Meeting the challenge of conducting long-term studies using amounts of foods in a typical diet, with a representative sample of participants, requires a significant commitment of resources. The health and functional levels of participants are other factors that influence study designs and outcomes. For example, studies on cognitive performance with both nuts and berries have assessed effects among those both with and without cognitive impairments. In such studies, short-term interventions may show little or no response after the addition of nuts or berries to the diet. Although the net change may not be statistically significant, this model does not address the ability of the food to prevent decline, which would require long-term testing. Further, an individual with cognitive impairments might demonstrate favorable responses compared to baseline measures following nut or berry intake but may still not reach the level of performance of a healthy individual. In both instances, neither change from baseline, nor absolute values of performance, fully captures the beneficial cognitive response. Dietary interventions require the incorporation of foods into an individual’s eating pattern, plastic round plant pots which may present a number of challenges. One is the creation of boredom with eating the same food on a regular basis. Second is that the caloric load of the test nut or berry may displace the intake of other nutrient-dense foods. These factors may make compliance for the entire study duration an issue, particularly if the intervention is weeks or months in duration.

A third challenge involves compliance. In berry research studies, compliance is often not reported, or the reported range of intake is so variable that it is hard to discern the significance of the results. The use of food intake metabolite markers is an emerging tool that can help verify compliance. In addition to compliance, dietary patterns are an important consideration needed for the interpretation of results because individuals do not eat a single food in the absence of other foods. Background or habitual intake is often not addressed in nutritional trials. The potential variability in habitual dietary intake of participants is often a confounding factor in nutrition research. Dietary assessment methods, with 24-h recalls, 3-d food records, and food frequency questionnaires, all have limitations. These subjective measures may also not accurately capture the potential for nutrient-nutrient interactions that may alter polyphenolic or other bio-active components attributed to nut and berry consumption. Further complicating this issue is the observation that study designs utilizing longer-term interventions or that require the intake of a large amount of the test food are more likely to result in over reporting food intake due to fear that participants may be dismissed from the intervention. Innovations in dietary assessment methodology using “smart” eyeglasses or other image-based technologies have been proposed to address this issue. Assessing the relationship between the intake of nutrients and bio-actives from a whole food product to physiologic responses is difficult, as a multitude of processes are affected, including regulation of vascular function, provision of oxidant defense, and changes in gut microbiome profiles and subsequent output of secondary metabolites.

Additionally, bio-actives from nuts and berries can interact with each other as well as other dietary components to alter bio-availability and health-promoting properties. For example, intake of dietary fats in conjunction with berries has been demonstrated to increase carotenoid bio-availability. Results could also be confounded by dietary changes made by participants in addition to incorporation of the test nut or berry. Habitual dietary intake is often measured through food frequency questionnaires or repeated 24-h dietary recalls. However, these subjective measures may not accurately capture the potential for nutrient-nutrient interactions that may alter polyphenolic or other bio-active components attributed to nut and berry consumption. Further complicating this issue is the observation that study designs utilizing longer-term interventions or that require the intake of a large amount of the test food are more likely to result in overreporting food intake due to fear that participants may be dismissed from the intervention. Most clinical trials using nuts and berries have been conducted in middle-aged or older Caucasian adults with one or more cardiometabolic risk factors. Whether these results extend to other population groups is either inferred or unknown. Future research would benefit from extending the study populations to include those from other racial and ethnic groups. This is particularly important inorder to address the current NIH research initiative in precision nutrition and health, the “Nutrition for Precision Health powered by the All of Us Research Program”. The inclusion of biological females in clinical nutrition trials is imperative, yet the current literature includes predominantly male participants. Because many studies on nuts and berries focus on cardiometabolic outcomes, the unique aspects of female physiology must be considered. For example, vascular function fluctuates with the phase of the menstrual cycle, which has largely been ignored in most past studies.

More studies are also needed in young children as well as in young adults up to about the age of 40. A pilot study reported a correlation between blueberry supplementation and acute positive effects on memory and executive function in 7- to 10-y old children. A large study among pregnant women-infant dyads reported positive protective neuropsychological effects on long-term cognitive development in children at 1, 5, and 8 y of age when nuts were consumed during gestation. Finally, translation of research results is challenging when considering socioeconomic status , particularly when food items are not accessible or affordable. Barriers to participation in clinical research studies among those of low SES include a low interest in clinical trials, inefficient or inadequate explanation of the study in culturally appropriate terms, participants’ distrust of biomedical research, and participant burden, including lack of transportation or the inability to prioritize participation in research over work obligations.Like many other dietary studies, research on nuts and berry studies often use acute studies evaluating postprandial effects. However, either a lack of or successful demonstration of benefits does not necessarily predict a similar outcome over extended periods of intake. Depending on the outcome measure, detectable effects may take weeks or months for the intervention. Only a limited number of studies exist assessing the impact of nut or berry intake on the incidence or severity of diseases or metabolic dysfunction, which require durations of months or years. Precision nutrition evaluates an individual’s unique biological characteristics such as genotype and phenotype, including DNA expression, influences of the gut microbiome, and metabolic response to specific foods or dietary patterns, as well as dietary habits and external factors influencing outcomes such as social determinants of health, to determine the most effective dietary strategies to improve health and prevent disease. Understanding the sources of inter individual variability that contribute to metabolic heterogeneity and applying mathematical modeling and computational algorithms will be essential to refining dietary recommendations. Several recent publications comprehensively review research gaps and study design considerations in the field of precision nutrition and specifically concerning phenolic-rich plant foods. Precision nutrition will lead to important discoveries pertaining to inter individual responsiveness to the intake of nuts and berries. Ultimately, this information can be applied via targeted recommendations to individuals and groups for achievable and sustainable dietary intake of nuts and berries to promote optimal health. The incorporation of bio-monitoring technologies into study designs may also be used for precision nutrition. Current and emerging mobile devices can provide continuous data collection in free-living populations with minimal participant burden. The study of nuts and berries would be enhanced with the use of devices that can capture real-time physiological outputs at home that reflect normal living conditions. Further collaborative efforts in the fields of bioengineering and artificial intelligencehold promise for advancing the understanding of benefits from nuts or berries. An emerging personal bio-monitoring technology is the Precision Health Toilet, hydroponic grow systems which collects and evaluates human urine and stool, which are then analyzed using artificial intelligence to determine flow rate and volume of urine, as well as fecal analysis via the Bristol Stool Scale. A second type of toilet seat, the Heart Seat, has recently been approved by the US Food and Drug Administration for home use to monitor heart rate and oxygen saturation, with future plans to add sensors that monitor systolic and diastolic blood pressure.

Assessment of metabolites in the excreta seems like a feasible goal for future development, which may be useful, for example in the detection of urinary and fecal metabolites that can reflect the metabolism of ellagic acid to urolithins and of -epicatechin to γ-valerolactone. A third example is an ingestible capsule containing a biological photosensor that can detect gut inflammation. Bioluminescence can be monitored from bacteria that have been engineered to illuminate when they come into contact with a molecule for which they have been coded, such as urolithins from berries or lipid-sensitive metabolites from nuts. Finally, another type of ingestible capsule has recently been detailed that collects samples from multiple regions of the human intestinal tract during normal digestion. This device has been used to explore the role of the gut microbiome in physiology and disease, with novel findings that intestinal and stool metabolomes differ dramatically. The ability of nut or berry intake to alter such metabolomes, and their association with changes in physiological function and health outcomes, would be an interesting area for future research. Although these technologies are still in their infancy, they have promise to further precision nutrition research efforts on nuts and berries. Research addressing the issue of “responders” compared with “nonresponders” is important in understanding the metabolic discrepancies in many studies on nuts and berries. For example, platelet aggregation phenotypes can vary significantly by individual responsiveness to oxylipins, bio-active lipid mediators derived from polyunsaturated fatty acids present in nuts as well as in extra virgin olive oil. Variations in circulating metabolites and microvascular function following the intake of freeze-dried strawberry powder have been reported. Those individuals producing increased nitrate and nitrite levels showed favorable changes in function whereas those showing no change in nitrate or nitrite levels did not. Another example is illustrated by a recent letter in response to a systematic review of almond intake and inflammatory biomarkers. The letter notes that while the review included amounts of almonds ranging from 10 to 113 g/d, favorable responses only occurred at intake of <60 g/d. Further, the authors note that although the review reports beneficial effects of almond intake on reduction in C-reactive protein and interleukin-6, subgroup analyses showed that the effects on these 2 outcomes were not significant among those with obesity or who were rated as unhealthy prior to the intervention. Characterizing participants according to precision nutrition, including the use of genetic phenotyping to identify target genes that may result in “responders” and “non-responders” prior to enrollment may be helpful for clinical trials but does not reflect responses in a free-living population. Furthermore, in addition to physiological variations, sociobehavioral differences amongurolithinfaciens. Urolithins may decrease symptoms of chronic metabolic diseases, including inflammation and dyslipidemia. Following a single intake of red raspberries, individuals with prediabetes and insulin resistance had lower concentrations of circulating urolithins compared to levels found in those who were metabolically healthy, a result related to gut microbiome composition. In the same population, consuming red raspberries for 4 wk improved hepatic insulin resistance and total and LDL cholesterol in the prediabetes group, and the effects were related to decreased R. gnavus and increased E. eligins. Overall, including a practical amount of red raspberry in the diet regularly is a low-calorie dietary strategy that improves gut microbiota composition and function in individuals with prediabetes and insulin resistance resulting in improvements in metabolic health. With a sustained emphasis on the role of gut microbiota in nutrition research, advances in our understanding of food-gut dynamics will provide new insights about the role of nuts and berries in human health and performance. Although research on a specific nut or berry provides insight into bio-activity and potential mechanisms of action, such focus also creates the potential for fragmentation because the search for overall dietary patterns is not addressed. The composition of fruits and nuts differ at the molecular level, and a broader view assessing similarities in chemistry and health benefits is critical for translational research as well as for messaging purposes. For example, blueberries, strawberries, pomegranate, walnuts, and grapes all have reported benefits for cardiovascular health, driven largely by the presence of similar polyphenols, which are present at varying quantities in each of these foods.