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Probiotics: an update on mechanisms of action and clinical applications

Mehdi Goudarzi, Hossein Goudarzi, Marjan Rashidan




Probiotics are live microbial feed supplement and can provide health benefit to the host if administered in sufficient amounts. The most predominant species that have been used as probiotic include Lactobacilli and bifidobacteria. Proper administration of probiotics could be efficient in the treatment of various disorders. However; their mechanism of action is poorly understood. The effects of probiotics may be classified in following modes: reinforcement of the intestinal mucosal barrier against pathogens, competition with pathogens for adherence to the mucosa and epithelium, competitive exclusion of pathogenic microorganisms, production of antimicrobial substances, modulation of the immune system and interference with quorum sensing signaling. Exploration of the clinical features of probiotic strains, their modes of action and investigation based on probiotic therapy may be beneficial in treatment of various diseases.


Probiotics, Lactobacillus, Bifidobacterium, UTI



FAOWHO. Probiotics in food. Health and nutritional properties. FAO Food and Nutrition Paper 85. Rome, Italy. 2006.

Metchnikoff E. The Prolongation of Life. New York: Putmans Sons, 1908.

Lactobacillus caseistrainShirota, Yakult Honsha Co. Ltd,Yakult Central Institute for Microbiological Research,Tokyo, Japan (1998).

Lilly DM & Stillwell RH. Growth promoting factors produced by micro-organisms. Science 1965; 147: 747-48.

Parker RB. Probiotics, the other half of the antibiotic story. Animal Nutrition and Health 1974; 29: 4–8.

Fuller R. Probiotics in man and animals. Journal of Applied Bacteriology 1989; 66: 365–378.

Salminen S, Bouley C, Boutron-Ruault MC et al. Functional food science and gastrointestinal physiology and function. British Journal of Nutrition 1998; 80: S147–S171.

Marteau P, Cuillerier E, Meance S et al. Bifidobacteriumanimalis strain DN-173 010 shortens the colonic transit time in healthy women: a double-blind, randomized, controlled study. Alimentary Pharmacology and Therapeutics 2002; 16: 587–593.

Brown M. Modes of Action of Probiotics: Recent Developments. J.Anim.Vet.Adv. 2011; 10: 1895-1900.

Guarner F andMalagelada J.R. Gut flora in health and disease. Lancet 2003; 361: 512–519.

Casula G, Cutting SM. Bacillus probiotics: spore germination in the gastrointestinal tract. Applied and environmental microbiology. 2002;68(5):2344-52.

McFarland LV. Meta-analysis of probioticsfor the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol 2006; 101: 812–822.

Madden J, Hunter J. A review of the role of the gut microflora in irritable bowel syndrome and the effects of probiotics. British Journal of Nutrition. 2002;88(S1):s67-s72.

Gibson G. R. and Roberfroid, M. B. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. Journal of Nutrition1995;125: 1401-1412.

Ohland CL, MacNaughton WK. Probiotic bacteria and intestinal epithelial barrier function. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2010;298(6):G807-G19.

Hooper LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI. Molecular analysis of commensal host-microbial relationships in the intestine. Science. 2001;291(5505):881-4.

Sartor R.B. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat ClinPractGastroenterol Hepatol2006; 3: 390–407.

Sakaguchi T, Kohler H, Gu X and et al. Shigellaflexneri regulates tight junction-associated proteins in human intestinal epithelial cells. Cell Microbiol. 2002;4:367–381.

Watts T, Berti I, Sapone A and et al. Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabeticprone rats. ProcNatlAcadSci U S A. 2005;102:2916 –2921.

Anderson RC, Cookson AL, McNabb WC, Park Z, McCann MJ, Kelly WJ, Roy NC: Lactobacillus plantarum MB452 enhances the function of the intestinal barrier by increasing the expression levels of genes involved in tight junction formation. BMC Microbiol2010; 10: 316.

Hummel S, Veltman K, Cichon C, Sonnenborn U, Schmidt M.A. Differential targeting of the E-cadherin/β-catenin complex by Gram-positive probiotic lactobacilli improves epithelial barrier function. Appl Environ Microbiol 2012; 78: 1140–1147.

Zyrek AA, Cichon C, Helms S, et al. Molecular mechanisms underlyingthe probiotic effects of Escherichia coliNissle 1917 involve ZO-2 and PKCzeta redistribution resulting in tight junction and epithelial barrier repair. Cell Microbiol. 2007;9:804–816.

Bruewer M, Samarin S, Nusrat A: Inflammatory bowel disease and the apical junctional complex. Ann NY AcadSci 2006; 1072: 242–252.

Yan F, Polk DB: Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells. J BiolChem 2002; 277: 50959–50965.

Yan F, Cao H, Cover T.L., Whitehead R, Washington M.K., Polk D.B. Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology 2007; 132: 562–575.

Mack D.R., Ahrne S, Hyde L, Wei S, Hollingsworth M.A. Extracellular MUC3mucin secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro. Gut 2003; 52: 827–833.

Otte J.M., Podolsky D.K. Functional modulation of enterocytes by Grampositive and Gram-negative microorganisms. Am J PhysiolGastrointest Liver Physiol. 2004; 286:613–626.

Furrie E, Macfarlane S, Kennedy A, Cummings JH, Walsh SV, O’neil DA, Macfarlane GT.Synbiotic therapy ( Bifidobacteriumlongum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial. Gut 2005; 54: 242–249.

Ayabe T, Satchell DP, Wilson CL, Parks WC, Selsted ME, Ouellette AJ. Secretion of microbicidalalphadefensins by intestinal Paneth cells in response to bacteria. Nat Immunol2000; 1: 113–118.

O‘neil DA, Porter EM, Elewaut D, Anderson GM, Eckmann L, Ganz T, Kagnoff MF. Expression and regulation of the human betadefensins hBD-1 and hBD-2 in intestinal epithelium. J Immunol 1999; 163: 6718–6724.

Takahashi A, Wada A, Ogushi K, Maeda K, Kawahara T, Mawatari K, Kurazono H, Moss J, Hirayama T, Nakaya Y. Production of betadefensin-2 by human colonic epithelial cells induced by Salmonella enteritidisflagella filament structural protein. FEBS Lett 2001; 508: 484–488.

Müller CA, Autenrieth IB, Peschel A. Innate defenses of the intestinal epithelial barrier. Cell Mol Life Sci 2005; 62: 1297–1307.

Kelsall B.L. Innate and adaptive mechanisms to control pathological intestinal inflammation. J Pathol 214: 242–259, 2008.

Juntunen M, Kirjavainen PV, Ouwehand AC, Salminen SJ, Isolauri E. Adherence of probiotic bacteria to human intestinal mucus in healthy infants and during rotavirus infection. ClinDiag Lab Immunol 2001; 8: 293–296.

Schiffrin EJ, Brassart D, Servin AL, Rochat F, Donnet-Hughes A. Immune modulation of blood leukocytes in humans by lactic acid bacteria: criteria for strain selection. Am J ClinNutr 1997; 66: 515–520.

Hirano J, Yoshida T, Sugiyama T, Koide N, Mori I, Yokochi T. The effect of Lactobacillus rhamnosus on enterohemorrhagic Escherichia coli infection of human intestinal cells in vitro. Microbiol Immunol 2003; 47: 405–409.

Van Tassell ML, Miller MJ.Lactobacillusadhesion to mucus. Nutrients 2011; 3: 613–636.

Buck BL, Altermann E, Svingerud T, Klaenhammer TR. Functional analysis of putative adhesion factors in Lactobacillus acidophilus NCNCFM. Appl Environ Microbiol 2005; 71: 8344–8351.

Ouwehand AC, Salminen S, Tolkko S, Roberts P, Ovaska J, Salminen E. Resected human colonic tissue: new model for characterizing adhesion of lactic acid bacteria. Clin Diag Lab Immunol 2002; 9: 184–186.

Conway PL, Goldin BR, Gorbach SL. Survival of lactic acid bacteria in the human stomach and adhesion to intestinal cells. J Dairy Sci, 1987; 70:1-12.

Mack DR, Michail S, Wei S, Macdougal L, Hollingsworth MA. Probiotics inhibit enteropathogenic E. coli adherence in vitro by inducing intestinal mucin gene expression. Am J Physiol, 1999; 39:G941-G950.

Rolfe RD: Population dynamics of the intestinal tract; in Blankenship LC (ed): Colonization Control of Human Bacterial Enteropathogens in Poultry. San Diego, Academic Press, 1991; 59–75.

Alakomi HL, Skytta E, Saarela M, Mattila- Sandholm T, Latva-Kala K, Helander IM. Lactic acid permeabilizes gram-negative bacteria by disrupting the outer membrane. Appl Environ Microbiol 2000; 66: 2001–2005.

Ouwehand AC: Antimicrobial components from lactic acid bacteria; in Salminen S, von Wright A (eds). Lactic Acid Bacteria: Microbiology and Functional Aspects. New York, Dekker, 1998, pp 139–159.

Nielsen DS, Cho GS, Hanak A, Huch M, Franz CM, Arneborg N: The effect of bacteriocin- producing Lactobacillus plantarum strains on the intracellular pH of sessile and planktonic Listeria monocytogenes single cells. Int J Food Microbiol 2010; 141:S53–S59.

Nemcova R. [Criteria for selection of lactobacilli for probiotic use]. Veterinární medicína. 1997;42(1):19-27.

Hassan M, Kjos M, Nes I, Diep D, Lotfipour F. Natural antimicrobial peptides from bacteria: characteristics and potential applications to fight against antibiotic resistance. Journal of applied microbiology. 2012;113(4):723-36.

O’Shea EF, Cotter PD, Stanton C, Ross RP, Hill C: Production of bioactive substances by intestinal bacteria as a basis for explaining probiotic mechanisms: bacteriocins and conjugated linoleic acid. Int J Food Microbiol 2012; 152: 189–205.

Lee K, Paek K, Lee HY, Park JH, Lee Y: Antiobesity effect of trans-10,cis-12-conjugated linoleic acid-producing Lactobacillus plantarumPL62 on diet-induced obese mice. J ApplMicrobiol 2007; 103: 1140–1146.

Oelschlaeger TA: Mechanisms of probiotic actions – a review. Int J Med Microbiol2010; 300: 57–62.

Coloretti F, Carri S, Armaforte E, Chiavari C, Grazia L, Zambonelli C: Antifungal activity of lactobacilli isolated from salami. FEMS MicrobiolLett 2007; 271: 245–250.

Lindgren SE, Dobrogosz WJ: Antagonistic activities of lactic acid bacteria in food and feed fermentations. FEMS Microbiol Rev1990; 7: 149–163.

Prema P, Smila D, Palavesam A, ImmanuelG: Production and characterization of an antifungal compound (3-phenyllactic acid) produced by Lactobacillus plantarum strain. Food Bioprocess Technol 2008; 3: 379–386.

Sjogren J, Magnusson J, Broberg A, Schnurer J, Kenne L: Antifungal 3-hydroxy fatty acids from Lactobacillus plantarumMiLAB14. Appl Environ Microbiol 2003; 69: 7554–7557.

Gómez-Llorente C, Muñoz S, Gil A: Role of Toll-like receptors in the development of immunotolerance mediated by probiotics. ProcNutrSoc 2010; 69: 381–389.

Akbari O, DeKruyff RH, Umetsu DT. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure toantigen. Nat Immunol. 2001; 2:725–731.

Williamson E, Bilsborough JM, Viney JL. Regulation of mucosaldendritic cell function by receptor activator of NF-kappa B (RANK)/RANK ligand interactions: impact on tolerance induction. J Immunol.2002; 169:3606 –3612.

Rescigno M, Urbano M, Valzasina B, et al. Dendritic cells express tightjunction proteins and penetrate gut epithelial monolayers to samplebacteria. Nat Immunol. 2001; 2:361–367.

Stagg A, Hart A, Knight S, Kamm M. The dendritic cell: its role in intestinal inflammation and relationship with gut bacteria. Gut. 2003;52(10):1522-9.

Hart AL, Lammers K, Brigidi P, et al. Modulation of human dendriticcell phenotype and function by probiotic bacteria. Gut. 2004; 53:1602–1609.

Pathmakanthan S, Li CK, Cowie J, et al. Lactobacillus plantarum 299:beneficial in vitro immunomodulation in cells extracted from inflamedhuman colon. J GastroenterolHepatol. 2004; 19:166 –173.

Kaila M, Isolauri E, Soppi E, et al. Enhancement of the circulatingantibody secreting cell response in human diarrhea by a human Lactobacillusstrain. Pediatr Res. 1992; 32:141–144.

Fang H, Elina T, Heikki A, et al. Modulation of humoralimmuneresponse through probiotic intake. FEMS Immunol Med Microbiol.2000; 29:47–52.##

Ogawa T, Asai Y, Tamai R, et al. Natural killer cell activities ofsynbioticLactobacilluscasei ssp. casei in conjunction with dextran.ClinExpImmunol. 2006; 143:103–109.

Cella M, Fuchs A, Vermi W, Facchetti F, Otero K, Lennerz JK, Doherty JM, MillsJC, and Colonna M. A human natural killer cell subset provides an innate source ofIL-22 for mucosal immunity. Nature 2009; 457: 722-725.

Chiang BL, Sheih YH, Wang LH, Liao CK, and Gill HS. Enhancing immunity bydietary consumption of a probiotic lactic acid bacterium (BifidobacteriumlactisHN019): optimization and definition of cellular immune responses. Eur J ClinNutr2000;54: 849-855.

Braat H, van den BJ, van Tol E, et al. Lactobacillus rhamnosusinducesperipheralhyporesponsiveness in stimulated CD4+ T cells via modulationof dendritic cell function. Am J ClinNutr. 2004; 80:1618 –1625.

Schauder, S. andBassler, B.L. (2001). The languages of bacteria. Genes and Development 15, 1468-1480.

Vilà B., Esteve-Garcia E and Brufau J. Probiotic microorganisms: 100 years of innovation and efficacy.Modes of action.World’s Poultry Science Journal. 2010; 66: 369-380.

Medellin-Pena, M.J., Wang, H., Johnson, R., Anand, S. and Griffiths,M.W. (2007). Probiotics Affect Virulence-Related Gene Expression in Escherichia coli O157:H7. Applied and Environmental Microbiology 73, 4259-4267.

Medina-Martinez, M.S., Uyttendaele, M., Rajkovic, A., Nadal, P. andDebevere, J. (2007). Degradation of N-Acyl-L-Homoserine Lactones by Bacillus cereusin Culture Media and Pork Extract. Applied and Environmental Microbiology 73, 2329-32.

Brown M. Modes of action of probiotics: recent developments. Journal of Animal and Veterinary Advances. 2011;10(14):1895-900.

Forestier C, De Champs C, Vatoux C, Joly B. Probiotic activities of Lactobacillus caseirhamnosus: in vitro adherence to intestinal cells and antimicrobial properties. Res Microbiol 2001; 152:167-73.

Shu Q, Qu F, Gill HS. Probiotic treatment using Bifidobacteriumlactis HN019 reduces weanling diarrhea associated with rotavirus and Escherichia coli infection in a piglet model. J PediatrGastroenterolNutr 2001; 33:171-7.

Arvola T, Laiho K, Torkkeli S, Mykkänen H, Salminen S, Maunula L, et al. Prophylactic LactobacillusGGReduces Antibiotic-Associated Diarrhea in Children With Respiratory Infections: A Randomized Study. Pediatrics. 1999;104(5):e64-e.

Castagliuolo I, Qiu BS, Lamont JT, Pothoulakis C. Saccharomyces boulardii protease inhibits Clostridium difficile toxin A effects in the rat ileum. Infect Immun 1996; 64:5225_/32.

Castagliuolo I, Riegler MF, Valenick L, Lamont JT, Pothoulakis C. Saccharomyces boulardii protease inhibits the effects of Clostridium difficile toxins A and B in human colonic mucosa.Infect Immun 1999; 67:302_/7.

Amdekar S, Singh V, Singh DD. Probiotic therapy: immunomodulating approach toward urinary tract infection. CurrMicrobiol.2011; 63(5):484-90.

Mack DR, Michail S, Wei S, McDougall L, Hollingsworth MA. Probiotics inhibit enteropathogenicE. coli adherence in vitro by inducing intestinal mucin gene expression. Am J Physiol.1999; 276(4 Pt 1):G941-50.

Shah N. Probiotics and prebiotics. Agro Food industry Hi Tech. 2004;15(1):13-7.

Kontiokari T, Laitinen J, Järvi L, Pokka T, Sundqvist K, Uhari M. Dietary factors protecting women from urinary tract infection. Am J Clin Nutr.2003; 77(3):600-4.

Silva de Ruiz C, Lopez de Bocanera ME, Nader de Macias ME,Pesce de Ruiz Holgado AA. Effect of lactobacilli and antibioticson E. coli urinary infections in mice. Biol Pharm Bull1996; 19(1):88–93.

Cremonini F, Canducci F, Di Caro S, et al. Helicobacter pyloritreatment: a role for probiotics. Digest Dis 2001; 19:144-7.

Midolo PD, Lambert JR, Hull R, Luo F, Grayson ML. In vitro inhibition of Helicobacter pyloriNCTC 11637 by organic acids and lactic acid bacteria. J ApplBacteriol 1995; 79:475_/9.

Mukai T, Asasaka T, Sato E, Mori K, Matsumoto M, Ohori H. Inhibition of binding of Helicobacter pylorito the glycolipid receptors by probiotic Lactobacillus reuteri. FEMS Immunol Med Microbiol 2002; 32:105_/10.

Pinchuk IV, Bressollier P, Verneuil B, et al. In vitro anti-Helicobacter pyloriactivity of the probiotic strain Bacillus subtilis3 is due to secretion of antibiotics. Antimicrob Agents Chemother2001; 45:3156_/61.

Kabir AMA, Aiba Y, Takagi A, Kamiya S, Miwa T, Koga Y. Prevention of Helicobacter pyloriinfection by lactobacilli in a gnotobiotic murine model. Gut 1997; 41:49 _/55.

Hilton E, Isenberg HD, Aplerstein P, France K, Borenstein MT. Ingestion of yoghurt containing Lactobacillus acidophilus as prophylaxis for candida vaginitis. Ann Int Med 1992; 116:353–7.

Hughes VL, Hilier SL. Microbiologic characteristics of Lactobacillus products used for colonisation of the vagina. ObstetGynecol 1990; 75(2):244–8.

Ocana VS, Pesce de Ruiz Holgado AA, Nader-Macias ME. Selection of vaginal H2O2-generating Lactobacillus for probiotic use. CurrMicrobiol 1999; 38(5):279–84.

Sütas Y, Soppi E, Korhonen H, Syväoja E-L, Saxelin M, Rokka T, et al. Suppression of lymphocyte proliferation in vitro by bovine caseins hydrolyzed with Lactobacillus casei GG–derived enzymes. Journal of Allergy and Clinical Immunology. 1996;98(1):216-24.

Kim HS, Gilliland SE. Lactobacillus acidophilusas dietary adjunctfor milk to aid lactose digestion in humans. J Dairy Sci1983; 66:959–66.

Ouwehand A.C. Antiallergic Effects of Probiotics. The Journal of Nutrition 2007; 794S- 797S.

Lovegrove J, Jackson K. Coronary heart disease. In: Mattila Sandholm T, Saarela M, eds. Functional dairy products. Cambridge, UK: Woodhill Publishing, 2003:54–87.

LindneR D.J.D., Pandey A and Thomaz-Soccol V. The Potential of Probiotics: A Review. Food Technol. Biotechnol.2010; 48:413–434.

Gill H.S. and Guarner F. Probiotics and human health: a clinical perspective. Postgrad Med J 2004;80:516–526.

DOI: https://doi.org/10.22037/nbm.v2i1.6127