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Clostridioides difficile is a spore-forming, anaerobic gram-positive bacterium colonizing the human gastrointestinal (GI) tract (23, 24). Discovered in 1935, initially thought to be a commensal gut microbiota member (25). In the 1970s, linked to significant diarrheal illness (26)
Since it was first isolated in 1935, several thousand Clostridioides difficile isolates have been collected and analyzed. These isolates belong to a diverse phylogeny consisting of five main clades and at least three cryptic clades. The differences between these clades can largely be explained by the variation found within the accessory C. difficile genome. This variation is frequently linked to mobile genetic elements, such as prophage, transposons, and plasmids. The movement of these elements between different strains plays a role in how antibiotic resistance and virulence factors are acquired and evolve together. The ongoing exchange of these elements among strains, along with their differences across the C. difficile family tree, highlights the importance of including strains from various ribotypes or clades in studies that look at their genetic relationships and characteristics (22).
Clostridioides (Clostridium) difficile is challenging to diagnose and treat as it forms spores and can persist asymptomatically within the gut. Some strains express multiple virulence factors, including adhesins and toxins (21).
Clostridioides difficile is a bacterial pathogen that causes a range of clinical diseases, from mild to moderate diarrhea to more severe conditions such as pseudomembranous colitis and toxic megacolon (2). The virulence of C. difficile is strain-dependent, with particularly virulent strains like the Clostridioides (Clostridium) difficile Hypervirulent Clade 2(brain://KZitF6GUVUC14XOu8XP2nw/ClostridioidesDifficileFormerlyNamedClostridiumDifficileHypervirule) (1).
Clostridioides (Clostridium) difficile is the most common healthcare-associated infectious agent in the US, causing over 460,000 infections and 20,000 deaths annually (16).
Clostridioides (Clostridium) difficile is acquired from the environment through fecal-oral transmission (15).
Several virulence factors have been identified, the most important of which are:
These toxins disrupt the Rho family of GTPases in host cells, leading to disease (8). TcdB is considered a dominant virulence factor (1)
Clostridioides (Clostridium) difficile induces the expression of numerous transcripts associated with inflammation and extracellular matrix (ECM) degradation. The toxin activity of C. difficile suppresses the Bacteroidaceae, which compete with C. difficile for amino acids. Additionally, toxin-mediated degradation of collagen supports C. difficile growth in vitro (2)
Clostridioides (Clostridium) difficile is part of the normal gut microbiota and is present in 2–5% of the adult population (12). In the healthy human gut, its abundance is about 2.10% of all species (7). It is the most common identifiable infectious agent of nosocomial antibiotic-associated diarrhea (8, 10).
Clostridioides (Clostridium) difficile spores exhibit a remarkable resistance to both oxygen and chemicals. The primary pathway for infection is through the ingestion of these spores. Consequently, strains that lack the ability to form spores are incapable of surviving in these conditions and spreading among hosts. Notably, the process of sporulation is opposed by the host and the commensal microbes. The spo0A gene of Clostridium difficile acts as a factor for persistence and transmission (13, 14).
When nutrients are limited, Clostridioides (Clostridium) difficile cells cease their growth and initiate the process of sporulation. The spores then develop into toxin-producing vegetative cells. This transformation takes place in the small intestine when taurocholate is present. This well-documented and regulated process is initiated by sensor histidine kinases, which subsequently lead to the phosphorylation and activation of the transcription factor Spo0A (17, 18).
Clostridioides (Clostridium) difficile spores are absorbed by intestinal epithelial cells (IECs) and macrophages, maintaining their ability to remain viable and capable of germination. Spores entering intestinal epithelial cells play a role in the recurrence of Clostridioides difficile infection (19, 20).
The conjugated primary bile acids taurocholate and taurochenodeoxycholate are powerful germinants for Clostridioides (Clostridium) difficile spores, with taurochenodeoxycholate being a weaker stimulant (11).
(1) Luo et al. 2022 Cell 185: 980-994
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(8) Mileto et al. 2019 Microbiol Spectrum 7(3): GPP3- 0015-2018
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(15) Smits et al. 2016 Nat Rev Dis Primers 2: 16020
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see also:
Bile salts / Bile acids & Clostridioides (Clostridium) difficile
Clostridioides difficile infection (CDI)
Clostridioides (Clostridium) difficile toxins
Sporulation / Spore