Clostridium difficile is an important emerging pathogen that can cause life-threatening diarrhea1. Although C. difficile infections (CDI) are widely considered to be hospital and antibiotic associated, our understanding of the epidemiology of C. difficile has rapidly evolved in recent years. We now know that the vast majority of infections are acquired outside of hospitals2, and only a handful of antibiotics carry a substantially elevated risk of developing a C. difficile infection3–5. These revelations help explain why sanitation and antibiotic stewardship programs have not appreciably reduced the incidence of infection in hospitals6,7, but also highlight how much we have yet to learn about the factors that influence C. difficile colonization and transmission.
Using publicly-available microbiome sequencing data, we discovered that C. difficile colonizes people as they recover from gastrointestinal (GI) disturbances, and that carriage can persist for years at a time. Although all the data we re-analyzed each reveal different aspects of how C. difficile colonizes and spreads, there was one person whose experiences exemplified the primary observations from our study. During a long-term study that involved collecting daily fecal samples, this person became colonized by C. difficile after getting food poisoning.
For the first 150 days this person was C. difficile negative, but became colonized immediately after recovering from the source infection, and remained C. difficile positive throughout the remainder of the study. During this time the abundance of C. difficile fluctuated from one day to the next by multiple orders of magnitude – often falling below the limit of detection for days at a time before experiencing a resurgence. The most dramatic increase in abundance in this person came during a secondary gut disturbance, which appears to have triggered a period of substantially increased shedding of C. difficile in their feces. Although this person never took antibiotics after becoming sick, they were now a long-term C. difficile carrier, and they were completely unaware of its presence.
Ultimately, our observations in humans suggest that C. difficile colonizes people in the days immediately following GI disturbances. Once colonized, C. difficile persists in the human gut for year-long time scales, fluctuating considerably in abundance day-to-day by several orders of magnitude. To test our hypothesis that GI disturbances drive susceptibility to C. difficile colonization, regardless of etiology, we developed a mouse model of colonization under variable disturbance intensity using osmotic laxatives to cause diarrhea that was able to reproduce the colonization dynamics we observed in humans.
Our study helps reconcile the disparate risk factors attributed to C. difficile infections, and reveals important aspects of the short- and long-term dynamics of C. difficile in the human gut. Our study also helps explain why C. difficile is often detected as a co-infecting pathogen in patients with diarrhea – suggesting these patients could be asymptomatic carriers and that C. difficile is not necessarily contributing to their symptoms. Although C. difficile was once considered a hospital and antibiotic associated pathogen, our results suggest that antibiotics and hospitals are merely common examples of large disturbances and locations with a high burden of exposure.
- CDC. Antibiotic Resistance Threats in the United States. (2019).
- Eyre, D. W. et al. Diverse sources of C. difficile infection identified on whole-genome sequencing. The New England journal of medicine 369, 1195–205 (2013).
- Guh, A. Y. et al. Risk Factors for Community-Associated Clostridium difficile Infection in Adults: A Case-Control Study. Open Forum Infect. Dis. 4, (2017).
- McFarland, L. V., Surawicz, C. M. & Stamm, W. E. Risk factors for Clostridium difficile carriage and C. difficile-associated diarrhea in a cohort of hospitalized patients. J. Infect. Dis. 162, 678–684 (1990).
- Brown, K. A., Khanafer, N., Daneman, N. & Fisman, D. N. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob. Agents Chemother. 57, 2326–32 (2013).
- Ray, A. J. et al. A multicenter randomized trial to determine the effect of an environmental disinfection intervention on the incidence of healthcare-associated clostridium difficile infection. Infect. Control Hosp. Epidemiol. 38, 777–783 (2017).
- Patton, A. et al. Impact of antimicrobial stewardship interventions on Clostridium difficile infection and clinical outcomes: segmented regression analyses. J. Antimicrob. Chemother. 73, 517–526 (2017).