Clostridium difficile infection and fecal bacteriotherapy: Difference between revisions

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[[Image:gene.png|thumb|right|Figure 4, The five genes endcoding toxin A and B as well as three regulatory gene products lie on a 19.6 KB pathogenicity locus. (Voth and Ballard 2005).]]
[[Image:gene.png|thumb|right|Figure 4, The five genes endcoding toxin A and B as well as three regulatory gene products lie on a 19.6 KB pathogenicity locus. (Voth and Ballard 2005).]]


[[Image:spores.png|thumb|right|Figure 3. C. difficile spore exposure causes germination in hosts with certain primary bile salts such as taurocholate. After germination, vegetative cells grow and release toxins into the human host. Starvation induces sporulation and spores are spread through feces. Image courtesy of Seekatz and Young (2014).]]





Revision as of 01:48, 22 April 2015

Introduction: History and Significance

Scanning electron micrograph of C. difficile bacteria obtained from the CDC Public Health Image Library.


By Rebecca Varnell

Endoscopic image of colon reveals presence of pseudomembranes caused by CDI. (Carrion et al. 2010).
Figure 4, The five genes endcoding toxin A and B as well as three regulatory gene products lie on a 19.6 KB pathogenicity locus. (Voth and Ballard 2005).




Clostridium difficile is a Gram-positive, spore-forming Firmicute that is found abundantly in nature (Figure 1). The rod-shaped bacteria was first noticed and described by Hall and O’Toole in 1935 because of its notable abundance in the intestine of infants (Poxton 2005). C. difficile can and often do live among the diverse microbiota of a healthy human and animal gut. They are found abundantly in soil as well as human and animal feces. However, in the absence of microbial competition, C. difficile can proliferate in individuals with compromised intestinal microbial communities such as in patients treated with heavy antibiotics. The bacterial lifecycle includes the formation of dormant spores, which can be passed from individuals infected with or carrying C. difficile by fecal-oral route. Dormant spores are known for their resilience and longevity, creating a public health crisis (Patel 2010). The presence and spread of C. difficile in hospitals and nursing homes is a major concern for doctors and patients alike. In 1978, researchers first isolated C. difficile in the stools of individuals suffering from antibiotic-associated pseudomembranous colitis (PMC), a severe inflammation of the colon exhibited by individuals treated with heavy courses of antibiotics (Patel 2010). In the following decades, a series of studies investigated these bacteria. Since a well-known study in 1990 by Borriello et al. articulated the pathogenesis and urgency of C. difficile, this bacteria and its management has been studied extensively. C. difficile infection (CDI) is the umbrella term that refers to colonization of C. difficile in a human host. CDI can present itself clinically in a diversity of ways, most notably antibiotic-associated diarrhea (AAD) and antibiotic-associated colitis (AAC) (Farooq et al. 2015). CDI is a major issue in the United States; it is one of the most common health-care associated infections in the US and most commonly affects hospitalized patients and individuals in nursing homes. Major CDI outbreaks in hospitals have caused healthcare providers to reevaluate liberal use of antibiotic treatment. Alternative treatment methods such as fecal microbiota therapy (FMT) that avoid the continued use of antibiotics may be the most sustainable, effective, and cost-efficient treatment for CDI (Boyle et al. 2015).

Life cycle and sporulation


C. difficile is a strict anaerobe. Though little is known about its metabolism, coupled amino acid fermentation is its primary source of ATP (Bouillaut 2012). Because it cannot metabolize in the presence of oxygen, C. difficile requires a metabolically dormant spore to allow for horizontal transfer of infection between patients in a hospital. The dormant spore is produced through the sporulation pathway initiated during infection. Certain strains incapable of producing dormant spores cannot be transferred between patients and thus remain confined to the gastrointestinal tract of the host. Spores, for the strains that can produce them, are resistant to antibiotics and immune responses from the host. Remarkably, the spores are also resistant to disinfectants commonly used in hospitals explaining the rapid spread of CDI in healthcare facilities (Burns and Minton 2011). The lack of homology between C. difficile spores and other spore-forming bacteria such as Bacillus subtilis profoundly limits scientists’ ability to study the structure of the spore coat and understand the specific structural nuances that confer the bacteria’s incredible resilience. However, research related to the spore structure of C. difficile spores indicates that the structure can be divided into compartments, the innermost compartment being the spore core. The spore core contains spore DNA, RNA and most enzymes (Paredes-Sabja et al. 2014). This core has incredibly low water content, which contributes to its resiliency. Surrounding the core is a compressed inner membrane protein with low permeability. A germ cell wall, cortex, outer membrane, coat, and exosporium all surround the inner membrane. The many layers protect the spore DNA from harsh conditions (Figure 2).




The formation of spores is incredibly important to the bacteria, as it is essential for its spread between human hosts. Sporulation is induced by lack of environmental nutrients and consequently, starvation (Weston 2008). A genome-wide approach conducted by Pettit et al. (2013) identified SpoOA as a positive regulator of sporulation. SpoOA encodes a transcriptional regulator, which dictates colonization and transmission. The regulator binds upstream of sporulation genes and is also associated with controlling toxin gene expression (Pettit et al. 2013). Thus, the presence of SPoOA in C. difficile is essential in its pathogenicity. When sporulation is signaled, the cell stops growing and begins growing the spore (Paredes-Sabja et al. 2014). The cell divides asymmetrically, producing a forespore and larger mother cell. The mother cell produces the cortex as well as the inner and outer coats for the forespore. When the spore is mature, the mother lyses and releases the spore. When appropriate environmental conditions are met, an unknown signaling mechanism causes the spore to germinate. Germination is an essential feature of CDI progression, as the vegetative cells proliferate within the host to cause infection (Howerton et al. 2010). The ingestion of spores does not necessarily lead to colonization and thus, infection. Certain environmental conditions must be met in order for germination and colonization to occur (Figure 3). Recent studies indicate the presence of primary bile acids such as taurocholate is necessary for the germination of C. difficile. Secondary bile acids, on the other hand, such as chenodeoxycholate, can inhibit the germination of the spores, thus preventing infection (Seekatz and Young 2014).

Section 2

Include some current research, with at least one figure showing data.

Section 3

Include some current research, with at least one figure showing data.

References

[1] Nazarko, L. (2015). Infection control: Clostridium difficile. British Journal Of Healthcare Assistants, 9(1), 20-25.


Andres F Carrion et al. “Severe colitis associated with docetaxel use: a report of four cases,” World Journal of Gastrointestinal Oncology, 10 (2010): 390-394, accessed April 17, 2015, doi: 10.4251/wjgo.v2.i10.390.

Daniel E. Voth and Jimmy D. Ballard, “Clostridium difficile Toxins: Mechanism of Action and Role in Disease,” Clinical Microbiology Reviews 18 (2005): 249-263, date accessed April 19, 2015, doi: 10.1128/CMR.18.2.247-263.2005.

Daniel Paredes-Sabja et al. “Clostridium difficile spore biology: sporulation, germination, and spore structural proteins,” Trends in Microbiology 22 (2014): 406, accessed April 15, 2015, doi: 10.1016/j.tim.2014.04.003.