The Genomeceutical Effect of Probiotics and Their Potential
Role in Quenching Autoimmune Diseases and Disorders of Inflammation
By Mark A. Brudnak, Ph.D., N.D.
and Llori M. Valenzuela, M.S., R.D.
Townsend Letter for Doctors and Patients
Probiotics are living
microorganisms, which when ingested or locally applied in sufficient
confer one or more specified
demonstrated functional or health benefits for the consumer (EFFCA,
European Food and Feed Culture Association, 2003). Probiotics
are also referred to as the "friendly", "beneficial",
or "good" bacteria which when ingested act to maintain
a healthy intestinal tract and help fight illness and disease.
Genomeceuticals are natural ingredients (in this case, probiotics),
which can beneficially affect gene expression. Our group has
spent decades studying the various health aspects of probiotics.
Our group has realized for years that there is probably a direct
correlation between the intestinal flora and health of the human
organism with regards to potential autoimmune diseases and disorders
of inflammation. In this paper, we will discuss the immunomodulatory
effects of probiotics, specifically their role in to down-regulating
certain immune responses. We propose the use of probiotics to
quench the immune system under certain conditions, as well as
a mechanism by which such beneficial modulation may be achieved.
More than 400 species of bacteria
naturally reside in the digestive tract. The bacteria function
to break down food, freeing nutrients
for absorption. Many vitamins and essential amino acids are only
absorbed after being broken down by gut microorganisms. The proper
balance of good bacteria prevents detrimental organisms from
invading the gut and leaving the gastrointestinal (GI) tract
susceptible to ailments. 1 The consumption of probiotics in cultured
milk products, such as yogurt, has been a daily part of the Japanese
and European healthy diet for many decades.
As far back as recorded history, communities have embraced certain
foods for their believed healing powers beyond basic nourishment.
For instance, dairy products have been used for centuries to
prevent and/or treat common intestinal problems. Two different
probiotics, Lactobacillus and Bifidobacteria, are present in
high numbers in fermented dairy products, including yogurt and
keifer, and are generally associated with the most probiotic
activity. For generations, people have consumed these foods to
improve the balance of beneficial microorganisms in the gut and
enhance their immune function.
How They Work
The exact mechanism by which probiotics function in
the gastrointestinal (GI) tract is not fully understood.
However, they are believed
to confer health benefits by at least one of the following
mechanisms: competitive exclusion of enteric pathogens, neutralization
dietary carcinogens, production of antimicrobial metabolites,
and modulation of mucosal immune responses.
The proper balance between good and bad bacteria largely determines
the health of the gut and as we are learning, the organism as
a whole. Probiotics may help prevent an imbalance in which too
many harmful bacteria reside in the digestive tract. A growing
body of evidence has emerged confirming the positive effect and
potential of probiotics in humans. Recent research has implicated
probiotics in the treatment of other diseases, including atopic
eczema, autism, cancer, and food allergies.2 However, to date,
the vast majority of studies have focused on the defense and
integrity of the intestinal flora and the immune system.
Probiotics may (not necessary for all benefits) take up residence
in the body and neutralize the effects of offending bacteria.
They colonize the exterior surface of cells in the GI tract and
prevent potentially detrimental pathogenic organisms from proliferation.
Probiotics also produce components shown to hinder the growth
of certain types of harmful bacteria, as well as lower the risk
for altered metabolic activity.
and potential health benefits
associated with probiotic use
- Prevention of diarrhea and
reduction of its duration
- Reduction of irritable bowel syndrome
- Reduction of inflammatory bowel disease
- Prevention of urogenital
- Reduction of stomach infections related to Helicobacter
- Enhanced mucosal immunity
- Reduction and treatment of autism
- Decreased risk of certain
- Reduction of oxaluria and serum cholesterol
- Prevention of
- Weight management
Strong scientific evidence supports
the effects of probiotics on the immune system, providing irrefutable
evidence that certain
probiotic strains play a role in modulating both nonspecific
and specific host immune responses. Nonspecific, or innate, immune
responses are a host’s first line of defense. Natural killer
cells and phagocytes, residing in the peripheral blood and tissues,
are the major cellular effectors of nonspecific immunity. Natural
killer cells effectively fight off viruses, whereas phagocytic
cells protect against microbial infections. Both produce a variety
of compounds that can destroy both invasive materials as well
as normal tissues. The enormous implications of this are discussed
Specific immune responses can be separated into two categories:
humoral immunity, and cell-mediated immunity. In the humoral
immune response B lymphocytes synthesize specific immunoglobulin
molecules, or antibodies, that are excreted from the cell and
bind to the invading substance. In the cellular immune response,
T lymphocytes, bearing immunoglobulin-like molecules on their
surfaces, recognize and kill foreign or aberrant cells. T cells
can be divided into 2 subtypes based on their cytokine profile,
Th1 and Th2. Th1 cells are essential to cell-mediated immunity
and produce IL-2, IFN-g and tumor necrosis factor a (TNF-a).
The main products of Th2 are IL-4, IL-5, and IL-10 and it is
associated with humoral immunity and allergic responses.
Data: Innate Immunity
Dietary consumption of
certain probiotic strains have been shown to enhance nonspecific
immunity, including phagocytosis and lymphocyte
proliferation3 demonstrating the effectiveness of probiotics
in stimulating cellular immune responses. Healthy middle-aged
and elderly men and women have been shown to experience a significant
enhancement of cell phagocytosis and natural killer cell tumor
killing activity following twice daily consumption of B. lactis.
The authors suggest that the enhanced immunity observed in
relation to the B. lactis may be largely related to the secretion
immunity cytokines such as interleukin-12 and interleukin-18,
which simulate natural killer cell activity and interferon
production. These results support that of another study in which
of B. lactis was positively associated with increases in the
total proportions of T lymphocytes and natural killer cells.4
Probiotics play an essential
role in the intestinal mucosa barrier, including modulating
intestinal immune response and competitively
inhibiting the adhesion of pathogenic bacteria to the epithelial
wall of the intestine. Intestinal epithelium plays an important
role in innate immunity. When stimulated by cytokines, such as
TNF-a, the intestinal epithelia release pro-inflammatory cytokines,
including IL-8 and IL-10. However, in some gastrointestinal diseases,
such as inflammatory bowel diseases (IBD) and acute gastroenteritis,
cytokines are activated and produce excessive inflammatory products
negatively affecting the immunological capacity of the epithelial
cells. Resident Bifidobacterium and Lactobacillus actively inhibit
the pro-inflammatory response by inhibiting the secretion of
IL-8, thereby suggesting the use of probiotics in the management
of intestinal diseases.5 This has vast applications for ‘quenching’ a
potentially out-of-control immune system seen in autoimmune diseases
and disorders of inflammation.
Many probiotic strains have been studied in relation to their
role in the control of inflammatory responses to intestinal antigens.6,7,8
Specifically, many clinical and experimental studies indicate
that imbalances in the microflora of the gut are associated with
intestinal inflammation. For example, one group studied the effect
of oral administration of Lactobacillus rhamnosus on cytokine
secretion and T lymphocyte activation, thus demonstrating the
positive immunomodulating effects of oral administration of lactic
acid bacteria.8 Healthy participants taking a daily oral dose
of 2 billion colony forming units (cfu) of L. rhamnosus experienced
a reduced secretion of pro-inflammatory TNF-a and increased IL-10
and IL-4 activity.
TNF-a is key to the pathogenesis
of altered mucosal immunity. A critical factor in the pathogenesis
of Crohn’s disease
is the secretion of TNF-a by T lymphocytes.6 Co-cultures of inflamed
tissue with various probiotic strains have been proven to significantly
reduce TNF-a secretion.5,6 Since transcriptional control of IL-8
is mediated by transcription factor NF-kb, it is hypothesized
the normal intestinal microflora down-regulates inflammation
by inhibiting NF-kb activation. This hints at a possible genomeceutical
intervention point for probiotics.
As supported here, therapeutic administration of probiotics
is often advocated for their immunomodulatory properties and
anti-inflammatory activities at mucosal barrier sites.3,4,8 However,
only recently have the molecular mechanisms by which probiotic
modulate immune responses been elucidated. Immunostimulating
DNA sequences have been shown to effectively reduce or prevent
symptoms of colitis in animal studies.9 Furthermore, administration
of irradiated probiotics significantly improve experimental colitis
in murine models, as do viable probiotic strains, suggesting
the anti-inflammatory activities associated with probiotics are
mediated by their own DNA, rather than products of their metabolism
or intestinal colonization.9 This theory is further supported
by data suggesting genomic DNA released by exogenous bifidobacteria
provide a stimulus for mucosal IL-10 production in human peripheral
blood mononuclear cells.7 The interesting conclusion that may
be made in light of this research is that dead bacteria ingested
during probiotic administration provide a therapeutic effect
in addition to the viable cells.
Ingestion of specific probiotics has been shown to have immunomodulatory
effects on many aspects of humoral and cell-mediated immunity.
In one study designed to examine the relationship between oral
administration of probiotics and immunity in mice, the results
indicate strain-dependent variation in the ability of probiotics
to influence T cell activation was observed. L. rhamnosus and
L. acidophilus were found to effectively stimulate Th1 cells,
whereas B. lactis showed no effect.10 Th1 cells are known to
suppress immunoglobulin E (IgE), an indicator of allergy. In
this study, Th1 cells inhibited IL-4 secretion, thereby suppressing
IgE production. It can then be postulated that certain strains
of probiotics may inhibit IgE-mediated allergic responses through
selective stimulation of Th1 cells.10 In fact, probiotics have
successfully been used to in the prevention and treatment of
allergic disorders in humans.
Mucosal inflammation is characteristic of most allergic disorders
occurring in the intestinal tract. Food allergies are able to
alter gut motility and are often accompanied with diarrhea, malabsorption,
and abdominal pain. Many experts believe that the increase in
allergic disease may be associated with the improved hygiene
of our society. By minimizing our exposure to antigens, we fail
to stimulate the gut immune system. As a result, lymphocytes
that would normally differentiate to become Th1 cells, differentiate
to Th2 cells capable of producing inflammatory cytokines.11 However,
by challenging the microflora of the gut, it is possible to alter
the balance of bacteria and boost the immune system. That is
to say, probiotics appear to be able to exert a genomeceutical
effect of T-cells and beneficially shift their expression profile
from a Th1 to a Th2 phenotype. Perhaps not with already formed
T-cells but with undifferentiated ones at the very least. The
former remains to be seen and should prove an interesting area
of future study.
Cow’s milk allergy is not uncommon in infants and children
and creates barrier to providing complete nutrition during this
crucial development phase. Intact milk proteins are known to
stimulate the secretion of proinflammatory cytokines in susceptible
patients, such as those with cow’s milk allergy. Specific
strains of lactic acid bacteria promote the gut mucosal barrier,
protecting the host against allergic sensitization. In particular,
Lactobacillus rhamnosus has been shown to down-regulate hypersensitivity
reaction and intestinal inflammation in patients with food allergy
through improved antigen specific immune responses, prevention
of permeability defects, and modulating antigen absorption of
the mucosal membrane.12
The ability of probiotics to confer enhanced humoral and cell-mediated
resistance against pathogens has been well documented.13,14,15,16
For example, it was demonstrated that a significant increase
in lymphocyte proliferative responses, phagocytic capacities,
and localized antibody production occurs in response to oral
administration lactic acid bacteria in mice infected with Salmonella
typhimurium.16 Lactobacillus casei has been associated with increases
in specific mucosal and serum antibody responses in children
with acute rotavirus diarrhea.15
The inhibitive effect of probiotics on pathogens is generally
dependent on the reduction of pathogen viability or through interference
with adhesion and/or invasion of the pathogen. However, in a
study where Lactobacillus strains were tested in an in vitro
model of enterohemorrhagic Escherichia coli infection of a human
colon epithelial cell line, the protective affect was due to
the presence of viable L. rhamnosus cells. In this model, killed
L. rhamnosus and other Lactobacillus strains did not have an
effect on the inhibitory effect. Because the positive effect
of L. rhamnosus was not dose-dependent, it was postulated that
an intimate interaction between the host cell responses occurred,
thereby minimizing the internalizing reaction.14
Finally, our group has been working
with others looking at the cyclo-oxygenases (Cox) 1 and 2.
Both Cox-1 and Cox-2 are both
important to GI health. It is also know that over expression
of Cox-2 is characteristic of inflammation and cancer, while
Cox-1 is a housekeeping enzyme and assists with GI integrity.
A confluent culture of MAKTech Lactobacillus acidophilus and
MAKTech Bifidobacteria bifidum were assayed for their ability
to exert a genomeceutical effect on the cox genes. The later
showed a > 3 X increase in the ratio of Cox-1 / Cox-2, signifying
a shift of the cyclooxygenase expression toward a healthy direction.
In other words, Cox-2 was down-regulated and Cox-1 was up regulated.
Previous work by our group had suggested a genomeceutical effect
dietary ingredients could be possible, however at that time,
little evidence was available.17 We believe that metabolites
of some probiotics can enter a cell and either directly or indirectly
(through some second or secondary metabolite) exert an effect
on the deoxyribonucleic acid (DNA). Having studied the molecular
regulation of DNA expression using various enzyme systems in
both bacteria and mammalian cells over the last two decades,
this seems most reasonable to us. 18
Herein we have shown evidence
that probiotics can successfully be used to quench the immune
system’s response when it
has gone astray. While the concept is reasonably simple, it has
taken by our account at least a century of work to understand
the importance probiotics are playing in inflammatory autoimmune
diseases. Recent reports that not just cytokine levels are altered
but also antibody levels such as IgE mentioned above support
us. The significance of this may not be easily seen. In landmark
papers describing how antibodies can, with proper substrates,
act as enzymes by catalyzing the formation of hydrogen peroxide
(HP),19 a strong link between the ability of probiotics to alter
the regulation of antibody production and chronic degenerative
diseases was established.
The substrate is singlet oxygen provided
by activated neutrophils, which help destroy invading bacteria.
The antibodies produced
both HP and ozone, establishing their link with an inflammatory
response. Because both humoral and cell mediated immune response
employ either antibody or antibody-like (TCR) molecules, these
findings are far reaching for probiotics. It is reasonable, given
all the evidence above, to suggest that probiotics may assist,
given appropriate conditions, in down-regulating the antibody-mediated
ozone production associated with a variety of inflammatory conditions
including rheumatoid arthritis, inflammatory bowel disease and
possibly such things as autism, which has been suggested to also
be linked to this.2
With the amazingly broad applications of probiotics including,
but not limited, to cancer, autism, detoxification, weight-loss,
heart disease and diabetes the next decade should be exiting
as the mechanisms of action become clearer.20,21,22 With such
clarity should come even great applications for probiotics.
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for Detoxification. Townsend
Letter for Doctors & Patients.
2. Brudnak, MA 2001 Application of Genomeceuticals to the Molecular
and Immunological Aspects of Autism. Medical Hypotheses. 57 (2),186-191.
3. Chiang BL, Sheigh YH, Wang LH, Liao CK, Gill HS. 2000. Enhancing
immunity be dietary consumption on a probiotic lactic acid bacterium
(Bifidobacterium lactis HN019): optimization and definition of
cellular immune responses. Eur J Clin Nutr. 54:849-55.
4. Gill HS, Rutherfurd KJ, Martin LC, Gopal PK. 2001. Enhancement
of immunity in the elderly by dietary supplementation with the
probiotic Bifidobacterium lactis HN019. Am J Clin Nutr. 74:833-9.
5. Bai A, Ouyang Q, Zhang W, Wang C, Li S. 2004. Probiotics
inhibit TNF-alpha-induced interleukin-8 secretion of HT29 cells.
World J Gastroenterol. Mar;10(3):455-7.
6. Borruel N, Carol M, Casellas F, Antolin M, de Lara F, Espin
E, Naval J, Guarner F, Malagelada JR.Increased mucosal tumour
necrosis factor alpha production in Crohn's disease can be downregulated
ex vivo by probiotic bacteria. Gut. 2002 Nov;51(5):659-64.
7. Lammers K, Bridgidi P, Vitali B, Gionchetti P, Rizzello F,
Caramelli E, Matteuzzi D, Campieri M. 2003. FEMS Immunol Med
Microbiol. Immunomodulatory effects of probiotic bacteria DNAL
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cells. Sep 22;38(2):165-72.
8. Schultz M, Linde H, Lehn N, Zimmermann K, Grossmann J, Falk
W, Scholmerich J. 2003. J Dairy Res Immunomodulatory consequences
of oral administration of Lactobacillus rhamnosus strain GG in
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9. Rachmilewitz D, Katakura K, Karmeli F, Hayashi T, Reinus
C, Rudensky B, Akira S, Takeda K, Lee J, Takabayashi K, Raz E.
2004. Toll-like receptor 9 signaling mediates the anti-inflammatory
effects of probiotics in murine experimental colitis. Gastroenterology.
10. Gill HS, Rutherfurd KJ, Prasad J, and Gopal PK. 2000. Enhancement
of natural and acquired immunity by Lactobacillus rhamnosus (HN001),
Lactobacillus acidophilus (HN017) and Bifidobacterium lactis
(HN019). Brit J Nutr. 83:167-76.
11. Vanderhoof J and Young R. 2003. Role of probiotics in the
management of patients with food allergy. Ann Allergy Asthma
Immunol. Jun;90(6 Suppl 3):99-103.
12. Majamaa H, Isolauri E. 1997. Probiotics: a novel approach
in the management of food allergy. L Allergy Clin Immunol. Feb;99(2):-179-85.
13. Dalloul RA, Lillehoj HS, Shellem TA, Doerr JA. 2003. Intestinal
immunomodulation by viamin A deficiency and lactobacillus-based
probiotic in Eimeria acervulina-infected broiler chickens. Avian
14. Hirano J, Yoshida T, Sugiyama T, Naoki K, Mori I, Yokochi
T. 2003. The effect of Lactobacillus rhamnosus on enterohemorrhagic
Eshcerichia coli infection of human intestinal cells in vitro.
Microbiol Immunol. 47(6):405-9.
15. Majamaa H, Isolauri E, Saxelin M, Vesikari T. 1995. Lactic
acid bacteria in the treatment of acute rotavirus gastroenteritis.
J Pediatr Gastroenterol Nutr. Apr;20(3):333-8.
16. Shu Q, Lin H, Rutherfurd Kj, Fenwick SG, Prasad J, Gopal
PK, Gill, HS. 2000. Dietary Bifidobacterium lactis (HN019) enhances
resistance to oral Salmonella typhimurium infection in mice.
Microbiol Immunol. 44(3):213-22.
17. Brudnak, MA 2001 Nutritional Regulation of Gene Expression.
Theory in Biosciences. 1 March, vol. 120, no. 1, pp. 64-75(12).
18. Miller, K.S. and Brudnak, M. (1994) Expression Cloning:
PCR Versus Episomal Vectors for Rescue of Transfected Genes.
In PCR in Neuroscience (Methods in Neuroscience Vol. 26) Volume
Editor G. Sarkar, Academic Press, Orlando, FL.
19. Wentworth P Jr, Jones LH, Wentworth AD, Zhu X, Larsen NA,
Wilson IA, Xu X, Goddard WA 3rd, Janda KD, Eschenmoser A, Lerner
RA. Antibody catalysis of the oxidation of water. Science. 2001
20. Brudnak, MA 2002 Natural Weight-loss Supplements: Are Safe
Alternatives Available? Positive Health April (75).
21. Brudnak, MA 2002 Probiotics
and Cancer. Townsend
Letter for Doctors & Patients. June:
22. Brudnak, Mark A. (2003) The
Probiotic Solution: Nature’s
Secret to Radiant Health. ISBN: 0-938045-75-X Dragon Door Publications.
Please feel free to contact
Mark A. Brudnak PhD, ND
957 Lake Shore Road
Grafton, WI 53024
(Wisconsin is in the Central