Comparing the Efficacy of Antibiotics Vs. Fecal Transplant in the Treatment of Clostridium Difficile Infection (CDI)

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Introduction

Electron micrograph of the Ebola Zaire virus. This was the first photo ever taken of the virus, on 10/13/1976. By Dr. F.A. Murphy, now at U.C. Davis, then at the CDC.

By: Yara Awwad

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Clostridium difficile infection (CDI) has become a major source of morbidity and mortality at hospitals in recent years. According to the CDC, around half a million Americans suffer from Clostridium difficile infection each year. Studies show that Clostridium difficile infections became more severe, prevalent, and difficult to treat. The infection is caused by the toxins produced by the bacteria Clostridium Difficile and it spreads through spores.

Clostridium difficile bacteria are found around the environment is soil, food, air, water and feces. Some people have C. diff in their large intestine in an inactive, non-infectious form. The bacteria also produces spores that ensure their survival under extreme conditions. If these spores are formed in the colon, they can survive antibiotics and could turn into a pathogenic active form.

Depending on the severity of the Clostridium difficile infection, it can be treated using antibiotics that stop the bacteria from growing. However, some strains are becoming more resistant to antibiotics which is making CDIs harder to treat. If the infection is severe, surgery is usually performed to remove the diseased portion of the colon. Around 20% of the people with C.diff get the infection again. In recurring cases, antibiotic therapy is conducted, but the effectiveness of this treatment has been declining. Recent research suggests that an alternative strategy for treating recurring CDI is fecal microbiota transplant (FMT) has promising results.

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A citation code consists of a hyperlinked reference within "ref" begin and end codes.
To repeat the citation for other statements, the reference needs to have a names: " The clostridium genus consists of relatively large, rod shaped, and motile bacteria in the Firmicutes phylum. The genus has more than 100 known species including harmful pathogens such as Clostridium tetani, C. butyricum, and Clostridium sordellii, which produce some of the most potent toxins in human’s history.

Clostridia are anaerobic and spore-forming bacteria that is commonly found in oxygen deficient soil. They produce spores under stress which makes them highly resistant to physical and chemical influences. C . difficile spores germinate in the colon and form vegitative cells that initiate CDI. Due to its anaerobic nature, c. difficile is unable to survive aerobically in the vegitative form. Therefore, during the course of the infection, C. difficile induces the sporulation pathway that produces more dormant spores, which remain stable for long times. The spores are responsible for the persistence and recurrence of the infection in patients. They are also the source of horizontal transmission that occurs between patients.

In the presence of cholic acid derivatives, the germination of spores plays a critical role in the pathogenesis of CDI. Germination of spores is a biophysical process that results in the loss of spore specific properties. This includes the transitioning from the metabolically dormant spore form to the active-growing, toxin forming vegitative form. In C. difficile, this process is initiated by cholate derivatives, bile acids, and amino acid signals from the host cells. Germination is activated when the germinants bind to Ger-type receptors that are found inside or on the surface of the inner spore membrane. The signals trigger cortex hydrolysis by cortex lytic enzymes which are found in the spore coat region. The spore cortex is a thick layer of modified peptidoglycan that surrounds the cell well and helps prevent osmolysis. The coat and the cortex degenerations release Ca-DPA and result in the full core rehydration and the initiation of the outgrowth of a new vegetative cell.

Pathogenic strains of C. difficile grow and produce two major toxins, Toxin A (TcdA) and toxin B (TcdB). Certain C.diff strains are also able to produce a binary toxin called C. diff transferase (CDT), which is not as prevalent or severe as the other two toxins. Only a few strains can produce CDT in the absence of toxins A and B.These toxins are part of the large clostridial glucosylating toxin (LCGT) family. TcdA and TcdB act on the colon epithelium and immune cells, inducing a cascade of complex reactions that result in the secretion of fluids, inflammations, and tissue damage, all of which are important marking features of CDI. Toxins A and B are produced in the Pathogenicity loci (PaLoc) by the genes tcdA and tcdB respectively. The expression of these genes is regulated by several environmental conditions including the availability of nutrients and temperature. PaLoc can be transferred horizontally to non-pathogenic strains converting them into pathogenic strains.

Toxins enter the cells by endocytosis then they are translocated to the host cell cytosol. In the cytosol, TcdA and TcdB glucosylate several members of the Rho subfamily and result in the inactivation of Rho proteins. These proteins have several functions and they interact with the kinases and phospholipases in the host cell that are responsible for signal transduction pathways. Rho proteins regulate actin cytoskeleton, the cell cycle progression, and the phagocytosis and cytokine production. Therefore, the toxins can induce cytopathic effects causing the loss of cell-cell contact and increase the epithelial permeability. All of which lead to cell apoptosis.

Toxin A results in the direct damage of the intestinal mucosa. This causes symptoms of CDI including pseudomembranous colitis, which is the swelling or inflammation of the colon due to the growth of C. difficile. During pseudomembranous colitis, the toxins are able to disrupt the tight junctions of epithelial barriers. This provides a way for neutrophils to accumulate in the intestines. In severe colitis cases, the toxins kill the tissues of the colon’s inner lining and cause the tissues to fall.

Toxin B is an essential virulence factor, but it is not as important as toxin A. This was proven when mutant cells with inactive tcdA still produced the same levels of tcdB, while mutant cells with inactive tcdB produced tcdA 2 to 3 times more.

Section 2

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Section 3

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References

Authored for BIOL 238 Microbiology, taught by Joan Slonczewski, 2018, Kenyon College.