Micronutrients encompass both vitamins and minerals, with vitamins being subdivided into both water-soluble and fat-soluble categories. The water-soluble vitamins include the B vitamins and vitamin C, and the fat-solubles include vitamins A, D, E, and K (1). The general properties of the different vitamin classes can impact the factors that modify their bioavailability. Fat soluble vitamin uptake, whether endogenous or supplemental, involves bile-acid mediated emulsification and formation into micelles for absorption. Adequate dietary fat improves the absorption of these vitamins, whereas any condition that decreases bile production can inhibit uptake (11). When compounding all these vitamins into enhanced vitamin forms for fortification/supplementation, the emulsion droplet size impacts bioavailability, where optimal absorption is achieved with sizes below 1 micron (see Section 7.4). This contrasts with water-soluble vitamins, which are absorbed directly from the intestines without being impacted by these same processes (1, 11). This is not to say that there aren’t other factors that impact water soluble vitamins, and many are discussed below, including binding by components of the plant matrix. In many instances, though, factors that inhibit uptake of water-soluble vitamins are more impactful on endogenous vitamins than supplemental vitamins (10, 21). Minerals are quite different in that they are inorganic ions often found as salts, or in complexes with amino acids, organic acids, or peptides (1). They tend to have relatively low bioavailability, and are highly susceptible to binding by antagonists such as phytate, polyphenols, fiber, and other constituents in plants which inhibit binding to their receptors and thus their uptake (10, 11). Supplemental forms of minerals can vary greatly in their bioavailability and reactivity with the food matrix. For example ferrous iron is more bioavailable yet more reactive than ferric iron, zinc sulfate is more bioavailable in general than zinc oxide, and complexed mineral forms tend to be more bioavailable than salt forms (18, 33, 35–38).

The food matrix can greatly impact bioavailability. A recent review on the bioavailability of 13 vitamins and choline concluded that in general, vitamins in foods from animal sources are more bioavailable than vitamins from plant sources (10). There are a variety of reasons for this. First, certain vitamins can be trapped in or bound to the food matrix in plants. Niacin for example can be linked to carbohydrates or peptides in grains and not fully released, in which case its bioavailability will be low unless the grains are subjected to alkaline treatment, as occurs with the making of tortillas (39, 40). Historically, poor bioavailability of the nicotinic acid form of niacin in corn was an important cause of pellagra (1). Similarly, entrapment in the insoluble cellular structure of certain plants has also been described to reduce the bioavailability of provitamin A carotenoids (41) and food folates and other B vitamins (11, 40, 42).

Second, plants contain several dietary antagonists that can reduce the absorbability of certain micronutrients. The classical example here is the presence of phytic acid, which is the primary storage form of phosphorus in legumes, cereal grains, and certain seeds. Phytic acid chelates metal ions, particularly calcium, zinc, and iron, and dramatically reduces their intestinal uptake (43–45). Other metal ion inhibitors include polyphenols and fibers (10, 11, 45). Indeed, plant-based iron is less bioavailable than heme-bound iron; the US IOM (now NAM) reports that iron is approximately 44% less bioavailable in a vegetarian diet than in a mixed Western diet (10% vs. 18%, respectively) (45, 46). Similarly, absorption of fat-soluble vitamins such as vitamin D and vitamin E, carotenoids, and fatty acids can be inhibited in diets high in fiber, including pectins and lignins (11). Vitamin B₆ commonly is found as pyridoxine-β-D-glucoside in plants. This form has a bioavailability of approximately 50%, in contrast to free pyridoxine HCl, which is nearly 100% bioavailable in fortified foods (22, 47).

The lower bioavailability of vitamins from plant vs. animal sources has important ramifications. A number of scientific and policy organizations now advocate for an overall reduction in the consumption of animal-based foods, both for health and environmental sustainability reasons (10, 48, 49). However, micronutrient bioavailability in plant-based foods needs to be considered. Supplementation and food fortification with vitamins represent low cost, safe, and effective strategies to ensure adequate intakes of highly bioavailable vitamins in all diets, including in vegetarian or vegan diets (18, 49–54).

Several vitamins come in multiple forms, or vitamers, and the form that is ingested can have an impact on bioavailability. For example, the most common forms of vitamin A in the human diet are preformed vitamin A (retinyl esters) and pro-vitamin A (β-carotene) (46). The absolute bioavailability of β-carotene has been reported to be around 8–10% for cooked carrots, 15% for sweet potatoes, and 5% in spinach (10). The absorption and conversion of all-trans-β-carotene in oil is estimated to lead to a bioavailability of 40%, and for pure retinol of 80% (10, 46).

The EFSA NDA Panel concluded in 2014 that the bioavailability of food folate is around 50%, i.e., half that of folic acid taken on an empty stomach, whereas the bioavailability of folic acid from fortified foods or from a supplement ingested with food is about 85% (55). Indeed, Dietary Folate Equivalents (DFEs) have been established by national and international expert bodies to reflect these findings—1 μg of DFE is equivalent to 1 μg of food folate, but only 0.6 μg of folic acid either from a fortified food or a dietary supplement consumed with food (25, 28). The earlier IOM (NAM) equivalents are similar, but make a minor distinction in relation to folic acid on an empty stomach: 1 μg of DFEs is equivalent to 1 μg of food folate, or 0.5 μg of folic acid taken on an empty stomach, or 0.6 μg of folic acid with meals (25). Similarly, in Europe EFSA has established a conversion factor for calcifediol as 2.5 times the bioavailability of cholecalciferol, thereby recognizing the variable bioavailability across various vitamin D forms (56).

Bioavailability of a nutrient can also depend on the intake of the nutrient. Vitamin C illustrates this well because its absorption is saturable. Clinical data indicate that between 80 and 100% of vitamin C at single doses up to 100–200 mg are fully absorbed into the bloodstream (57–59). However, bioavailability diminishes at higher doses, and is less than 50% at doses exceeding around 1,000 mg (58). At doses between 30 and 100 mg per day there is a steep, dose-dependent increase in circulating vitamin C levels, with saturation in the plasma at doses of 200–400 mg per day (Figure 2). Certain technologies, such as lipid-based formulations have been reported to increase the absorption into the bloodstream, both with respect to peak levels and total absorption as indicated by area under the curve (see below) (60).

Zinc also provides an illustrative example. As the content of absorbable zinc in the diet increases, the proportion of this zinc that is taken up decreases. This modulation of absorption efficiency is an important mechanism by which the body maintains zinc homeostasis (21, 61). Similarly, homeostasis also is maintained by variable rates of zinc excretion, and thus the balance of absorption and excretion. Indeed, substantial increases in absorbed zinc can be counterbalanced by increases in intestinal zinc excretion (61).

While not strictly a bioavailability issue, micronutrient stability can affect the outcome of micronutrient interventions if the consumer does not ingest the intended or labeled quantity of micronutrients. Vitamins are variously sensitive to heat (for example during cooking, pasteurization, or sterilization), moisture, oxygen, oxidizing and reducing agents, metallic ions, pH and other food components in different degrees (62). In addition to heating, other aspects of food processing can be destructive. For example, slicing or dicing of fruits and vegetables can increase the losses of vitamin C due to increasing the surface area of the food that is exposed to oxygen. Dehydration can lead to increased losses of vitamin C, niacin, and thiamin in vegetables. Other considerations of the food matrix itself can also be important. For example, thiaminase enzymes are present in certain foods including seafood and beans and can promote degradation of thiamin. On the other hand, the presence of egg albumin and casein enhance thiamin stability. All of these factors conspire to impact the stability of vitamins during processing and over the shelf-life, often necessitating the addition of an “overage” of vitamins during the formulation of fortified foods (62). These are important considerations—a wheat flour and maize meal fortification program of excellent design brought little impact due to insufficient dosing of the premix and perhaps stability issues as well (63). As vitamins can be formulated to withstand specific conditions in particular foods, there is an urgent need for the establishment of quality as a critical driver for effectiveness of food fortification programs.

With respect to life stage, the maturation of the digestive tract and the concomitant absorption of nutrients (perhaps especially macronutrients) is still developing in infants in the first weeks and months after birth (11, 64). The elderly also experience differences in nutrient absorption when compared to younger adults, because of changes in secretory and absorptive capacity in the stomach or intestines that occur with aging. These changes do not impact macronutrient bioavailability, but do reduce the bioavailability of specific micronutrients, including certain B vitamins, vitamin D, and (primarily as a result of problems with vitamin D metabolism) calcium (11, 65, 66). Vitamin B₁₂ malabsorption and deficiency are also common in older adults (67). Indeed, it has been estimated that between 20 and 40% of older individuals are deficient, with up to 70% of those cases due to malabsorption issues (68). Vitamin B₁₂ absorption is mediated by its binding to intrinsic factor (IF), which is a protein secreted by parietal cells in the stomach. B₁₂-IF complexes are bound by receptors in the ileum, in the presence of calcium, for absorption (67). The elderly are vulnerable to reduced IF secretion due to loss of parietal cells from pernicious anemia or atrophic gastritis. Decreased production of stomach acid and proteases are also common, and can lead to decreased release of B₁₂ from ingested food proteins and thus decreased absorption (69). Similarly, common medications such as proton-pump and H2-receptor blockers also reduce gastric acid production, again reducing B₁₂ bioavailability (68). For this reason, certain experts recommend supplemental vitamin B₁₂ in older adults significantly exceeding published requirements (67).

Physiological adaptations can occur in response to states of rapid growth, pregnancy, and lactation to increase the bioavailability of nutrients in response to elevated requirements. In addition, these changes can occur in the face of prolonged low nutrient intakes (11). These changes include increased absorptive capacity in the intestines and increased renal nutrient retention, among other mechanisms (11). These adaptations can be reversed when nutrient requirements decrease, or nutritional intakes increase.

Pregnancy and lactation provide examples of physiological states with increased nutritional requirements. Data indicate that calcium, zinc, iron, and copper intestinal absorption increases, and/or renal conservation increases during pregnancy and/or lactation (11). These effects appear to be at least partly due to the hormonal changes associated with pregnancy, particularly estrogen. Indeed, estrogen has been reported to regulate intestinal calcium absorption in humans and rodent models, with estrogen stimulating increased expression of calcium transport proteins in the duodenum (70, 71). Likewise, the increase in circulating copper concentrations observed during pregnancy has also been ascribed at least partly to increased estrogen levels (72).

Conversely, calcium absorption starts to decline during the transition to menopause, and circulating estradiol concentrations are reported to be a primary determinant of absorption rates (73). Furthermore, calcium absorption continues to decrease in postmenopausal women. These findings make sense, given the mechanistic studies described above. The health impact is enormous, as about a third of postmenopausal women will develop osteoporosis (74). Consistent with these data estrogen therapy improves calcium absorption, which is accompanied by increases in blood calcitriol, in postmenopausal women with osteoporosis (75, 76). For these reasons groups such as the NAM and the International Osteoporosis Foundation recommend increased calcium intakes in women over 50 years old compared to the same aged men or younger female adults (77, 78).

Apart from overall physiological status, the activation or inhibition of individual metabolic pathways across tissues and nutrient-induced transporter desensitization can also influence bioavailability (79). A prominent example is the secretion of hepcidin following iron exposure in the GI tract, which acts to inhibit further iron uptake via its influence on the cellular iron exporter ferroportin (discussed in more detail below) (80).

A wide variety of disease states can alter nutrient bioavailability and/or status. Diabetes is one notable example. Metformin is the first-line drug prescribed for glycemic control in type 2 diabetes mellitus (T2DM) and is reported to be among the top 10 of medicines prescribed globally. Although metformin has a good safety profile, its use is well-described to be associated with an increase in vitamin B₁₂ deficiency, at least partially by reducing B₁₂ absorption in the small intestine (81, 82). Metformin-induced B₁₂ deficiency is likely a cause of diabetic neuropathy, which can affect up to half of type 2 diabetics (81). Metformin may also contribute to reduced status of other B vitamins, including thiamine and folate, as well as potentially vitamin D and magnesium. Furthermore, a substantial percentage of type 2 diabetics are prescribed medications including proton pump inhibitors and histamine H2 receptor antagonists, both of which also negatively impact vitamin B₁₂ and magnesium status (81). Vitamin B₁₂ supplementation has shown to be effective at preventing or treating metformin-induced B₁₂ deficiency, and potentially at alleviating neuropathy (82, 83).

Cancer is among the leading causes of death globally, and has substantial impact on nutritional status (84, 85). Indeed, malnutrition is a serious cancer co-morbidity that impacts between 40 and 80% of cancer patients, negatively influencing quality of life, numerous treatment outcomes, and survival rates (86). The malnutrition can result from systemic inflammation that leads to reduced food intake (anorexia) and ultimately weight loss. Other contributing factors to reduced intake include alterations in taste and smell perception, mouth sores, early satiety, nausea and vomiting, swallowing difficulties, reduced intestinal motility, and side effects from medications (86, 87). Due to reduced intake, the bioavailability of the nutrients that are ingested is critical. Unfortunately, malabsorption is also common in these patients (87). Malnutrition in these patients contribute to sarcopenia and cancer cachexia, although cachexia is not treatable by conventional nutritional support alone. Indeed, the most pressing nutritional problem in cancer is muscle loss, which predicts negative outcomes including decreased survival. Micronutrient status and supply can also be a concern (86). For these reasons, regular nutritional screening for cancer patients is recommended, including assessment of nutritional intakes, weight changes, and BMI (87, 88). Both the 2017 and 2021 ESPEN guidelines for clinical nutrition in cancer patients recommend nutritional interventions, including oral nutritional supplements, for those who can eat but are at risk of malnutrition. These guidelines include a strong recommendation for protein intakes above 1 g/kg/d and up to 1.5 g/kg/d, and a strong recommendation that “vitamins and minerals be supplied in amounts approximately equal to the RDA” (87, 88). Use of micronutrient supplements is also supported by the American Cancer Society and the American Institute for Cancer Research (86).

Furthermore, a wide variety of common medications can impact nutrient bioavailability or status (89). As mentioned above, proton pump inhibitors reduce absorption of dietary (but not supplemental) vitamin B₁₂ and may also reduce calcium uptake. Certain oral contraceptives appear to reduce the status of many vitamins and minerals, including folate (90). Certain classes of anti-epileptic drugs reduce folate absorption and increase folate metabolism (91). Diuretic use increases urinary excretion of magnesium and potassium (89). Methotrexate, which is a cancer drug and is also used to treat autoimmune diseases, is a folate antagonist (91). Likewise, statins are reported to reduce vitamin D synthesis, because vitamin D is synthesized by the body from cholesterol (92). Unsurprisingly, certain medications that reduce absorption of fat (often as a treatment to support weight loss) also reduce the absorption of fat soluble vitamins, including vitamins A, D, E, and K (93). Additionally, glucagon-like peptide-1 (GLP-1) modulating drugs which have become widely used, reduce micronutrient absorption through reduced food intake and gastrointestinal effects (see below). These micronutrient-drug interactions can result in micronutrient inadequacy or deficiency, especially with long term medication use, and in many cases can necessitate dietary supplementation.

A classic example of the impact of nutritional status on nutrient bioavailability occurs with iron. The human body regulates the absorption of iron such that absorption diminishes as iron status improves (94). In addition, in the case of iron inadequacy, other mechanisms allow the “export” from iron stores to regulate the status (95). Plasma iron concentrations and total iron content of the body are regulated by hepcidin, which inhibits the iron transporter ferroportin to regulate iron absorption from the duodenum, and the release of iron from hepatocytes and macrophages. Inhibition occurs by direct binding, as well as inducing ferroportin ubiquitination, endocytosis, and degradation. Hepcidin production by hepatocytes is regulated by status—an iron deficient individual will produce less hepcidin, and one who is replete will produce more. Notably, serum hepcidin levels are reported to decrease during menstruation, and subsequently increase during the second half of the menstrual cycle (96).

Hepcidin production also is regulated in pregnancy in order to meet the increased demand for iron from both the mother and fetus (80). It has been elegantly demonstrated that iron supplementation increases hepcidin levels, whereby the iron supplementation paradoxically drives reduced iron bioavailability, and that therefore alternate day supplementation is more effective than daily supplementation, showing that also timing of intake can influence bioavailability of nutrients (97).

The status of one (or several) micronutrients can also affect the bioavailability of others. For example, in humans, vitamin A deficiency can impair intestinal iron absorption and mobilization, and vitamin A supplementation can enhance the efficacy of iron supplementation through the enhancement of absorption, mobilization and erythropoiesis (98). The net result is an improvement in hematological indicators. Vitamin C also enhances the absorption of dietary iron, influences its mobilization, and dampens the prooxidant effect of iron, together with vitamin E (98–100). Riboflavin enhances the hematological response to iron, and as such riboflavin deficiency may be a primary cause of anemia in many populations due to the condition of immature intestinal villi associated with riboflavin deficiency, and its role in iron mobilization (98). Adequate status of all these vitamins, along with folate, vitamin B₆, vitamin B₁₂, and potentially vitamin D, plays roles in reducing the incidence of anemia (101). The anemia example, demonstrating the interdependency of multiple micronutrients in iron metabolism, highlights the importance of a holistic approach to nutrition, and that simply providing higher doses of a single nutrient (in this case, iron) is not the right strategy (98, 101).

Understanding the contribution of the gut microbiota to nutrient bioavailability is still an emerging area of research, but it is clear that commensal species exert an impact on vitamin supply and bioavailability to the host. The so-called “micronutrient-microbiome axis” operates in both directions—the microbiota both consume nutrients including vitamins in the gut, and produce them as well (102). As such, increasing evidence demonstrates that commensal species can both positively and negatively impact the amount and/or absorption and bioavailability of a wide range of vitamins and minerals (103, 104). For example, supplementation with vitamins A, B₁₂, C, and D are reported to promote growth of beneficial species from a variety of genera, including Bifidobacterium, Lactobacillus, and Roseburia. Certain bacterial genera, including Bifidobacterium, Enterococcus, and Bacteroides synthesize substantial amounts of both B and K vitamins (102, 103, 105). Moreover, B vitamin absorption may be enhanced by probiotics that regulate intestinal pH (104). Associational studies suggest a relationship between the gut microbiota and fat soluble vitamin status, even though the microbiota are not known generally to produce most of these vitamins (vitamin K being an exception) (103). Finally, there are also reports that supplementation with certain probiotic strains can lead to an increased vitamin status. For example, supplementation with a Lactobacillus reuteri strain was associated with an increase in vitamin D status (106).

Increased bioavailability of minerals seems to be related to the availability of bacterial enzymes or production of short-chain fatty acids (SCFA) by the microbiota. Bacterial phytase may be capable of breaking down chelated complexes with iron, calcium, magnesium and phosphorous, thus making these minerals available in the lumen. Human studies have shown that iron absorption is enhanced when providing specific probiotics (102). In animal studies, a higher production of SCFA appears to facilitate calcium and phosphorus absorption. In human studies, supplementation with a prebiotic increased calcium absorption; the postulated mechanism is a decrease in pH due to higher microbiota activity which facilitates minerals remaining in their soluble form (102). Finally, zinc bioavailability increases when combining supplementation with certain probiotics (103).

Dysbiosis can negatively impact nutrient bioavailability. Small intestinal bacterial overgrowth (SIBO) is a condition that exemplifies this. SIBO is characterized by both an increase in the amount of bacteria in the proximal small intestine, as well as a change in the bacterial profile of certain groups such as coliforms, more commonly seen in the distal intestine (107, 108), with varying degrees of severity (107). SIBO is reported to be accompanied by villous atrophy and inflammation of the intestinal epithelium, resulting in decreased absorptive surface area and capacity, deconjugation of bile acids by the microbiota leading to malabsorption of fat and fat-soluble vitamins, bacterial degradation of sugars, and reduced activity of brush border enzymes (108). From a micronutrient perspective, SIBO is linked to reductions in bioavailability (and increased risk of deficiency) in vitamins A, D, E, B₁₂, as well as iron (107, 108).