Fig 1.
Developmental life cycle of Clostridium difficile during infection.
Spore germination occurs in the small intestine [13] and likely within the ileum [12,23]. Germinating spores are shown degrading the cortex layer (orange figure), a thick layer of modified peptidoglycan that maintains metabolic dormancy [19]. The times at which Koenigsknecht et al. detected the indicated developmental stages following C. difficile infection (CDI) are shown; the time at which sporulation is induced is unclear [12]. Koenigsknecht et al. propose a link between sporulation and toxin production, but whether sporulating cells themselves produce toxin during CDI requires further investigation. The effect of antibiotic exposure on bile acid composition of the indicated anatomical regions is summarized based on studies in mice [12,21,22], although it should be noted that antibiotics have differing effects on microbiota composition [21], and muricholic acids are murine-specific [20]. Weingarden et al. made similar observations in fecal extracts from patients with recurrent CDI [24]. Green arrows demarcate increases in germination-promoting bile acids, while red arrows indicate decreases in C. difficile growth-inhibitory bile acids. Deoxycholate promotes spore germination (dotted green arrow), but it also strongly inhibits C. difficile growth [14]. hpi designates hours post-infection.
Fig 2.
Effect of bile acid metabolism on the developmental life cycle of C. difficile.
The figure represents an update of the schematic by Britton et al. [3]. The liver synthesizes bile acids from cholesterol and secretes them as conjugated bile acids. Ileum gut microbiota produces bile salt hydrolases that deconjugate bile acids to primary bile acids, chenodeoxycholate, and cholate [23]. Primary bile acids serve as substrates for 7-dehydroxylases, made by a small subset of clostridial organisms such as C. scindens, which generate secondary bile acids lithocholate and deoxycholate. Chenodeoxycholate and secondary bile acids are toxic to vegetative C. difficile (red lines) [20,21], while cholate derivatives promote germination when combined with amino acid co-germinants like glycine (dotted line) [14].