Role of the intestinal microbiota in resistance to colonization by Clostridium difficile

Abstract

Antibiotic-associated infection with the bacterial pathogen Clostridium difficile is a major cause of morbidity and increased health care costs. C difficile infection follows disruption of the indigenous gut microbiota by antibiotics. Antibiotics create an environment within the intestine that promotes C difficile spore germination, vegetative growth, and toxin production, leading to epithelial damage and colitis. Studies of patients with C difficile infection and animal models have shown that the indigenous microbiota can inhibit expansion and persistence of C difficile. Although the specific mechanisms of these processes are not known, they are likely to interfere with key aspects of the pathogen's physiology, including spore germination and competitive growth. Increasing our understanding of how the intestinal microbiota manage C difficile could lead to better means of controlling this important nosocomial pathogen.

Keywords: Antibiotics; C difficile; Colonization Resistance; Microbial Ecology; Microbiome.

Figure 1. Cycle of CDI

Antibiotic administration alters the indigenous intestinal microbiota, producing an environment that permits germination of C difficile spores and expansion of the pathogen. C difficile produces toxins that cause colitis and other symptoms. Antibiotics directed against C difficile can decrease the load of the pathogen and toxin production. Returning the microbiota to a state of colonization resistance cures CDI. However, if the microbiota is unable to restore resistance to colonization by C difficile patients have recurring CDI. In certain cases, repeat courses of anti-C difficile antibiotic therapy can eradicate the pathogen. In other cases, therapeutic restoration of a diverse microbiota via FMT is required to overcome CDI.

Figure 2. Bile Acids Affect the Ability of C difficile to Colonize the Intestinal Tract

In the healthy microbiota, levels of cholate (CA) and chenodeoxycholate (CDCA) are high in the small intestine, and chenodeoxycholate inhibits germination. Because cholate is less well absorbed than chenodeoxycholate in the terminal ileum, the net effect is an increased ratio of cholate: chenodeoxycholate, resulting in increased spore germination ^–. As vegetative C difficile cells move into the colon, they are exposed to the toxic effects of deoxycholate (DCA), further preventing C difficile from gaining a foothold in the colon. When the microbiota is disrupted with antibiotics bacterial transformation of primary bile acids (such as CA to DCA) can be greatly suppressed. In this case CA levels remain high while bacterial transformation of CA to DCA does not occur. This results in increased CA mediated spore germination and a loss of inhibitory effects of deoxycholate on C difficile growth. The net effect is the expansion of this pathogen will readily occur in the colon.