Gut Microbiota-Produced Succinate Promotes C. difficile Infection after Antibiotic Treatment or Motility Disturbance

Jessica A. Ferreyra, Katherine J. Wu, Andrew J. Hryckowian, Donna M. Bouley, Bart C. Weimer, and Justin L. Sonnenburg. Cell Host Microbe (2014) 16: 770-777

Speaker: Wei-Ting Li (李瑋庭)                    Time: 13:10~14:00, Mar. 25, 2015

Commentator: Dr. I-Hsiu Huang (黃一修 老師)      Place: Room 601

Abstract:

Clostridium difficile, a Gram-positive and spore-forming anaerobic bacterium, is responsible for most common antibiotic-associated diarrhea. C. difficile asymptomatically exists in 2–5% of the adult gastrointestinal tract, but it can also lead to severe colitis, toxic megacolon, and other C. difficile associated diseases (CDAD) after microbiota disturbance¹. Researches on the mechanism of C. difficile expansion in gut after microbiota disturbance are just emerging. The authors have previously found that the enteric microbiota can release sialic acid from the host mucosal monosaccharides to serve as a nutrient source for C. difficile during postantibiotic expansion². In this study, they intended to identify other microbiota-produced metabolites that are necessary and also utilized by C. difficile for postantibiotic spread in the gut. The authors first observed that, in the presence of a gut symbiont Bacteroides thetaiotaomicron (Bt), C. difficile attains higher population density in the gut of germ-free (GF) mice fed polysaccharide-rich standard diet. In addition, by transcriptional profile analysis, they found that the genes involved in succinate-to-butyrate pathway were highly expressed under this condition. Succinate is a common anaerobic microbiota fermentation end-product, but only a few anaerobic organisms are known to ferment succinate to provide energy for growth³. By gas chromatography mass spectrometry and radio-labeling assay, they demonstrated that, indeed, C. difficile can use Bt-generated succinate to produce butyrate. AC. difficile mutant (Cd-CD2344^-) compromised in succinate utilization was colonization-defective in Bt-associated GF mice, suggesting that succinate is required for C. difficile expansion in the gut. Finally, the concentration of succinate present in the microbiota of conventional mice was elevated upon antibiotic treatment or polyethylene glycol-induced intestinal motility disturbance, andC. difficile may exploit this succinate accumulation to expand in the perturbed gut. Understanding the metabolic mechanisms involved in microbiota-C. difficile interactions may help us better treat or prevent CDAD.

References:

1.      He, M., et al. (2013). Emergence and global spread of epidemic healthcare-associated Clostridium difficile. Nat. Genet. 45, 109–113.

2.      Ng, K.M., et al. (2013). Microbiota-liberated host sugars facilitate postantibiotic expansion of enteric pathogens. Nature 502, 96–99.

3. Wolff, R.A., et al. (1993). Dehydrogenases involved in the conversion of succinate to 4-hydroxybutanoate by Clostridium kluyveri. Appl. Environ. Microbiol. 59, 1876–1882.