C. difficile Infection: The Biochemistry

Regan Bunting, Muhlenberg College

C. difficile Annotated Bibliography

1935 – 1979

  1. HALL, IVAN C., and ELIZABETH O’TOOLE. “INTESTINAL FLORA IN NEW-BORN INFANTS: WITH A DESCRIPTION OF A NEW PATHOGENIC ANAEROBE, BACILLUS DIFFICILIS.” American Journal of Diseases of Children 49, no. 2 (February 1, 1935): 390–402. https://doi.org/10.1001/archpedi.1935.01970020105010.

First finding of C.diff, originally referred to as B. difficilis due to its difficulty to isolate and study, to be recorded. Located during a bacterial study of infant stool during the first 10 days of life. They regard this finding as inevitable from the infant coming into contact with the vaginal flora of the mother, her nipples, and from other sources of bacteria.

  1. Smith, Louis Ds., and Elizabeth O. King. “OCCURRENCE OF CLOSTRIDIUM DIFFICILE IN INFECTIONS OF MAN.” Journal of Bacteriology 84, no. 1 (July 1962): 65–67. https://doi.org/10.1128/jb.84.1.65-67.1962 

C. diff strains were isolated from infections like gas gangrene, abscesses and fluid. Strains were regarded as non pathogenic. 

  1. Bartlett, John G., Te Wen Chang, Marc Gurwith, Sherwood L. Gorbach, and Andrew B. Onderdonk. “Antibiotic-Associated Pseudomembranous Colitis Due to Toxin-Producing Clostridia.” New England Journal of Medicine 298, no. 10 (March 9, 1978): 531–34. https://doi.org/10.1056/NEJM197803092981003.

Clostridia strains were isolated  from patients suffering from pseudomembranous colitis due to antibiotic use and determined to be causing cytotoxicity. 

  1. Lance George, W., EllieJ. C. Goldstein, VeraL. Sutter, ShellyL. Ludwig, and SydneyM. Finegold. “ÆTIOLOGY OF ANTIMICROBIAL-AGENT-ASSOCIATED COLITIS.” The Lancet, Originally published as Volume 1, Issue 8068, 311, no. 8068 (April 15, 1978): 802–3. https://doi.org/10.1016/S0140-6736(78)93001-5. 

C. diff was isolated from the feces of patients suffering from clindamycin-associated pseudomembranous colitis. They regard this pathogen as the major or even sole cause of this colitis.

  1. Chang, T W, S L Gorbach, and J B Bartlett. “Neutralization of Clostridium Difficile Toxin by Clostridium Sordellii Antitoxins.” Infection and Immunity 22, no. 2 (November 1978): 418–22. https://doi.org/10.1128/iai.22.2.418-422.1978 

C.diff toxins could be neutralized instantaneously by C. Sordellii antitoxins but the ability of the antitoxin to prevent cytotoxicity decreased with pre-exposure time. The union between toxin and antitoxin was found to be easily dissociated. 

  1. George, W L, V L Sutter, D Citron, and S M Finegold. “Selective and Differential Medium for Isolation of Clostridium Difficile.” Journal of Clinical Microbiology 9, no. 2 (February 1979): 214–19. https://doi.org/10.1128/jcm.9.2.214-219.1979 

A selective and differential medium was developed to isolate C.diff from fecal samples and named CCFA. This was found to provide a rapid method for the screening of fecal specimens from patients with antimicrobial agent-associated diarrhea or colitis for C. difficile based on the fluorescent and morphological properties of the pathogen in this medium.

  1. Onderdonk, A B, B R Lowe, and J G Bartlett. “Effect of Environmental Stress on Clostridium Difficile Toxin Levels during Continuous Cultivation.” Applied and Environmental Microbiology 38, no. 4 (October 1979): 637–41. https://doi.org/10.1128/aem.38.4.637-641.1979 

It was found that subjecting cultures of C.diff to environmental stress like altering temperature increases the level of toxin secreted into the medium.

1980-1989

  1. Wilson, Kenneth H., Joseph Silva, and F. Robert Fekety. “Suppression of Clostridium Difficile by Normal Hamster Cecal Flora and Prevention of Antibiotic-Associated Cecitis.” Infection and Immunity 34, no. 2 (November 1981): 626–28. https://doi.org/10.1128/iai.34.2.626-628.1981.

Cecal homogenates were found to suppress viable C. diff counts and prevent antibiotic associated cecitits in hamsters.

  1. Welkon, Celeste J. “Clostridium Difficile in Patients With Cystic Fibrosis.” Archives of Pediatrics & Adolescent Medicine 139, no. 8 (August 1, 1985): 805. https://doi.org/10.1001/archpedi.1985.02140100067032.

Phenomena discovered in which cystic fibrosis patients who had toxic C.diff in their fecal samples did not experience diarrhea or exaggerated symptoms. All explanations for this were speculative including possible high counts of C.diff inhibitory bacteria in CF patients stool. 

  1. *Rybolt, AnnH., BarbaraE. Laughon, WilliamB. Greenough, RichardG. Bennett, DavidR. Thomas, and JohnG. Bartlett. “PROTEIN-LOSING ENTEROPATHY ASSOCIATED WITH CLOSTRIDIUM DIFFICILE INFECTION.” The Lancet, Originally published as Volume 1, Issue 8651, 333, no. 8651 (June 17, 1989): 1353–55. https://doi.org/10.1016/S0140-6736(89)92803-1.

Scientists measured serum alpha-1-antitrypsin levels in stool samples from older subjects as a marker of protein-losing enteropathy. It was found that patients with C.diff infections have serum protein loss into the gastrointestinal tract that can exacerbate symptoms. 

1990-1999

  1. *Dove, C H, S Z Wang, S B Price, C J Phelps, D M Lyerly, T D Wilkins, and J L Johnson. “Molecular Characterization of the Clostridium Difficile Toxin A Gene.” Infection and Immunity 58, no. 2 (February 1990): 480–88. https://doi.org/10.1128/iai.58.2.480-488.1990 

Sequencing of the gene that encodes for the toxin A protein of C.diff showed an open reading frame located between this toxin gene and the toxin B gene. Its role remains unknown but toxin A also has epitopes for the monoclonal antibody PCG-4 and includes the binding region for the Gal alpha 1-3Gal beta 1-4GlcNAc carbohydrate receptor. 

  1. *Just, I., J. Selzer, M. Wilm, C. von Eichel-Streiber, M. Mann, and K. Aktories. “Glucosylation of Rho Proteins by Clostridium Difficile Toxin B.” Nature 375, no. 6531 (June 8, 1995): 500–503. https://doi.org/10.1038/375500a0.

Tandem electrospray mass spectroscopy was used to localize and identify a modification in which toxin B incorporates up to one mole of glucose per mole of RhoA at the amino acid thre-onine at position 37. Injecting this modified RhoA into a layer of cells caused the actin filaments to break apart. This suggests that the modified RhoA interferes with its normal function.

  1. Souza, M H, A A Melo-Filho, M F Rocha, D M Lyerly, F Q Cunha, A A Lima, and R A Ribeiro. “The Involvement of Macrophage-Derived Tumour Necrosis Factor and Lipoxygenase Products on the Neutrophil Recruitment Induced by Clostridium Difficile Toxin B.” Immunology 91, no. 2 (June 1997): 281–88. https://doi.org/10.1046/j.1365-2567.1997.00243.x 

Scientists studied the ability of C.diff toxin B to encourage neutrophils to move into the abdominal cavity and air pockets under the skin of rats. After 4 hours it was found that toxin B caused a dose dependent influx in neutrophils that could be mediated by macrophage-derived TNF-α and lipoxygenase products.

2000-2009

  1. McDonald, L. Clifford, George E. Killgore, Angela Thompson, Robert C. Owens, Sophia V. Kazakova, Susan P. Sambol, Stuart Johnson, and Dale N. Gerding. “An Epidemic, Toxin Gene–Variant Strain of Clostridium Difficile.” New England Journal of Medicine 353, no. 23 (December 8, 2005): 2433–41. https://doi.org/10.1056/NEJMoa051590.

A rare strain of C. diff, with variations in toxin genes, developed increased resistance to fluoroquinolones and caused widespread outbreaks of C. difficile–associated disease across different regions.

  1. *Loo, Vivian G., Louise Poirier, Mark A. Miller, Matthew Oughton, Michael D. Libman, Sophie Michaud, Anne-Marie Bourgault, et al. “A Predominantly Clonal Multi-Institutional Outbreak of Clostridium Difficile–Associated Diarrhea with High Morbidity and Mortality.” New England Journal of Medicine 353, no. 23 (December 8, 2005): 2442–49. https://doi.org/10.1056/NEJMoa051639.

An outbreak of C. diff–associated diarrhea in Canadian hospitals was caused by a strain resistant to fluoroquinolones, possessing binary toxin and a partial deletion of the tcdC gene. The use of fluoroquinolones or cephalosporins were identified in this study as risk factors for infection.

  1. Janoir, Claire, Séverine Péchiné, Charlotte Grosdidier, and Anne Collignon. “Cwp84, a Surface-Associated Protein of Clostridium Difficile, Is a Cysteine Protease with Degrading Activity on Extracellular Matrix Proteins.” Journal of Bacteriology 189, no. 20 (October 2007): 7174–80. https://doi.org/10.1128/JB.00578-07.

The Cwp84 protease of C. difficile was found to possibly contribute to the degradation of the host tissue integrity and to the dissemination of the infection through cleavage of the extracellular matrix host proteins.

2010-2014

  1. Kuehne, Sarah A., Stephen T. Cartman, John T. Heap, Michelle L. Kelly, Alan Cockayne, and Nigel P. Minton. “The Role of Toxin A and Toxin B in Clostridium Difficile Infection.” Nature 467, no. 7316 (October 7, 2010): 711–13. https://doi.org/10.1038/nature09397.

By constructing the first ever double-mutant strain of C. difficile, in which both toxin genes were inactivated, it was found that without Toxin A or B, there is no virulence. In strains with just A or B or those with both A and B, there is virulence. Isogenic mutants of C. diff producing either toxin A or toxin B alone can induce fulminant disease in hamsters. Using a gene knock-out system to permanently inactivate the toxin genes, they observed that C. diff strains producing either one or both toxins exhibited cytotoxic activity in vitro, which directly correlated with virulence in vivo. They also made the first double mutant strain of C. diff with both toxin genes inactivated which allowed them to achieve complete reduction of virulence. They hope to determine why the A+B- strain is virulent as this is a contradicting finding to previous work. They conclude that both toxins have a distinct role in C.diff infection.

  1. Louie, Thomas J., Mark A. Miller, Kathleen M. Mullane, Karl Weiss, Arnold Lentnek, Yoav Golan, Sherwood Gorbach, Pamela Sears, and Youe-Kong Shue. “Fidaxomicin versus Vancomycin for Clostridium Difficile Infection.” New England Journal of Medicine 364, no. 5 (February 3, 2011): 422–31. https://doi.org/10.1056/NEJMoa0910812.

Fidaxomicin demonstrated clinical cure rates comparable to vancomycin but significantly reduced the recurrence of C. difficile infection caused specifically by non–North American Pulsed Field type 1 strains.

  1. Ryan, Anthony, Mark Lynch, Sinead M. Smith, Sylvie Amu, Hendrik J. Nel, Claire E. McCoy, Jennifer K. Dowling, et al. “A Role for TLR4 in Clostridium Difficile Infection and the Recognition of Surface Layer Proteins.” PLoS Pathogens 7, no. 6 (June 2011): e1002076. https://doi.org/10.1371/journal.ppat.1002076.

The findings from this study indicate that surface layer proteins isolated from C. difficile can activate innate and adaptive immunity and that these effects are mediated by toll-like receptor 4, with TLR4 having a functional role in experimental C. difficile infection. This suggests an important role for SLPs in the recognition of C. difficile by the immune system.

  1. Oka, Kentaro, Takako Osaki, Tomoko Hanawa, Satoshi Kurata, Mitsuhiro Okazaki, Taki Manzoku, Motomichi Takahashi, et al. “Molecular and Microbiological Characterization of Clostridium Difficile Isolates from Single, Relapse, and Reinfection Cases.” Journal of Clinical Microbiology 50, no. 3 (March 2012): 915–21. https://doi.org/10.1128/JCM.05588-11.

Recurrent C.diff infection patients were separated into two groups based on reinfection or relapse. The isolates recovered from relapse cases showed a significantly higher germination rate when incubated in a medium lacking sodium taurocholate, indicating that the germination ability of C. diff may be a potential risk factor for the recurrence of C.diff associated disease.

  1. Dubberke, Erik R., and Margaret A. Olsen. “Burden of Clostridium Difficile on the Healthcare System.” Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 55, no. Suppl 2 (August 1, 2012): S88–92. https://doi.org/10.1093/cid/cis335.

Data analysis from 2008 indicates that C.diff infection cases resulted in $4.8 billion in excess costs in US acute-care facilities. Other areas of attributable excess costs are proposed to be investigated. 

  1. Khanna, Sahil, Larry M. Baddour, W. Charles Huskins, Patricia P. Kammer, William A. Faubion, Alan R. Zinsmeister, W. Scott Harmsen, and Darrell S. Pardi. “The Epidemiology of Clostridium Difficile Infection in Children: A Population-Based Study.” Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 56, no. 10 (May 15, 2013): 1401–6. https://doi.org/10.1093/cid/cit075.

In this pediatric study in Minnesota, C.diff infection cases in children were found to increase significantly from 1991 to 2009, although children were thought to be at low risk for the infection. Since the estimates of the incidence of infection included only hospitalized children, it was stated that this may even significantly underestimate the burden of disease in children.

  1. *Chen, Kangni, Stephanie d’Arc, Naveen Setty, Kathy Bamford, Neil Fairweather, and Jonathan Tyrrell-Price. “In Recurrent C. Difficile, the CRP Response to the Primary C. Difficile Infection Predicts Whether the Same Strain or a Different Strain Will Cause a Second Infection.” Digestive Diseases and Sciences 58, no. 6 (June 1, 2013): 1683–88. https://doi.org/10.1007/s10620-012-2534-4.

It was determined via ribotyping if patients suffering from recurrent C.diff infections had the same strain or a different strain reinfect them. Patients with a different strain for the second infection had significantly higher C-reactive protein responses during the first infection and a significantly lower CRP on reinfection while same strain patients had a non-significant increase in CRP response on second infection. This suggests that the inflammatory response to C. diff is determined by an interaction between host immunobiology, previous exposure and identity of C. diff strain. 

  1. Mattila, Eero, Perttu Arkkila, Petri S. Mattila, Eveliina Tarkka, Päivi Tissari, and Veli-Jukka Anttila. “Extraintestinal Clostridium Difficile Infections.” Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 57, no. 6 (September 2013): e148-153. https://doi.org/10.1093/cid/cit392.

Based on a 10 year evaluation of extraintestinal C.diff infections, it was determined that they occur mainly in hospitalized patients with significant comorbidities and mortality is based on the severity of underlying diseases. 

  1. Merrigan, Michelle M., Anilrudh Venugopal, Jennifer L. Roxas, Farhan Anwar, Michael J. Mallozzi, Bryan A. P. Roxas, Dale N. Gerding, V. K. Viswanathan, and Gayatri Vedantam. “Surface-Layer Protein A (SlpA) Is a Major Contributor to Host-Cell Adherence of Clostridium Difficile.” PloS One 8, no. 11 (2013): e78404. https://doi.org/10.1371/journal.pone.0078404.

It was found that surface layer protein A was a major contributor to bacterial adherence, and individual subunits of the protein (varying in sequence between strains) mediated host-cell attachment to different extents. This means that surface layer protein A plays a major role in C. difficile infection, and that it may represent an attractive target for interventions aimed at abrogating gut colonization by this pathogen.

  1. See, Isaac, Yi Mu, Jessica Cohen, Zintars G. Beldavs, Lisa G. Winston, Ghinwa Dumyati, Stacy Holzbauer, et al. “NAP1 Strain Type Predicts Outcomes from Clostridium Difficile Infection.” Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America 58, no. 10 (May 2014): 1394–1400. https://doi.org/10.1093/cid/ciu125.

Strain type was determined for over 2000 cases of C.diff infection and the fluoroquinolone-resistant North American pulsed-field gel electrophoresis type 1 (NAP1) strain was the most common and associated with severe disease rates and death. They suggest reducing the use of fluoroquinolone.

  1. Kassam, Zain, Christine H. Lee, and Richard H. Hunt. “Review of the Emerging Treatment of Clostridium Difficile Infection with Fecal Microbiota Transplantation and Insights into Future Challenges.” Clinics in Laboratory Medicine, The Human Microbiome, 34, no. 4 (December 1, 2014): 787–98. https://doi.org/10.1016/j.cll.2014.08.007.

Current treatment practices include using vancomycin for secondary infections and fecal microbiota transplantations. Standard procedures to prepare for this transplantation, the ideal volume to use, and the best delivery method are not currently set as various methods are being used. Clinical trials are occurring to determine the safest methods. 

2015 – Present

  1. Darkoh, Charles, Herbert L. DuPont, Steven J. Norris, and Heidi B. Kaplan. “Toxin Synthesis by Clostridium Difficile Is Regulated through Quorum Signaling.” mBio 6, no. 2 (February 24, 2015): e02569. https://doi.org/10.1128/mBio.02569-14.

Scientists discovered that C. diff toxin synthesis is regulated by an accessory gene regulator quorum-signaling system, which is mediated/activated through a small thiolactone that can be detected directly in stools of C. diff infection patients. These findings provide direct evidence of the mechanism of regulation of C. diff toxin synthesis and offer exciting new avenues both for rapid detection of C. diff infection and development of quorum-signaling-based non-antibiotic therapies to combat this life-threatening emerging pathogen.

  1. Bhattacharjee, Disha, Michael B. Francis, Xicheng Ding, Kathleen N. McAllister, Ritu Shrestha, and Joseph A. Sorg. “Reexamining the Germination Phenotypes of Several Clostridium Difficile Strains Suggests Another Role for the CspC Germinant Receptor.” Journal of Bacteriology 198, no. 5 (December 14, 2015): 777–86. https://doi.org/10.1128/JB.00908-15.

Certain C. diff strains have been identified whose spores germinate in the absence of bile acids or are not blocked by known inhibitors of C. difficile spore germination. This study investigated these strains and reestablished that bile acid activators and inhibitors of germination affect these strains. Scientists also proposed that CspC, a germinant receptor, may activate C.diff spore germination and then inhibit downstream processes.

  1. Smits, Wiep Klaas, Dena Lyras, D. Borden Lacy, Mark H. Wilcox, and Ed J. Kuijper. “Clostridium Difficile Infection.” Nature Reviews. Disease Primers 2 (April 7, 2016): 16020. https://doi.org/10.1038/nrdp.2016.20. 

This review discussed the current understandings of C.diff infection. They say that the primary mediators of inflammation in C. diff infection are large clostridial toxins, toxin A and toxin B, and, in some bacterial strains, the binary toxin CDT. The toxins trigger a complex cascade of host cellular responses to cause diarrhea, inflammation and tissue necrosis. The scientists also discuss a hallmark feature of C. diff that sets it apart from other species in the class Clostridia is its ability to decarboxylate parahydroxyphenylacetic acid to produce p-cresol, which gives C. diff its characteristic tar-like smell.

  1. Khanafer, Nagham, Philippe Vanhems, Frédéric Barbut, and Christine Luxemburger. “Factors Associated with Clostridium Difficile Infection: A Nested Case-Control Study in a Three Year Prospective Cohort.” Anaerobe 44 (April 1, 2017): 117–23. https://doi.org/10.1016/j.anaerobe.2017.03.003.

C.diff infection was determined to me more likely in men, those with prior hospitalizations or antibiotic use, liver disease, malnutrition and previous C. diff infections. They recommended careful monitoring of antibiotic prescription to at risk patients. 

  1. Giancola, S. E., R. J. Williams, and C. A. Gentry. “Prevalence of the Clostridium Difficile BI/NAP1/027 Strain across the United States Veterans Health Administration.” Clinical Microbiology and Infection 24, no. 8 (August 1, 2018): 877–81. https://doi.org/10.1016/j.cmi.2017.11.011.

Patients with C.diff infections at a veteran affairs hospital were tested for strain type and the prevalence of C. diff with the BI/NAP1/027 strain was 22% between 2012 and 2016. Overall prevalence decreased over the years, corresponding to the statistically significant reductions in rates from 2012 to 2016 that occurred in seven of nine US Census Bureau regions.

  1. Kokai-Kun, John F, Chenxiong Le, Kenneth Trout, Julia L Cope, Nadim J Ajami, Andrew J Degar, and Sheila Connelly. “Ribaxamase, an Orally Administered β-Lactamase, Diminishes Changes to Acquired Antimicrobial Resistance of the Gut Resistome in Patients Treated with Ceftriaxone.” Infection and Drug Resistance 13 (July 22, 2020): 2521–35. https://doi.org/10.2147/IDR.S260258.

It was found that ribaxamase, an orally administered β-lactamase, reduced changes to the gut resistome subsequent to ceftriaxone administration and may help limit the emergence of antimicrobial resistance and therefore C.diff infection. It is recommended for use with patients prescribed intravenous β-lactam antibiotics as it degrades excess antibiotics in the upper GI before they can disrupt the gut microbiome.

  1. Sehgal, Kanika, and Sahil Khanna. “Gut Microbiome and Clostridioides Difficile Infection: A Closer Look at the Microscopic Interface.” Therapeutic Advances in Gastroenterology 14 (February 23, 2021): 1756284821994736. https://doi.org/10.1177/1756284821994736.

It was concluded that not only can antibiotic use lead to a C.diff infection but a C.diff infection in itself can alter the gut microbiome. Its spore-forming capabilities makes the management of the infection more difficult and contributes to its recurrence. Microbial restoration efforts like fecal microbiota transplants are proving to be beneficial. 

  1. Heuler, Joshua, Harish Chandra, and Xingmin Sun. “Mucosal Vaccination Strategies against Clostridioides Difficile Infection.” Vaccines 11, no. 5 (April 23, 2023): 887. https://doi.org/10.3390/vaccines11050887.

It is thought that a mucosal vaccine could be a particularly promising strategy that prevents colonization of C.diff and disease. They are investigating the best methods for delivering these antigens to mucosal sites. 

  1. Eeuwijk, Jennifer, Gui Ferreira, Juan Pablo Yarzabal, and Mirna Robert-Du Ry van Beest Holle. “A Systematic Literature Review on Risk Factors for and Timing of Clostridioides Difficile Infection in the United States.” Infectious Diseases and Therapy 13, no. 2 (February 2024): 273–98. https://doi.org/10.1007/s40121-024-00919-0.

A literature review determined that primary C.diff infection risk factors were older age, comorbidities, antibiotic use, proton pump inhibitor use, female sex, prior hospitalization, and the length of stay in hospital.

Additional References:

  1. Diseases, The Lancet Infectious. “C Difficile—a Rose by Any Other Name….” The Lancet Infectious Diseases 19, no. 5 (May 1, 2019): 449. https://doi.org/10.1016/S1473-3099(19)30177-X. 
  1. O’Connor DHynes P, Cormican MCollins E, Corbett-Feeney G, Cassidy M.2001.Evaluation of Methods for Detection of Toxins in Specimens of Feces Submitted for Diagnosis of Clostridium difficile- Associated Diarrhea. J Clin Microbiol39:.https://doi.org/10.1128/jcm.39.8.2846-2849.2001 
  1. Madan, Rajat, and William A. Petri. “Immune Responses to Clostridium Difficile Infection.” Trends in Molecular Medicine 18, no. 11 (November 2012): 658–66. https://doi.org/10.1016/j.molmed.2012.09.005. 
  2. Arrich, Jasmin, Gottfried-H. Sodeck, Gurkan Sengolge, Christoforos Konnaris, Marcus Mullner, Anton-N. Laggner, and Hans Domanovits. “Clostridium Difficile Causing Acute Renal Failure: Case Presentation and Review.” World Journal of Gastroenterology 11, no. 8 (February 28, 2005): 1245–47. https://doi.org/10.3748/wjg.v11.i8.1245. 
  3. “KEGG PATHWAY: Regulation of Actin Cytoskeleton – Homo Sapiens (Human).” Accessed March 31, 2025. https://www.genome.jp/pathway/hsa04810. 
  4. Jank, Thomas, Torsten Giesemann, and Klaus Aktories. “Rho-Glucosylating Clostridium Difficile Toxins A and B: New Insights into Structure and Function.” Glycobiology 17, no. 4 (April 2007): 15R-22R. https://doi.org/10.1093/glycob/cwm004. 
  5. Kelly, C. P., S. Becker, J. K. Linevsky, M. A. Joshi, J. C. O’Keane, B. F. Dickey, J. T. LaMont, and C. Pothoulakis. “Neutrophil Recruitment in Clostridium Difficile Toxin A Enteritis in the Rabbit.” The Journal of Clinical Investigation 93, no. 3 (March 1994): 1257–65. https://doi.org/10.1172/JCI117080. 
  6. Kelly, Ciarán P., and J. Thomas LaMont. “Clostridium Difficile–More Difficult than Ever.” The New England Journal of Medicine 359, no. 18 (October 30, 2008): 1932–40. https://doi.org/10.1056/NEJMra0707500. 
  1. Piccolo, Francesco, Anna Sze Tai, Hooi Ee, Siobhain Mulrennan, Scott Bell, and Gerard Ryan. “Clostridium Difficile Infection in Cystic Fibrosis: An Uncommon but Life‐threatening Complication.” Respirology Case Reports 5, no. 1 (December 7, 2016): e00204. https://doi.org/10.1002/rcr2.204. 
  1. Voth, Daniel E., and Jimmy D. Ballard. “Clostridium Difficile Toxins: Mechanism of Action and Role in Disease.” Clinical Microbiology Reviews 18, no. 2 (April 2005): 247–63. https://doi.org/10.1128/CMR.18.2.247-263.2005. 
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  1. Sun, Chunli, Haiying Wang, Shuyi Chen, Zhendong Li, Shan Li, and Jufang Wang. “Recombinant Clostridium Difficile Toxin B Induces Endoplasmic Reticulum Stress in Mouse Colonal Carcinoma Cells.” Acta Biochimica Et Biophysica Sinica 46, no. 11 (November 2014): 973–81. https://doi.org/10.1093/abbs/gmu091.
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  3. Arcay, Ricardo, Maria Barceló-Nicolau, Loreto Suárez, Luisa Martín, Rebeca Reigada, Marcus Höring, Gerhard Liebisch, et al. “Gut Microbiome and Plasma Lipidome Analysis Reveals a Specific Impact of Clostridioides Difficile Infection on Intestinal Bacterial Communities and Sterol Metabolism.” mBio 15, no. 10 (n.d.): e01347-24. https://doi.org/10.1128/mbio.01347-24. 
  1. Bank, RCSB Protein Data. “RCSB PDB – 2BVL: Crystal Structure of the Catalytic Domain of Toxin B from Clostridium Difficile in Complex with UDP, Glc and Manganese Ion.” Accessed March 31, 2025. https://www.rcsb.org/structure/2BVL. 
  1. Health. “Why Your Large Intestine Is Such a Big Deal.” Accessed March 31, 2025. https://www.health.com/large-intestine-8706814. 
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