Has C. difficile Met Its Match?

Clostrdioides difficile, a gram-positive anaerobic bacterium, infects the human gut. Symptoms of C. difficile infection (CDI) range from mild, self-limiting diarrhea to worsening inflammatory bowel disease, sepsis, or even death.¹ CDI presents an enormous burden to health care as the most diagnosed health care-associated infection in the United States. Antibiotic resistance and high infection recurrence rates limit available treatment options.²

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The discovery of the ferrosome, an iron storage organelle, in the membrane of C. difficile offers new research avenues in the fight against CDI.³

Many pathogens need iron from the host. Host organisms protect their iron storage from pathogens using nutritional immunity, meaning they sequester trace minerals to starve invading pathogens. Pathogens frequently evolve to overcome nutritional immunity and survive regardless of iron availability.³

Calprotectin, an iron sequestering protein, provides one line of defense for human hosts to keep iron stores from pathogens. Inflammatory states in the gut induce calprotectin to store more protein away from pathogens. Studies in mice infected with reduced ferrosome C. difficile show lower bacterial burden and less weight loss in the host compared to mice infected with wild type C. difficile. This study outcome indicates ferrosomes could factor into C. difficile’s ability to overcome calprotectin-mediated nutritional immunity.³

Conversely, pathogens must also protect themselves from exposure to toxic amounts of iron. Excessive iron exposure is common in the gut due to bleeding, inflammation, or the presence of undigested food.³

Controlled studies in Kenyan children who received iron supplements showed increased bacterial burden of multiple Clostridioides strains and potentially less antibacterial efficacy. Orally administered iron is poorly absorbed and leads to high colonic iron concentrations. Such studies suggest the ferrosome allows C. difficile to withstand high iron surges.³

The discovery of the ferrosome and C. difficile’s response to varying iron levels is a novel study area. The role and importance of the ferrosome is inconclusive at this point. Ferrosomes potentially help C. difficile develop resistance to toxic iron surges, as seen in the study in Kenya. Alternatively, ferrosomes might help C. difficile adapt to low iron availability mediated by calprotectin.

References

1. Lee HS, Plechot K, Gohil S, Le J. Clostridium difficile: Diagnosis and the Consequence of Over Diagnosis. Infect Dis Ther. 2021;10(2):687-697. doi:10.1007/s40121-021-00417-7

2. Leffler DA, Lamont JT. Treatment of Clostridium difficile-associated disease. Gastroenterology. 2009;136(6):1899-1912. doi:10.1053/j.gastro.2008.12.070

3. Drakesmith H, Zimmermann MB. Another iron in C. difficile's fire. Cell Host Microbe. 2024;32(1):1-2. doi:10.1016/j.chom.2023.12.008