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.
- Antimicrobial activity — Bacteria in probiotic preparations produce acids that lower the pH of the local gut environment as well as toxins that inhibit the growth of other bacteria . S. boulardii has been shown in vitro to secrete a protease that inhibits binding of enterotoxin A [17-19], and Lactococcus lactis has been shown to secrete a cationic peptide that has antimicrobial activity against several strains of C. difficile in vitro .
- Intestinal barrier protection — The initial site of interaction between commensal and pathogenic bacteria in the human host is the gut epithelium. Probiotics may be capable of interfering with the binding of C. difficile toxins A and B to intestinal epithelial cells. In animal models and in vitro, probiotic strains have been shown to inhibit adhesion and decrease invasion of pathogenic organisms to the colonic epithelium [21-25]. Specifically, Lactobacilli increase expression of intestinal mucins [26,27] and decrease bacterial translocation [28-30]. Several probiotic preparations, including Lactobacillus rhamnosus GG , Bifidobacterium breve , and Streptococcus thermophilus , have been shown in animal models to stabilize gut permeability. In vitro studies have also demonstrated the ability of S. boulardii to inhibit adherence of C. difficile .
- Immunomodulation — Probiotics modulate both the innate and adaptive immune systems by stimulating toll like receptors (TLRs) [34-36] and upregulating cytokine expression in dendritic cells and peripheral blood monocytes [37,38]. Ingestion of Lactobacilli has been associated with enhanced phagocytic activity . In addition, several strains of Lactobacillus [40-42], Bifidobacterium [43,44], and Sacchromyces [45,46] have been associated with increased IgA secretion in both stool and serum.