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REVIEW

ARTICLE

JIACM 2005; 6(1): 67-72

Probiotics in Health and Disease


S Anuradha*, K Rajeshwari**
Probiotics have been with us for as long as people have eaten fermented milk, but their association with health benefits dates only from the turn of the last century, when Metchnikoff drew attention to the adverse effects of some gut microflora on the host, and suggested that ingestion of fermented milk ameliorated this so-called auto-intoxication. In 1965, Lilley and Stillwell used the term probiotic to describe them as beneficial micro-organisms1. Finally, in 1989 Fuller defined them as A live microbial food supplement which beneficially affects the host animal by improving its microbial balance2. term consumption of cheese containing Lactobacillus GG and Lactobacillus rhamnosus LC 705 showed a trend indicating that probiotic intervention might reduce the risk of the highest levels of Streptococcus mutants and salivary yeasts4.

Currently used probiotics


The majority of probiotics are bacteria with the species of lactobacillus and bifidobacterium being the most common type of bacteria used. Table I shows the list of micro-organisms used as probiotics. Table I : Micro-organisms used as probiotics. A. Bacteria i. Lactobacillus: acidophilus, sporogenes, plantarum, rhamnosum, delbrueck, reuteri, fermentum, lactus, cellobiosus, brevis Bifidobacterium: bifidum, infantis, longum, thermophilum, animalis

What is the need for probiotics?


The vast majority (> 90%) of the total cells in the body are present as bacteria in the colon, reaching 1012 for every gram of large intestinal contents. Under natural conditions, a protective gut microflora develops and there is no need for a bacterial supplement. But the changing food habits and lifestyle force us to take processed and sterile food, which affects our access to, and colonisation, by certain type of bacteria. Moreover, we also consume antibacterial substances ranging from vinegar to antibiotics.

ii.

iii. Streptococcus: lactis, cremoris, alivarius, intermedius iv. Leuconostoc v. Pediococcus vi. Propionibacterium

Potential of everyday standard food items to promote healthy GI microflora


Some standard food items, e.g., yogurt, sauerkraut, garlic, and cheese contain probiotics in the form of live lactic acid bacteria and/or probiotics in the form of fructans, a dietary fibre 3. Cheese contains both probiotic bacteria and the prebiotic dietary fibre inulin. The regular consumption of cheese has been associated with a reduction in the risk of Campylobacter enteritis. Further, cheese is known to contain compounds that reduce the risk of dental caries. In a study by Ahola et al, results from logistic regression showed that short-

vii. Bacillus viii. Enterococcus ix. E. faecium B. Yeast and moulds A. cerevisiae, A. niger, A. oryzue, C. Pintolopesii, Sacharomyces boulardii. A bacteria, before being selected as a probiotic, should be non-pathogenic, non-toxigenic, should retain viability during storage and use, should have the capacity to survive and metabolise in the gut, and finally should have documented health effects. L. rhamnosus strain GG meets most of these criteria.

* Assistant Professor, Department of Medicine, ** Associate Professor, Department of Paediatrics, Maulana Azad Medical College, New Delhi - 110 002.

Table II : Indications for probiotics5. Proven indications Rotavirus diarrhoea Reduction of antibiotic-associated side effects Food allergies and lactose intolerance Atopic eczema Prevention of vaginitis Urogenital infections Irritable bowel syndrome Inflammatory bowel disease Cystic fibrosis Travellers diarrhoea Dental caries Enhance oral vaccine administration H. pylori infection Various cancers

Probiotics in Diarrhoea
Saavedra et al showed that supplementation of infant milk formula with B. bifidum and S. thermophilus reduced rotavirus shedding and episodes of diarrhoea in children in hospital10. In a study of HIV associated acute diarrhoea, Saint Marc reported that 56% of patients who were treated with S. boulardii had their symptoms resolved compared with only 6% of placebo treated patients11. Gorbach et al demonstrated that Lactobacillus GG successfully eradicated C. difficile in five patients with relapsing colitis, when they were fed viable lactobacilli in skimmed milk daily12. Further reduction in incidence of travellers diarrhoea has been reported by many studies13,14. These studies demonstrate that a probiotic can be effective in treating antibiotic induced diarrhoea, diarrhoeal disease acquired during travel, which most likely has a mixed bacterial and viral etiology, and diarrhoeal diseases in young children caused by rotavirus.

Possible indications

Probiotics in lactose intolerance


Kim and Gilliland found that feeding fermented milk to lactose intolerant subjects resulted in a significantly lower level of hydrogen in the breath when compared to the hydrogen level for subjects fed unfermented milk15. Hydrogen in the breath is a marker for bacterial metabolism of lactose in the large bowel. A lower hydrogen level indicates that lactose has been metabolised prior to entering the large intestine.

Protective effects of probiotics


Probiotics generally enhance the intestinal microflora by replenishing suppressed bacteria and inhibiting the growth of more pathogenic flora6. Some probiotics including Lactobacillus GG actively secrete an antimicrobial substance which inhibits the growth of certain other organisms7. Volatile fatty acids produced by the indigenous microflora, of which lactic acid bacteria form a part, are responsible for controlling the colonisation of gut by S. Sonnei and Enteropathogenic E. coli. Probiotics like S. faecalis, C. butyricum and B. mesentericus grow profusely and also accelerate the growth of bifidobacterium 8,9. Bifidobacterium is not only an antagonist of pathogenic organisms, but it also produces glutamine from NH4+ and glutamic acid. Glutamine is well known as a major supplement for intestinal epithelium and maintains mucosal integrity. Additionally, metabolites of these three bacteria, butyrate, and acetate, create a harmful environment for pathogenic E. coli, Salmonella and methicillin resistant S.-aureus, by lowering intestinal pH8. Butyrate is also required by intestinal epithelial cells as a supplement to stimulate proliferation of normal epithelium and plays a role in maintaining mucosal barrier defenses. 68

Antimutagenic and anticarcinogenic properties of probiotics


Probiotics can be antimutagenic in several ways. The enteropathogens such as E. coli and Clostridium perfringens produce enzymes such as beta-glucuronidase, and nitroreductase. Beta-glucosidase and urease can convert procarcinogens to proximate carcinogens16. The colonising cells of bifidobacterium produce lactic acid and lower the intestinal pH and create a bactericidal environment for these putative enteropathogens, and thus develop a favourable microenvironment which modulates the bacterial enzymes. Purified bifidobacterial has cell wall antitumour activities and induces activation of phagocytes to destroy growing tumour cells17. RAS activation represents one of the earliest and most Vol. 6, No. 1 January-March, 2005

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frequently occurring genetic alterations associated with human cancers, especially carcinoma of colon. Elevated levels of ras P-21 have been correlated with increased cell proliferations, histologic grade, nuclear aplasia and degree of undifferentiation18. Reddy et al demonstrated that dietary B. longum cultures significantly suppressed the expression of total and neonated ras P-21 in the colonic mucosa and tumours compared with control diet19. An additional mechanism of tumour suppression may involve a role for B. Longum as an immunomodulator and biological response modifier20. Probiotics also stimulate apoptosis through end-product formation.

organism with varying results26,27. The role of Lactobacillus casei strain GG (LGG) in IBS was studied in a randomised double blind cross-over trial28. The authors concluded that LGG alone did not have an effect on symptoms of IBS. The evidence of the use of probiotic bacteria in IBS is so far inconclusive. The trials that have been performed have centred on a symptomatic reduction or cure and have produced varying results. Currently, no organism can be confidently recommended to patients as being likely to help their symptoms. However, the abnormalities seen in colonic flora of IBS suggest that a probiotic approach will ultimately be justified.

Food allergy and probiotics


Loskutova et al and Trapp et al in two different studies reported that administration of probiotics was associated with disappearance of food allergy manifestation with decrease in concentration of IgE in the serum and with a lower frequency of allergies29,30. Probiotics, by their potentiating effect on the non-immunologic and immunologic defense barrier of the gut, alleviate the inflammatory response in food allergy. Bifidobacteria and lactobacilli have been shown to enhance IgA production in Peyers patches, and potentiate IgA response to potentially harmful antigens31. Probiotics reduce the secretion of Th2 cytokines which are IL-4, IL-5, IL-6, IL-9, IL10 and IL-13. These cytokines are responsible for strong antibody (esp IgG and IgE) responses and eosinophila found in helminthic infections and allergic disorders. Probiotics induce the secretion of IL-12 by activated macrophages. IL-12 increases resistance to intracellular bacteriae and parasites. Lactobacilli modify the immunomodulatory properties of native food protein32. Thus, probiotics influence the immune system by activating the lymphoid cells of the gastrointestinal lymphoid tissue.

Probiotics and immune enhancement


The colonic microflora affects mucosal and systemic immunity in the host. Intestinal epithelial cells, blood leucocytes, B and T lymphocytes, and accessory cells of the immune system are all complicated targets for probiotics21. The effect is produced either by absorption of a soluble antigen or by translocation of lactobacilli through the gut wall into the blood stream22. Lactobacilli which adhere to human intestinal epithelial cells are capable of activating macrophages23.

Probiotics and irritable bowel syndrome (IBS)


There have been few studies involving probiotics and IBS. This may be because IBS is a multifactorial condition making it difficult to study homogenous groups of patients. Halpern et al conducted a randomised double blind cross-over trial using Lacteol Fort, an antidiarrhoeal drug containing 5x1010 heat killed organisms/capsule of Lactobacllus acidophilus or a placebo 24 . They demonstrated a statistically significant difference in overall GI function, defined by clinical criteria, in the Lacteol group in comparison to those receiving placebo. Hunter et al administered 1010 cfu/d of Enterococcus faecium PR88 to twenty eight patients with high volume diarrhoea caused by food intolerance for twelve weeks25. There was a symptomatic improvement in nineteen of the twenty eight patients, and a significant decrease in faecal weight. Several trials of probiotics in IBS have used Lactobacillus plantarum 299v as the main probiotic

Atopic dermatitis and probiotics


Studies have been conducted to assess the role of probiotics in atopic disease. A study was conducted by Kirjavainen PV et al to assess the efficacy of oral supplementation of viable and heat inactivated probiotic bacteria in the management of atopic disease33. The study population included 35 infants with atopic eczema and

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allergy to cows milk. At a mean age of 5.5 months, they were assigned in a randomised double blind manner to receive either extensively hydrolysed whey formula (placebo group) or the same formula supplemented with viable Lactobacillus GG (viable LGG group) or heat inactivated Lactobacillus GG (heat inactivated LGG group) respectively. Within the study population, atopic eczema and subjective symptoms were significantly alleviated in all the groups. It was concluded that supplementation of infant formulae with viable but not heat inactivated LGG is a potential approach for the management of atopic eczema and cow milk allergy.

environment less receptive to bacterial vaginosis organisms.

Urinary tract infections


The basis for use of probiotics emerged from clinical observations in 1973, where a study of healthy women showed an association between lactobacilli presence in the vagina and no history of UTI38. Extensive studies of various lactobacilli strains led to the selection of a twostrain combination for vaginal use. This comprises distal urethral isolate L rhamnosus GR-1, selected primarily for its anti gram-negative activities and resistance to spermicide and L fermentum B-54 replaced more recently by RC-14, for anti gram-positive cocci activities and hydrogen peroxide production. In order to optimise a consistent dose with a good shelf life in a formulation preferred by patients, the organisms are freeze dried and placed in gelatin capsules with dosage at 109 per capsule higher than the total microbial content of the vagina39. Results from various studies indicate that the recurrence rate of UTI can be significantly reduced using one or two capsules vaginally per week for a year with no side effects or yeast infections39.

Probiotics and vaccine adjuvants


Isolauri et al noted an increase in rotavirus specific IgM secreting cells when the children were given Lactobacillus GG as an adjuvant to an oral vaccine to rotavirus compared to placebo on 8th post-vaccination day34. LGG also increased IgA and IgM seroconversion when measured in paired sera measured prior to vaccination, and after 30 days of vaccination.

Probiotics in vaginitis and other urogenital infections


Although antimicrobial therapy is generally effective in eradicating urogenital infections, there is still a high incidence of recurrence. There is good clinical evidence to show that the intestinal and urogenital microbial flora have a central role in maintaining both the health and wellbeing of humans.

Blood lipids and probiotics


Since the early work of Mann and Spoerry, probiotics have been reported to have cholesterol lowering properties in humans. The proposed mechanism is that probiotics cause direct assimilation of lipids, convert them into other metabolites and end products, which affects synthesis of cholesterol40. Many studies have been conducted since then to prove this fact but because of many limitations and confounding factors, none of the studies had sufficient statistical power to detect changes in cholesterol of < 15%. It is clear that if probiotics do have a cholesterol lowering effect, it is a relatively weak one compared with the effect of powerful cholesterol lowering drugs.

Bacterial vaginosis
Essentially, bacterial vaginosis is considered as an overgrowth of anaerobic organisms combined with a loss of the protective lactobacilli normally found in the healthy vagina35. Recently, daily oral intake of probiotic strains Lactobacillus rhamnosus GR-I and Lactobacillus fermentum RC-14, resulted in asymptomatic bacterial vaginosis patients reverting to normal lactobacilli dominated vaginal microflora 36,37. The mode of action might compromise increased ascension of probiotic and/or indigenous lactobacilli from the rectal skin to the vagina and enhancement of the intestinal mucosal immunity which effects vaginal immunity rendering the

Inflammatory bowel diseases


The luminal bacterial flora and immunological responses play a major role in initiation and perpetuation of chronic inflammatory bowel disease. Probiotics by their immunomodulatory and bowel flora manipulating properties, show a promising effect in treatment of chronic

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inflammatory bowel disease41. More clinical trials are needed to evaluate the true place of probiotics within a treatment regimen for chronic inflammatory bowel disease.

consumption of probiotic containing cheese and its effects on dental caries risk factors. Arch Oral Biol 2002; 47 (11): 799804. 5. 6. Gorbach SL. Probiotics in the third millennium. Dig Liver Dis 2002; 34 (Suppl 2): S2-7. Salminen S, Deighton M. Lactic acid bacteria in the gut in normal and disordered states. Dig Dis Sci 1992; 10: 227-38. Golden BR, Gorbach SL, Saxelin M et al. Survival of lactobacillus species (strain GG) in human gastrointestinal tract. Dig Dis Sci 1992; 37: 121-8. Seo G, Shimizu K, Kono M et al. Inhibition of growth of some enteropathogenic strain in mixed cultures of streptococcus faecalis and clostridium butyricum. Microbios Letter 1989; 40: 151-60. Lino H, Seo G, Shimuzu K et al. Stimulation of bacterial growth of some strain of Bifidobacterium by crude preparation of some strain of bifidobacterium by a crude preparation of metabolites from bacillus mesenteries. TOA Blome Letter 1993; 48: 73-8.

Side effects and safety profile of probiotics


Cases of infection due to lactobacilli and bifidobacterium are extremely rare and are estimated to represent 0.05 0.4% of cases of infective endocarditis and bacteraemia42,43. Of interest, increasing consumption of probiotic lactobacilli and bifidobacteria has not led to an increase in such opportunistic infections in consumers. Immunocompromised patients generally are more vulnerable to infection with pathogens and have a higher incidence of opportunistic infections. However, there is no published evidence that consumption of a probiotic that contains lactobacilli or bifidobacteria increases the risk of opportunistic infection among such individuals. In addition, 2 clinical studies have been conducted to assess the safety of probiotics in small groups of specific immunocompromised patients (e.g., patients with HIV infection), and the findings of these studies support the safety of probiotics consumed by such groups44,45. There is no evidence that ingested probiotic lactobacilli or bifidobacteria pose any risk of infection greater than that associated with commensal strains. In quantitative terms, the existing data suggests that the risk of bacteraemia which is the most commonly reported of these infections is < 1 case per million individuals. It is virtually impossible to propose a risk of death because of the common association of infections involving lactobacilli with fatal underlying conditions or the presence of polymicrobial infections46. Vigilance regarding the detection of possible rare cases of infections due to probiotics should be maintained and isolates should be sent to reference centres for molecular characterisation and confirmation.
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10. Saavedra JM, Bauman NA, Oung I et al. Feeding of bifidobacterium bifidum and streptococcus thermophilus to infants in hospitals for prevention of diarrhea and shedding of rotavirus. Lancet 1994; 344: 1046-9. 11. Saint Marc T, Rosse HO, Prats L, Touraine JL. Efficacit Saccharomyces boulardii dans let treatment des diarrheas di SIDA. Ann Med Intern (Paris) 1999; 142: 64-5. 12. Gorback SL, Chary T, Golden B. Successful treatment of relapsing clostridium difficle colitis with lactobacillus GG. Lancet 1987; (ii): 1519. 13. Black FT, Andersen PL, Orskov J et al. Prophylactic efficacy of lactobacilli on travellers diarrhea. In: Stiffen Re ed. Travel Medicine, conference on international travel medicine. Zurich Switzerland, Berlin: Springer, 1989; 333-5. 14. Oksanen PJ, Salminen S, Saxelin M et al. Prevention of travellers diarrhea by lactobacillus GG. Annals of Medicine 1990; 22: 53-6. 15. Kim HS, Gilliland SE. Lactobacillus acidophilus as dietary milk adjunct to aid lactose digestions in humans. Journal of Dairy Science 1983; 66: 959-66. 16. Kulkarni N, Reddy BS. Inhibitory effect of B Longum cultures on the azoxymethane induced aberrant crypt foci formation on focal bacterial beta-gluconidase. Proc Soc Exp Bid Med 1994; 207: 278-83. 17. Sekine K, Watanabe Sekine E, Ohta J et al. Induction and activation of tumoricidal cells in vitro and (in vivo by the bacterial cell wall of B infants). Bifidobacteria and Microflora 1994; 13: 54-77. 18. Kotsinas A, Spandidos DA, Romanowski P et al. Relative expression of wild type and activated ki-ras2 oncogene on colorectal carcinomas. Int J Oncol 1993; 3: 841-5. 19. Reddy BS, Riverson A. Inhibitory effect of B ongum on colon, mammary and liver carcinogenesis induced by 2 amino-3methylimidazo (4, 5-+) quinoline, a food mutagen. Cancer Res 1993; 53: 3914-8. 20. Okawa T, NiibeH, Arai T et al. Effect of LC 9018 combined

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with radiation therapy on carcinoma of the uterine cervix. Cancer 1993; 72: 1949-54. 21. Schiffrin, EJ, Brassart D, Serving AL et al. Immune modulation of blood leukocytes in human by lactic acid bacteria: Criteria for strain selection. Am J Nutr 1997; 66 (Suppl) 15: 205. 22. Berg RD. Translocation of indigenous bacteria from the intestinal tract, In: ed Hentges DJ, Human intestinal Microflora in health and diseases; 1983; New York; Academic Press 333-52. 23. Kleeman EF, Klaenhammet TR. Adherence of lactobacillus species to human fetal intestinal cells. J Parry Sci 1982; 65: 2063-9. 24. Halpern GM, Prindiville TS, Blankenburg M et al. Treatment of irritable bowel syndrome with Lacteol fort: a randomised, double blind, cross over trial. Am J Gastroenterol 1991; 1579-85. 25. Hunter JO, Lee AJ, King Ts et al. Enterococcus faecium strain PR88 - an effective probiotic. Gut 1996; 38 (Suppl 1): A62. 26. Niedzielin K, Kordecki H, Kosik R. New possibility in the treatment of irritable bowel syndrome: probiotics as a modification of the microflora of the colon. Gastroenterology 1998; 114: A402. 27. Nobaeck S, Johansson ML, Molin G et al. Alteration of intestinal microflora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome. Am J Gastroenterol 2000; 95: 1231-38. 28. OSullivan MA, O Morain CA. Bacterial supplementation in the irritable bowel syndrome. A randomised double blind placebo controlled cross over study. Dig Dis Sci 2000; 32: 302-4. 29. Loskutova IE. Effectiveness of using maluitka and Malysh adapted propronic acidophilus mixtures in the combined treatment of congenital hypertrophy. Vopr Pitan 1985; 1720. 30. Trapp CL, Charg CC, Halpern GM et al. The influence of chronic yogurt consumption on population of young and elderly adults. Int J Imunother 1993; 9: 53-64. 31. Yasui H, Nagaoka N, Mike A et al. Detections of bifidobacterium strains that induce large quantities of IgA. Microb Ecol Health Dis 1992; 5: 155-62. 32. Sutas Y, Hurme M, Isolauri. Down-regulation of anti-Co3 antibody induced IL-4 production by bovine caseins hydrolysed with LGG derived enzymes. Scand J Immunol 1996; 98: 216-24. 33. Kirjavainem PV, Salminen SJ, Isolauri E. Probiotic bacteria in the management of atropic disease: underscoring the importance of viability. JPGN 2003; 36 (2): 223-7. 34. Isolauri E, Joensuu J, Suomalainen H et al. Improved immunogenecity of oral Dx RRV reassortant rotavirus vaccine by L casei. GG vaccine 1995; 13: 310-2. 35. Sobel JD. Bacterial vaginosis. Annu Rev Med 2000; 51: 349-56. 36. Reid G, Bruce AW, Fraser N et al. Oral probiotics can resolve urogenital infections. FEMS Immunol Med Microbiol 2001; 30: 49-52. 37. Reid G, Charbonnaeau D, Erb J et al. Oral use of Lactobacillus

rhamnosus GR-1 and L. Fermentum RC-14 significantly alters vaginal flora: randomised placebo controlled trial in 64 healthy women. FEMS Immunol Med Microbiol 2003; 35: 131-4. 38. Bruce AW, Chadwick P, Hassan A et al. Recurrent urthritis in women. Can Med Assoc J 1973; 108: 973. 39. Reid G, Bruce AW, Taylor M. Instillation of Lactobacillus and stimulation of indigenous organisms to prevent recurrence of urinary tract infections. Microecology Therapy 1995; 23: 32-45. 40. Mann GV, Spoery A. Studies of a surfactant and cholesteremia in the maassai. Am J Clin Nut 1974; 23: 464-9. 41. Schultz M et al. Probiotics and inflammatory bowel disease. Am J Gastroenterol 2000; (1 Suppl): S19-21. 42. Gasser F. Safety of lactic acid bacteria and their occurrence in human clinical infections. Bulletin de L Institut Pasteur 1994; 92: 45-67. 43. Saxelin M, Chuang NH, Chassy B et al. Lactobacilli and bacteremia in southern Finland, 1989-1992. Clin Infect Dis 1996; 22: 564-6. 44. Wolf BW, Wheeler KB, Ataya DG, Garleb KA. Safety and tolerance of Lactobacillus reuteri supplementation to a population infected with human immunodeficiency virus. Food Chem Toxicol 1998; 36: 1085-94. 45. Cunnigham Rundler S, Ahrne S, Bengmark S et al. Probiotics and immune response. Am J Gastroenterol 2000; 95: S22-5. 46. Borriello SP, Hammes WP, Holzapfel W et al. Safety of probiotics that contain Lactobacilli or Bifidobacteria. Clin Infect Dis 2003; 36: 775-80.

List of Prime-Reviewers of JIACM


(January - December 2004) JR Sankaran SH Talib Rita Sood Rohini Handa RSKSinha RK Garg Rajesh Rajput (Chennai) (Aurangabad) (New Delhi) (New Delhi) (New Delhi) (Lucknow) (Rohtak)

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