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Probiotics are living microorganisms, which when ingested or locally applied in sufficient numbers, 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.
Introduction 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 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.
Established
and potential health benefits
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 later. 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 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. Specific Immunity 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
Discussion 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.
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 IL-1 and IL-10 response in human peripheral blood mononuclear 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 healthy volunteers. May;70(2):165-73. 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. Feb;126(2);520-8. 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. 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 Dis. Oct-Dec;47(4):1313-20. 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 Sep 7;293(5536):1806-11. 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: 62-65. 22. Brudnak, Mark A. (2003) The
Probiotic Solution: Nature’s
Secret to Radiant Health. ISBN: 0-938045-75-X Dragon Door Publications.
MN March Please feel free to contact me. Mark A. Brudnak PhD, ND (Wisconsin is in the Central Time Zone)
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