and minoritized populations.

Impact of Research/Endpoints: We expect the multidisciplinary, translational research driven by the W4002 investigators to have significant impact on human health, which will be identified as measurable, scientifically rigorous endpoints. At the broadest level, outcomes of this research will result in evidence-based strategies using foods and/or their dietary bioactive compounds to contribute to optimal health and reduce chronic disease risk. Specifically, expected outcomes will help to establish novel biomarkers for nutrient status, (re)define dietary requirements for Americans, especially specialized and vulnerable cohorts that likely have unique metabolic requirements. Without the research to be undertaken by this multistate group, our understanding of the metabolism and mechanistic role of these health-promoting dietary agents will be significantly hampered. Other endpoints for the W4002 group include collaborative research grants, publications, the organization of scientific meetings, and efforts directed at public outreach and support of local extension leaders in developing important educational materials that translate our research findings.

This multi-state team of researchers are a transdisciplinary team spanning fields of agriculture, food science and technology, molecular/cellular nutrition, clinical nutrition and population health. Together, the team is able to address key issues relevant to food and its bioactive compounds and human health, both in the United States and across the globe.

This research is innovative and novel in that it utilizes a translational approach to understand the role of dietary bioactive compounds, especially those consumed as a “whole food” on optimal health. The collaboration among basic, clinical, epidemiological and extension faculty from diverse academic institutions across the United States affords the opportunity to advance scientific understanding of the role of, and requirements for, nutrients and bioactive food components in maintaining optimal health. Further, our robust scientific interactions, which are possible through this collaborative agreement, afford an opportunity to translate research findings to public health practice in a time and cost-efficient manner.

National Information Management and Support System (NIMSS) Search: A NIMSS search with the keyword “bioavailability” returned 12 active projects. There are no similar regional projects therefore supporting a critical need for multidisciplinary research through this Multi-state project. A recent review of active multi-state projects suggests only one project has the potential for overlap with our efforts, W5122” Beneficial and adverse effects of natural chemicals on human health and food safety.” However, there are several important distinctions between the projects. First, the planned project focuses on dietary constituents to achieve optimal health whereas W5122 addresses issues related to environmental toxicology, cancer, foodborne toxins, and antimicrobials. Our project focuses much more heavily on micronutrients and health-promoting phytochemicals, and with direct consideration of research translation, compared to the W5112. Also, food safety/toxicology is the central theme of their research and is not represented in the focus of our project. Moreover, issues regarding global health, bioavailability and potential interactions among food, nutrients and processing are not addressed by the W5112 group. Without question, the information derived from the proposed research is innovative and unique, and the proposed dissemination of information to both the scientific community and lay public will provide part of the framework on which future nutrient recommendations can be based. Table 1 outlines a list of proposed nutrients and phytochemicals for initial analysis, their biomarkers and endpoints/clinical outcomes.