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More reasons to use Whey
Lactoferrin: The Bioactive Peptide that Fights Diseasee
As regular readers of the Life Extension magazine are aware, whey protein
appears to function as a natural food against cancer, HIV, overtraining syndrome
in athletes and a host of pathologies. In particular, whey's effects on
glutathione levels and immunity are well documented in many animal studies with
a growing number of human studies confirming the results with animals. Whey is
one of two major proteins found in milk (the other being casein). When we talk
about whey we are actually referring to a complex protein made up of many
smaller protein subfractions (peptides), including beta-lactoglobulin, alpha-lactalbumin,
immunoglobulins (IgGs), glycomacropeptides, bovine serum albumin (BSA), and
minor peptides such as lactoperoxidases, lysozyme and lactoferrin. Each of the
subfractions found in whey has its own unique biological properties. Up until
quite recently, separating these subfractions on a large scale was either
impossible or prohibitively expensive. Modern filtering technology has improved
dramatically in the past few years allowing a handful of companies to separate
some of the highly bioactive peptides from whey, such as lactoferrin. Many of
these subfractions are only found in very minute amounts in cows milk, normally
at less than 1%. For example, lactoferrin makes up approximately 0.5% - 1% or
less of whey protein derived from cows milk (where as human mothers milk will
contain up to 15% lactoferrin). Lactoferrin appears to be the subfraction of
whey with documented anti-viral, anti-microbial, anti-cancer and immune
modulating/enhancing effects. There is little doubt that lactoferrin could
become the natural compound of choice in the treatment and prevention of a host
of human ailments. To follow is a summary of what lactoferrin might have to
offer.
Found in human mothers milk, lactoferrin appears to have a wide variety of uses
in biological systems and is considered a first line immune defense in the human
body.
Immunity
A minor fraction of whey, lactoferrin appears to have a wide variety of uses in
biological systems and is considered a first line immune defense in the human
body. Though a natural component of cows and human mothers milk, lactoferrin is
found throughout the human body and occurs in all secretions that bathe mucous
membranes such as saliva, tears, bronchial and nasal secretions, hepatic bile,
pancreatic fluids, and is an essential factor in the immune response.
Lactoferrin is concentrated in oral cavities where it will come in direct
contact with pathogens (i.e. viruses, bacteria, etc.) and kills or greatly
suppresses these pathogens through a variety of different mechanisms. Exactly
how lactoferrin exerts all of its immune modulating or immune enhancing
functions is not entirely clear, but it is known to enhance the immune response
both directly and indirectly (passively) in response to a wide range of immune
challenges. Specific receptors for lactoferrin are found on many key immune
cells such as lymphocytes, monocytes and macrophages, and is known to be
directly involved in the upregulation of natural killer (NK) cell activity. Most
research points to lactoferrin as being more of an immune modulator rather than
a simple immune stimulant.
Published studies that have examined the use of lactoferrin as a supplement and
its effects on immunity have been quite promising. Research using various
animals models (i.e., rats, sheep, pigs and cats, as well as others) has found
the ingestion of lactoferrin to have direct protective effects on the regulation
and modulation of the immune system.
For example, one study that examined the immune response to an endotoxin (lipopolysaccharide)
known to cause severe septic shock found that feeding lactoferrin to mice
dramatically reduced the lethality of this endotoxin while improving immune
response parameters.(1) Another study with baby pigs found only 17% of the pigs
died when fed lactoferrin and injected with the endotoxin escherichia coli as
opposed to 74% of the pigs that died without the lactoferrin!(2) This could be a
major finding, as septic shock is the most frequent cause of death for intensive
care patients and the 13th leading cause of death in the United States. Two
studies using healthy human volunteers found the ingestion of lactoferrin
derived from cows milk had positive immunoregulatory effects that were specific
to the individual. That is, depending on the initial profile of the immune
system of each person, lactoferrin ingestion augmented the immune response,
leading the researchers to conclude ???. . .the data suggests that bovine (cows)
lactoferrin may be applied in the clinic to improve the immune status of the
patients.???(3) A similar human study using ten people who ingested lactoferrin
concluded ???these results suggest that lactoferrin administration may influence
the primary activation of the host defense system.???(4)
Lactoferrin appears to be particularly important in the health and function of
the intestinal tract and has been found to greatly reduce systemic and
intestinal inflammation in such conditions as inflammatory bowel disease and
others. Animals subjected to a variety of pathogens known to cause both systemic
and intestinal inflammation and damage show much greater resistance and reduced inflammation when fed lactoferrin.
The gastrointestinal tract must be viewed as an ecologic system in which a balance between both good and bad bacterial flora
(micro flora) exists. An overgrowth of bad bacteria in the intestinal tract is known to cause a wide range of sever problems
that cause a myriad of pro-inflammatory mediators to be released, causing disruptions throughout the
entire body.
When fed to adult animals and human infants, lactoferrin showed a dramatic
increase in good micro flora???such as bifidus???and a decrease in bad bacteria,
such as E. coli, streptococcus, clostridium and others. The result was desirable
intestinal flora, which is known to be essential for optimal health, immunity
and resistance to disease. An extensive review that examined the role of
lactoferrin in inflammation and the health of the intestinal tract stated, ???The
possibility that lactoferrin limits the autodestructive inflammatory response
presents a new alternative for the future management of systemic
inflammation.???(5) Some research also suggests that lactoferrin is able to
stimulate intestinal cell growth and may lead to better digestive functions, in
addition to its ability to enhance the growth of ???good??? microflora in the
intestine. There is little doubt that in addition to its immunomodulating
effects, this natural peptide derived from whey has powerful pro-biotic
properties.
How to Obtain Lactoferrin
Lactoferrin is a natural constituent of whey protein found in milk. High quality
whey protein supplements contain about 0.5% lactoferrin. That means a 20 gram
scoop of high quality whey protein isolate provides about 100mg of lactoferrin.
An adequate and cost effective dose of lactoferrin for the adjunctive treatment
of disease is estimated to be 300 mg a day. There are dietary supplements that
provide potent doses of lactoferrin extracted from whey. When using these
supplements, it is important to use a form of lactoferrin called "apolactoferrin"
that is depleted of iron. The apolactoferrin form has been shown in studies to
provide the benefits of lactoferrin as an antioxidant, and studies show the "apo"
form may have additional benefits over that of other forms of lactoferrin.
Anti-viral effects
Lactoferrin has been found to both directly and indirectly inhibit several
viruses that cause disease in humans. It directly inhibits viruses by binding to
viral receptor sites, thus preventing the virus from infecting healthy cells.
For example, in vitro studies have found that lactoferrin strongly binds to the
V3 loop of the gp120 receptor on HIV-1 and HIV-2, resulting in inhibition of
virus-cell fusion and entry of the virus into cells.10 In addition, lactoferrin
indirectly kills or inhibits viruses by augmenting the systemic immune response
to a viral invasion. It???s interesting to note that there is a systemic
deficiency of lactoferrin in people with HIV infection. One study that examined
22 asymptomatic and 45 symptomatic patients with HIV compared to 30 healthy
controls found that ???levels of plasma lactoferrin are decreased in HIV-1
infected patients in relation to the progression of the disease.???(6) Another
study found that the lack of lactoferrin (and secretory Iga) found in the oral
cavities of people with HIV correlated strongly with the frequent infections in
those areas often seen with patients with AIDS.(11) Lactoferrin was also found
to have ???potent??? anti-viral effects against the replication of both human HIV
and cytomegalovirus (CMV) virus in several in vitro studies with no cytopathic
effects on healthy cells.
In addition to HIV and CMV, additional studies have found that lactoferrin
inhibits herpes simplex type 1 infection of healthy cells. The latter likely
occurs by preventing viral attachment to healthy cells via the blocking of viral
proteins and direct immune interactions with natural killer cells, lymphocytes
and phagocytes.(7,8,9,10)
The importance of lactoferrin in viral infections warrants a great deal of
further research and use by clinicians. There is little doubt that lactoferrin
is a key molecule for the body and the immune system in the fight against
viruses and other microbes, and could be an effective supplement for people with
viral infections.
Anti-cancer effects
Perhaps one of the most promising uses for lactoferrin may be in its potential
as a nontoxic adjuvant cancer treatment agent. Extensive in-vitro (test tube)
and in-vivo research with animals has shown lactoferrin to be a powerful
anti-cancer agent.
Two studies using healthy human volunteers found the ingestion of lactoferrin
derived from cow's milk had positive immunoregulatory effects.
Multiple studies using both rats and mice exposed to a toxic chemical (azoxymethane)
known to cause tumors throughout the gastrointestinal tract, administered
concomitantly with lactoferrin, showed a large reduction in intestinal polyp
development.(12,13) Just as important, there were no toxic effects to intestinal
epithelial tissues. Another study found the addition of lactoferrin to cancer
prone mice subjected to cancer causing chemicals reduced the number of tumors
and suppressed angiogenesis (the production of new blood vessels), which tumors
need to survive. This study also found lactoferrin ???significantly inhibited???
liver and lung metastasis of cancer cells in these animals.(14) In addition to
what appears to be direct cancer inhibiting properties of lactoferrin,
additional studies have found it increased natural killer (NK) cell toxicity to
several cancer cell lines at low concentrations. This shows lactoferrin plays a
systemic role in improving immune cell effectiveness to cancer cells, as well as
a direct effect through mechanisms that are not fully clear at this time.
Yet another study found lactoferrin to be very effective at suppressing the
growth of human pancreatic cancer cells. So much so the researchers concluded
that lactoferrin ??????might become one of the new drugs of choice for the adjuvant
therapy against pancreatic cancer.???(15) Additional published studies have found
both direct cancer suppressing activities of lactoferrin as well as systemic
immune improvements in animals fed lactoferrin with chemical induced cancers.
One study that examined lactoferrin???s effects on chemically induced colon cancer
found that ???no effects indicative of toxicity were noted [from the use of
lactoferrin], but significant reductions in both incidence and number of
adenocarcinomas (tumors) of the large intestine were observed in almost all
treatments.???(12)
Anti-microbial effects
Probably lactoferrin???s best known role is as an iron binding protein. It???s
referred to as hololactoferrin in its iron bound form and apolactoferrin in its
iron depleted form. Studies have found it???s the apolactoferrin form that has the
most powerful effects as an anti-microbial agent. Directly related to
lactoferrin???s previously mentioned ability to suppress certain health degrading
bacteria in the intestine, lactoferrin is a powerful anti-microbial that
inhibits a wide range of pathogenic bacteria and other microbes. The mechanism
appears to lie with lactoferrin???s ability to bind iron, as it is known to have
an extremely high affinity for this metal. Many pathogenic bacteria need a
supply of free iron to multiply???in the presence of lactoferrin, they are
strongly inhibited or killed.
Extensive in-vitro (test tube) and in-vivo research with animals has shown
lactoferrin to be a powerful anti-cancer agent.
One study looked at lactoferrin as a ???natural antibiotic??? and found that
lactoferrin both in-vitro and in-vivo strongly inhibited the toxic bacteria
helicobacter pylori. They stated ???It is concluded that bovine (cows) lactoferrin
has significant antimicrobial activity against helicobacter species in-vitro and
in-vivo.???(16) Another study using both in-vitro and in-vivo methods added
lactoferrin to the drinking water of mice and subjected them to the toxic
microbe staphylococcal. The study found that the mice getting the lactoferrin as
2% of calories reduced kidney infections by 40% to 60% and reduced bacterial
counts 5- to 12-fold. They concluded ???the results suggest a potential for the
use of lactoferrin as natural anti-bacterial proteins for preventing bacterial
infections.???(17) Interestingly, some studies have found lactoferrin from cows to
be more effective than lactoferrin from humans for anti-bacterial properties(18)
(though it???s well established that human mothers milk confers a great deal of
protection to the newborn due to many factors, including a high lactoferrin
content). Several studies have found lactoferrin to inhibit a wide range of gram
positive and gram negative bacteria, yeasts and even certain intestinal
parasites. Cholera, escherichia coli, shigella flexneri, staphylococcus
epidermidis, pseudomonas aeruginosa, candida albicans and others have all been
found to be strongly or partially inhibited in the presence of
lactoferrin.(19,20) (It should be noted not every microbe that is pathogenic to
humans is suppressed by lactoferrin).
Maybe most promising and interesting, there is research that points to
lactoferrin being able to improve the efficiency of antibiotic treatments in the
fight against pathogenic microbes. Considering the out of control use of
antibiotics and the rise in antibiotic resistant strains of ???bad bugs,??? this is
very good news. Would the combination of lactoferrin and antibiotics be the
knockout punch to certain bacteria that are not being killed by antibiotic
treatments alone? More research is needed, but the evidence is very compelling.
Lactoferrin as an antioxidant
Finally, lactoferrin is an antioxidant that scavenges free iron, helping to
prevent uncontrolled iron based free radical reactions, thus protecting certain
cells from peroxidation. Though lactoferrin is both an iron scavenger and donor
(depending on the cellular environment), it has been found to scavenge or donate
iron at the appropriate times when the body is in need of the reaction. At
normal physiological PH, lactoferrin binds iron tightly thus diminishing
oxidative stress to tissues (from free radical production of iron). As would be
expected, apolactoferrin, but not hololactoferrin, has been shown to prevent
lipid peroxidation. However, there are times in fact when iron is needed as part
of a controlled oxygen radical generating system by certain immune cells to kill
microorganisms. Lactoferrin has been found to be an iron donor to this system
under reduced PH conditions.
Several studies suggest lactoferrin reduces oxidative stress. Diseases such as
cancer, heart diseases and AIDS are all closely related to oxidative stress
either as a causative factor or as a factor in progression of the disease. One
study that examined the role of whey proteins, multifermented whey proteins and
lactoferrin in oxidative stress made the bold statement, ???We can conclude that
whey protein, lactoferrin and multifermented whey are good candidates as dietary
inhibitors of oxidative stress and should be considered as potential medicinal
foods in various pathologies as HIV infection and cancer.???(21) We couldn???t have
said it better ourselves!
Conclusion
There is little doubt that lactoferrin is a major find and a potential
breakthrough as a natural nontoxic treatment in an array of human ailments.
Though a handful of companies are able to produce lactoferrin at this time,
there is only one company producing the apolactoferrin (iron depleted) form in
large quantity. Studies suggest that the superior form to supplement with is
apolactoferrin.
By Will Brink
Further Reading
Arao S, Matsuura S, Nonomura M, Miki K, Kabasawa K, Nakanishi H. Measurement of
urinary lactoferrin as a marker of urinary tract infection. J Clin Microbiol
1999 Mar;37(3):553-7.
Damiens E, Mazurier J, el Yazidi I, Masson M, Duthille I, Spik G, Boilly-Marer
Y. Effects of human lactoferrin on NK cell cytotoxicity against haematopoietic
and epithelial tumour cells. Biochim Biophys Acta 1998 Apr 24;1402(3):277-87.
Fillebeen C, Descamps L, Dehouck MP, Fenart L, Benaissa M, Spik G, Cecchelli R,
Pierce A. Receptor-mediated transcytosis of lactoferrin through the blood-brain
barrier. J Biol Chem 1999 Mar 12;274(11):7011-7.
Hammerschmidt S, Bethe G, H Remane P, Chhatwal GS. Identification of
pneumococcal surface protein A as a lactoferrin-binding protein of streptococcus
pneumoniae. Infect Immun 1999 Apr;67(4):1683-7.
Manev V, Maneva A, Sirakov L. Effect of lactoferrin on the phagocytic activity
of polymorpho-nuclear leucocytes isolated from blood of patients with autoimmune
diseases and Staphylococcus aureus allergy. Adv Exp Med Biol 1998;443:321-30.
Marchetti M, Longhi C, Conte MP, Pisani S, Valenti P, Seganti L. Lactoferrin
inhibits herpes simplex virus type 1 adsorption to Vero cells. Antiviral Res
1996 Mar;29(2-3):221-31.
Portelli J, Gordon A, May JT. Effect of compounds with antibacterial activities
in human milk on respiratory syncytial virus and cytomegalovirus in vitro. J Med
Microbiol 1998 Nov;47 (11):1015-8.
Roozendaal C, Horst G, Pogany K, van Milligen de Wit AW, Kleibeuker JH, Haagsma
EB, Limburg PC, Kallenberg CG. Prevalence and clinical significance of
anti-lactoferrin auto-antibodies in inflammatory bowel diseases and primary
sclerosing cholangitis. Adv Exp Med Biol 1998;443:313-9.
Swart PJ, Kuipers ME, Smit C, Pauwels R, deBethune MP, de Clercq E, Meijer DK,
Huisman JG. Antiviral effects of milk proteins: acylation results in polyanionic
compounds with potent activity against human immunodeficiency virus types 1 and
2 in vitro. AIDS Res Hum Retroviruses 1996 Jun 10;12(9):769-75.
Yoo YC, Watanabe S, Watanabe R, Hata K, Shimazaki K, Azuma I. Bovine lactoferrin
and Lactoferricin inhibit tumor metastasis in mice. Adv Exp Med Biol
1998;443:285-91.
References
1. Zhang GH, Mann DM, Tsai CM. Neutralization of endotoxin in vitro and in vivo
by a human lactoferrin-derived peptide. Infect Immun 1999 Mar;67(3):1353-8.
2. Lee WJ, Farmer JL, Hilty M, Kim YB. The Protective Effects of Lactoferrin
Feeding against Endotoxin Lethal Shock in Germfree Piglets. Infect Immun Apr.
1999: Vol 66 No 4, 1421-1426.
3. Zimecki M, Wlaszczyk A, Cheneau P, Brunel AS, Mazurier J, Spik G, Kubler A.
Immunoregulatory effects of a nutritional preparation containing bovine
lactoferrin taken orally by healthy individuals. Arch Immunol Ther Exp (Warsz)
1998;46(4):231-40.
4. Yamauchi K, Wakabayashi H, Hashimoto S, Teraguchi S, Hayasawa H, Tomita M.
Effects of orally administered bovine lactoferrin on the immune system of
healthy volunteers. Adv Exp Med Biol 1998;443:261-5.
5. Kruzel ML, Harari Y, Chen CY, Castro GA. The gut. A key metabolic organ
protected by lactoferrin during experimental systemic inflammation in mice. Adv
Exp Med Biol 1998;443:167-73.
6. Defer MC, Dugas B, Picard O, Damais C. Impairment of circulating lactoferrin
in HIV-1 infection. Cell Mol Biol (Noisy-le-grand) 1995 May;41(3):417-21.
7. Puddu P, Borghi P, Gessani S, Valenti P, Belardelli F, Seganti L. Antiviral
effect of bovine lactoferrin saturated with metal ions on early steps of human
immunodeficiency virus type 1 infection. Int J Biochem Cell Biol 1998
Sep;30(9):1055-62.
8. Superti F, Ammendolia MG, Valenti P, Seganti L. Antirotaviral activity of
milk proteins: lactoferrin prevents rotavirus infection in the enterocyte-like
cell line HT-29. Med Microbiol Immunol (Berl) 1997 Oct;186(2-3):83-91.
9. Harmsen MC, Swart PJ, de Bethune MP, Pauwels R, De Clercq E, The TH, Meijer
DK. Antiviral effects of plasma and milk proteins: lactoferrin shows potent
activity against both human immunodeficiency virus and human cytomegalovirus
replication in vitro. J Infect Dis 1995 Aug;172(2):380-8.
10. Swart PJ, Kuipers EM, Smit C, Van Der Strate BW, Harmsen MC, Meijer DK.
Lactoferrin. Antiviral activity of lactoferrin. Adv Exp Med Biol
1998;443:205-13.
11. Muller F, Holberg-Petersen M, Rollag H, Degre M, Brandtzaeg P, Froland SS.
Nonspecific oral immunity in individuals with HIV infection. J Acquir Immune
Defic Syndr 1992;5(1):46-51.
12. Tsuda H, Sekine K, Nakamura J, Ushida Y, Kuhara T, Takasuka N, Kim DJ,
Asamoto M, Baba-Toriyama H, Moore MA, Nishino H, Kakizoe T. Inhibition of
azoxymethane initiated colon tumor and aberrant crypt foci development by bovine
lactoferrin administration in F344 rats. Adv Exp Med Biol 1998;443:273-84.
13. Ushida Y, Sekine K, Kuhara T, Takasuka N, Iigo M, Tsuda H. Inhibitory
effects of bovine lactoferrin on intestinal polyposis in the Apc(Min) mouse.
Cancer Lett 1998 Dec 25;134(2):141-5.
14. Yoo YC, Watanabe S, Watanabe R, Hata K, Shimazaki K, Azuma I. Bovine
lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin,
inhibit tumor metastasis in mice. Jpn J Cancer Res 1997 Feb;88(2):184-90.
15. Sakamoto N. Antitumor effect of human lactoferrin against newly established
human pancreatic cancer cell line SPA. Gan To Kagaku Ryoho 1998
Aug;25(10):1557-63.
16. Dial EJ, Hall LR, Serna H, Romero JJ, Fox JG, Lichtenberger LM. Antibiotic
properties of bovine lactoferrin on Helicobacter pylori. Dig Dis Sci 1998
Dec;43(12):2750-6.
17. Bhimani RS, Vendrov Y, Furmanski P. Influence of lactoferrin feeding and
injection against systemic staphylococcal infections in mice. J Appl Microbiol
1999 Jan;86(1):135-44.
18. Vorland LH, Ulvatne H, Andersen J, Haukland H, Rekdal O, Svendsen JS,
Gutteberg TJ. Lactoferricin of bovine origin is more active than lactoferricins
of human, murine and caprine origin. Scand J Infect Dis 1998;30(5):513-7.
19. Percival M. Intestinal Health. Clin. Nutri. Insights. 1997, Vol 5. No 5,
1-6.
20. Kuwata H, Yip TT, Tomita M, Hutchens TW. Direct evidence of the generation
in human stomach of an antimicrobial peptide domain (lactoferricin) from
ingested lactoferrin. Biochim Biophys Acta 1998 Dec 8;1429(1):129-41.
21. Stella V, Postaire E. Evaluation of the antiradical protector effect of
multifermented milk serum with reiterated dosage in rats. C R Seances Soc Biol
Fil 1995;189(6):1191-7.
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