Clostridium difficile and probiotics
- Lisa E Davidson, MD
Lisa E Davidson, MD
- Medical Director, Antimicrobial Support Network
- Carolinas HealthCare System
- Patricia L Hibberd, MD, PhD
Patricia L Hibberd, MD, PhD
- Chief, Division of Global Health
- Massachusetts General Hospital for Children
Clostridium difficile is an anaerobic, gram positive, spore-forming bacillus that colonizes the intestinal tract after alteration of the normal gastrointestinal flora, usually by antibiotic therapy . It causes a range of illness from mild diarrhea to pseudomembranous colitis and death. The frequency and severity of Clostridium difficile associated diarrhea (CDAD) are increasing, as are relapsed disease and infection refractory to standard antibiotic therapy (vancomycin and metronidazole). With increased morbidity and mortality associated with CDAD, new approaches for prevention and treatment are needed. (See "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology" and "Clostridium difficile in adults: Clinical manifestations and diagnosis" and "Clostridium difficile in adults: Treatment".)
Probiotics are live, nonpathogenic bacteria capable of colonizing the colonic mucosa . Several probiotics are available over the counter and in health food stores. Most are sold in fermented foods or dairy products as formulations, including the bacteria species Lactobacillus or Bifidobacteria, which are part of the normal gastrointestinal microbiota [3-7]. Saccharomyces boulardii is a yeast (fungal) probiotic agent . The role of intestinal commensal organisms in maintenance of the intestinal epithelium and immune system is an area of increasing interest . The alteration of gut microflora in the setting of CDAD has raised interest in a potential role for probiotics to restore a diverse intestinal microflora after disruption by antimicrobial therapy and CDAD.
The role of probiotics for treatment and prevention of C. difficile will be reviewed here. The role of probiotics for antibiotic-associated diarrhea and other gastrointestinal diseases is discussed in detail separately. (See "Probiotics for gastrointestinal diseases".)
MECHANISMS OF PROBIOTICS
Probiotics may be effective for prevention and treatment of Clostridium difficile associated diarrhea (CDAD) by means of several mechanisms:
●Alteration of intestinal flora — The gastrointestinal tract is colonized by a complex balance of diverse microorganisms. Administration of antibiotics disrupts this balance and is a key factor in the pathogenesis of C. difficile colonization and disease. Patients with recurrent CDAD have markedly diminished bacterial diversity compared with controls . Most probiotics colonize the gut temporarily, producing bactericidal acids and peptides and promoting "competition" among microbes by competing for nutrients and epithelial adhesion. These effects appear to reduce the favorability of the environment for C. difficile [11-13]. Both lactobacilli  and S. boulardii  have been shown to suppress the growth of C. difficile in hamsters.
- Bartlett JG. Historical perspectives on studies of Clostridium difficile and C. difficile infection. Clin Infect Dis 2008; 46 Suppl 1:S4.
- Food and Agriculture Organization of the United Nations and World Health Organization. Health and Nutritional Properties of Probiotics in Food including Powder Milk with Live Lactic Acid Bacteria. Available at: ftp://ftp.fao.org/es/esn/food/probio_report_en.pdf (Accessed on November 19, 2008).
- Saarela M, Mogensen G, Fondén R, et al. Probiotic bacteria: safety, functional and technological properties. J Biotechnol 2000; 84:197.
- Heller KJ. Probiotic bacteria in fermented foods: product characteristics and starter organisms. Am J Clin Nutr 2001; 73:374S.
- Mattia A, Merker R. Regulation of probiotic substances as ingredients in foods: premarket approval or "generally recognized as safe" notification. Clin Infect Dis 2008; 46 Suppl 2:S115.
- Ishibashi N, Yamazaki S. Probiotics and safety. Am J Clin Nutr 2001; 73:465S.
- Tuohy KM, Probert HM, Smejkal CW, Gibson GR. Using probiotics and prebiotics to improve gut health. Drug Discov Today 2003; 8:692.
- Edwards-Ingram L, Gitsham P, Burton N, et al. Genotypic and physiological characterization of Saccharomyces boulardii, the probiotic strain of Saccharomyces cerevisiae. Appl Environ Microbiol 2007; 73:2458.
- Surawicz CM. Role of probiotics in antibiotic-associated diarrhea, Clostridium difficile-associated diarrhea, and recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol 2008; 42 Suppl 2:S64.
- Chang JY, Antonopoulos DA, Kalra A, et al. Decreased diversity of the fecal Microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis 2008; 197:435.
- Orrhage K, Sjöstedt S, Nord CE. Effect of supplements with lactic acid bacteria and oligofructose on the intestinal microflora during administration of cefpodoxime proxetil. J Antimicrob Chemother 2000; 46:603.
- Hopkins MJ, Macfarlane GT. Nondigestible oligosaccharides enhance bacterial colonization resistance against Clostridium difficile in vitro. Appl Environ Microbiol 2003; 69:1920.
- Wullt M, Johansson Hagslätt ML, Odenholt I, Berggren A. Lactobacillus plantarum 299v enhances the concentrations of fecal short-chain fatty acids in patients with recurrent clostridium difficile-associated diarrhea. Dig Dis Sci 2007; 52:2082.
- Naaber P, Mikelsaar M. Interactions between Lactobacilli and antibiotic-associated diarrhea. Adv Appl Microbiol 2004; 54:231.
- Elmer GW, McFarland LV. Suppression by Saccharomyces boulardii of toxigenic Clostridium difficile overgrowth after vancomycin treatment in hamsters. Antimicrob Agents Chemother 1987; 31:129.
- Gill HS. Probiotics to enhance anti-infective defences in the gastrointestinal tract. Best Pract Res Clin Gastroenterol 2003; 17:755.
- Pothoulakis C, Kelly CP, Joshi MA, et al. Saccharomyces boulardii inhibits Clostridium difficile toxin A binding and enterotoxicity in rat ileum. Gastroenterology 1993; 104:1108.
- Castagliuolo I, Riegler MF, Valenick L, et al. Saccharomyces boulardii protease inhibits the effects of Clostridium difficile toxins A and B in human colonic mucosa. Infect Immun 1999; 67:302.
- Castagliuolo I, LaMont JT, Nikulasson ST, Pothoulakis C. Saccharomyces boulardii protease inhibits Clostridium difficile toxin A effects in the rat ileum. Infect Immun 1996; 64:5225.
- Rea MC, Clayton E, O'Connor PM, et al. Antimicrobial activity of lacticin 3,147 against clinical Clostridium difficile strains. J Med Microbiol 2007; 56:940.
- Bernet MF, Brassart D, Neeser JR, Servin AL. Lactobacillus acidophilus LA 1 binds to cultured human intestinal cell lines and inhibits cell attachment and cell invasion by enterovirulent bacteria. Gut 1994; 35:483.
- Gopal PK, Prasad J, Smart J, Gill HS. In vitro adherence properties of Lactobacillus rhamnosus DR20 and Bifidobacterium lactis DR10 strains and their antagonistic activity against an enterotoxigenic Escherichia coli. Int J Food Microbiol 2001; 67:207.
- Bernet-Camard MF, Liévin V, Brassart D, et al. The human Lactobacillus acidophilus strain LA1 secretes a nonbacteriocin antibacterial substance(s) active in vitro and in vivo. Appl Environ Microbiol 1997; 63:2747.
- Kalliomäki MA, Walker WA. Physiologic and pathologic interactions of bacteria with gastrointestinal epithelium. Gastroenterol Clin North Am 2005; 34:383.
- Hudault S, Liévin V, Bernet-Camard MF, Servin AL. Antagonistic activity exerted in vitro and in vivo by Lactobacillus casei (strain GG) against Salmonella typhimurium C5 infection. Appl Environ Microbiol 1997; 63:513.
- Mack DR, Michail S, Wei S, et al. Probiotics inhibit enteropathogenic E. coli adherence in vitro by inducing intestinal mucin gene expression. Am J Physiol 1999; 276:G941.
- Madsen K, Cornish A, Soper P, et al. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 2001; 121:580.
- Dong MY, Chang TW, Gorbach SL. Effects of feeding lactobacillus GG on lethal irradiation in mice. Diagn Microbiol Infect Dis 1987; 7:1.
- Naaber P, Mikelsaar RH, Salminen S, Mikelsaar M. Bacterial translocation, intestinal microflora and morphological changes of intestinal mucosa in experimental models of Clostridium difficile infection. J Med Microbiol 1998; 47:591.
- Otte JM, Podolsky DK. Functional modulation of enterocytes by gram-positive and gram-negative microorganisms. Am J Physiol Gastrointest Liver Physiol 2004; 286:G613.
- Isolauri E, Majamaa H, Arvola T, et al. Lactobacillus casei strain GG reverses increased intestinal permeability induced by cow milk in suckling rats. Gastroenterology 1993; 105:1643.
- Terpend K, Blaton MA, Candalh C, et al. Intestinal barrier function and cow's milk sensitization in guinea pigs fed milk or fermented milk. J Pediatr Gastroenterol Nutr 1999; 28:191.
- Tasteyre A, Barc MC, Karjalainen T, et al. Inhibition of in vitro cell adherence of Clostridium difficile by Saccharomyces boulardii. Microb Pathog 2002; 32:219.
- Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, et al. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004; 118:229.
- Lan JG, Cruickshank SM, Singh JC, et al. Different cytokine response of primary colonic epithelial cells to commensal bacteria. World J Gastroenterol 2005; 11:3375.
- Sartor RB. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology 2004; 126:1620.
- Gill HS, Rutherfurd KJ, Cross ML, Gopal PK. Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019. Am J Clin Nutr 2001; 74:833.
- Sougioultzis S, Simeonidis S, Bhaskar KR, et al. Saccharomyces boulardii produces a soluble anti-inflammatory factor that inhibits NF-kappaB-mediated IL-8 gene expression. Biochem Biophys Res Commun 2006; 343:69.
- Gill HS, Rutherfurd KJ, Cross ML. Dietary probiotic supplementation enhances natural killer cell activity in the elderly: an investigation of age-related immunological changes. J Clin Immunol 2001; 21:264.
- Kaila M, Isolauri E, Soppi E, et al. Enhancement of the circulating antibody secreting cell response in human diarrhea by a human Lactobacillus strain. Pediatr Res 1992; 32:141.
- Link-Amster H, Rochat F, Saudan KY, et al. Modulation of a specific humoral immune response and changes in intestinal flora mediated through fermented milk intake. FEMS Immunol Med Microbiol 1994; 10:55.
- Majamaa H, Isolauri E, Saxelin M, Vesikari T. Lactic acid bacteria in the treatment of acute rotavirus gastroenteritis. J Pediatr Gastroenterol Nutr 1995; 20:333.
- Fukushima Y, Kawata Y, Hara H, et al. Effect of a probiotic formula on intestinal immunoglobulin A production in healthy children. Int J Food Microbiol 1998; 42:39.
- Yasui H, Shida K, Matsuzaki T, Yokokura T. Immunomodulatory function of lactic acid bacteria. Antonie Van Leeuwenhoek 1999; 76:383.
- Buts JP, Bernasconi P, Van Craynest MP, et al. Response of human and rat small intestinal mucosa to oral administration of Saccharomyces boulardii. Pediatr Res 1986; 20:192.
- Qamar A, Aboudola S, Warny M, et al. Saccharomyces boulardii stimulates intestinal immunoglobulin A immune response to Clostridium difficile toxin A in mice. Infect Immun 2001; 69:2762.
- McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol 2006; 101:812.
- Pillai A, Nelson R. Probiotics for treatment of Clostridium difficile-associated colitis in adults. Cochrane Database Syst Rev 2008; :CD004611.
- Biller JA, Katz AJ, Flores AF, et al. Treatment of recurrent Clostridium difficile colitis with Lactobacillus GG. J Pediatr Gastroenterol Nutr 1995; 21:224.
- Gorbach SL, Chang TW, Goldin B. Successful treatment of relapsing Clostridium difficile colitis with Lactobacillus GG. Lancet 1987; 2:1519.
- Bennett RG, Gorbach SL, Chang TW. Treatment of relapsing Clostridium difficile diarrhea with Lactobacillus GG. Nutr Today 1996; 31:35S.
- Schellenberg D, Bonington A, Champion CM, et al. Treatment of Clostridium difficile diarrhoea with brewer's yeast. Lancet 1994; 343:171.
- McFarland LV, Surawicz CM, Greenberg RN, et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA 1994; 271:1913.
- Surawicz CM, McFarland LV, Greenberg RN, et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis 2000; 31:1012.
- Lawrence SJ, Korzenik JR, Mundy LM. Probiotics for recurrent Clostridium difficile disease. J Med Microbiol 2005; 54:905.
- Thomas MR, Litin SC, Osmon DR, et al. Lack of effect of Lactobacillus GG on antibiotic-associated diarrhea: a randomized, placebo-controlled trial. Mayo Clin Proc 2001; 76:883.
- Wullt M, Hagslätt ML, Odenholt I. Lactobacillus plantarum 299v for the treatment of recurrent Clostridium difficile-associated diarrhoea: a double-blind, placebo-controlled trial. Scand J Infect Dis 2003; 35:365.
- Pochapin M. The effect of probiotics on Clostridium difficile diarrhea. Am J Gastroenterol 2000; 95:S11.
- Gorbach SL. Probiotics and gastrointestinal health. Am J Gastroenterol 2000; 95:S2.
- Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA 2012; 307:1959.
- Ritchie ML, Romanuk TN. A meta-analysis of probiotic efficacy for gastrointestinal diseases. PLoS One 2012; 7:e34938.
- Goldenberg JZ, Ma SS, Saxton JD, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev 2013; 5:CD006095.
- Johnston BC, Ma SS, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Ann Intern Med 2012; 157:878.
- Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2013; 382:1249.
- Johnston BC, Ma SS, Goldenburg JZ, et al. Probiotics for the prevention of clostridium difficile–associated diarrhea: A systematic review and meta-analysis. Ann Int Med 2012. https://annals.org/article.aspx?articleid=1390418 (Accessed on December 03, 2012).
- Belet N, Dalgiç N, Oncel S, et al. Catheter-related fungemia caused by Saccharomyces cerevisiae in a newborn. Pediatr Infect Dis J 2005; 24:1125.
- Graf C, Gavazzi G. Saccharomyces cerevisiae fungemia in an immunocompromised patient not treated with Saccharomyces boulardii preparation. J Infect 2007; 54:310.
- Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr 2006; 83:1256.
- Muñoz P, Bouza E, Cuenca-Estrella M, et al. Saccharomyces cerevisiae fungemia: an emerging infectious disease. Clin Infect Dis 2005; 40:1625.
- Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371:651.