Lactoferrin:
The Bioactive Peptide
that Fights Disease
by Will Brink
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.
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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.
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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. |
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.
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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.
William D. Brink is a well known medical, fitness and
health writer for a variety of publications. He graduated from Harvard
University with a degree in the natural sciences, and is a regular guest on
national radio shows and a speaker at various conventions around the U.S.
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Further Reading |
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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Lactoferrin The latest report from the National Cancer Center Research
Institute in Tokyo, Japan suggests that whey protein, particularly its major
component bovine lactoferrin (bLF), may inhibit colon cancer [Mutat Res 2000 Apr;462(2-3):227-33]. Results from
earlier research they had conducted in a rat model showed a lower incidence
and number of adenocarcinomas in bLF-fed animals. After administering various
doses of bLF for 36 weeks, in conjunction with three weekly injections of a
carcinogen, results showed that the incidence of adenocarcinomas in rats
receiving 2% and 0.2% bLF were 15% and 25%, respectively. In contrast, the
control rats had an incidence rate of 57.5%. These results basically show
bLF’s ability to reduce colon cancer by about 50%. |