Duration: 10/01/2022 to 09/30/2027

Administrative Advisor(s):

NIFA Reps:

Non-Technical Summary

Statement of Issues and Justification

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.

Related, Current and Previous Work

W4122 researchers have made significant contributions in understanding the role of natural chemicals found in the diet on human health and food safety for decades.  Our research over the last 2-5 years has focused on understanding the mechanisms by which beneficial dietary components and dietary toxins influence disease development, how diet impacts the gut microbiome and intestinal health, discovering novel bioactive components relevant to human disease risk, and determining how to increase the health benefits and safety aspects of food through novel processing approaches. Some tangible outputs of this work include new analytical and experimental tools for studying the impacts of dietary nutrients on health and detecting trace levels of bioactive chemical present in food and following endogenous metabolism, which have been shared through interactions and collaboration across our multi-state group and others.  Along these lines, W4122 members were awarded at least 33 new grants in during the last two reporting periods (since September 2019), contributing to over $14 million in current research funding to study effects of bioactive nutrients on cancer, diabetes, fetal programming by maternal diet, gut health, and cardiovascular disease risk). This work has resulted in at least 158 new publications by W4122 members during the same period, addressing the effects of bioactive nutrients on health and chronic disease risk, basic insights into nutrient metabolism, and the development of new methodology and technologies for studying these processes in humans and model systems. The specific impacts of this work on topics related to the USDA mission and multi-state group objectives are summarized below.

Interactions between the diet, gut microbiome and human health  

Our members have made substantial contributions to understanding how diet impacts the gut microbiome and intestinal health, which support future efforts to further characterize how these factors govern overall human health and disease risk across diverse populations.  W5122 researchers in Colorado led by Dr. Weir are establishing mechanistic links between gut microbiota and intestinal function and early predictors of cardiovascular disease risk that may lead to novel therapeutic approaches for heart disease prevention (1,27-30). They have completed several human clinical trials that linked intake of specific foods and probiotic supplements to improvements in gut health, immune parameters, inflammation, and vascular function in humans.  In addition, they recently established that dry bean and pulse consumption offsets the negative metabolic effects of a high fat diet in diet-induced obesity in rodent models, and are currently exploring how pulse diversity and intake doses impact these outcomes.  Dr. Izard in Nebraska performed transdisciplinary work combining microbiome research with nutritional epidemiology, cancer research, traditional and high-dimensional statistics (big data), and biocomputing to develop a standardized tool for evaluating the impact of food compounds on human digestion and health (31-37).  Recent results have provided the first demonstration that food consumption contributing to high sulfur microbial diet scores, including increased intake of processed meats and low-calorie drinks and fewer vegetables and legumes, are associated with development of distal colorectal cancers (35,36). These efforts also led to the development of a new course at the University of Nebraska at Lincoln targeting graduate and undergraduate students titled “Omnivore’s Digestive-Tract Microbiome”, and a 3D printed representation of the human microbiome as an educational tool for K12 and college level courses (https://doi.org/10.1525/abt.2021.83.3.188), and a new self-assessment tool for digestive output (https://doi.org/10.33552/AJGH.2021.03.000554).

Several other group members have performed studies establishing the impact of specific dietary nutrients on the gut microbiome, intestinal health and colorectal cancer risk.  Dr. Turner in Michigan demonstrated that diets containing bioactive compounds (phenolic compounds and fiber) in fruits, vegetables and grains that impact the gut microbiota and their metabolism have significant impacts on pathways involved in inflammation and colorectal cancer (38-41).  Dr. Benninghoff in Utah found that short-term (two weeks) consumption of whole, freeze-dried black raspberries markedly shifts composition of the gut microbiome in favor of some health-promoting taxa, but these changes appear unconnected to severity of gut inflammation or colon tumorigenesis in a mouse model of colitis.  Impacts on obesity-related disorders were also investigated, including work by Dr. Maier in Oregon revealing that hops‐derived xanthohumol (XN) and its derivatives reduce high‐fat diet (HFD)‐induced obesity and metabolic syndrome in part by modulate the gut microbiota, altering bile acid metabolism and lower adipose inflammation (in rodents) (42,43). They also found that these compounds decrease ceramide content in liver and hippocampus, which may serve to reverse obesity-associated neurocognitive decline (44-46). Dr. Marco in California worked to understand and improve microbe-based therapies to optimize human health, with a particular focus on characterizing how dietary fibers and resistant starches and specific bacteria taxa act through the intestinal epithelium to reduce the prevalence of obesity and type 2 diabetes (47-49).

Finally, W4122 researchers have performed fundamental research on microbial biology to better understand how the diet impacts bacterial populations in the human intestine.  Dr. Chen in Minnesota observed novel metabolic functions of processed food on microbial metabolism of phytochemicals, which improve our understanding of the metabolic consequences of dietary bioactives (50,51).  Dr. Verma at Purdue University developed a platform for obtaining high-throughput growth profiles in anaerobic conditions for bacteria growing in defined media (52). He also developed methods for analyzing these complex growth profiles and quantifying behavior of bacteria under different nutrient sources (e.g., oligosaccharides present in milk).

 

Study of specific dietary components on human health and disease risk

Our group members have expertise in studying the subcellular impacts of specific dietary nutrients on processes linked to the development obesity and related cardiometabolic disorders (diabetes and cardiovascular disease), as well as cancer.  These studies are often integrated with feeding studies in animal models and humans to translate basic (“mechanistic”) and applied research approaches to clinically feasible interventions for improving human health. 

Dr. Majumder (Nebraska) is performing studies to develop clinically applicable dietary peptides for the improved treatment of atherosclerosis and associated cardiovascular diseases (53,54). Studies to date indicate dry bean-derived kokumi active γ-glutamyl peptides can reduce vascular inflammation and modulate gastro-renal axis by activating the calcium sensing-receptor (CaSR) (55,56), with far-reaching implications for the effect of these peptides on cardiometabolic disease outcomes.   Dr. Meijun Zhu in Washington found that dietary raspberry, which is enriched with polyphenols and dietary fibers, have beneficial effects against obesity and metabolic dysfunction through inducing browning of white adipose tissue and activation of AMPK (57). Dr. Bello (Rutgers) discovered that a component of red raspberries (raspberry ketone) has anti-obesity effects in mice, perhaps in part through metabolites of gut microbes and their effect on adipose tissue biology and feeding behavior (58,59). Because polyphenols and dietary fibers are widely available in fruits and vegetables, our data emphasize the importance of fruits and vegetables in preventing metabolic diseases and obesity in general population.   This work is complimented by that of Dr. Nerurkar in Hawaii, who is studying the effect of Hawaii-grown coffee on plasma adipocytokine levels known to link obesity with metabolic disorders (60,61).   Finally, Dr. Ock Chun in Connecticut provided epidemiological evidence of the risk of furocoumarins on skin health to the public health arena, which will help the public understand the effects of citrus fruits and furocoumarin-rich foods on skin cancer risk. Results suggested that higher consumption of citrus juices may increase risk of melanoma among women spending at least 30 minutes outdoors daily during the summer as adults, and are being followed up by biological studies in animal models to better understand these interactions. 

 Dr. Pestka (Michigan) and Dr. Benninghoff (Utah) have conducted preclinical studies on how the dietary lipidome impacts lupus, a systemic autoimmune disease typified by uncontrolled inflammation, disruption of immune tolerance, and intermittent flaring – events triggerable by environmental factors such as the occupational respiratory toxicant silica (62-73). They have found that consumption of the omega-3 fatty acid (DHA) suppresses silica triggering of lupus hallmarks 1) expression of interferon-regulated genes, proinflammatory cytokine production, leukocyte infiltration, and ectopic lymphoid structure development in the lung, 2) pulmonary and systemic autoantibody production, and 3) glomerulonephritis.

Multiple group members are also investigating the impacts of maternal and neonatal dietary components on metabolic health and disease risk.   Dr. Chicco in Colorado developed a new ovine model of maternal-fetal metabolic programming, which revealed that maternal consumption of a high-fat/high-sugar diet during pregnancy shifts fetal metabolism to use fat over glucose as a fuel as previously demonstrated in non-human primates (18). This initiated signs of muscle and liver insulin resistance at mid-gestation, perhaps predisposing the offspring to obesity/diabetes. Ongoing studies are investigating the impact of omega-3 fatty acid (DHA) supplementation during pregnancy, which appears to support greater serum glucose disposal and fatty acid oxidation in the fetus, which could reduce risk of obesity and diabetes in offspring.  Complimentary work by Dr. Natarajan in Nebraska found that omega-3 fatty acids are metabolized into bioactive pro-inflammation resolution lipids that confer protection against inflammation in the placenta, perhaps through the novel discovery of GPR18, a RvD2 receptor in placental trophoblasts, providing a potential mechanisms by which maternal omega-3 fatty acid intake benefits the developing fetus (22,74).  Finally, W5122 researchers in Wisconsin have been defining how iron metabolism and red blood cell production is coordinated during postnatal growth relevant to both production animals and humans.  Understanding the mechanisms that coordinate iron metabolism and red cell production may lead to better ways to optimize iron supplementation in swine, and determine the impact on interorgan iron distribution and its potential pathological impacts in humans.

 

Advances in food processing and methodology for studying bioactive food components.

Our group members also have expertise in developing and using state-of-the-art instrumentation for studying bioactive food components, and how these chemicals are impacted by food processing or endogenous metabolism.  Dr. Chen in Minnesota demonstrated that chemometrics and metabolomics are effective analytical approaches for defining the chemical composition and metabolic fates of feed ingredients. Unique chemical components in foods were identified, and the associations of feed ingredients and growth performance were established in our studies (75). LC-MS-based untargeted profiling was performed on the lipid extracts from wild rice, white rice, and brown rice, and the phytosterol content of wild rice, and further analyzed to illustrate enrichment of particular phytosterols due to its unique processing after harvesting.  Dr. Weir in Colorado have identified metabolomic signatures associated with high and low fruit and vegetable intake that may be more precise in predicting intake of these foods than the currently used self-report methods. Dr. Maier in Oregon studied the effects of Centella asiatica extracts on neurological and functional resilience in pre-clinical models by developing a MS-based chemical fingerprinting method that is broadly applicable to other botanical extracts (45). This methodology also enabled studies demonstrating that these extracts have low potential for P450 drug interactions, which is an analysis required by the FDA to move forward with clinical trials with such compounds.  Dr. Nerurkar in Hawaii used metabolomics and lipidomics approach to identify environmental effects on polyphenols and signatures of secondary metabolites of cacao, a food component associated with several health benefits including improving metabolic disorders . Finally, Dr. Williams (OR), in collaboration with Lawrence Livermore National Laboratory and Pacific Northwest National Laboratory, found that the common dietary carcinogen BaP in humans is rapidly metabolized following ingestion (76-78), and the metabolites have pharmacological activities that could be incorporated into future risk assessment protocols by regulatory agencies.

Group members have also developed creative approaches to food processing that have led to discoveries of potential benefit to humans and production animals.  W4122 researchers in Guam found that indigenous mango leaves can be processed into a functional food, such as herbal tea, with anti-diabetic activity. Dr. Weir in Colorado demonstrated that crickets grown using materials and substrate preparation methods available in east African countries (79), where micronutrient deficiencies are common, provide a good source of bioavailable iron, according to the US RDI guidelines. In addition, they have explored the bioavailability and physiologic effects of different orally-delivered CBD formulations (80,81).  Dr. Delgado in New Mexico found that the expression of oleosin from glandless cottonseed meal protein that can serve as an emulsifying protein in food products and aquaculture feed (82).  Insights to the potentially harmful effects of common food processing methods were also provided by Dr. Helferich in Illinois, who have shown a clear effect of thermally-abused frying oil on cancer risk in mice, suggesting links between consumption of fried foods using these oils and the development of cancer (83).         

 

In summary, research by W4122 and W5122 researchers has successfully met the objectives of improving human health and food safety through a better understanding of the mechanisms of action of natural products in health and disease and through discovery of novel compounds/extracts that can reduce food-borne pathogens. The revised objectives in the current application represent the natural expansion of this work and stem from collaborative efforts of current project members and the new research initiatives funded in our laboratories.  In addition to our continued focus on modulation of gut health, understanding mechanisms of action of natural products and determining how food processing affects the bioactivity and safety of natural chemicals, the investigation of maternal and neonatal nutrition has been added as a new direction to compliment emerging interests that synergize with existing strengths and collaborations across the group.

Recent and ongoing member interactions, collaborations, and joint-projects.

As noted above, members of W-122 have a long history of collaborative manuscripts, grant proposals, and other professional activities involving two or more members that have been documented in our recent annual reports, which have contributed to multiple Multistate Research Excellence Awards (most recently in 2019).  Current members have several budding and active collaborations involving the shared resources and expertise described in the sections above, which have led to over a dozen joint manuscripts authored by at least two members including Benninghoff (UT), Pestka (MI), Chicco (CO) and Weir (CO) over the past 5 years, with many more planned or in progress. 

 

To foster new and continued interactions of this nature, we have included group breakout sessions in our recent W4122 annual meetings to discuss the writing of joint review articles or article collections, multi-PI grant applications, and the organization of research symposia or conferences, which we plan to continue and expand into the W5122 period.  Tangible evidence of these interactions include:

 

1) A pending application for a special issue of the journal Frontiers in Nutrition focused on “The Combined Microbiome and Metabolome Influence on Gut Health” co-edited by Nancy Turner (MI), Jacques Izard (NE) and Tiffany Weir (CO). 

 

2) The joint participation of Jacques Izard, Kaustav Majumder and Sathish Natarajan (all in NE) in the 2021 Ag and Health Summit organized by the Nebraska Food for Health Center of the University of Nebraska. This event was the first of its kind bringing together plant breeders, nutritionists and microbiome scientists to understand how to improve crop development and productivity to better benefit the health of the community.  The same event will be organized in 2023, involving the same members and perhaps including other members of the W5122 multistate group as new relationships and interactions continue to develop and evolve.

 

3) Dr. Pestka (MI) recently submitted an NIH R01 application involving Dr. Benninghoff (UT; Co-Investigator with subcontract) to investigate the impact of omega-3 fatty acids on alveolar macrophage function in Silica-Triggered Autoimmunity (Award # ES027353; 12/01/2022-11/30/2027; Total costs: $3,600,000).  

 

4) Efren Delgado (NM), together with Universidad Autonoma de Chihuahua (UACH) in Mexico and the W4122 members listed below co-organized and participated in the “2nd International Food Research Workshop in the Chihuahua Desert Region of North America” in Chihuahua, Mexico. April 7 – 8, 2022.  Members organized a microbial metabolite session that attracted over 86 attendees (virtual format) to discuss a broad array of topics including value-added foods, food safety, microbial metabolites, and food processing issues related to the border region between US and Mexico to intensify International Collaboration in the Chihuahua Desert Region:

 

New Mexico State University (Efren Delgado)

Ohio State University (Rachel Kopec)

University of Minnesota (Chi Chen)

Purdue University (Mohit Verma)

University of Nebraska – Lincoln (Jacques Izard)

Oregon State University (Claudia Maier)

 

5) It is important to acknowledge that there have also been numerous informal relationships between W-122 members over the past 5-10 years that have facilitated dissemination of scientific information, student recruitment, and career advancement. These include invited seminars between members/member institutions, reviews of tenure/promotion packages, writing letters of recommendation for awards, and critiquing grant proposals prior to submission (e.g., involving Weir (CO), Nerurkar (HI), Izard (NE), Marco (CA), Turner (MI)), as well as formal and informal mentoring between junior and senior members of the group (e.g., involving Weir (CO), Chicco (CO), Majumder (NE), Turner (MI), Helfrich (IL)).  These interactions are likely to increase into the W5122 period with the addition of several new members over the past 3 years, many of whom are junior faculty who have interests and expertise that compliment those of more senior members in similar or related research areas, as described above. 

Objectives

1. Examine the effects of dietary supplements and food components on the gut microbiome, and the impacts of these effects on human health
   Comments: Accumulating evidence indicates that the intestinal milieu, including the gut microbiota and its metabolites, has a profound impact on the development of many chronic diseases. W5122 researchers will explore how dietary components influence the gut microbiota and intestinal environment to influence health outcomes using a combination of cellular/molecular studies, animal and cell culture models, and human feeding trials. These studies will elucidate precise molecular mechanisms via which microorganisms and their metabolites induce localized effects in the digestive tract and systemically at other sites in the body.
2. Identify the cellular and molecular mechanisms responsible for the beneficial or adverse effects of specific dietary components on human health
   Comments: Although we know that dietary components can positively or negatively impact human health, the cellular bases of these effects are often poorly understood. W5122 researchers will examine the mechanisms by which specific nutrients influence metabolic, hematological, cardiovascular, immune and endocrine systems at a cellular level to impact risk of chronic diseases such as cancer, cardiovascular disease, lupus and diabetes.
3. Determine the impact of maternal diet on developmental programming and neonatal health
   Comments: The intrauterine environment exerts a profound influence on placental function and fetal development, which may determine the success of the pregnancy and health trajectory of the offspring. W5122 researchers will investigate the how maternal diet and selected bioactive nutrients impact placental function, fetal metabolism and neonatal health using a combination of cellular/molecular studies and animals models.
4. Determine how food processing alters the chemical composition of dietary components and their potential impact on human health
   Comments: In addition to investigating the effects of raw dietary nutrients on human health, it is important to understand how common food processing practices alter the chemical composition, bioavailability/bioaccessibility, and potential biological effects of these components. W5122 researchers will explore how food processing practices alter food chemistry and subsequent impacts on human health. We are also exploring value-added uses of food wastes that may contain components that can support human and animal health and food safety.

Methods

Introduction. Through years of interactions, coordination of research efforts and active collaborations, PIs at different stations in the region have developed and maintained expertise and facilities in specific areas that complement and facilitate the work of group members. When these various research capabilities are shared through active collaborations, they greatly enhance and synergize the research productivity of W5122 scientists. Data resulting from these projects will be shared among all project members at annual meetings and via regular collaborative research interactions. Summarized activities will be accessible to the public via scientific presentations at meetings, publications and the W5122 website.

Objective 1: Examine the effects of dietary supplements and food components on the gut microbiome, and the impacts of these effects on human health.

Current members are proposing the following core research activities over the next five years as areas for engagement and collaboration within the multistate group and related affiliates. The overall aim is to use our collective expertise in characterizing the intestinal microbiota, ingested probiotics, digestive tract function, epithelial cell biology in both animal models and humans, to develop collaborative basic and clinical/translational research aimed at improving gut health through dietary interventions:  

Dr.  Abby Benninghoff (Utah) recently secured a new USDA seed grant to delve further into the dynamics of the gut microbiome response to a wide array of anthocyanin-rich functional foods. Proposed activities include preparation of manuscript detailing results of ongoing and future research exploring the effects of short, long, and intermittent dietary intakes of eight anthocyanin-rich functional foods with diverse anthocyanin profiles on dynamic composition of the gut microbiome in mice.

Dr. Jacques Izard (Nebraska) will work in collaboration with Harvard T.H. Chan School of Public Health on statistical methodology to analyze microbiome data concomitantly with dietary data to better understand the links between dietary nutrient intake and the gut microbiome and human health. Preliminary analysis of stool samples from 60 individuals in the context of digestive resections are also opening the door to understand the role of human digestive mid-gut microbiome on human health outcomes and disease risk profiles.

Dr. Mohit Verma (Purdue) will use his new logistic growth-based model to characterize how growth of bacteria from the human gut microbiome in modulated by dietary nutrient intake. In particular, a series of thirteen carbohydrates (monosaccharides and disaccharides) that are building blocks of human milk oligosaccharides will be used to modulate the growth profiles of Bacteroides fragilis, Ruminococcus, and other microbe species - both individually and in combinations/mixtures - and optimize working statistical models to quantify these effects.

Dr. Chi Chen (Minnesota) will expand upon studies to characterize the chemical, physical, and biological properties of processed versus “functionalized” wheat bran (prepared through a combination of milling, alkaline hydrolysis, high-shear mixing, and high-pressure homogenization) using a short-term feeding model in mice.  He will specifically investigate effects of each fiber preparation on fecal sequestration of bile acids, amino acids and cholesterol, serum triacylglycerols and cholesterol, fermentation to short-chain fatty acids by gut microbiota, bioavailability of ferulic acid (a natural antioxidant) and its microbial metabolites, and systemic redox balance.   The goal of these studies is to determine how best to achieve the balance between the functionalization of wheat bran bioactives and its potential disruption of nutrient bioavailability to optimize human health benefits.

Dr. Tiffany Weir (Colorado) will explore the impact of cricket-derived chitin and other functional foods (e.g., dry bean pulses, blueberries) on the gut microbiota and intestinal function. In particular, following up on their recent work demonstrating increased bioavailability of iron in Caco2 intestinal cells incubated with ground crickets, they will perform a clinical trial to examine the effects of a 4g daily dose of cricket-derived chitin in individuals with Irritable Bowel Syndrome (IBS) on gastrointestinal symptoms, gut inflammation, bowel habits, and microbiota composition. They will also continue to utilize in vitro models (such as Caco cell monolayers and TEER) to explore underlying mechanisms of chitin-gut-microbiota interactions. Finally, Drs. Weir and Chicco will also continue their collaborative efforts to understand the links between diet, gut microbiota and cardiometabolic health outcomes using clinical and animal models.

Dr. Nancy Turner (Michigan) will investigate the impacts of quercetin and chlorogenic acid (enriched in plums and prunes) on inflammatory bowel disease and colon cancer risk in humans, with a particular focus on intestinal injury and inflammation. Building on their recent evidence for beneficial effects of these molecules on the expression of injury repair molecules, pro-inflammatory cytokines, SCFA transport proteins, and NF-κB inhibitory molecules, they will expand investigations to understand the major pathways involved in these effects, including changes in the intestinal microbiota and their metabolism.   

Dr. Meijun Zhu (Washington) will continue her investigation of natural compounds in foods that influence intestinal epithelial cell metabolism to mitigate the severity of inflammatory bowel diseases (IBDs). In particular, they will follow their studies with alpha-ketoglutarate (aKG) in a murine dextran sulfate sodium (DSS) induced - colitis model to explore new foods and dietary components that target the intestinal epithelium to reduce the risk and severity of IBDs in humans, and attempt to link these processes to shifts in the intestinal microbiome.

Dr. Maria Marco (California) will investigate the ecology, metabolism, and host-microbe interactions of the gut microbiome to understand how specific bacteria and their pathways and metabolites reduce inflammation and dampen the effects of obesogenic diets. Her work will determine the interactive effects of diets and food matrices on probiotic function. Through (inter)national collaborations, she will also investigate how the gut microbiome is affected by early-life, weaning transitions to result in short and long term effects on the heath and function of the digestive tract.

Dr. Claudia Maier (Oregon State) will use MS based approaches to explore the effects of diet on gut microbiota-derived xenobiotic ligands for FX receptors as a potential mechanism to combat obesity and metabolic syndrome, based on evidence that hops‐derived xanthohumol (XN)-derivatives appear to impact bile acid/lipid metabolism, likely responsible for observed health benefits in mice.

 

Objective 2: Identify the cellular and molecular mechanisms responsible for the beneficial or adverse effects of specific dietary components on human health.

Current members have a productive history of investigating the impact of selected dietary nutrients on a variety of human health outcomes. Goals for the next 5 years are to leverage the technical and intellectual expertise of our member research programs toward larger, more collaborative projects with broader impacts and translational relevance. Below are a summary of planned research projects and how they might be integrated across member labs and disciplines:

Dr. Nick Bello (Rutgers, NJ) will continue research efforts to identify the cellular mechanisms by which raspberry ketone (RK) influences human health. In particular, he will conduct further experiments to determine the dose-dependent acute effects of RK on metabolic and toxicological endpoints in white adipose and hepatic tissues. Results suggest that RK (200 mg/kg daily oral gavage) has diet-induced weight gain preventative actions (Kshatriya et al, Nutrition Research, 2019; Kshatriya et al, Nutrients, 2020), whereas RK 640 mg/kg (acute oral gavage) has toxicological endpoints (Hao et al., Food and Chemical Toxicology, 2020). Since the differences between beneficial and toxicological effects are a difference of only ½ log increment, he plans to investigate whether the preventative actions of RK on weight gain overlap with the toxicological effects. He has identified some molecular targets of RK by cheminformatics and are conducting in vitro and in vivo experiments to investigate their potential roles in these contexts.  Potential interactions with group members include collaborative studies testing the impact of RK on other models of cardiometabolic disease utilized by several members, along with the cheminformatics expertise to identify interactions of other dietary nutrients with targets that influence these outcomes.

Dr. Ock Chun (Connecticut) will examine the links between citrus intake and cancer risk. Population-levels analyses of postmenopausal women from the Women's Health Initiative (WHI) Observational Study suggested that citrus juice consumers might have a slightly higher risk of incident skin cancer.  Ongoing and future studies will determine the mechanisms by which furocoumarin-rich (citrus) foods impact skin health in this manner using an animal model, and expand epidemiological studies to further examine the relationship between citrus intake and skin cancer risk in US men and women by utilizing the data of NIH-AARP Diet and Cancer Cohort.

Dr. Ilce Medina (Michigan) will use multi-omics approaches to determine the roles of oxysterols and other lipid peroxides as risk assessment markers in highly susceptible populations, and fingerprint plant secondary metabolites as potential biomarkers for the prevention and treatment of cardiovascular and neurodegenerative diseases.

Dr. Pestka (Michigan) and Dr. Benninghoff (Utah) will employ in vitro and in vivo approaches to test the hypothesis that the balance of macrophage death and clearance of the resulting corpses is the central target for both silica triggering of autoimmune diseases and  mitigating effects of omega-3 fatty acids.

Dr. Kaustav Majumder (Nebraska) will continue his work testing the hypothesis that dietary bioactive peptides (kokumi active γ-glutamyl peptides; γ-EV) can inhibit inflammation in arteries to protect against atherosclerosis, hypertension and related vascular disorders associated with obesity and inflammation.  Studies to date have elucidated the mechanisms of γ-EV absorption by intestinal epithelial cells, and demonstrated vasculo-protective effects (lower ICAM-1, VCAM-1, and LOX-1) in atherosclerosis-prone (ApoE-/-) mice both at low (50mg/kgBW) and high doses (250mg/kgBW).  Future studies will evaluate further the anti-inflammatory role of γ-peptides in reducing vascular damage and metabolic disorders (glucose intolerance) in an animal model of diabetes, as well as its potential effects on renal sodium/water retention (a major contributor to hypertension).

Based on studies in a preclinical model of vascular injury (84), Dr. Jay Whelan (Tennessee), in collaboration with the vascular surgeons of the University of Tennessee Medical Center, Graduate School of Medicine, will perform a clinical trial investigating the impact of a combination of dietary bioactives in the stability of peripheral stents. Given potential limitations imposed by COVID-19, alternative approaches including additional animal studies in collaboration with group members who have expertise in cardiometabolic disease modeling in rodents.

Dr. Pratibha Nerurkar (Hawaii) will explore the potential mechanisms responsible for recent studies indicating that drinking moderate amounts of coffee (up to 4 cups/day) may reduce metabolic abnormalities and improve mortality rates in humans. Current studies are in progress to identify the specific effect of Hawaii-grown coffee on the plasma metabolome among healthy individuals.

Dr. Rachel Kopec (Ohio State) will investigate the interactions of dietary nutrients and bioactive compounds on absorption and subsequent effects on human health. Specifically, she will investigate the role of dietary vitamins A and D absorption in the risk for metabolic syndrome, and elucidate the synergistic interactions of iron and chlorophyll to develop methods for enriching the iron content in plant-based foods.

Dr, Claudia Maier (Oregon) will continue collaborative research efforts to characterize botanical extracts from Centella asiatica (CA), commonly used in herbal teas with putative anti-aging properties. Ongoing efforts are to utilize our novel chemical fingerprinting methods to ensure product integrity of extracts used in preclinical studies, evaluating potential interactions of CA and P450 enzymes (drug interactions), follow-up studies suggesting that caffeoylquinic acids contribute to the bioactivity of CA on cognition in rodent models.

  

Objective 3.  Determine the impact of maternal diet on developmental programming and neonatal health.   

Dr. Adam Chicco (Colorado) will investigate the impact of maternal dietary fat intake during pregnancy on fetal metabolism and cardiometabolic risk parameters using a novel ovine model of fetal metabolic programming. Recent studies have shown that excess fat in the maternal diet promotes a greater capacity of fetal muscle to uptake and oxidize fatty acids, but a reduced capacity for insulin-dependent glucose uptake and oxidation.  This resembles what is seen in obese/insulin-resistant adults and a non-human primate model (18), suggesting that the offspring of mothers who consume excess dietary fat during pregnancy may be “programmed” with a greater risk of obesity/diabetes later in life. Future studies will evaluate the mechanisms that govern placental lipid transport to the fetus and the impact of specific dietary fatty acids (omega-3 vs. omega-6 polyunsaturated fatty acids) on fetal metabolic parameters using this ovine model.  Based on emerging evidence from our lab for an important influence of FADS2 gene expression (encoding the rate-limiting enzymes in essential polyunsaturated fatty acid metabolism) on cardiometabolic health, we will investigate the role the maternal FADS2 on cardiac and metabolic parameters in neonates, juvenile and young adult offspring using murine models.

W5122 researchers in Wisconsin have worked on defining how iron metabolism and red blood cell production is coordinated during postnatal growth, which is relevant to both animals and humans.   Recent projects have produced data on the impact of IRP1 deficiency in controlling iron metabolism and erythropoiesis.  Similarly, we are collecting data on expression of various mRNAs in renal erythropoietin (Epo; the primary hormone driving red blood cell production) producing cells under a range of conditions.  We anticipate submission of a manuscript on the impact of IRP1 deficiency on systemic iron distribution and heart function in 2022.  Future studies will determine the impacts of postnatal erythrocytosis on muscle function in mouse models, and the expression of iron metabolism mRNAs in Epo-generating cells of the kidney.

Dr. Sathish Natarajan (Nebraska) will investigate the effects of omega-3 polyunsaturated fatty acid-derived Resolvin D2 (RvD2) on placental trophoblast activities, which is important for healthy pregnancy and neonatal development. Recent studies have demonstrated that RvD2 confers protection against inflammation in the placenta, perhaps through the novel discovery of GPR18, a RvD2 receptor in placental trophoblasts.  Future work aims to elucidate how RvD2 and omega-3 PUFA impact placental function through the use of cell studies, animal models and human tissue analyses. Studies many include collaboration with Dr. Chicco at CSU, given our common interests in PUFAs and teal metabolic programming.

 

Objective 4. Determine how food processing alters the chemical composition of dietary components and their potential impact on human health.

Dr. Pratibha Nerukar (Hawaii) will explore the role of fermenting bacteria in preparations of traditional Hawaiian medicine noni (Morinda citrifolia) and its effects on obesity and glucose metabolism in mice fed a high-fat diet (manuscript in preparations). She will also investigate the role of bacteria in fermented foods such as sauerkraut and their effects on antioxidant capacity using cell culture models.

Dr. Efren Delgado (New Mexico) will continue his research exploring the use of hydrolyzed food waste as an economical and sustainable alternative to be employed as a culture medium and add-value to Agroindustrial byproducts.  In particular, he will investigate the benefit of hydrolyzed agro-industrial wastes as liquid culture mediums to grow the modified yeast Yarrowia lipolytica to express oleosin from glandless cottonseed protein. The proposed technology may be useful for obtaining specific heterologous proteins, single-cell proteins and single-cell oils derived from the yeast.

Dr. Chi Chen (Minnesota) will perform studies to characterize the chemical, physical, and biological properties of processed wheat bran. Health-promoting activities of wheat bran are limited by the high-degree crosslinking of its dietary fiber and the low bioavailability of its phenolics. This is resolved somewhat by “functionalizing” wheat bran (FWB) through a combination of milling, alkaline hydrolysis, high-shear mixing, and high-pressure homogenization treatments that dramatically enhanced the function-associated physicochemical properties of wheat bran, including viscosity, fiber compositions, free ferulic acid, and antioxidant capacity. FWB feeding led to diverse positive metabolic effects, including fecal sequestration of bile acids and cholesterol, reduced serum triacylglycerols and cholesterol, elevated fermentation for short-chain fatty acids, increased bioavailability of ferulic acid and its microbial metabolites, and improved redox balance. However, FWB feeding also negatively affected the nutritional status by decreasing the bioavailability of essential amino acids through the excessive loss of amino acids in feces and disrupting lipid homeostasis by reducing choline supply in the liver. These double-edged metabolic effects will be further investigated in hopes of optimizing the balance between the functionalization of wheat bran bioactives and the disruption of nutrient bioavailability.

Dr. Weir (Colorado) will explore differences in iron bioavailability of meat compared to plant and insect-based meat alternatives. Plant-based meat alternatives are growing in popularity and are often formulated to mimic the nutrient profile of meats, particularly with regard to protein and iron content. However, animal-based iron is mainly found in the heme form, while plant iron is in the non-heme form. In addition, factors such as vitamin C and phytates that are often found in plants can either positively or negatively impact iron absorption. Therefore, it is important to gain a better understanding of iron bioavailability in these different formulations. Dr. Weir’s lab utilizes simulated digestion protocols and Caco-2 cell models to explore iron bioavailability from different products.

Measurement of Progress and Results

Outputs

• Evidence-based information on the beneficial and adverse impacts of bioactive, dietary compounds on human health and chronic disease for consumers and clinicians.
• Improved recommendations for use, standardization and processing of bioactive dietary compounds in herbal supplements and functional foods.
• Gut microbiome targeted dietary approaches for all life stages.
• Improved hazard and risk assessment data of dietary toxicants for policy makers.
• Identification of novel value added crops and foods that can be exploited by farmers and processors, respectively.
• Data on the effects of various dietary components on gut health that can be used by dietitians and other clinicians.
• Identification of new packaging/processing methods to reduce the risk of food-borne toxicants and microorganisms.
• Dissemination of data in scientific meetings, extension publications, and peer-reviewed journals.
• Development of curricula and other educational materials.
• Creation and archiving of resources and data such as purified natural chemicals, extracts with biological activity, biological reagents such as antibodies, cell lines, RNA from treated cells, laboratory animals, and big datasets generated from “omics” technologies to be made available for further study by W5122 participants and other researchers.

Outcomes or Projected Impacts

• Safer and more efficacious dietary supplements and functional foods The work of W5122 researchers in determining mechanisms of natural chemicals derived from foods or micro-organisms will help in determining specific beneficial compounds or combinations and doses needed to activate molecular targets. Research outputs will also be useful in determining manufacturing processes and delivery mechanisms that increase efficacy and improve safety.
• Reduce the health burden of chronic diseases such as cancer, cardiovascular disease and metabolic syndrome. Information from studies conducted by W5122 researchers will help identify dietary chemicals and whole foods that are efficacious in preventing or reversing chronic diseases by identifying beneficial dietary chemicals that that confer health benefits to the host such as, preventing development of colonic lesions and improving gut barrier function, increasing insulin sensitivity, and modulating inflammation.
• Improved dietary recommendations for optimizing health throughout the lifespan. W5122 work in areas such as diet-microbiome and epigenetic effects of dietary components will help inform how dietary recommendations can be tailored for improved outcomes related to maternal-child health, healthy aging, and other milestone throughout the lifespan.
• Development of new tools for nutritional research and epidemiological studies. W5122 researchers are developing cutting edge model systems, nutritionally relevant animal diets, and identifying biomarkers of dietary intake and disease that will be valuable tools for nutrition researchers, educators, and possible clinical applications.

Milestones

(2022):A general outline of planned milestones associated with current research aims linked to each of our four objectives over the next five-year period is summarized in the attached PowerPoint slide. In addition to publications and research presentations resulting from this work by individual members each year, we aim to publish an average of at least 2 collaborative research papers each year that include multiple W5122 members, and submit at least 1 collaborative research proposal addressing each of our main objectives as a result of these activities.

Projected Participation

View Appendix E: Participation

Outreach Plan

New information and conceptual insights resulting from this research will be communicated to a variety of stakeholder groups through varying media. Research details will be published for distribution in peer-reviewed scientific journals and translational findings will be communicated through extension literature. Findings will also be incorporated into teaching modules for K-12 education and integrated into undergraduate and graduate curricula. Several W5122 researchers have already developed university-level classes that highlight the role of natural chemicals present in the diet and produced by microorganisms.  Lectures, webinars and online certification offerings will also be available to groups of professionals such as registered dieticians, clinical laboratory scientists, and other medical professionals as continuing education opportunities. Findings that are considered important for public distribution will be placed into a format that is suitable for dissemination through the media. When our level of understanding of new findings and their significance so dictate, the information can become the focus of workshops and training sessions for Cooperative Extension Specialists. W5122 will also establish a website and social media pages for rapid distribution of important information and for communication of constituents with W5122 members.

W5122 investigators work closely with community information organizations to provide perspectives on the possible role of diet in disease. Contributing Experiment Stations have developed effective means of communicating with poor and minority populations through cooperation with community organizations and food distribution and nutrition education programs, such as and food stamp advisory organizations. Undergraduate minority student training programs are also effective means of providing information to consumers and potential future community leaders. Several Experiment Stations also have well developed lines of communication with grower's associations for which W5122 findings will be useful. In addition, Drs. Izard and Majumder, as part of the Nebraska Food for Health Center, will continue to promote the W5122 work among the Center and via the bi-annual Agriculture and Health Summit.

Organization/Governance

The Technical Committee consists of the Administrative Advisor, representatives of the various Research Divisions of the U.S. Department of Agriculture, the CSREES-USDA, and a designated representative from each participating experiment station. An Executive Committee will consist of the chairman, vice-chairman, and secretary. Each year a new secretary will be elected and the officers advanced, the secretary becoming vice-chairman, the vice-chairman becoming chairman. Thus, each person elected shall serve as secretary, vice-chairman, and chairman during a consecutive three year term. The Executive Committee will conduct annual business meetings as called by the Administrative Advisor, and will be empowered to act for the Technical Committee between annual meetings. At the annual meetings, research will be reviewed and cooperative efforts and research priorities within the objectives of the regional research proposal will be established.

Literature Cited

1. Gentile, C. L., and Weir, T. L. (2018) The gut microbiota at the intersection of diet and human health. Science 362, 776-780
2. Sekirov, I., Russell, S. L., Antunes, L. C., and Finlay, B. B. (2010) Gut microbiota in health and disease. Physiol Rev 90, 859-904
3. Festi, D., Schiumerini, R., Eusebi, L. H., Marasco, G., Taddia, M., and Colecchia, A. (2014) Gut microbiota and metabolic syndrome. World J Gastroenterol 20, 16079-16094
4. Wu, X., He, B., Liu, J., Feng, H., Ma, Y., Li, D., Guo, B., Liang, C., Dang, L., Wang, L., Tian, J., Zhu, H., Xiao, L., Lu, C., Lu, A., and Zhang, G. (2016) Molecular Insight into Gut Microbiota and Rheumatoid Arthritis. Int J Mol Sci 17, 431
5. Sampson, T. R., Debelius, J. W., Thron, T., Janssen, S., Shastri, G. G., Ilhan, Z. E., Challis, C., Schretter, C. E., Rocha, S., Gradinaru, V., Chesselet, M. F., Keshavarzian, A., Shannon, K. M., Krajmalnik-Brown, R., Wittung-Stafshede, P., Knight, R., and Mazmanian, S. K. (2016) Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell 167, 1469-1480 e1412
6. Cani, P. D., Amar, J., Iglesias, M. A., Poggi, M., Knauf, C., Bastelica, D., Neyrinck, A. M., Fava, F., Tuohy, K. M., Chabo, C., Waget, A., Delmee, E., Cousin, B., Sulpice, T., Chamontin, B., Ferrieres, J., Tanti, J. F., Gibson, G. R., Casteilla, L., Delzenne, N. M., Alessi, M. C., and Burcelin, R. (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761-1772
7. Kasubuchi, M., Hasegawa, S., Hiramatsu, T., Ichimura, A., and Kimura, I. (2015) Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation. Nutrients 7, 2839-2849
8. Davie, J. R. (2003) Inhibition of histone deacetylase activity by butyrate. J Nutr 133, 2485S-2493S
9. Kelly, C. J., Zheng, L., Campbell, E. L., Saeedi, B., Scholz, C. C., Bayless, A. J., Wilson, K. E., Glover, L. E., Kominsky, D. J., Magnuson, A., Weir, T. L., Ehrentraut, S. F., Pickel, C., Kuhn, K. A., Lanis, J. M., Nguyen, V., Taylor, C. T., and Colgan, S. P. (2015) Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function. Cell Host Microbe 17, 662-671
10. Hughes, R., Magee, E. A., and Bingham, S. (2000) Protein degradation in the large intestine: relevance to colorectal cancer. Curr Issues Intest Microbiol 1, 51-58
11. Koeth, R. A., Wang, Z., Levison, B. S., Buffa, J. A., Org, E., Sheehy, B. T., Britt, E. B., Fu, X., Wu, Y., Li, L., Smith, J. D., DiDonato, J. A., Chen, J., Li, H., Wu, G. D., Lewis, J. D., Warrier, M., Brown, J. M., Krauss, R. M., Tang, W. H., Bushman, F. D., Lusis, A. J., and Hazen, S. L. (2013) Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19, 576-585
12. Weiss, R., Dziura, J., Burgert, T. S., Tamborlane, W. V., Taksali, S. E., Yeckel, C. W., Allen, K., Lopes, M., Savoye, M., Morrison, J., Sherwin, R. S., and Caprio, S. (2004) Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 350, 2362-2374
13. Han, J. C., Lawlor, D. A., and Kimm, S. Y. Childhood obesity. Lancet 375, 1737-1748
14. Daviglus, M. L., Liu, K., Yan, L. L., Pirzada, A., Manheim, L., Manning, W., Garside, D. B., Wang, R., Dyer, A. R., Greenland, P., and Stamler, J. (2004) Relation of body mass index in young adulthood and middle age to Medicare expenditures in older age. JAMA 292, 2743-2749
15. Catalano, P. M., and Ehrenberg, H. M. (2006) The short- and long-term implications of maternal obesity on the mother and her offspring. BJOG 113, 1126-1133
16. Plagemann, A., Harder, T., Kohlhoff, R., Rohde, W., and Dorner, G. (1997) Overweight and obesity in infants of mothers with long-term insulin-dependent diabetes or gestational diabetes. Int J Obes Relat Metab Disord 21, 451-456
17. Catalano, P. M., Farrell, K., Thomas, A., Huston-Presley, L., Mencin, P., de Mouzon, S. H., and Amini, S. B. (2009) Perinatal risk factors for childhood obesity and metabolic dysregulation. Am J Clin Nutr 90, 1303-1313
18. McCurdy, C. E., Schenk, S., Hetrick, B., Houck, J., Drew, B. G., Kaye, S., Lashbrook, M., Bergman, B. C., Takahashi, D. L., Dean, T. A., Nemkov, T., Gertsman, I., Hansen, K. C., Philp, A., Hevener, A. L., Chicco, A. J., Aagaard, K. M., Grove, K. L., and Friedman, J. E. (2016) Maternal obesity reduces oxidative capacity in fetal skeletal muscle of Japanese macaques. JCI Insight 1, e86612
19. Lucia Bergmann, R., Bergmann, K. E., Haschke-Becher, E., Richter, R., Dudenhausen, J. W., Barclay, D., and Haschke, F. (2007) Does maternal docosahexaenoic acid supplementation during pregnancy and lactation lower BMI in late infancy? J Perinat Med 35, 295-300
20. Mace, K., Shahkhalili, Y., Aprikian, O., and Stan, S. (2006) Dietary fat and fat types as early determinants of childhood obesity: a reappraisal. Int J Obes (Lond) 30 Suppl 4, S50-57
21. Vlaardingerbroek, H., and Hornstra, G. (2004) Essential fatty acids in erythrocyte phospholipids during pregnancy and at delivery in mothers and their neonates: comparison with plasma phospholipids. Prostaglandins, leukotrienes, and essential fatty acids 71, 363-374
22. Ulu, A., Sahoo, P. K., Yuil-Valdes, A. G., Mukherjee, M., Van Ormer, M., Muthuraj, P. G., Thompson, M., Anderson Berry, A., Hanson, C. K., Natarajan, S. K., and Nordgren, T. M. (2019) Omega-3 Fatty Acid-Derived Resolvin D2 Regulates Human Placental Vascular Smooth Muscle and Extravillous Trophoblast Activities. Int J Mol Sci 20
23. Wadhwani, N., Patil, V., Pisal, H., Joshi, A., Mehendale, S., Gupte, S., Wagh, G., and Joshi, S. (2014) Altered maternal proportions of long chain polyunsaturated fatty acids and their transport leads to disturbed fetal stores in preeclampsia. Prostaglandins, leukotrienes, and essential fatty acids 91, 21-30
24. Wang, Y., Walsh, S. W., and Kay, H. H. (2005) Placental tissue levels of nonesterified polyunsaturated fatty acids in normal and preeclamptic pregnancies. Hypertension in pregnancy 24, 235-245
25. Cetin, I., Giovannini, N., Alvino, G., Agostoni, C., Riva, E., Giovannini, M., and Pardi, G. (2002) Intrauterine growth restriction is associated with changes in polyunsaturated fatty acid fetal-maternal relationships. Pediatric research 52, 750-755
26. Jasarevic, E., and Bale, T. L. (2019) Prenatal and postnatal contributions of the maternal microbiome on offspring programming. Front Neuroendocrinol 55, 100797
27. Battson, M. L., Lee, D. M., Weir, T. L., and Gentile, C. L. (2018) The gut microbiota as a novel regulator of cardiovascular function and disease. J Nutr Biochem 56, 1-15
28. Lutsiv, T., Weir, T. L., McGinley, J. N., Neil, E. S., Wei, Y., and Thompson, H. J. (2021) Compositional Changes of the High-Fat Diet-Induced Gut Microbiota upon Consumption of Common Pulses. Nutrients 13
29. Sheflin, A. M., Melby, C. L., Carbonero, F., and Weir, T. L. (2017) Linking dietary patterns with gut microbial composition and function. Gut Microbes 8, 113-129
30. Trikha, S. R. J., Lee, D. M., Ecton, K. E., Wrigley, S. D., Vazquez, A. R., Litwin, N. S., Thomas, K. N., Wei, Y., Battson, M. L., Johnson, S. A., Kuhn, K. A., Colgan, S. P., Gentile, C. L., and Weir, T. L. (2021) Transplantation of an obesity-associated human gut microbiota to mice induces vascular dysfunction and glucose intolerance. Gut Microbes 13, 1940791
31. Everett, C., Li, C., Wilkinson, J. E., Nguyen, L. H., McIver, L. J., Ivey, K., Izard, J., Palacios, N., Eliassen, A. H., Willett, W. C., Ascherio, A., Sun, Q., Tworoger, S. S., Chan, A. T., Garrett, W. S., Huttenhower, C., Rimm, E. B., and Song, M. (2021) Overview of the Microbiome Among Nurses study (Micro-N) as an example of prospective characterization of the microbiome within cohort studies. Nat Protoc 16, 2724-2731
32. Ma, W., Nguyen, L. H., Song, M., Wang, D. D., Franzosa, E. A., Cao, Y., Joshi, A., Drew, D. A., Mehta, R., Ivey, K. L., Strate, L. L., Giovannucci, E. L., Izard, J., Garrett, W., Rimm, E. B., Huttenhower, C., and Chan, A. T. (2021) Dietary fiber intake, the gut microbiome, and chronic systemic inflammation in a cohort of adult men. Genome Med 13, 102
33. Abu-Ali, G. S., Mehta, R. S., Lloyd-Price, J., Mallick, H., Branck, T., Ivey, K. L., Drew, D. A., DuLong, C., Rimm, E., Izard, J., Chan, A. T., and Huttenhower, C. (2018) Metatranscriptome of human faecal microbial communities in a cohort of adult men. Nat Microbiol 3, 356-366
34. Mehta, R. S., Abu-Ali, G. S., Drew, D. A., Lloyd-Price, J., Subramanian, A., Lochhead, P., Joshi, A. D., Ivey, K. L., Khalili, H., Brown, G. T., DuLong, C., Song, M., Nguyen, L. H., Mallick, H., Rimm, E. B., Izard, J., Huttenhower, C., and Chan, A. T. (2018) Stability of the human faecal microbiome in a cohort of adult men. Nat Microbiol 3, 347-355
35. Nguyen, L. H., Cao, Y., Hur, J., Mehta, R. S., Sikavi, D. R., Wang, Y., Ma, W., Wu, K., Song, M., Giovannucci, E. L., Rimm, E. B., Willett, W. C., Garrett, W. S., Izard, J., Huttenhower, C., and Chan, A. T. (2021) The Sulfur Microbial Diet Is Associated With Increased Risk of Early-Onset Colorectal Cancer Precursors. Gastroenterology 161, 1423-1432 e1424
36. Nguyen, L. H., Ma, W., Wang, D. D., Cao, Y., Mallick, H., Gerbaba, T. K., Lloyd-Price, J., Abu-Ali, G., Hall, A. B., Sikavi, D., Drew, D. A., Mehta, R. S., Arze, C., Joshi, A. D., Yan, Y., Branck, T., DuLong, C., Ivey, K. L., Ogino, S., Rimm, E. B., Song, M., Garrett, W. S., Izard, J., Huttenhower, C., and Chan, A. T. (2020) Association Between Sulfur-Metabolizing Bacterial Communities in Stool and Risk of Distal Colorectal Cancer in Men. Gastroenterology 158, 1313-1325
37. Sikavi, D. R., Nguyen, L. H., Haruki, K., Ugai, T., Ma, W., Wang, D. D., Thompson, K. N., Yan, Y., Branck, T., Wilkinson, J. E., Akimoto, N., Zhong, R., Lau, M. C., Mima, K., Kosumi, K., Morikawa, T., Rimm, E. B., Garrett, W. S., Izard, J., Cao, Y., Song, M., Huttenhower, C., Ogino, S., and Chan, A. T. (2021) The Sulfur Microbial Diet and Risk of Colorectal Cancer by Molecular Subtypes and Intratumoral Microbial Species in Adult Men. Clin Transl Gastroenterol 12, e00338
38. Seidel, D. V., Azcarate-Peril, M. A., Chapkin, R. S., and Turner, N. D. (2017) Shaping functional gut microbiota using dietary bioactives to reduce colon cancer risk. Semin Cancer Biol 46, 191-204
39. Turner, N. D., Ritchie, L. E., Bresalier, R. S., and Chapkin, R. S. (2013) The microbiome and colorectal neoplasia: environmental modifiers of dysbiosis. Curr Gastroenterol Rep 15, 346
40. Banerjee, N., Kim, H., Talcott, S. T., Turner, N. D., Byrne, D. H., and Mertens-Talcott, S. U. (2016) Plum polyphenols inhibit colorectal aberrant crypt foci formation in rats: potential role of the miR-143/protein kinase B/mammalian target of rapamycin axis. Nutr Res 36, 1105-1113
41. Ritchie, L. E., Taddeo, S. S., Weeks, B. R., Carroll, R. J., Dykes, L., Rooney, L. W., and Turner, N. D. (2017) Impact of Novel Sorghum Bran Diets on DSS-Induced Colitis. Nutrients 9
42. Logan, I. E., Shulzhenko, N., Sharpton, T. J., Bobe, G., Liu, K., Nuss, S., Jones, M. L., Miranda, C. L., Vasquez-Perez, S., Pennington, J. M., Leonard, S. W., Choi, J., Wu, W., Gurung, M., Kim, J. P., Lowry, M. B., Morgun, A., Maier, C. S., Stevens, J. F., and Gombart, A. F. (2021) Xanthohumol Requires the Intestinal Microbiota to Improve Glucose Metabolism in Diet-Induced Obese Mice. Mol Nutr Food Res 65, e2100389
43. Zhang, Y., Bobe, G., Revel, J. S., Rodrigues, R. R., Sharpton, T. J., Fantacone, M. L., Raslan, K., Miranda, C. L., Lowry, M. B., Blakemore, P. R., Morgun, A., Shulzhenko, N., Maier, C. S., Stevens, J. F., and Gombart, A. F. (2020) Improvements in Metabolic Syndrome by Xanthohumol Derivatives Are Linked to Altered Gut Microbiota and Bile Acid Metabolism. Mol Nutr Food Res 64, e1900789
44. Gray, N. E., Alcazar Magana, A., Lak, P., Wright, K. M., Quinn, J., Stevens, J. F., Maier, C. S., and Soumyanath, A. (2018) Centella asiatica - Phytochemistry and mechanisms of neuroprotection and cognitive enhancement. Phytochem Rev 17, 161-194
45. Matthews, D. G., Caruso, M., Alcazar Magana, A., Wright, K. M., Maier, C. S., Stevens, J. F., Gray, N. E., Quinn, J. F., and Soumyanath, A. (2020) Caffeoylquinic Acids in Centella asiatica Reverse Cognitive Deficits in Male 5XFAD Alzheimer's Disease Model Mice. Nutrients 12
46. Wright, K. M., Magana, A. A., Laethem, R. M., Moseley, C. L., Banks, T. T., Maier, C. S., Stevens, J. F., Quinn, J. F., and Soumyanath, A. (2020) Centella asiatica Water Extract Shows Low Potential for Cytochrome P450-Mediated Drug Interactions. Drug Metab Dispos 48, 1053-1063
47. Curtasu, M. V., Tafintseva, V., Bendiks, Z. A., Marco, M. L., Kohler, A., Xu, Y., Norskov, N. P., Nygaard Laerke, H., Bach Knudsen, K. E., and Hedemann, M. S. (2020) Obesity-Related Metabolome and Gut Microbiota Profiles of Juvenile Gottingen Minipigs-Long-Term Intake of Fructose and Resistant Starch. Metabolites 10
48. Marlatt, K. L., White, U. A., Beyl, R. A., Peterson, C. M., Martin, C. K., Marco, M. L., Keenan, M. J., Martin, R. J., Aryana, K. J., and Ravussin, E. (2018) Role of resistant starch on diabetes risk factors in people with prediabetes: Design, conduct, and baseline results of the STARCH trial. Contemp Clin Trials 65, 99-108
49. Heeney, D. D., Zhai, Z., Bendiks, Z., Barouei, J., Martinic, A., Slupsky, C., and Marco, M. L. (2019) Lactobacillus plantarum bacteriocin is associated with intestinal and systemic improvements in diet-induced obese mice and maintains epithelial barrier integrity in vitro. Gut Microbes 10, 382-397
50. Qiu, X., Chen, C., and Chen, X. (2021) Lipocalin 2 Deficiency Restrains Aging-Related Reshaping of Gut Microbiota Structure and Metabolism. Biomolecules 11
51. Qiu, X., Macchietto, M. G., Liu, X., Lu, Y., Ma, Y., Guo, H., Saqui-Salces, M., Bernlohr, D. A., Chen, C., Shen, S., and Chen, X. (2021) Identification of gut microbiota and microbial metabolites regulated by an antimicrobial peptide lipocalin 2 in high fat diet-induced obesity. Int J Obes (Lond) 45, 143-154
52. Maruthamuthu, M. K., Raffiee, A. H., De Oliveira, D. M., Ardekani, A. M., and Verma, M. S. (2020) Raman spectra-based deep learning: A tool to identify microbial contamination. Microbiologyopen 9, e1122
53. Ganguly, A., Sharma, K., and Majumder, K. (2019) Food-derived bioactive peptides and their role in ameliorating hypertension and associated cardiovascular diseases. Adv Food Nutr Res 89, 165-207
54. Guha, S., and Majumder, K. (2019) Structural-features of food-derived bioactive peptides with anti-inflammatory activity: A brief review. J Food Biochem 43, e12531
55. Guha, S., Alvarez, S., and Majumder, K. (2021) Transport of Dietary Anti-Inflammatory Peptide, gamma-Glutamyl Valine (gamma-EV), across the Intestinal Caco-2 Monolayer. Nutrients 13
56. Guha, S., Paul, C., Alvarez, S., Mine, Y., and Majumder, K. (2020) Dietary gamma-Glutamyl Valine Ameliorates TNF-alpha-Induced Vascular Inflammation via Endothelial Calcium-Sensing Receptors. J Agric Food Chem 68, 9139-9149
57. Xing, T., Kang, Y., Xu, X., Wang, B., Du, M., and Zhu, M. J. (2018) Raspberry Supplementation Improves Insulin Signaling and Promotes Brown-Like Adipocyte Development in White Adipose Tissue of Obese Mice. Mol Nutr Food Res 62
58. Hao, L., and Bello, N. T. (2021) Reduced Body Fat and Epididymal Adipose Apelin Expression Associated With Raspberry Ketone [4-(4-Hydroxyphenyl)-2-Butanone] Weight Gain Prevention in High-Fat-Diet Fed Mice. Front Physiol 12, 771816
59. Kshatriya, D., Hao, L., Li, X., and Bello, N. T. (2020) Raspberry Ketone [4-(4-Hydroxyphenyl)-2-Butanone] Differentially Effects Meal Patterns and Cardiovascular Parameters in Mice. Nutrients 12
60. Nerurkar, P. V., Gandhi, K., and Chen, J. J. (2021) Correlations between Coffee Consumption and Metabolic Phenotypes, Plasma Folate, and Vitamin B12: NHANES 2003 to 2006. Nutrients 13
61. Nerurkar, P. V., Orias, D., Soares, N., Kumar, M., and Nerurkar, V. R. (2019) Momordica charantia (bitter melon) modulates adipose tissue inflammasome gene expression and adipose-gut inflammatory cross talk in high-fat diet (HFD)-fed mice. J Nutr Biochem 68, 16-32
62. Bates, M. A., Akbari, P., Gilley, K. N., Wagner, J. G., Li, N., Kopec, A. K., Wierenga, K. A., Jackson-Humbles, D., Brandenberger, C., Holian, A., Benninghoff, A. D., Harkema, J. R., and Pestka, J. J. (2018) Dietary Docosahexaenoic Acid Prevents Silica-Induced Development of Pulmonary Ectopic Germinal Centers and Glomerulonephritis in the Lupus-Prone NZBWF1 Mouse. Front Immunol 9, 2002
63. Bates, M. A., Benninghoff, A. D., Gilley, K. N., Holian, A., Harkema, J. R., and Pestka, J. J. (2019) Mapping of Dynamic Transcriptome Changes Associated With Silica-Triggered Autoimmune Pathogenesis in the Lupus-Prone NZBWF1 Mouse. Front Immunol 10, 632
64. Benninghoff, A. D., Bates, M. A., Chauhan, P. S., Wierenga, K. A., Gilley, K. N., Holian, A., Harkema, J. R., and Pestka, J. J. (2019) Docosahexaenoic Acid Consumption Impedes Early Interferon- and Chemokine-Related Gene Expression While Suppressing Silica-Triggered Flaring of Murine Lupus. Front Immunol 10, 2851
65. Chauhan, P. S., Wagner, J. G., Benninghoff, A. D., Lewandowski, R. P., Favor, O. K., Wierenga, K. A., Gilley, K. N., Ross, E. A., Harkema, J. R., and Pestka, J. J. (2021) Rapid Induction of Pulmonary Inflammation, Autoimmune Gene Expression, and Ectopic Lymphoid Neogenesis Following Acute Silica Exposure in Lupus-Prone Mice. Front Immunol 12, 635138
66. Gilley, K. N., Wierenga, K. A., Chauhuan, P. S., Wagner, J. G., Lewandowski, R. P., Ross, E. A., Lock, A. L., Harkema, J. R., Benninghoff, A. D., and Pestka, J. J. (2020) Influence of total western diet on docosahexaenoic acid suppression of silica-triggered lupus flaring in NZBWF1 mice. PLoS One 15, e0233183
67. Pestka, J. J., Akbari, P., Wierenga, K. A., Bates, M. A., Gilley, K. N., Wagner, J. G., Lewandowski, R. P., Rajasinghe, L. D., Chauhan, P. S., Lock, A. L., Li, Q. Z., and Harkema, J. R. (2021) Omega-3 Polyunsaturated Fatty Acid Intervention Against Established Autoimmunity in a Murine Model of Toxicant-Triggered Lupus. Front Immunol 12, 653464
68. Pestka, J. J., Pollard, K. M., and Rosenspire, A. J. (2021) Editorial: The Role of the Environment in Autoimmunity. Front Immunol 12, 641171
69. Rajasinghe, L. D., Chauhan, P. S., Wierenga, K. A., Evered, A. O., Harris, S. N., Bates, M. A., Gavrilin, M. A., and Pestka, J. J. (2020) Omega-3 Docosahexaenoic Acid (DHA) Impedes Silica-Induced Macrophage Corpse Accumulation by Attenuating Cell Death and Potentiating Efferocytosis. Front Immunol 11, 2179
70. Rajasinghe, L. D., Li, Q. Z., Zhu, C., Yan, M., Chauhan, P. S., Wierenga, K. A., Bates, M. A., Harkema, J. R., Benninghoff, A. D., and Pestka, J. J. (2020) Omega-3 fatty acid intake suppresses induction of diverse autoantibody repertoire by crystalline silica in lupus-prone mice. Autoimmunity 53, 415-433
71. Wierenga, K. A., Harkema, J. R., and Pestka, J. J. (2019) Lupus, Silica, and Dietary Omega-3 Fatty Acid Interventions. Toxicol Pathol 47, 1004-1011
72. Wierenga, K. A., Strakovsky, R. S., Benninghoff, A. D., Rajasinghe, L. D., Lock, A. L., Harkema, J. R., and Pestka, J. J. (2020) Requisite Omega-3 HUFA Biomarker Thresholds for Preventing Murine Lupus Flaring. Front Immunol 11, 1796
73. Wierenga, K. A., Wee, J., Gilley, K. N., Rajasinghe, L. D., Bates, M. A., Gavrilin, M. A., Holian, A., and Pestka, J. J. (2019) Docosahexaenoic Acid Suppresses Silica-Induced Inflammasome Activation and IL-1 Cytokine Release by Interfering With Priming Signal. Front Immunol 10, 2130
74. Thoene, M., Van Ormer, M., Yuil-Valdes, A., Bruett, T., Natarajan, S. K., Mukherjee, M., Thompson, M., Nordgren, T. M., Van Lippevelde, W., Overby, N. C., Adu-Bonsaffoh, K., Anderson-Berry, A., and Hanson, C. (2020) Fat-soluble nutrients and Omega-3 fatty acids as modifiable factors influencing preterm birth risk. Placenta 98, 38-42
75. Peng, L., Yuan, J., Yao, D., and Chen, C. (2021) Fingerprinting triacylglycerols and aldehydes as identity and thermal stability indicators of camellia oil through chemometric comparison with olive oil. Food Sci Nutr 9, 2561-2575
76. Madeen, E., Siddens, L. K., Uesugi, S., McQuistan, T., Corley, R. A., Smith, J., Waters, K. M., Tilton, S. C., Anderson, K. A., Ognibene, T., Turteltaub, K., and Williams, D. E. (2019) Toxicokinetics of benzo[a]pyrene in humans: Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing. Toxicol Appl Pharmacol 364, 97-105
77. Ngo, S. N. T., and Williams, D. B. (2021) Protective Effect of Isothiocyanates from Cruciferous Vegetables on Breast Cancer: Epidemiological and Preclinical Perspectives. Anticancer Agents Med Chem 21, 1413-1430
78. Pande, P., Madeen, E. P., Williams, D. E., Crowell, S. R., Ognibene, T. J., Turteltaub, K. W., Corley, R. A., and Smith, J. N. (2021) Translating dosimetry of Dibenzo[def,p]chrysene (DBC) and metabolites across dose and species using physiologically based pharmacokinetic (PBPK) modeling. Toxicol Appl Pharmacol, 115830
79. Stull, V. J., Finer, E., Bergmans, R. S., Febvre, H. P., Longhurst, C., Manter, D. K., Patz, J. A., and Weir, T. L. (2018) Impact of Edible Cricket Consumption on Gut Microbiota in Healthy Adults, a Double-blind, Randomized Crossover Trial. Sci Rep 8, 10762
80. Hobbs, J. M., Vazquez, A. R., Remijan, N. D., Trotter, R. E., McMillan, T. V., Freedman, K. E., Wei, Y., Woelfel, K. A., Arnold, O. R., Wolfe, L. M., Johnson, S. A., and Weir, T. L. (2020) Evaluation of pharmacokinetics and acute anti-inflammatory potential of two oral cannabidiol preparations in healthy adults. Phytother Res 34, 1696-1703
81. Williams, N. N. B., Ewell, T. R., Abbotts, K. S. S., Harms, K. J., Woelfel, K. A., Dooley, G. P., Weir, T. L., and Bell, C. (2021) Comparison of Five Oral Cannabidiol Preparations in Adult Humans: Pharmacokinetics, Body Composition, and Heart Rate Variability. Pharmaceuticals (Basel) 14
82. Delgado, E., Valverde-Quiroz, L., Lopez, D., Cooke, P., Valles-Rosales, D., and Flores, N. (2019) Characterization of Soluble Glandless Cottonseed Meal Proteins Based on Electrophoresis, Functional Properties, and Microscopic Structure. J Food Sci 84, 2820-2830
83. Cam, A., Oyirifi, A. B., Liu, Y., Haschek, W. M., Iwaniec, U. T., Turner, R. T., Engeseth, N. J., and Helferich, W. G. (2019) Thermally Abused Frying Oil Potentiates Metastasis to Lung in a Murine Model of Late-Stage Breast Cancer. Cancer Prev Res (Phila) 12, 201-210
84. Buckley, M. R., Terry, P. D., Kirkpatrick, S. S., Arnold, J. D., McNally, M. M., Grandas, O. H., Freeman, M. B., Goldman, M. H., Whelan, J., and Mountain, D. J. (2019) Dietary supplementation with Zyflamend poly-herbal extracts and fish oil inhibits intimal hyperplasia development following vascular intervention. Nutr Res 68, 34-44

 

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