Mechanistic Insights in the Success of Fecal Microbiota Transplants for the Treatment of Clostridium difficile Infections

Abstract

Fecal microbiota transplantation has proven to be an effective treatment for infections with the gram-positive enteropathogen Clostridium difficile. Despite its effectiveness, the exact mechanisms that underlie its success are largely unclear. In this review, we highlight the pleiotropic effectors that are transferred during fecal microbiota transfer and relate this to the C. difficile lifecycle. In doing so, we show that it is likely that multiple factors contribute to the elimination of symptoms of C. difficile infections after fecal microbiota transplantation.

Keywords: Clostridium difficile infection; antimicrobial peptides; bacteriocins; bacteriophages; bile acids; fecal microbiota transplant; short chain fatty acids; sialic acids.

FIGURE 1

Selected mechanisms by which the gut microbiota, metabolites and peptides can affect C. difficile. (A) The lifecycle of C. difficile. Spores germinate into vegetative cells, which then proliferate and start to produce toxins. The lifecycle is completed by the formation of spores from vegetative cells again. (B) A simplified overview of the effects of bile acid metabolism on C. difficile. Secondary bile acids are formed from primary bile acids via 7α-dehydroxylation by gut bacteria. Primary bile acids promote germination of spores into vegetative cells, while secondary bile acids generally inhibit this process. Secondary bile acids can inhibit toxin production. (C) A simplified view of the effects of specific nutrients on C. difficile. Dietary fibers are fermented by the gut microbiota and short-chain fatty acids (SCFAs) are released. Succinate can stimulate C. difficile expansion, whereas other SCFAs potentially inhibit growth. Certain bacterial species in the gut cleave sialidated carbohydrates, releasing sialic acid that stimulates C. difficile expansion. (D) Schematic view of naturally occurring antimicrobial factors. The human gut has a high abundance of microbial species, some of which produce bacteriocins that are bacteriostatic or bactericidal for C. difficile. Certain bacteriophages present in the gut microbiota use C. difficile as a host. Antimicrobial peptides (AMP) are produced by host cells that inhibit C. difficile growth and inhibit toxin activity.