The following is a transcription of the Fourth Quarter 1979 issue of Dr. Royal Lee’s Applied Trophology newsletter, originally published by Standard Process Laboratories.
“Logical consequences are the scarecrows of fools and the beacons of wise men.”
—Thomas H. Huxley
Our last essay examined some basic concepts in human nutrition and reviewed some practical aspects of nutrient function. The next logical step to consider is nutrient bioavailability. That is, will ingested nutrients be assimilated and metabolized for their intended usage? Bioavailability refers to the efficacy of nutrient assimilation. Simply put, it is the extent to which a nutrient can be utilized by the organism.
We usually think of nutrients in terms of milligrams or other forms of measurement. Yet when it comes to actual absorption and usage, it is often not a question of how much but of what form. It should also be evident that many external as well as internal factors may affect bioavailability. We will examine these interesting aspects, some of which are the subject of current research.
Factors Affecting Bioavailability
At least four major factors can be said to affect or influence bioavailability. As already stated, the form of a nutrient can have a significant effect on its degree of absorption. This will be examined more fully. Secondly, the presence or absence of one nutrient may affect the utilization of another. As we noted in the last issue of this publication, increased zinc intake reduces copper absorption. Increased calcium intake can reduce uptake of several trace minerals. Cadmium and mercury reduce mineral bioavailability. Another example involves the transport of vitamin A. The liver does not manufacture retinal-binding protein and prealbumin when dietary protein intake is deficient. The esterified form of the vitamin remains stored in the liver. It is present, but its bioavailability is nil. A person may ingest vitamin A or its precursor beta-carotene, yet still show signs of vitamin A deficiency. Increasing intake is not the answer, obviously.
A third factor involves sites of absorption in the gastrointestinal tract and consequently involves intestinal motility. Genetic factors may play a role here. Whatever slows down or speeds up motility will have an effect on bioavailability. Remember that the autonomic nervous system has a major part to play: parasympathetic activity stimulates or speeds up motility of the gastrointestinal tract, while sympathetic activity inhibits or slows it down.
A fourth factor may involve bacteria living in the large gut. These organisms live on organic molecules not absorbed by the small intestine. In a symbiotic relationship they synthesize such nutrients as vitamin K and small quantities of the B vitamins. Whatever factors modify bowel flora may affect bioavailability.
A brief review of digestive physiology is in order. Rather than go into great detail, suffice it to remind the reader that it is an incredibly sophisticated series of actions, reactions, and interactions involving precisely defined structures, enzymes, and feedback mechanisms. Remember, too, that it is strongly influenced by emotion and by activity. The following material makes no attempt to be definitive, but simply notes significant principles that will have practical considerations.
Aside from the cephalic or brain phase, digestion begins in the mouth. Chewing is important to the digestion of all foods, but especially for fruits and raw vegetables. These have undigestible cellulose membranes around their nutrient portions that must be broken down before they are utilized. Note an important principle: the rate of digestion is dependent on the total surface area exposed to digestive secretions, since enzymes can act only on the surface of a food or nutrient particle. Most salivary secretion of ptyalin (an amylase enzyme) takes place in the parotid, submaxillary and sublingual salivary glands. Saliva has a pH between 6.0 and 7.4 and has an especially large quantity of potassium.
The stomach’s initial function is mixing and storage. It controls the passage of food over a period of time from three to five hours, depending upon its contents. Fatty foods are released more slowly than carbohydrate or protein. Fat entering the duodenum triggers the release of substances that inhibit gastric emptying. Gastric juice contains the hormone gastrin, released by the mere presence of food in the stomach by a mechanical stretching of the antrum. Gastrin stimulates the chief and parietal cells. The parietal cells produce hydrochloric acid, as much as a cup an hour under strong stimulation. The viscous mucous coating of the stomach lining prevents the stomach from digesting itself.
Other proteolytic (protein-breakdown) enzymes include pepsin (produced by the chief cells), which can break up some protein molecules into smaller peptides within seconds. Despite this efficiency, it should be noted that only about 10 percent of hydrolysis, or protein breakdown, takes place in the stomach. The rest takes place in the small bowel. The optimum pH for the proteolytic activity of pepsin is 2.0, thus the need for hydrochloric acid secretion. All of the proteolytic enzymes are very specific for hydrolyzing individual peptide linkages. A specific enzyme is required for each specific type of linkage. This explains why there are so many proteolytic enzymes. No one enzyme can digest a protein all the way to its constituent acids.
(Some molecules of protein are never digested at all, and some remain in the stages of proteases, peptones, and varying sizes of polypeptides. It is postulated that whole proteins can be absorbed by the process of pinocytosis and not the usual absorptive mechanisms. This cellular process is the phenomenon in which minute incuppings or invaginations are formed in the surface of the cell membrane and close to form fluid-filled vesicles.)
Other gastric enzymes include lipases that attack short-chain and medium-chain fatty acids, but almost all hydrolysis of carbohydrate and fat takes place in the small bowel. Parietal cells also generate the production of the intrinsic factor, which combines in the stomach with vitamin B12 and remains attached to it until it passes through and reaches the terminal ileum, where it is absorbed. As stomach acidity returns to normal, release of gastrin automatically stops.
Mixed, acidified, and partially emulsified, food gradually goes into the duodenum. Buffer systems then operate to neutralize the chyme. This mechanism is partly hormonal, partly nervous. The hormones secretin and pancreozymin are released from the duodenal mucosa. Secretin stimulates release of bicarbonate from the ductal cells of the pancreas, rendering pancreatic juice the most alkaline secretion in the body. Pancreatic fluid averages a pH of 8.0. Pancreozymin acts to release a number of enzymes including amylase, lipases, trypsinogen, chymotrypsins A and B, several ribonucleases, elastase, and collagenase. Simply put, pancreatic juice works for further hydrolysis. Proteins are broken down into peptides. Neutral fats become glycerol, fatty acids, and monoglycerides. Carbohydrates become small fragments containing several glucose molecules. These products will be broken down yet further at the brush border of the small bowel, where the microvilli secrete appropriate enzymes.
When fatty foods enter the duodenum, the gallbladder empties its contents. The hormone cholecystokinin is released, causing the relaxation of the sphincter of Oddi, leading to the outflow of stored bile into the duodenum. Bile is secreted by the liver in the form of spherical globules, or molecular aggregates called micelles, which consist of bile salts, cholesterol, and lecithin and contain many negative charges that bind cations, primarily sodium and calcium. Bile acids play an important role in fat digestion, both by aiding in the solubilization of lipids by micelle formation and by the activation of pancreatic lipase. The bile salt molecules are the key to making water-insoluble lipids soluble in the aqueous medium of the small intestinal contents, rendering them ready for absorption.
Bile salts aid in the complex absorption of long-chain fatty acids in the proximal small bowel. These are then reabsorbed in the ileum, pass through the liver, and complete an enterohepatic circulation. The short-chain and medium-chain fatty acids are carried away through portal blood, not needing the micellular solubilization. Within the epithelial cell, long-chain fatty acids are enveloped with a lipoprotein membrane to form chylomicrons and carried away via the lymphatics into the vena cava.
The entire surface of the small intestine is lined by a single layer of epithelial cells, supported by a loose layer of connective tissue and crisscrossed by vascular and lymphatic channels through which absorbed nutrients are carried into the body. The actual process of absorption of the major nutrients in the small intestine consists of the transport of individual nutrients from the intestinal lumen across the cell membranes of individual intestinal cells. Recall that the surface of the small intestine is lined by the villi, with further extensions of these finger-like projections called microvilli about a micron in length and a tenth of a micron in diameter.
Absorption or transfer of substances across the cell lining involves several mechanisms. Very small molecules cross through pores by simple diffusion. Water travels in either direction to equalize osmotic pressure on both sides of the epithelial membrane. Some small water-soluble molecules including some sugars and amino acids enter by means of carrier systems. Glucose and other sugars require active processes, and it is common to speak of these systems as pumps. It should be remembered that almost all nutrients are absorbed in the first inches of the small intestine. Notable exceptions are bile salts and vitamin B12. These are absorbed in the distal ileum, which is equipped with special receptor cells.
A practical consideration: fear and anger inhibit gastrointestinal motility, while pleasurable thoughts tend to stimulate vagus-mediated activity. Psychogenic effects on gastrointestinal motility may rush the passage of nutrients so much that breakdown and absorption cannot take place despite apparently adequate intake.
Mineral Absorption and Bioavailability
The primary factors involved in the absorption of minerals are solubility of the mineral, whether they are in the free ionic state, and the concentration of other competitive mineral constituents in the gut. If the concentration of, say, calcium salts is higher than iron salts, more calcium would be absorbed than iron. The reverse is true also.
In order for a mineral to be absorbed, the organic bond by which it is carried in food must be broken down so the mineral is in its free ionic state. One cannot utilize inorganic chromium or cobalt, however. These must be in organic complexes to be bioavailable. With these exceptions, all the trace minerals can be absorbed better by the intestine in their free ionic state. This explains why substances such as calcium magnesium carbonate (dolomite) are less soluble and thus less bioavailable. Breakdown of mineral complexes is not completely efficient; some of the mineral is lost.
For those who like to argue about which came first, the chicken or the egg, we should note the observed association of calcium with lactose in milk and the observed beneficial effects of lactose in calcium absorption. No matter which side of the argument one takes, the two are in fact associated and their simultaneous presence in the gut has been shown to improve the absorption of calcium. (Early work with radioactively tagged substances was done by Lengemann et al., J. Nutri. 68:443–456, 1959.) We have already noted that ionized minerals are in a form ready for transport, but in this latter case suggestions have also been made that beneficial effects derive from the effect of lactose on the intestinal flora and the consequent lowering of the pH toward the acid side (Nutrition: An Integrated Approach, Second Edition, Pike and Brown, 1975).
As with other nutrients, mineral bioavailability thus depends upon a number of complex interacting mechanisms. Within these mechanisms may be yet other factors that govern uptake and utilization. Iron metabolism is an example.
Despite food fortification and the TV ads extolling the virtues of medicinal iron supplements, iron deficiency remains a common form of malnutrition. Most of the iron in natural foods is present in the ferric form. In the digestive processes ferric iron complexes are broken down and the ionic iron that is released is reduced to the more readily absorbed ferrous form. Yet recent work has shown that chelated or complexed forms of iron are absorbed better than ferrous sulfate (Saltman et al., Ann. Clin. Lab. Med., 6:167, 1976). The absorption of ionic iron is stimulated by ascorbic acid, also by fructose, and by amino acids such as histidine and lysine, which form absorbable ferrous iron complexes.
Phosphate and oxalate ingestion decrease iron absorption, tending to form insoluble compounds in the alkaline environment of the small intestine. Phosphorous in cereals is present as phytic acid, which can also form in soluble combinations unless whole food is present. There are enzymes present in the complete food source that hydrolyze the phytate. In the case of the calcium magnesium salt, phytase splits the phytate into inositol and phosphoric acid. Vitamin D appears to counteract the effect of phytic acid in binding the calcium ion (Biochemistry, Cantarow and Schepartz, Fourth Edition). This may be due in part to enhancement of activity of phytase in the mucosal cells. Too, phytin is insoluble only about pH 3 to 4. Hydroxy acids such as lactic acid shift the point of precipitation and favor absorption.
One encounters unexplained phenomena and apparent paradoxes in iron metabolism as well as other minerals. An FAO/WHO report points out that some of the high vegetable diets consumed in various parts of the world contain sufficient phytate to precipitate all the calcium in the diet, theoretically. Yet it is noted that habitual consumers of such diets are not known to suffer from calcium deficiency. The above-mentioned facts may be significant by way of explanation (World Health Organization Technical Series, No. 230, Geneva, 1962).
The proper combination of foods in a meal can enhance iron utilization. For example, absorption of iron from beans is increased substantially by a small amount of meat consumed during the same meal. More than twice as much iron is necessary with a primarily vegetarian diet than with a diet containing more protein of animal origin. Studies involving radioactively tagged iron show that absorption exceeds 10 percent from animal foods, except for eggs. Of vegetable foods, absorption was poor from rice and spinach and tended to be better from soybeans.
The rate of iron absorption is extremely slow, with a maximum rate of only a fraction of a gram per day. This means that when tremendous quantities of iron are ingested, only small proportions will be absorbed. On the other hand, if only minute quantities are present, essentially all will be absorbed (Textbook of Medical Physiology, Fifth Edition, Guyton, 1976).
Iron is absorbed via the brush border of the jejunum. In the mucosal cells, it can be either bound to the globulin transferrin and absorbed into the bloodstream or combined with another protein, apoferritin. The ferritin so formed remains within the cells and is excreted when the mucosal cells are shed into the lumen. Although there are many unanswered questions about the precise mechanism, control of iron absorption depends on the amount of iron deposited in the “ferritin curtain.” This iron curtain or mucosal blocking mechanism is a classic case in point to refute the adage, “If a little is good then more is better.”
Another interesting point appears in the many studies being done in connection with iron absorption. Not only is there wide variation in absorption depending on combinations with other foods, there is considerable variability between subjects. This certainly underscores the concept of individual biochemical uniqueness.
Causes of Impaired Bioavailability
What can reduce absorptive capacity? With the foregoing foundation, it is not difficult to understand the causes. They can be widespread and varied. Food poisoning organisms such as staphylococci severely reduce intestinal uptake. Infectious diseases such as influenza will act similarly. Tropical or non-tropical sprue produces malabsorption of fats. Parasitic infections, bacterial overgrowth, hormonally mediated disorders, and drugs can all cause steatorrhea (excretion of undigested fats), with the subject complaining of weakness and easy bruising (due to vitamin K malabsorption). The list could go on: pancreatic problems, defective secretion of amylase, trypsin or lipase, bile obstruction, and so on. Allergies must also be considered, as well as celiac disease or gluten intolerance. Lactose intolerance may be a complicating factor.
Anything that tends to draw fluid into the gut and thus increases motility may be a problem, such as rapid influx of sugar or other such substances.
Also to be considered is simple anxiety or nervousness, which may speed up bowel motility. State of mind is important, whether the environment is relaxed or hurried. Those factors influencing parasympathetic activity versus sympathetic activity must be taken into consideration.
This brings up the problem of overzealous use of laxatives, which also may have a profound effect on bioavailability, ranging from mineral oil to other substances. Certain drugs interfere with nutrient uptake. One can easily reason out the effects of antacids, diuretics, and certain antibiotics. In an attempt to increase bulk intake, a person could go overboard with the consumption of large quantities of fiber, which may also reduce absorptive capacity. To the other extreme, lack of bulk can adversely affect motility. Anything that tends to interfere with enzymatic activity, either mechanically or chemically, can pose problems.
Genetic errors may interfere with synthesis of enzymes or accessory factors essential for absorption. Examples are the genetic loss of ability to secrete the intrinsic factor, producing a vitamin B12 deficiency no matter what the intake. A number of such inborn errors of metabolism involve pyridoxine, perhaps because it plays such an important role in enzyme systems.
In passing we should also call attention to the approximately 100 billion bacteria per gram of fecal matter that flourish in the colon, including coliform organisms that break down food residue and synthesize vitamins. Incompletely absorbed foods may alter the flora. The fermenting action of colonic bacteria on such products can lead to the production of irritating and potentially harmful metabolites and organic acids, with diarrhea a common result. A vicious cycle may ensue, even if temporary.
Excessive heat treatment can reduce protein quality by causing chemical modifications of essential amino acids by means of oxidation. It may also alter peptide linkages and produce new amino acids that are not subject to hydrolysis by the digestive enzymes. This principle also has practical considerations.
Cooking and Bioavailability
Cooking of meat allows the digestive enzymes more rapid access to protein. As noted, most plant cells are surrounded by tough cellulose walls that may be little disrupted by chewing. Cooking causes interior walls to swell, bursting the cell wall, making nutrients available for enzymatic action.
Other changes may be less desirable. The Maillard reaction is an example. Amino acid radicals react on warming with reducing sugars to give brown products, forming new odors and flavors. But some amino acids such as lysine form bonds with these sugars, which are resistant to digestive enzymes, reducing the nutritive value of the protein. The heat of baking can considerably lessen the bioavailability of lysine when breads are used that contain nonfat dry milk. Tryptophan absorption can be somewhat impaired during the heating process, as can arginine, histidine, and threonine, which react with carbohydrate-reducing materials.
In frying, repeatedly used or overheated fats may become oxidized or polymerized to products that are toxic to experimental animals. Most fat-soluble vitamins may be preserved in deep frying, but shallow-pan frying may completely destroy vitamin A due to the combined effects of heat and free access to air. There is obvious loss through leaching of nutrients into cooking water—a subject beyond the scope of this essay.
An interesting point. Ascorbic acid oxidase is an enzyme that destroys a major component of the vitamin C complex. In intact plant cells it is inactive. When leaves or fruits are bruised or otherwise traumatized, the enzyme begins its work. It is rapidly inactivated at temperatures of 60°C or more. Therefore, the destruction of ascorbic acid is minimal when fruits and vegetables are immediately placed in boiling water but maximal if placed in cold water and slowly brought to a boil.
Oxidation is enhanced by an alkaline medium and by free access to atmospheric oxygen. Thus baking soda should not be added to cooking vegetables to preserve their color. Aside from obviously cooking for the shortest possible time, access to oxygen can be eliminated if the water is first boiled to drive off dissolved oxygen and if a lid is placed on the cooking pot to exclude air.
Alcohol and Bioavailability
No consideration such as this would be complete without at least a brief reference to alcoholism and its concomitant problems of metabolism. On the average, an alcoholic will consume some 120 to 140 grams of alcohol a day—some 1,200 calories by itself. Although he may take in a nearly normal daily caloric content, the alcoholic becomes deficient in protein, vitamins, and minerals. Over half of all alcoholics suffer intestinal damage, so that both active and passive absorption of nutrients are diminished. Particular problems are the malabsorption of the fat-soluble vitamins, the amino acids, thiamine, folic acid, and xylose. To make matters worse, the requirement for vitamins such as B6 and B12 goes up. Liver cell damage impairs the conversion from the absorbed form of vitamin to an active one. With alcohol blood level fluctuations, the subject also loses potassium, magnesium, and zinc in his urine. Deficiencies may be clinical or subclinical, at the biochemical level. As an example, studies indicate 75 percent of severe alcoholics have a biochemical deficiency of protein, yet only about one out of five shows physical signs of protein deficiency. The same holds true with other deficiencies: they may be subclinical yet have far-reaching effects. As an example, folic acid deficiency prevents leukocytic responses to bacterial invasion. Folic acid is fundamental to cellular replication, and thus it is needed for healing as well. Other problems are obvious, such as the neurological syndromes brought about by B deficiencies. Most alcoholics have an impairment of endocrine and exocrine pancreatic function, with progressive destructive activity in the pancreas itself. Fatty liver is yet another of the sequelae.
Bioavailability and the Computer
Modern technology allows for sophisticated studies of nutrient uptake. It is not terribly difficult to research what happens to a single nutrient. But combine this with other nutrients, a complete meal, or other variables, and the difficulty of accurate assessment becomes enormous—not to mention variability between subjects. Someone might say, “Can’t you simply figure out the mineral, vitamin, or nutrient content of a given foodstuff, program a computer with this information, then ask a patient what he regularly eats?” The resultant printout would appear most sophisticated and impressive. One could obtain nutrient content from standard food composition tables, but what about other factors such as those we have been considering? What about variable food processing procedures? What about seasonal crop variations? Home cooking methods? Genetic factors? Even chewing and particle size? Dietary levels of other nutrients ingested at the same time? These questions merely scratch the surface of the problems encountered when trying to figure out a way of calculating what the organism actually absorbs and utilizes. What comes out of the computer is only as good as the information that has gone into it. “Garbage in, garbage out” is still a useful way of looking at computer printouts.
Even the best of computer analyses can only serve as guidelines and should never replace the acumen and insightful thought of the healthcare professional who cares for the whole patient. Any concept that ignores biochemical individuality has an inherent capacity to err. Each organism possesses a complex and unique metabolic pattern that encompasses every aspect of his biochemistry.
After these considerations, some interesting facts come into focus:
- It is not simply the quantity but the form of an ingested nutrient that may be more important.
- No matter what the nutritional potential of a given substance, its value is nil unless there is uptake in the intestine.
- Intact mucosal cells are essential to uptake and utilization.
- The ratios or balances of substances taken in together will affect bioavailability.
- Nervous mechanisms affect bioavailability, including emotions.
- Food processing, handling, or cooking affect bioavailability.
- Ingestion of substances foreign to the body impairs bioavailability—laxatives, drugs, and such like are included.
- For these reasons, assessing precise utilization of nutrients is a complex task. Routine analyses are insufficient and do not replace the thoughtful physician who must always look at the whole patient.
Bioavailability is not just an interesting concept. It is of real and practical concern and can have far-reaching consequences if ignored. Future research in this fascinating area should provide some satisfying answers—but doubtless more thought-provoking questions.
“Thus the things of our world are simple or complex, according to the techniques that we select for studying them. In fact, functional simplicity always corresponds to a complex substratum. This is a primary datum of observation, which must be accepted just as it is.”