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 a barrier to providing complete nutrition during this crucial developmental phase. Intact milk proteins are known to stimulate the secretion of pro-inflammatory 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. (13-16) 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 of 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 effect was due to the presence of viable L. rhamnosus cells. In this model, killed L. rhamnosus and other Lactobacillus strains did not have 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 important to GI health. It is also known 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 latter 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 of 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
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 of probiotics in inflammatory autoimmune diseases. Recent reports that not just cytokine levels are altered, but also antibody levels such as IgE mentioned above, support this. 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, 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 autism, which has also been 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 exciting as the mechanisms of action become clearer. (20-22) With such clarity should come even great applications for probiotics.

Table 1. Established and potential health benefits associated with probiotic use

Prevention of diarrhea and reduction of its duration
Reduction of irritable bowel syndrome (IBS)
Reduction of inflammatory bowel disease
Prevention of urogenital infections
Reduction of stomach infections related to Helicobacter pylori
Enhanced mucosal immunity
Reduction and treatment of autism
Decreased risk of certain cancers
Reduction of oxaluria and serum cholesterol
Prevention of atopic dermatitis
Weight management

References

1. Brudnak, MA 2002 High-dose Probiotics for Detoxification. Townsend Letter for Doctor's & Patients. May; 58(5):382-5.
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 Mierobiol. 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.
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. Auian 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.

Probiotics, Pg1

Probiotics, Pg3