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by Peter R. Rothschild, M.D., Ph. D.
at State Academy of Medicine, Tamaulipas, Mexico / 1985
Abstract
Much has been written about the antibacterial mechanisms of polymorph nuclear leukocytes and several excellent reviews on this topic are available (Root & Choan 1981; Ryter & Chastellier; Spitznagel 1983). However, only a very few researchers paid attention to the quantitative relationships between photolytic cells and bacteria, which is ultimately decisive for the outcome of any infection. For instance, if the number of the polymorphs is fixed and the bacteria continue multiplying in the extra cellular fluids, then the mission of the polymorphs of opposing the infection becomes increasingly difficult. The exact opposite is true when the availability of polymorphs is unhindered which renders the body plasma bactericidal. These relationships which are of paramount importance are best studied in vivo allowing all circumstances to come into play. Studies in vitro are indeed also essential, but usually only for a particular purpose. Ultimately, it is their relevance to in vivo conditions that really matter.
In real live physiology, phagocytic efficacy is contingent of the following parameter: The bacteria/phagocyte ration; the rate of ingestion of the bacteria and the rate of destruction or growth of extra cellular bacteria. The medium in which polymorphs functions are either regular body plasma or inflammatory exudates, both happen to contain unsaturated, iron-binding proteins which, depending on individual circumstances, consist of transferrin, lactoferrin, or a mixture of both. The influence of these polypeptides in combination with other antibacterial factors – such as specific antibodies, complement and lysozyme – can be of decisive importance. The SBO Probiotics Consortia formulas, whose properties are discussed in this paper, appear to contain significant concentrations of lactoferrin, whose properties are discussed in this paper.
Discussion
The Biology of Lactoferrin
Lactoferrin is a member of the family of iron-binding proteins that also encompass transferrin and ovotransferrin. These proteins are widely distributed in the physiological fluids of all vertebrates. All contain a single polypeptide chain of about 700 amino acid residues. Its molecular weight is approximately 80,000. Each of them is able to bind reversibly two iron atoms. The 3-D study of the structure of lactoferrin revealed that each atom of iron is captured by side chains of four specific amino acids: Two tyrosines, one histidine and one aspartate.
The affinity of lactoferrin for iron is very high: Approximately 10{30}. This allows lactoferrin to retain iron in the presence of the chelators such as citrate, even at a pH as low as 4.0 or even lower. Such high affinity also permits the transport of iron by lactoferrin through the gastric environment – pH 2.0 – to the small intestine, where it can be absorbed by specific receptors extent on the epithelial cells.
The Role of Iron In Life System
In one way or another, iron is essential to most forms of life. It is the most abundant transition-metal in living organisms and is endowed with unique properties that enable it to both initiate and participate in certain paramount chemical reactions. Though iron is very important in the metabolism of many life forms, in humans its chief usefulness is addressed to redox mechanisms, of which the most important is breathing.
However, if this potential is left uncontrolled, it often gives rise to quite harmful reactions such as generating free radicals and the pervasive stimulation on infectious agent – such as harmful bacteria, yeast and viruses – whose metabolic processes rely heavily on iron. Therefore, iron normally remains bound to carrier molecules, such as heme or other proteins, for instance ferritin, which prevents undesired reaction and at the same time, allows the exploitation of biologically useful properties of iron. Living organisms develop different mechanisms to sequester and transport iron. In humans, it is lactoferrin that retrieves iron from the environment and delivers it to where it is needed.
Nutritional Bio-Accessibility of Iron
For nutritional purposes, iron is obtained from the food we eat. Thus, our ability to assimilate iron from our food – its bio-accessibility, that is – has a direct correlation to our health. Yet, iron deficiencies are regarded as the most prevalent single syndrome in man. According to UNESCO’s World Health Organization statistics, about 750 Million people suffer from iron deficiency on our planet. In reality this number is probable even higher. Alas, what these statistics do not disclose is that less than half of these lack iron due to malnutrition. More than half of these suffer from iron deficiency because of metabolic problems that hinder or inhibit the assimilation of iron from the ingested food or because of low bio-accessibility of the ingested iron.
Iron that is used today to complement foods has a very low bio-accessibility rate. Only a very small portion – about 7% – is absorbed by the gastrointestinal tract and an even lesser percentage is actually assimilated by the organs that require it. In a useless effort to compensate for this shortcoming, persistently excessive amounts of iron are added to food in general. The iron that remains unassimilated supports infectious bacterial and viral growth in the entire organism.
On the other hand, iron carried by lactoferrin is extremely bio-accessible – greater than 95% – yet it will not deliver it to noxious micro-organisms. Lactoferrin is identified by specific receptors and delivers iron to the epithelial cells of the small intestine. Iron is released only at the point of recognition and does, therefore, not become available from any other microorganism that may abound in the intestinal tract.
It has been demonstrated in breast fed infants that lactoferrin is a key factor in both the absorption and assimilation of iron. Studies have revealed, for instance, that the absorption of iron from human milk – which is rich in Lactoferrin – is far more efficient than any of the so-called infant formulas that contain iron. The higher level of iron absorption from human milk yields a much lower incidence of iron deficiency anemia and much fewer intestinal derangements among breast fed infants.
The human body is programmed to control its iron supplies very carefully by limiting iron absorption and reusing non-heme iron proteins. Other than the insertion of bile into the feces – bile contains iron atoms locked into the hematoporphyrin prominent from the red blood cell breakdown – there is no other iron excretion in the physiological sense. Thus, the average human body requires about 1 milligram of iron to replace the volume eliminated in the bile. (Red cell breakdown yields the hematoporphyrin, which is the chemical sense, is a pyrrholic ring for which the human body does not produce any lytic enzymes. The kidneys are unable to dispose of this complex molecule; this hematoporphyrin must be eliminated through the feces. In fact, it is the ferrous oxide it contains that is chiefly responsible for the color of the feces). The excreted iron must be re-acquired through intestinal absorption.
The Anti-Infectious Functions of Lactoferrin
A number of collateral activities have been attributed to lactoferrin. Most of these relate to the high affinity of lactoferrin to iron. Which bring us to one of the chief facts this essay is addressing? Once iron is sequestered by lactoferrin, it cannot be utilized by bacteria, viruses or yeast or other parasites whose continuous metabolic need for iron is paramount. Although such microorganisms do complete with lactoferrin for iron by releasing minute molecular weight compound called siderophores, they are unable to capture iron in the presence of lactoferrin. This implies that one of lactoferrin’s primary functions is to act as a first line of defense against all pathogens.
The defenses of human hosts are the ultimate factors that determine whether an infection will progress or not. These defenses encompass anatomic barriers – such as the intact skin – the ciliated respiratory mucosa and nasal, vaginal and/or conjunctiva secretions. Of all of these which are involved in protecting the body from environmental aggressions, lactoferrin is found in high concentrations. As an iron sequestrant, lactoferrin has the ability to neutralize pathogens at the points of entry and, consequently, inhibit the spread of infections. It was demonstrated beyond doubt the lactoferrin in these secretions is always iron-free, constantly ready to sequester all locally extant iron that is an element so vital for the survival of all potential invaders.
In addition, lactoferrin also cooperates with other proteins in the human body in order to deprive these from their vital iron. Transferrin, for instance, has a much lower affinity for iron; thus aggressive bacteria are able to retrieve iron from it. Therefore, during the early stages of infection, in a process known as hypoferremia, lactoferrin is sent to capture the iron pool accumulated in transferring, thus preventing its utilization by invading bacteria or viruses.
Because of it high affinity for iron and its obvious role in maintaining proper iron balances, Lactoferrin can also be considered as a “quality control” protein of sorts. By withholding iron from certain metabolically active sectors, it appears that lactoferrin also diminishes remarkable the occurrence of free radicals in that area. In this context, we can propose that it is probable that lactoferrin reduces the “oxidative stress” of cells that would be otherwise targeted and damaged by free radicals.
Uses of Lactoferrin
We have shown that lactoferrin is the first line of defense against invading bacteria, parasites and viruses. Thus, it can be considered as nature’s main, endogenous antibiotic. It is found in significant concentrations in human milk, saliva, tears and a few other external secretions.
The Use of Commercially Prepared Lactoferrin
Lactoferrin also represents a significant increase in our ability to deliver nutrition to human tissues. Examples of how lactoferrin could be used in commercial products are described in the following paragraphs.
As A Nutritional Agent:
The fact that, Lactoferrin is able to present iron in a bio-accessible form makes it a far superior supplement than traditional inorganic iron. We have shown the high risks represented by indiscriminately available iron in the body. Where as inorganic iron – such as contained in supplements and vitamin pills – is absorbed only at the rate of 5% to 10% and where unabsorbed circulating iron becomes automatically obtainable for invaders. The iron in lactoferrin is not only absorbed at the rate of 95%, but remains exclusively available to the cells that can make legitimate use of it.
On a global basis, the need for iron as a food supplement is at a critical stage in both developed and developing countries. In a pretense of meeting the need of iron, competing food manufacturers add indiscriminate amounts of inorganic iron to their products. The result is hardly improved, completely inadequate nutrition, aggravated with a collection of unpleasant intestinal side effects.
Iron-saturated lactoferrin, such as the SBO Probiotics Consortia formula tested prior to this article, could solve this problem because low doses of organic iron would be totally unavailable to invaders and would be channeled directly to the cells that can legitimately require it. Whereas, in developing countries, dry powdered infant formulas and cereals would be the most likely candidates to incorporate a SBO Probiotics Consortia.
As An Anti-Microbial Agent:
Lactoferrin can inhibit in vitro strains of bacteria, except lactobacilli and bacilli subtilis, as a function of its iron sequestering ability. As we have already explained, this occurs because all microorganisms require iron for growth and lactoferrin successfully prevents their access to it. What this implies is that the growth of any undesirable microorganism can be abrupt if local iron is monopolized by lactoferrin. Therefore, opportunistic infections regardless of where and how received can be successfully treated with SBO Probiotics Consortia products that contain acquirable lactoferrin.
Endogenous- body owned Lactoferrin can be enhanced by supplemental provisions. This would also hold true for topical applications. For example, bacteria on the skin can be better resisted if lactoferrin were present in cosmetics and skin conditioners. Other items, such has eye care products, first aid articles, oral hygiene preparation and so forth, would be all similarly enhanced.
The most common lethal infection to man is the acute infection of pulmonary parenquima, including the alveolar spaces and interstitial tissues. This condition is commonly known as pneumonia and affects about 20 million Americans every year, of which approximately 40 to 70 thousand die. It is highly viable to support and reduce traditional antibiotic therapy with lactoferrin supplementation of the proper SBO Probiotics Consortia. Used this way, lactoferrin could minimize the impact of not only pneumonia, but also of many other severe infections, some of which frequently threaten with epidemic developments.
As An Antagonist Of Iron Overload Conditions:
Hard as this may be to believe, over 10 million Americans are afflicted with disorders that arise from iron overload in the body. Chronic iron overload, known as siderosis or hemosiderosis is characterized by greater than normal local or generalized deposition of iron within certain body tissues. When such concentration is associated to tissue injury, it is known as hemochromatosis. Two forms of hemochromatosis are known:
a) Primary: A genetically determined error associated with increased absorption of iron from a conventional nutrition and
b) Secondary: Caused by dietary abnormalities. The therapy of genitical hemochromatosis involves the removal of the excess body iron plus specifically supportive treatment of the damaged organs. The current trend to remove excess iron consists of weekly blood transfusions of 500 ml. This therapy is not only expensive and debilitating, but also entails the risk of inducing an immune reaction that turns the patient allergic against blood sera for life.
As an alternative, recombinant human, human compatible, lactoferrin could be used as a natural iron chelating agent in the treatment of almost all iron overload disorders. The SBO Probiotics Consortia tested, offers a novel and highly efficient approach for sequestering excess iron from blood, and could replace other high cost and highly inconvenient therapies.
As A Food Preservative:
As mentioned above, sequestering iron retards bacterial growth and inhibits lipid oxidation, which causes rancidity of meat, fish, and poultry. Oxidation, particularly atmospheric oxidation, is the chief factor in the degradation of fats in foods which often results in spoilage. Fats and lipid form substances undergo oxidative deterioration, which also results in unpleasant odors. In extreme cases sundry extremely toxic substances are regular by-products from oxidative reactions.
Lactoferrin as a sequestrate reacts with iron to form an efficient complex that prevents bacterial growth, and yet still allows the iron to be utilized by humans. By contrast, most currently used sequestrates react with iron to form non accessible complexes with iron and other metals, which no longer remain bio-available. (Regrettably, these sequestrates do not react with heavy metals that are so deadly for the human organisms). Thus, the nutritional value of processed food is significantly decreased. Fish and red meat contain high concentrations of nutritional metals: e.g. 100 ppm iron, 400 ppm copper and 600 ppm zinc. These metals are key Micro Nutrients in the human diet, which current food preservatives block from the human body. Lactoferrin has the ability to act both as a natural food preservative and as an intermediary to access bio-available nutrients.
Conclusion
Potentials for both recombinant human lactoferrin and human compatible recombinant lactoferrin embrace a wide spectrum of uses. Both critical and mundane medical treatments have demonstrated that many life threatening diseases suffer from unsolvable shortcomings which can, however, be successfully addressed and bridged by the iron sequestering power of lactoferrin or of products, such as the SBO Probiotics Consortia formulas tested, that contain within them therapeutically significant concentrations.
In addition, the nutritional aspects of lactoferrin address other important human needs and offer improved treatments for under-nourished populations that range from formula-fed infants to human iron induced pathologies. The ever more complex problems of food preservation can be naturally and physiologically enhanced as well with the assistance of lactoferrin or products that contain it in meaningful concentrations.
