Development and Validation of a Chemostat Gut Model To Study Both Planktonic and Biofilm Modes of Growth of Clostridium difficile and Human Microbiota

Crowther, Grace S.; Chilton, Caroline H.; Todhunter, Sharie L.; Nicholson, Scott; Freeman, Joseph T.; Baines, Simon D.; Wilcox, Mark H.

doi:10.1371/journal.pone.0088396

“…A piglet model is of particular interest to study C. difficile strains that are problematic in both animal and human populations 13,35,150 . In vitro gut models have been developed to study interactions of C. difficile with therapeutics in the context of a complex microbiome 13,151,152 . Each model is greatly influenced by variables such as qualitative and quantitative differences in inoculum and the choice of C. difficile strain 147 .…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Clostridium difficile infection

Smits

¹

,

Lyras

²

,

Lacy

³

et al. 2016

Nat Rev Dis Primers

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Infection of the colon with the Gram-positive bacterium Clostridium difficile is potentially life threatening, especially in elderly people and in patients who have dysbiosis of the gut microbiota following antimicrobial drug exposure. C. difficile is the leading cause of health-care-associated infective diarrhoea. The life cycle of C. difficile is influenced by antimicrobial agents, the host immune system, and the host microbiota and its associated metabolites. The primary mediators of inflammation in C. difficile infection (CDI) are large clostridial toxins, toxin A (TcdA) and toxin B (TcdB), and, in some bacterial strains, the binary toxin CDT. The toxins trigger a complex cascade of host cellular responses to cause diarrhoea, inflammation and tissue necrosis — the major symptoms of CDI. The factors responsible for the epidemic of some C. difficile strains are poorly understood. Recurrent infections are common and can be debilitating. Toxin detection for diagnosis is important for accurate epidemiological study, and for optimal management and prevention strategies. Infections are commonly treated with specific antimicrobial agents, but faecal microbiota transplants have shown promise for recurrent infections. Future biotherapies for C. difficile infections are likely to involve defined combinations of key gut microbiota.

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“…RCDI is more frequent in patients infected with the 027 strain than in those infected with non-027 strains (P < 0.001). Besides, the clinical cure rate has been reported to be lower in 027-infected patients than in those with non- Long persistence/protection of C. difficile [36,[42][43][44][45][46] Accumulation of spores Reduced susceptibility to antibiotics [45,47] SlpA (S-layer protein A)…”

Section: Ribotypes Associated With Relapse or Reinfectionmentioning

confidence: 99%

“…Notably, in a chemostat gut model, C. difficile (vegetative and spore forms) has been shown to participate in multispecies communities forming a robust biofilm that accumulates toxins. In addition, this biofilm is a potential reservoir for the reestablishment of C. difficile after primary antimicrobial therapy has finished, when gut levels of antimicrobials are at subminimal inhibitory concentration [36,43,44]. Furthermore, the biofilm matrix showed a preferential localization of spores that have a higher resistance to some antibiotics (metronidazole and vancomycin) ( Table 1).…”

Section: Biofilm Productionmentioning

confidence: 99%

Virulence Factors of Clostridioides (Clostridium) difficile Linked to Recurrent Infections

Tijerina-Rodríguez

¹

,

Villarreal-Treviño

²

,

Morfín‐Otero

³

et al. 2019

Canadian Journal of Infectious Diseases and Medical Microbiolog

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From 20 to 30% of Clostridioides (Clostridium) difficile infection (CDI), patients might develop recurrence of the infection (RCDI) and, after the first recurrence, the risk of further episodes increases up to 60%. Several bacterial virulence factors have been associated with RCDI, including the elevated production of toxins A and B, the presence of a binary toxin CDT, and mutations in the negative regulator of toxin expression, tcdC. Additional factors have shown to regulate toxin production and virulence in C. difficile in RCDI, including the accessory-gene regulator agr, which acts as a positive switch for toxin transcription. Furthermore, adhesion and motility-associated factors, such as Cwp84, SlpA, and flagella, have shown to increase the adhesion efficiency to host epithelia, cell internalization, and the formation of biofilm. Finally, biofilm confers to C. difficile protection from antibiotics and acts as a reservoir for spores that allow the persistence of the infection in the host. In this review, we describe the key virulence factors of C. difficile that have been associated with recurrent infections.

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“…A piglet model is of particular interest to study C. difficile strains that are problematic in both animal and human populations 13,35,150 . In vitro gut models have been developed to study interactions of C. difficile with therapeutics in the context of a complex microbiome 13,151,152 . Each model is greatly influenced by variables such as qualitative and quantitative differences in inoculum and the choice of C. difficile strain 147 .…”

Section: Experimental Modelsmentioning

confidence: 99%

Clostridium difficile Infection

Wilcox¹,

Vehreschild²,

Nord³

2015

Annual Update in Intensive Care and Emergency Medicine

0

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Infection of the colon with the Gram-positive bacterium Clostridium difficile is potentially life threatening, especially in elderly people and in patients who have dysbiosis of the gut microbiota following antimicrobial drug exposure. C. difficile is the leading cause of health-care-associated infective diarrhoea. The life cycle of C. difficile is influenced by antimicrobial agents, the host immune system, and the host microbiota and its associated metabolites. The primary mediators of inflammation in C. difficile infection (CDI) are large clostridial toxins, toxin A (TcdA) and toxin B (TcdB), and, in some bacterial strains, the binary toxin CDT. The toxins trigger a complex cascade of host cellular responses to cause diarrhoea, inflammation and tissue necrosis -the major symptoms of CDI. The factors responsible for the epidemic of some C. difficile strains are poorly understood. Recurrent infections are common and can be debilitating. Toxin detection for diagnosis is important for accurate epidemiological study, and for optimal management and prevention strategies. Infections are commonly treated with specific antimicrobial agents, but faecal microbiota transplants have shown promise for recurrent infections. Future biotherapies for C. difficile infections are likely to involve defined combinations of key gut microbiota. Competing interests statement W.K.S. has performed research for Cubist. D.L. has performed research for Immuron and Adenium Biotech. D.B.L. has performed research for MedImmune and Merck. M.H.W. has received consulting fees from Abbott, Actelion Pharmaceuticals, Astellas, AstraZeneca, Bayer, Cerexa, Cubist, Durata, The European Tissue Symposium, The Medicines Company, MedImmune, Merck, Motif Biosciences, Nabriva, Optimer, Paratek, Pfizer, Roche, Sanofi Pasteur, Seres Therapeutics, Summit Pharmaceuticals, and Synthetic Biologics. M.H.W. has also received lecture fees from Abbott, Alere, Astellas, AstraZeneca, Pfizer and Hoffmann La Roche, and received grant support from Abbott, Actelion, Astellas, bioMérieux, Cubist, Da Volterra, The European Tissue Symposium, Merck and Summit Pharmaceuticals. E.J.K. has performed research for Cubist, Novartis and Qiagen, and has participated in advisory forums of Astellas, Optimer, Actelion, Pfizer, Sanofi Pasteur and Seres Therapeutics. These companies had no role in the writing of this Primer. HHS Public AccessAuthor manuscript Nat Rev Dis Primers. Author manuscript; available in PMC 2017 June 01. Published in final edited form as:Nat Rev Dis Primers. ; 2: 16020. doi:10.1038/nrdp.2016.20. Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptClostridium difficile is a Gram-positive obligate anaerobic bacterium that was originally identified as part of the flora of healthy infants in 1935, described as an "actively motile, heavy-bodied rod with elongated subterminal or nearly terminal spores" (REF. 1) (FIG. 1). At that time, the strain was named Bacillus difficilis to reflect the difficulty experienced in isolating and culturing it. De...

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Development and Validation of a Chemostat Gut Model To Study Both Planktonic and Biofilm Modes of Growth of Clostridium difficile and Human Microbiota

Cited by 42 publications

References 41 publications

Clostridium difficile infection

Clostridium difficile infection

Virulence Factors of Clostridioides (Clostridium) difficile Linked to Recurrent Infections

Clostridium difficile Infection

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