Historically, the nutritional sciences are built on the study of single nutrients or food components in relation to health outcomes. Although this has been a useful concept when it comes to specific deficiency diseases, the picture became blurry when studying the role of nutrition in complex diseases. The notion that the sum of the parts does not necessarily explain the result of the whole has prompted a shift in focus from single nutrients to whole foods, meals, and dietary patterns. Studying the biological activity of single nutrients in their interaction with other nutrients and food components from whole foods, especially during their stay in the gastro-intestinal tract, helps to better understand the underlying positive and adverse health effects of whole foods, meals, and dietary patterns.

Bioavailability of nutrients from whole foods is a research area that has received ample attention in the past decades, although studies in humans are still limited. Over time, some consensus has been reached on the definition of bioavailability, which is the fraction of an ingested nutrient that becomes available for use and storage in the body (1). In this definition, bioavailability goes beyond mere absorption from the gut and also includes the use and storage (retention) in body tissue. The study of absorption and bioavailability of nutrients from foods in humans requires sophisticated methods that take into account endogenous nutrient losses through the enterohepatic circulation as well as incorporation of nutrients into storage tissue. Use of isotopes, both radio-isotopes and stable isotopes, have greatly improved accuracy and precision of in vivo nutrient bioavailability studies, either as a single nutrient or as part of a food, meal, or dietary pattern (2). Although in vitro methods are much cheaper and faster than in vivo methods, allowing for large numbers and experimental conditions, translation of findings to full body human conditions is still cumbersome (3, 4). Therefore, this review uses only bioavailability data from in vivo studies in humans, although the underlying mechanisms of interactions between food components are mostly based on in vitro or animal studies.

The main objective of this review is to provide an overview of insights into nutrient bioavailability from complex foods in humans, thereby highlighting the current state of knowledge on synergistic and antagonistic processes among food components. Two different food groups are put in the spotlight for this purpose, i.e., dairy, and fruits and vegetables. Both of these food groups contain a myriad of nutrients, for some of which the bioavailability is now well-understood, whereas others still require further study. Both food groups also contain many bioactive components and have a complex matrix, which affect the kinetics of nutrient release, absorption, and bioavailability. Understanding of these processes will help to better predict the true nutrient value of foods and to incorporate this information into diet scores in the future.

Dairy refers to food products that have milk—mostly cow's milk—as their main ingredient such as buttermilk, yogurt, cheese, and all closely related products. Dairy is characterized by a relatively high amount of protein and fat, and can therefore make an important contribution to calorie intake unless low-fat alternatives are consumed. Intake of dairy varies greatly between and within world regions, with an estimated average intake of milk (excluding other dairy products) of ~200–240 g per day in Western Europe and North America, ~130–300 g per day in Latin America, ~100–200 g per day in Africa, and 20–150 g in Asia¹. Despite controversy around the healthfulness of dairy with respect to non-communicable disease risk, scientific evidence consistently points toward either beneficial or neutral effects (5–10). In addition, positive effects on bone mineral density have been found, as well as reduced fracture risk in some populations (9, 11). Such beneficial effects have been attributed to calcium as well as to various other nutrients and bioactive components present in milk (11).

In industrialized countries, dairy stands out as source of calcium, but it also contributes for 20–40% to the intake of vitamins A, B2, B12, and K as well as of phosphorous, magnesium, zinc, and iodine (12– 23)². In the next sections, the absorption and bioavailability of these nutrients from milk and dairy foods will be described, with special attention for calcium.

Dairy is by far the most important source of calcium in the human diet and it has therefore been studied most extensively among the nutrients derived from dairy. Bovine milk contains an average of 120 mg calcium per 100 mL. In Europe and North America, ~75% of dietary calcium is derived from milk and dairy products, with an additional 15% from vegetables and fruits, 5% from mineral water and the rest from other foods (24, 25). Approximately 40% of calcium from dairy sources is absorbed under normal circumstances, with higher absorption in children and lower absorption in elderly (26, 27). In the body, 99% of calcium is present in the skeleton. The efficiency of calcium storage in bone tissue is mainly determined by physiological factors (e.g., related to growth, pregnancy, and lactation), and is regulated by several hormones, such as PTH, calcitonin, calcitriol, and estrogens. Excessive absorbed calcium is excreted in urine, feces, and sweat. Adults are generally in negative calcium balance after their peak bone mass (~35 y) and loose ~10 mg of calcium each day, although in post-menopausal women the daily loss may be 40 mg per day or more (28). Bioavailability of calcium is determined by absorption in the small intestine on the one hand and by incorporation into bone tissue on the other hand. Both of these processes can be influenced by dietary factors. The bioavailability of calcium may therefore be defined as the fraction of dietary calcium that is absorbed by the intestine and is used for bone mineralization.

Intestinal absorption of calcium mostly happens by passive diffusion, whereas active transport at low and moderate calcium intake is under regulation of vitamin D (24). Fortification of milk with vitamin D2 was shown to enhance calcium absorption (29). A number of milk and dairy components have been found to aid in the passive absorption of calcium (and also of other divalent cations), such as phosphopeptides, casein and whey proteins, lactose and phosphorous (Table 1). Phosphopeptides, which are products of the enzymatic hydrolysis of casein, sequester calcium thereby protecting it from precipitation by anions like phosphates in the intestine (30–32). The same is true for alpha lactalbumin and beta lactoglobulin, both whey proteins (24), and for amino acids such as L-lysine and L-arginine (30). The calcium bound to these amino acids, peptides, and proteins is readily released during digestion by bringing it slowly into solution, which is an important prerequisite for passive diffusion.

Lactose also seems to enhance calcium absorption, although the mechanism has long been unclear (42). The most likely explanation is that, like other sugars, lactose widens the paracellular spaces in the enteric cell lining, thereby enhancing passive diffusion (33). However, studies have shown that this mostly happens at relatively high doses of lactose (43, 44), whereas in the amounts present in milk and dairy it is less likely to contribute much to absorption (45, 46). When lactose is hydrolyzed, such as in yogurt, or absent, such as in cheese, calcium absorption does not seem to be affected (47). Nevertheless, lactose seems to be important for calcium absorption in case of high calcium intake in combination with poor solubility, such as seen in babies and the elderly (48, 49). It may be that, similar to galactic-oligosaccharides, lactose functions as a prebiotic and stimulates calcium absorption in the cecum and colon by enhancing the growth of bifidobacteria and thereby maintaining low pH (50, 51). This hypothesis is supported by evidence from lactose-deficient patients, who do not seem to have compromised calcium absorption (52).

Apart from factors that enhance calcium absorption, several dairy components can inhibit the uptake of calcium (Table 1). Protein, especially sulfur-containing protein, has been shown to lead to a negative calcium balance through increased urinary calcium excretion (24). Nevertheless, the conclusion of a working group that more recently reviewed the current evidence linking dietary protein intake with bone health was that, although a high protein diet—either of animal or vegetable origin—is associated with increased urinary calcium excretion, this is more likely due to higher intestinal calcium absorption than to bone resorption (53, 54). Milk fats can form insoluble soaps with calcium; however, these are dissociated at the low pH of the stomach and therefore do not affect calcium bioavailability negatively (41). This explains that calcium from cheese is readily available for absorption despite the high content of saturated long chain fatty acids (24, 55).

Phosphorous plays a dual role in calcium absorption, by, on the one hand, binding calcium and inhibiting its absorption in the small intestine resulting in increased fecal excretion of calcium, and, on the other hand, after being absorbed, by increasing the reabsorption of calcium in the distal part of the nephron or by enhancing the uptake of absorbed calcium into bone (24, 54). The inhibitory properties of phosphorous on intestinal calcium absorption may partly be countered by phosphorylation of lactose, thereby keeping calcium in solution (24). However, this hypothesis has not yet been confirmed (41, 55). Also, the high phosphorous content of milk may counter the hypercalciuria induced by protein (54, 56). The recommended dietary intake ratio for calcium (mg) to phosphorous (mg) ranges from 1:1 to 1.5:1, with ratios <0.5 being associated with decreases in bone mineral density (57). Moreover, excessive intake of phosphorous has been shown to induce the secretion of fibroblast growth factor 23 (FGF-23) from bone, thereby decreasing the formation of 1,25-dihydroxyvitamin D3 and decreasing intestinal calcium absorption (57, 58). Cow's milk provides calcium and phosphorus in a reasonable balanced ratio of ~1.2:1.

Overall, although intestinal absorption of calcium from milk and dairy is very similar compared to other sources such as calcium salts, vegetables, or mineral water, its net effect on calcium retention is generally higher (59) with little difference between the various dairy products (milk, acidified milk, yogurt, skim milk, cream cheese, hard cheeses) (24). Diets including dairy products can therefore be considered as the most optimal calcium-dense option to prevent adverse health effects related to a negative calcium balance.

Vegetables and fruits form a widely diverse food group that contains a broad range of essential nutrients. Vegetables and fruits are generally low in fat and proteins and therefore contribute relatively little to energy intake. Ample consumption of vegetables and fruits is promoted worldwide. Such recommendations are based on studies consistently showing that higher intake of vegetables and fruits is negatively associated with all-cause mortality and mortality from cardiovascular disease and cancer (89, 90). Close to 75% of the world population consumes less than the recommended 400 g of vegetables and fruits on a daily basis (91). Low consumption of vegetables and fruits is estimated to contribute 1.8% to the total global burden of disease, primarily through cardiovascular diseases and cancer (92).

So far, studies have failed to attribute the healthful effects of vegetables and fruits to any of its isolated components. Therefore, health benefits from vegetable and fruit consumption are rather to be explained as the resultant of additive and synergistic effects of its components (63–66). They are a particular rich source of pro-vitamin A carotenoids, vitamin C, folate, vitamin K-1, potassium, calcium, magnesium, iron, and several other trace elements (14, 93)².

Non-nutritive bioactive compounds are also present in multitude, comprising of phenolics, carotenoids, and glucosinolates. Although these bioactive compounds are regarded as non-essential for human survival, they may exert health effects such as reduced risk of non-communicable and degenerative diseases (71–76). Delivery of fiber, both digestible and indigestible, is another important nutritional aspect of vegetables and fruits. It has an important impact on satiety, gastrointestinal processing, metabolic parameters, and microbiota composition. It constitutes a group of heterogeneous polymers such as non-starch polysaccharides, cellulose, resistant starch, inulin, lignins, chitins, pectin, beta-glucans, and oligosaccharides. Dietary fiber may stimulate intestinal fermentation, thereby altering the production of microbial phenolic metabolites and enhancing mineral absorption (94, 95). However, dietary fiber can also negatively affect the absorption of nutrients because of gel formation, increased viscosity, or binding and entrapment (96–98). Other compounds present in vegetables and fruits may have negative consequences for human nutrition and health, such as alkaloids, oxalates, phytic acid, lectins, trypsin and protease inhibitors, tannins, and cyanogens. Anti-nutrients can be removed or inactivated by various food processing procedures, such as fermentation, germination, boiling, leaching, and extraction (99).

Both milk as well as vegetables and fruits are nutrient-dense foods that provide a myriad of nutrients which impact human metabolism and health. Bioavailability is an important explanatory step between the food source and potential health effects of its food components. Much of the health benefits of foods may be explained by additive, antagonistic and synergistic processes at the level of uptake and absorption of nutrients. As has become clear from this review, bioavailability values from whole foods have been established in humans for some nutrients, but are still lacking or need confirmation for others. Translation of this information to individual diet scores will require detailed dietary intake information, preferably at the meal level, while taking information on bioavailability of nutrients from separate foods as well as food-to-food interactions into account. This is all the more complex, since bioavailability estimates are currently already incorporated into dietary reference intakes at the population (group) level to a certain extent. Furthermore, host-related factors, e.g., nutrient status, disease state and genetics, also play an important role in nutrient uptake and bioavailability at the individual level and are often unknown. Nevertheless, accounting for nutrient bioavailability based on food intake pattern may result in better estimates of true individual absorbable nutrient intake in relation to health outcomes. Moreover, such knowledge may help in the design of foods, meals and diets that aid in the supply of nutrients to specific target groups.

AM-B conducted the literature review and wrote the manuscript.

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with the author AM-B.