Materiały źródłowe

• #1

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9815241/

  Clostridioides difficile is the most common cause of nosocomial antibiotic-associated diarrhea, and is responsible for a spectrum of diseases characterized by high levels of recurrence, morbidity, and mortality. […] As a consummate opportunist, C. difficile is well equipped for promoting disease, owing to its arsenal of virulence factors: transmission of this anaerobe is highly efficient due to the formation of robust endospores, and an array of adhesins promote gut colonization. C. difficile produces multiple toxins acting upon gut epithelia, resulting in manifestations typical of diarrheal disease, and severe inflammation in a subset of patients. […] This review focuses on such virulence factors, as well as the importance of antimicrobial resistance and genome plasticity in enabling pathogenesis and persistence of this important pathogen.

• #2 Clostridioides (Clostridium) Difficile Colitis: Background, Etiology, Pathophysiology

  https://emedicine.medscape.com/article/186458-overview

  Clostridioides difficile (formerly Clostridium difficile) is a gram-positive, anaerobic, spore-forming bacillus that is responsible for the development of antibiotic-associated diarrhea and colitis. C difficile colitis results from a disturbance of the normal bacterial flora of the colon, colonization by C difficile, and the release of toxins that cause mucosal inflammation and damage. […] C difficile colitis results from a disruption of the normal bacterial flora of the colon, colonization with C difficile, and release of toxins that cause mucosal inflammation, mucosal damage, and diarrhea. […] C difficile forms heat-resistant spores that can persist in the environment for several months to years. Outbreaks of C difficile diarrhea may occur in hospitals and outpatient facilities where contamination with spores is prevalent. Although the normal gut flora resists colonization and overgrowth with C difficile, the use of antibiotics, which alter and suppress the normal flora, allows proliferation of C difficile, toxin production, and diarrhea.

• #3 Clostridioides difficile infection – Wikipedia

  https://en.wikipedia.org/wiki/Clostridioides_difficile_infection

  C. difficile is transmitted from person to person by the fecal-oral route. […] The organism forms heat-resistant spores that are not killed by alcohol-based hand cleansers or routine surface cleaning. […] Thus, these spores survive in clinical environments for long periods. […] Because of this, the bacteria may be cultured from almost any surface. […] Once spores are ingested, their acid-resistance allows them to pass through the stomach unscathed. […] Upon exposure to bile acids, they germinate and multiply into vegetative cells in the colon. […] The presence of the bile acid deoxycholic acid in the intestinal environment can promote induction of C. difficle biofilm formation. […] People without a history of gastrointestinal disturbances due to antibiotic use or diarrheal illness are less likely to become colonized by C. difficile.

• #4 Fact Sheet – Clostridium difficile (C. difficile) – Canada.ca

  https://www.canada.ca/en/public-health/services/infectious-diseases/fact-sheet-clostridium-difficile-difficile.html

  Most cases of C. difficile occur in patients who are taking certain antibiotics in high doses or over a prolonged period of time. […] When this occurs, the C. difficile bacteria produce toxins, which can damage the bowel and cause diarrhea. […] Certain antibiotics used in high doses or over a prolonged period of time will increase the chance of developing a C. difficile infection. Antibiotics alter the normal levels of bacteria found in the gut. When there are fewer bacteria in our gut, C. difficile bacteria have the chance to thrive and produce toxins. These toxins can damage the bowel and cause diarrhea. […] The presence of C. difficile bacteria, together with a large number of patients receiving antibiotics in healthcare settings, can lead to frequent C. difficile outbreaks.

• #5

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9815241/

  As an anaerobe, C. difficile must overcome the formidable barrier of atmospheric oxygen to spread to a new host. […] The efficiency of sporulation also varies widely between C. difficile strains and it has been suggested that this feeds into the differences observed in transmission. […] Given the pivotal role the spore plays in disease transmission, it is not surprising that this has been an area of intense research in recent years. […] The core contains a high concentration of dipicolinic acid coordinated to calcium ions (Ca-DPA) which functions to dehydrate the spore and protects the DNA from heat-induced damage. […] Clinical presentation of CDI is influenced by a range of C. difficile virulence factors, including production of various toxins and surface proteins. […] Primarily, pathogenesis is driven by the activity of toxins A and B, encoded within the pathogenicity locus (PaLoc).

• #6 Clostridium difficile Infection: Pathogenesis, Diagnosis and Treatment | IntechOpen

  https://www.intechopen.com/chapters/54496

  The sporulation process has been widely studied in Bacillus subtilis. The sporulation decision in the genus Bacillus is regulated by some orphan histidine kinases whose function is to phosphorylate the master transcriptional regulator Spo0A. […] Once a strain of B. subtilis has committed to sporulation (i.e. Spo0A has been phosphorylated), a cascade of activation of RNA polymerase sporulation-specific sigma factor occurs. […] Studies of the spore surface have identified surface receptors that interact with intestinal epithelial cells. In vitro experiments have shown that spores can become cytotoxic to macrophages and that spores disrupt the phagosomal membrane with the aid of their surface receptors. […] Bacteria usually germinate when specific germinant receptors detect specific small molecules in the environment. However, C. difficile germinates after detecting some bile salts and L-glycine in the environment.

• #7 Clostridioides difficile infection – Wikipedia

  https://en.wikipedia.org/wiki/Clostridioides_difficile_infection

  The use of systemic antibiotics, including broad-spectrum penicillins/cephalosporins, fluoroquinolones, and clindamycin, causes the normal microbiota of the bowel to be altered. […] In particular, when the antibiotic kills off other competing bacteria in the intestine, any bacteria remaining will have less competition for space and nutrients. […] The net effect is to permit more extensive growth than normal of certain bacteria. […] C. difficile is one such type of bacterium. […] In addition to proliferating in the bowel, C. difficile also produces toxins. […] Without either toxin A or toxin B, C. difficile may colonize the gut, but is unlikely to cause pseudomembranous colitis. […] The colitis associated with severe infection is part of an inflammatory reaction, with the „pseudomembrane” formed by a viscous collection of inflammatory cells, fibrin, and necrotic cells.

• #8 Clostridioides (formerly Clostridium) difficile–Induced Diarrhea – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/anaerobic-bacteria/clostridioides-formerly-clostridium-difficile-induced-diarrhea

  Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. […] The organism secretes both an enterotoxin and a cytotoxin, typically referred to as toxins A and B. However, not all strains of C. difficile produce toxins, and some people are asymptomatic carriers of toxin-producing strains. The main effect of the toxin is on the colon, which secretes fluid and develops characteristic pseudomembranes discrete yellow-white plaques that are easily dislodged. […] Antibiotic-induced changes in gastrointestinal flora are the dominant predisposing factors. Although most antibiotics have been implicated, the following pose the highest risk: Cephalosporins (particularly 3rd-generation), Penicillins (particularly ampicillin and amoxicillin), Clindamycin, Fluoroquinolones.

• #9 Clostridium difficile infection: molecular pathogenesis and novel therapeutics

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4306399/

  The Gram-positive anaerobic bacterium Clostridium difficile produces toxins A and B, which can cause a spectrum of diseases from pseudomembranous colitis to C. difficile-associated diarrhea. […] Here, the structure and the mechanism of action of these toxins as well as their role in disease are reviewed. […] The pathogenesis of C. difficile is based upon the action of at least one of the two major toxins, A and B (encoded by TcdA and TcdB), that belong to the family of clostridial glucosylating toxins. […] TcdA and TcdB are structurally large (270308 kDa) single-subunit polypeptides, which can be divided into four main domains: N-terminal glucosyltransferase domain, cysteine protease domain, central translocation domain and C-terminal receptor-binding domain. […] The crucial step for pathogenicity of the toxins TcdA and TcdB is the translocation of the catalytic domains that occur when the C-terminal region of toxins first interact with cell-surface carbohydrates.

• #10 Clostridium difficile Toxins A and B: Insights into Pathogenic Properties and Extraintestinal Effects

  https://www.mdpi.com/2072-6651/8/5/134

  The expression of TcdA and TcdB is dependent upon environmental conditions and global regulators, including the availability of specific nutrients, temperature changes, and alteration of the redox potential. […] Once expression of the toxin genes is induced, the toxin proteins accumulate inside the cell and are slowly released over the course of several hours. […] The intoxication process begins with the endocytic uptake of TcdA and TcdB through a clathrin- and dynamin-dependent mechanism. […] TcdA and TcdB, at the end of their autocatalytic process, are released into the host cell cytosol where they glucosylate several members of the Rho subfamily by transferring a glucose moiety from the UDP-glucose to the Thr35/37 residue of Rho proteins. […] Glucosylation of Rho proteins causes inactivation, thus supporting the notion that the glucosyltranferase activity of C. difficile toxins is essential for the disease pathogenesis.

• #11 Clostridioides difficile infection – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/clostridioides-difficile-infection/

  C. difficile possesses a range of virulence factors, the most important of which are toxins A and B. […] The C. difficile strain must be toxigenic to cause the disease. Intestinal colonization by nontoxigenic strains will result in asymptomatic carriage. […] Toxin A (enterotoxin) mechanism of action: binding to brush border of enterocytes: receptor-mediated endocytosis change of conformation exposure of active domain glycosylation of target proteins (e.g., Rac, Cdc42, RhoA) disruption of actin cytoskeleton functioning increase in epithelial permeability and apoptosis diarrhea. […] Toxin B (cytotoxin) mechanism of action: same as in toxin A, but can also cause pore formation within the endosomal membrane via insertion of the translocation domain release of endosomal content into the cytosol cytopathic effect.

• #12 Exploring the Toxin-Mediated Mechanisms in Clostridioides difficile Infection

  https://www.mdpi.com/2076-2607/12/5/1004

  The endocytosis and release of TcdA and TcdB into the cytosol of the host cell can be distinguished into five stages: (i) binding of the toxins to cell surface receptors; (ii) cellular uptake via endocytosis; (iii) formation of pores in endosomal membrane; (iv) translocation of the toxin into the cytosol; (v) glycosylation of Rho/Ras GTPases; and (vi) cellular impacts. […] Once GTD is released into the cytosol, it selectively transfers UDP-glucose to Rho and Ras proteins, leading to their inactivation. Primary targets of glycosylation include RhoA, B, C, Rac1, 2, Cdc42, and isoforms of the Rho family such as RhoG and TC10. The functions of Rho and Ras GTPases exhibit distinct differences, as Rho GTPases are the main regulators of the actin cytoskeleton, while Ras primarily controls cell differentiation and proliferation, angiogenesis, and cell adhesion. Glycosylation retains GTPases in their inactive form, disrupting a series of cellular pathways.

• #13 Clostridium difficile infection: molecular pathogenesis and novel therapeutics

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4306399/

  These TcdA and TcdB units catalyze the monoglucosylation of the threonine 35/37 residue of small GTP-binding proteins Rho, Rac and Cdc42 within target cells, and thus modulate several physiological cellular events resulting in cell death. […] In fact, glucosylation leading to the depolymerization of the actin cytoskeleton, followed by disruption of tight cellular junctions and ultimately leading to apoptosis in colonic epithelial cells. […] The autoprotease domain is known to undergo structural rearrangement in the presence of inositol hexakisphosphate (InsP6) which causes the release of the glucosyltransferase domain into the cell. […] Thus, a multistep mechanism of receptor-mediated endocytosis, membrane translocation, autoproteolytic processing and monoglucosylation are important to the action of TcdA and TcdB on mammalian target cells. […] The identification of effectors that can cause C. difficile spore germination gives a clue to how inhibition of germination may be achieved.

• #14 Clostridioides difficile Infection | AMBOSS Rotation Prep

  https://resident360.amboss.com/adult-medicine/infectious-diseases/clostridioides-difficile-infection/clostridioides-difficile-infection.html

  C. difficile is transmitted via the fecal-oral route through highly resistant spores that can withstand heat, antibiotics, air, and acid. […] Once ingested, C. difficile releases exotoxins A and B that inactivate pathways mediated by the Rho family of guanosine triphosphatases (Rho GTPases) and cause colitis, colonocyte-cell death, and loss of intestinal barrier integrity, resulting in diarrhea. […] Areas of cell death coalesce to form pseudomembranous colitis.

• #15 Clostridioides difficile infection – Wikipedia

  https://en.wikipedia.org/wiki/Clostridioides_difficile_infection

  C. difficile strains produce multiple toxins. […] The most well-characterized are enterotoxin (Clostridium difficile toxin A) and cytotoxin (Clostridium difficiletoxin B), both of which may produce diarrhea and inflammation in infected people, although their relative contributions have been debated. […] Toxins A and B are glucosyltransferases that target and inactivate the Rho family of GTPases. […] Toxin B (cytotoxin) induces actin depolymerization by a mechanism correlated with a decrease in the ADP-ribosylation of the low molecular mass GTP-binding Rho proteins. […] Antibiotic treatment of CDIs may be difficult, due both to antibiotic resistance and physiological factors of the bacteria (spore formation, protective effects of the pseudomembrane). […] The emergence of a new and highly toxic strain of C. difficile that is resistant to fluoroquinolone antibiotics such as ciprofloxacin and levofloxacin, said to be causing geographically dispersed outbreaks in North America, was reported in 2005.

• #16 Exploring the Toxin-Mediated Mechanisms in Clostridioides difficile Infection

  https://www.mdpi.com/2076-2607/12/5/1004

  While CDI primarily affects the colon, it can precipitate systemic complications. Animal studies have demonstrated manifestations such as cardiopulmonary injury, ascites, organ failure, and acute respiratory distress syndrome. In pigs and mice infected with BI/NAP1/027 spores, high toxin levels have been detected in their sera, pleural, and ascitic fluids. Toxin presence in systemic circulation directly correlated with systemic CDI manifestations, absent in animals without systemic complications. […] There are some C. difficile strains, such as the BI/NAP1/027 strain, that can also produce the binary toxin CDT. CDT was first isolated from strain CD196 (RT 027) from a patient with severe pseudomembranous colitis. It is produced by 5–30% of clinical isolates of C. difficile and is associated with more severe complications, longer hospitalization, and increased mortality rates. The production of CDT has also been correlated with increased antibiotic resistance, and the detection of its gene could be used as a marker for antimicrobial susceptibility.

• #17 Clostridium difficile Infection: Pathogenesis, Diagnosis and Treatment | IntechOpen

  https://www.intechopen.com/chapters/54496

  Clostridium difficile can produce three toxins: A, B and binary toxin. Toxins A and B were the first identified in this bacterium; both are encoded by genes in the pathogenicity locus (PaLoc) and are included in the large clostridial toxins (LCT), a family known to modify small GTPases. These toxins act as glycosyltransferases that modify Rho and Ras proteins within the intestinal epithelial cells and disrupt the actin cytoskeleton, causing loss of intercellular junctions and the severe secretory diarrhoea associated with CDI. […] Some 10% of C. difficile strains are capable of producing binary toxin. This toxin is classified as an ADP-ribosyltransferase and is encoded by the cdtA gene (the enzymatic component) and the cdtB gene (the binding component). Binary toxin acts on the actin cytoskeleton, producing microtubule-based protrusions on the surface of epithelial cells. A number of studies have indicated that strains that produce binary toxins usually cause severe CDI.

• #18 Exploring the Toxin-Mediated Mechanisms in Clostridioides difficile Infection

  https://www.mdpi.com/2076-2607/12/5/1004

  CDT consists of two components, CDTa (enzymatic component) and CDTb (binding component). The genes encoding CDT are located in a 6.2 kb genetic region, distinct from the PaLoc, known as the CDT locus or CdtLoc. CDTa alters the structure of monomeric G-actin through ADP-ribosylation at arginine-177. CDT introduces ADP-ribose onto arginine 177 of G-actin, disrupting the F-actin structure and terminating its polymerization. […] CDT induces an increased local and systemic inflammatory response in the host and enhances the disruption of the host defense mechanisms caused by TcdA and TcdB. The induced production of IL-1β by cells of the innate immune system depends on signaling through Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4). […] In conclusion, while significant progress has been made in understanding the role of toxins in CDI pathogenesis, the further understanding of virulence factors, pathogenicity, and host interactions will aid the development of novel alternative therapeutics.

• #19 Exploring the Toxin-Mediated Mechanisms in Clostridioides difficile Infection

  https://www.mdpi.com/2076-2607/12/5/1004

  The induction of glycosylation by toxins on Rho/Ras proteins, followed by the redistribution of the actin cytoskeleton, results in dramatic changes in cell morphology. These disruptions include the loss of stress fiber formation, the rounding of cells referred to as the cytopathic effect (CPE), and the contraction of the cellular body leading to the formation of irregular structures. Many have attributed CPE to the inactivation of RhoA. […] The diarrhea caused by CDI is characterized by increased secretion and/or decreased absorption in the gastrointestinal tract. Prolonged TcdA and TcdB exposure significantly decreases NHE3 and DRA levels, leading to dysfunctional water and solute absorption, causing osmotic diarrhea. TcdA and TcdB induce cell death (referred to as cytotoxic effect) in various cell types such as epithelial and endothelial cells, monocytes, lymphocytes, and neurons of the enteric nervous system within 18–48 h post-exposure. The deactivation of Rho GTPases leads to apoptosis, which occurs after the appearance of CPE.

• #20 Clostridium difficile colitis: pathogenesis and host defence | Nature Reviews Microbiology

  https://www.nature.com/articles/nrmicro.2016.108

  Disease that is associated with infection by Clostridium difficile represents an urgent public health threat. The severity of C. difficile infection is determined by strain virulence, interactions with intestinal commensal microbial communities, and the host immune response to damage of the intestinal epithelium that is induced by C. difficile. […] The ability to sporulate and germinate is essential to C. difficile virulence. Hundreds of genes that are involved in sporulation and germination have been identified as well as a bile acid receptor that induces germination. […] C. difficile secretes toxin proteins that are internalized by host cells through receptor-mediated endocytosis and cause disruption to cytoskeletal architecture, which leads to cell death. Toxin-mediated cell death results in the loss of intestinal barrier integrity and the translocation of bacteria into underlying tissues.

• #21 Clostridium difficile colitis: pathogenesis and host defence | Nature Reviews Microbiology

  https://www.nature.com/articles/nrmicro.2016.108

  Toxin-mediated damage to the epithelium activates the host inflammatory immune response. The role of the immune system is to limit epithelial damage and the dissemination of intestinal bacteria into the circulation. However, an overly robust inflammatory response can be damaging to the host and contribute to disease pathology.

• #22 Clostridium difficile Infection and the Role of Adaptive Immunity in the Microbiome – Gastroenterology & Hepatology

  https://www.gastroenterologyandhepatology.net/archives/may-2017/clostridium-difficile-infection-and-the-role-of-adaptive-immunity-in-the-microbiome/

  G&H What is the pathogenesis of Clostridium difficile infection? […] MFClostridium difficile infection usually occurs in susceptible patients after antibiotic therapy kills a good portion of the native microbiota. In these vulnerable individuals, when C difficile spores are ingested, they germinate upon exposure to primary bile acids in the small bowel and travel down to the colon. There, the vegetative forms proliferate and produce enterotoxins that cause severe inflammation, resulting in debilitating diarrheal disease. […] […] […] G&H What is thenext step in the mechanism of action in the development of C difficile infection and colitis? […] MF The next step is that the gut barrier breaks down, mainly due to toxin A and B, which are produced by C difficile infection. These toxins lead to weakening of the tight junctions and apoptosis of the colonocytes. The mucin layer is already injured and broken down in part because of prior antibiotic treatment. The indigenous flora can then translocate into the mucosa and be exposed to the immune cells. This will recruit neutrophil granulocytes, which are an important part of the innate immune reaction, as they are responsible for starting a fairly significant primary inflammatory response. Interestingly, in order to patch up the holes in the gut barrier, neutrophil granulocytes create what are called neutrophil extracellular traps, which are the building blocks of the pseudomembranes that are a typical finding or hallmark of C difficile colitis.

• #23 Clostridioides difficile biofilms: A mechanism of persistence in the gut? | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009348

  Biofilms are structured bacterial communities encased in an extracellular matrix. The structure and complexity of biofilms depend on the microorganism and the local environment. Biofilms form on tissues and foreign implants during human infections and confer pathogens resistance to drugs and immune responses, making biofilm-associated infections extremely difficult to treat. Clostridioides difficile, a major healthcare-associated gastrointestinal pathogen, causes C. difficile infection (CDI), which is associated with high rates of recurrence, especially in the elderly. CDI is strongly associated with long-term antibiotic therapy, which results in disruption of the native gut microbiota. W C. difficile biofilms have been considered to be important for persistence of the bacterium in the gut and for recurrent infections. Here we review the current knowledge on C. difficile biofilms in the context of the gut environment and infection.

• #24 Clostridioides difficile biofilms: A mechanism of persistence in the gut? | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009348

  Biofilm formation by C. difficile was first reported by Donelli and colleagues where they identified the role of polymicrobial biofilms in clogging of biliary stents using confocal and field emission scanning electron microscopy. Soon after, biofilm formation by C. difficile strains of clinical origin (strains 630, R20291) on abiotic surfaces was reported, as quantitated by crystal violet staining. Viable cell counts, as well as LIVE/DEAD viability staining showed that bacterial viability was higher in 1- to 3-day-old biofilms and decreased in 6-day-old biofilms. C. difficile biofilms are multilayered, encased in a thick matrix composed of bacterial proteins, extracellular DNA (eDNA), and polysaccharide II; however, it is noteworthy that the composition and structure of biofilms are both time- and strain-dependent. Numerous C. difficile factors which modulate biofilm formation have been identified, including pili, flagella proteins, the S-layer, Cwp84, quorum sensing, germination receptor SleC, and sporulation.

• #25 Clostridioides difficile biofilms: A mechanism of persistence in the gut? | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009348

  Interestingly, the toxins TcdA and TcdB were identified in the biofilm matrix of 3- and 6-day-old biofilms, suggesting that biofilms may play a role in C. difficile virulence. Cyclic di-GMP (c-di-GMP) is thought to play an important role in the motile to sessile biofilm state shift through repression of flagellar synthesis and induction of pili. […] Spores are critical for transmission of CDI, and sporulation is a key pathway in C. difficile pathogenesis which is initiated under conditions of stress. Viable cell counts from biofilms formed by the clinically relevant strain, R20291, show that the majority of C. difficile cells are vegetative in 3-day-old biofilms. However, the number of spores increased over time, with spores forming the majority of cells in 6-day-old biofilms. A sporulation-deficient C. difficile strain lacking Spo0A, a master transcriptional regulator which induces the sporulation pathway upon phosphorylation, formed significantly reduced biofilms compared to the wild type.

• #26

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9815241/

  Clostridioides difficile is a gram-positive obligate anaerobe, capable of causing disease through the fecal-oral transmission of robust endospores. […] The significant mortality associated with C. difficile typically arises from more severe manifestations, including pseudomembranous colitis, fulminant colitis, and toxic megacolon. […] Infection recurrence, characterized by the reappearance of symptoms after treatment completion, is also common, largely due to the nature of available CDI treatments. […] Paradoxically, antibiotics constitute both the main treatment and a main risk factor for C. difficile infection. […] This results in complex treatment plans and worsened prognosis. […] The phylogenetic diversity of C. difficile has allowed for the emergence of several epidemic strains in recent years. […] Ribotype 027 strains display increased expression of toxins, due to a deletion in tcdC (encoding a negative regulator of toxin expression) and production of an additional binary toxin.

• #27 Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology – UpToDate

  https://www.uptodate.com/contents/clostridioides-difficile-infection-in-adults-epidemiology-microbiology-and-pathophysiology

  Clostridioides difficile is the causative organism of antibiotic-associated colitis. Colonization of the intestinal tract occurs via the fecal-oral route and is facilitated by disruption of normal intestinal flora (often due to antimicrobial therapy). […] This strain appears to be more virulent than other strains, which may be attributable to increased toxin production compared with previous strains. […] Fluoroquinolone use has strongly correlated with the emergence of this strain, and development of fluoroquinolone resistance by outbreak strains appears to have been associated with the increasing frequency of CDI outbreaks. […] Since 2005, CDI due to ribotype 078 has emerged in the Netherlands; the severity is similar to CDI caused by ribotype 027.

• #28

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9815241/

  The C. difficile PaLoc spans a 19.6 kb region, with a typically highly conserved genomic localization and organization, and encodes 5 proteins involved in toxin-mediated pathogenesis. […] TcdR is an alternative sigma factor and likely positive regulator of toxin production, since purified C. difficile RNA polymerase was unable to bind to the tcd promoter regions in the absence of TcdR, and interaction of TcdR with the RNA polymerase holoenzyme allowed transcriptional activation. […] Characterization of the hypervirulent ribotype 027 epidemic strain, first reported at the start of the millennium, showed a combination of factors putatively involved in increased virulence: high-level fluoroquinolone resistance, tcdC mutation leading to increased PaLoc expression, and possession of a further toxin C. difficile binary toxin (CDT).

• #29 Clostridioides (Clostridium) Difficile Colitis: Background, Etiology, Pathophysiology

  https://emedicine.medscape.com/article/186458-overview

  The NAP1 hypervirulent strain of C difficile is associated with the most serious sequelae of CDI, causing severe and fulminant colitis that is characterized by leukocytosis, renal failure, and toxic megacolon. […] Fecal bacteriotherapy and immunotherapy are investigative treatment strategies that have potential for managing patients with severe CDI.

• #30

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9815241/

  The success of C. difficile as a pathogen is inherently linked to its ability to resist antibiotics. […] This multidrug resistance was the driving force of the CDI epidemic at the start of the millennium, in addition to emergence of novel epidemic lineages, highlighting the importance of such factors in pathogenesis. […] Of course, being resistant to a wealth of antibiotics poses two challenges: (i) the extensive resistance displayed greatly reduces treatment options for CDI, warranting the status of C. difficile as an urgent threat; and (ii) such treatment options are likely to be further limited through the high degree of adaptation and flexibility in the C. difficile genome. […] The increasing threat of antimicrobial resistance, coupled with the diminishing number of available treatments has driven interest in both novel antimicrobials and alternative therapeutics for the treatment of CDI.

• #31

  https://www.jci.org/articles/view/72336

  Clostridium difficile infection (CDI) is the leading health care-associated illness. Both human and animal models have demonstrated the importance of the gut microbiota’s capability of providing colonization resistance against C. difficile. Risk factors for disease development include antibiotic use, which disrupts the gut microbiota, leading to the loss of colonization resistance and subsequent CDI. […] An understanding of the pathogenesis of CDI is crucial in disease treatment and prevention. C. difficile is an obligate anaerobe, acquired by the ingestion of spores via the fecal-oral route. These spores can survive even in harsh environmental conditions. […] Infection with a toxigenic strain of C. difficile results in a range of clinical signs and symptoms, from diarrhea and cramping in mild cases to the development of pseudomembranous colitis and even death in severe disease.

• #32

  https://www.jci.org/articles/view/72336

  Once colonized, C. difficile can lead to toxin-mediated inflammation and disease. C. difficile produces 2 major toxins responsible for disease, the large clostridial toxins A and B (TcdA and TcdB). These toxins, produced during the stationary phase of vegetative growth, are largely responsible for the damage to the mucosal epithelium and induction of an inflammatory response. […] At the core of CDI pathogenesis is disruption of the microbiota. A healthy gut microbiota is necessary for protection against pathogen colonization, termed colonization resistance. […] The host immune response also has the capability to modulate the microbiota. The observation that IBD can aggravate disease outcome of CDI suggests that inflammation may contribute to the development of CDI. […] Although a basic picture of CDI pathogenesis is known, a better understanding of the microbiota’s role in disease prevention is necessary. The role of the gut microbiota is integral throughout the life cycle of C. difficile from spore transmission, germination, and growth, into disease development.

• #33 The Gut Microbiota\’s Role in Clostridioides difficile Infection: Pathogenesis and Management Perspectives

  https://www.hilarispublisher.com/open-access/the-gut-microbiotas-role-in-clostridioides-difficile-infection-pathogenesis-and-management-perspectives-108334.html

  Antibiotic therapy is one of the most significant risk factors for CDI as it disrupts the normal balance of gut microbiota. Antibiotics not only kill susceptible bacteria but also disturb the ecological equilibrium, creating an environment conducive to C. difficile colonization and proliferation. The reduction of beneficial bacteria, such as Bacteroidetes and Firmicutes, allows C. difficile to thrive and produce toxins. C. difficile produces two major toxins, toxin A (TcdA) and toxin B (TcdB), which are essential virulence factors in the pathogenesis of CDI. These toxins are responsible for causing inflammation and damage to the intestinal epithelium. Toxin A (enterotoxin) disrupts the tight junctions between intestinal epithelial cells, leading to increased intestinal permeability and secretion of fluid into the intestinal lumen, resulting in diarrhea. Toxin B (cytotoxin) induces cytopathic effects, such as cell rounding and detachment, leading to tissue damage and inflammation.

• #34 C. Diff Infection: Symptoms, Causes, Diagnosis and Treatment

  https://www.webmd.com/digestive-disorders/clostridium-difficile-colitis

  The more severe your C. diff infection is, the higher the likelihood of complications. If you get C. diff a second time, there’s a 40% chance you’ll get it again. […] Doctors sometimes recommend a treatment to help repopulate the colon with healthy bacteria. It’s often done by putting another person’s stool in your colon using a device called a colonoscope. The procedure is called fecal microbiota transplant (FMT).

• #35 C. diff Infection: What It Is, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/15548-c-diff-infection

  Complications can occur with more severe infections. How severe your infection becomes will depend on several factors, including the strain of the bacteria you have and how strong your immune system is. […] Common complications include: Recurrent infection. As many as 20% of people will experience a relapse within two to eight weeks of completing treatment. As many as 40% will have another relapse after that. […] If you have severe complications, you might need intensive care. In rare cases, providers recommend emergency surgery to remove the source of the infection in your colon. This is called colectomy. […] Fecal transplantation involves transferring a poop sample from a healthy donor into a diseased colon. The sample will restore balance to your gut microbiome.

• #36 Food for thought—The link between Clostridioides difficile metabolism and pathogenesis | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011034

  Clostridioides difficile (C. difficile) is an opportunistic pathogen that leads to antibiotic-associated diarrhoea and is a leading cause of morbidity and mortality worldwide. Antibiotic usage is the main risk factor leading to C. difficile infection (CDI), as a dysbiotic gut environment allows colonisation and eventual pathology manifested by toxin production. […] C. difficile possesses a large and mosaic genome, capable of metabolising a diverse range of nutrients for growth. […] The ability of a pathogen to successfully colonise the gut relies on its ability to acquire and metabolise nutrients from its environment. C. difficile is proposed to act as a bacterial generalist, capitalising on the broad range of available nutrients present within a dysbiotic gut environment. […] C. difficile is then thought to manage Stickland metabolism in a hierarchical manner, preferentially utilising specific amino acids as substrates to maximise energy intake during growth.

• #37 Food for thought—The link between Clostridioides difficile metabolism and pathogenesis | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011034

  The WLP may then allow adaptation to decreasing nutrient availability during CDI when Stickland acceptors are low, representing a means to sustain flux of carbohydrate fermentation. […] C. difficile can metabolise ethanolamine as a carbon and nitrogen source and occurs within a macromolecular bacterial microcompartment (BMC). […] C. difficile metabolises a number of carbohydrates including, glucose, fructose, mannose, mannitol, melezitose, sorbitol, cellobiose, trehalose, and derivatives of mucin. […] The cellobiose operon plays a role in C. difficile pathogenesis by affecting the rate of sporulation and toxin production. […] Mucin degradation by commensal microorganisms may then play a key role in C. difficile pathogenesis, whereby the release of monosaccharide by-products is thought to facilitate colonisation of the intestinal mucous layer by chemotaxis while also providing substrates for growth. […] Understanding the processes C. difficile uses to suppress growth of the gut microbiota is critical in order to fully understand its pathogenesis.

• #38 Overview of Clostridium difficile Infection: Life Cycle, Epidemiology, Antimicrobial Resistance and Treatment | IntechOpen

  https://mts.intechopen.com/redirector/articles/overview-of-clostridium-difficile-infection-life-cycle-epidemiology-antimicrobial-resistance-and-tre

  These symptoms are mainly caused by two potent proinflammatory cytotoxins, TcdA and TcdB, that following release from the bacterium, translocate to the cytosol of target host cells and inactivate, by monoglucosylation, small GTP-binding proteins, including Rho, Rac and Cdc42. […] Importantly, the expression of tcdR is also activated from a promoter responsive to D, the main regulatory protein involved in the final stages of flagellar assembly. […] Some C. difficile strains, as those of RT027 and RT078, also produce a binary toxin known as CDT. […] Since C. difficile is a strict anaerobe, its virulence potential is linked to the ability to form spores. […] When ingested, the spores are able to pass the gastric barrier and reach the intestine where they are thought to attach to the epithelial cells in order to achieve proper germination, which is induced by certain bile salts.

• #39 Overview of Clostridium difficile Infection: Life Cycle, Epidemiology, Antimicrobial Resistance and Treatment | IntechOpen

  https://mts.intechopen.com/redirector/articles/overview-of-clostridium-difficile-infection-life-cycle-epidemiology-antimicrobial-resistance-and-tre

  Spore germination and outgrowth, in the absence of a competitive microbiota, will result in the establishment of a population of vegetative cells that will expand, produce the TcdA and TcdB toxins and eventually more spores. […] The toxins will cause damage to the colonic mucosa and eventually severe diarrhoea; shedding of the spores to the environment allows the infection of new hosts. […] Spores are the vehicle for transmission as well as for environmental persistence. […] Evidence suggests that C. difficile forms biofilms in vivo and in vitro and that the main virulence and persistence factors (toxins and spores) are produced within these structures. […] The spore thus has a central role in the persistence of the organism in the environment, infection, recurrence and transmission of the disease.

• #40 Clostridioides difficile biofilms: A mechanism of persistence in the gut? | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009348

  C. difficile initially attaches to the mucosal layers in the gut, when the native gut microbiota is disrupted by broad spectrum antibiotics. Increased c-di-GMP levels resulting in decreased bacterial motility enables attachment and establishment of microaggregates or communities. These communities could exist as single species or in close association with the gut microbiota, serve as a niche for production of spores and toxins (toxins A, B, and binary C. difficile toxin), and provide protection from oral antibiotics using for treatment (e.g., vancomycin, metronidazole) in the lumen.

• #41 The role of toxins in Clostridium difficile infection. | Lacy Lab

  https://www.vumc.org/lacy-lab/publication/role-toxins-clostridium-difficile-infection

  Clostridium difficile is a bacterial pathogen that is the leading cause of nosocomial antibiotic-associated diarrhea and pseudomembranous colitis worldwide. […] The pathogenesis of C. difficile is primarily mediated by the actions of two large clostridial glucosylating toxins, toxin A (TcdA) and toxin B (TcdB). […] These toxins act on the colonic epithelium and immune cells and induce a complex cascade of cellular events that result in fluid secretion, inflammation and tissue damage, which are the hallmark features of the disease. […] In this review, we summarize our current understanding of the structure and mechanism of action of the C. difficile toxins and their role in disease.

• #42

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