Materiały źródłowe

• #1 Clostridioides difficile infection – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK431054/

  Clostridioides difficile is a gram-positive and spore-forming bacterium. This obligate anaerobic bacillus is recognized for its ability to produce toxins and cause diarrhea, which is often associated with antibiotic usage. […] The emergence of the newer, hypervirulent, antibiotic-resistant, epidemic strain ribotype 027, also known as the North American pulsed-field gel electrophoresis type 1 (or NAP1) strain has resulted in increased frequency and severity of infections over the last 2 decades. […] C difficile produces 2 types of toxins A and B which are virulent factors in its pathogenicity. Most pathogenic strains associated with C difficile infection produce toxins A and B. However, globally, there are reports of strains producing only toxin B. […] In 2005, due to the increasing incidence and virulence of Cdifficile associated disease, a newer strain was identified that contained a binary toxin (referred to as binary toxin CDT) in addition to toxins A and B. Deletions in the gene tcd, which serves as a negative regulator of toxins A and B, have been identified, potentially leading to overproduction of these virulence factors.

• #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.

• #2 Clostridioides difficile infection – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK431054/

  The emergence of the newer, hypervirulent, antibiotic-resistant, epidemic strain ribotype 027, commonly known as NAP1/B1/027 or the North American pulsed-field gel electrophoresis type 1 strain, restriction endonuclease analysis type B1, or polymerase chain reaction ribotype 027 is characterized by increased production of toxins A and B, as well as the production of a binary toxin CDT, and fluoroquinolone resistance. […] The link between antibiotics and the onset of C difficile infections stems from the dysbiosis within the gut microbiome ecosystem induced by antibiotic use. […] Diarrhea and pseudomembranous colitis, characteristic symptoms of C difficile infection, result from clostridial glycosylation exotoxins toxin A (TcdA), an enterotoxin, and toxin B (TcdB), which is cytotoxic.

• #3 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. […] 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 (270-308 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.

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

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

  Clostridioides difficile infection (CDI) is the leading cause of nosocomial antibiotic-associated diarrhea, and colitis, with increasing incidence and healthcare costs. Its pathogenesis is primarily driven by toxins produced by the bacterium C. difficile, Toxin A (TcdA) and Toxin B (TcdB). Certain strains produce an additional toxin, the C. difficile transferase (CDT), which further enhances the virulence and pathogenicity of C. difficile. These toxins disrupt colonic epithelial barrier integrity, and induce inflammation and cellular damage, leading to CDI symptoms. Significant progress has been made in the past decade in elucidating the molecular mechanisms of TcdA, TcdB, and CDT, which provide insights into the management of CDI and the future development of novel treatment strategies based on anti-toxin therapies.

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

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

  The production of TcdA and TcdB are essential for the pathogenesis of CDI, while TcdB plays a crucial role, as evidenced by strains producing only the TcdB inducing all CDI symptoms, sometimes more severely than strains producing both TcdA and TcdB. Initially, TcdA was considered the primary virulence factor, but subsequent studies showed that both toxins contribute synergistically to disease progression. While TcdA was thought to enhance the action of TcdB, strains solely producing TcdB exhibited significant virulence, challenging the notion of TcdA’s primary role. Recent findings indicate that TcdB is more closely associated with CDI severity, supported by clinical strains predominantly producing TcdB and strains lacking TcdA but causing severe disease. These insights highlight the intricate interplay of TcdB as an emerging key determinant of disease severity.

• #5 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.

• #6 Clostridioides difficile infection – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK431054/

  Toxin A has a carbohydrate receptor binding site that facilitates the intracellular transport of toxins A and B. After becoming intracellular, both toxins cause the inactivation of pathways mediated by the Rho family of proteins, resulting in damage to colonocytes, disruption of intercellular tight junctions, and colitis. […] Furthermore, toxin A directly activates neutrophils, while toxins A and B contribute to neutrophil chemotaxis.

• #7 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. […] 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.

• #8 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.

• #9

  https://step2.medbullets.com/infectious-dis/121798/clostridium-difficile-c-diff

  Clostridium difficile produces 2 toxins that bind to intestinal mucosal cells. […] Toxin A is an enterotoxin that binds to the intestinal brush border. […] Toxin B is a cytotoxin and depolymerizes actin, disrupting the cytoskeleton. […] Clostridium difficile causes a pseudomembranous colitis and diarrhea characterized by yellow-white plaques in intestinal mucosa.

• #10 Clostridium difficile–Associated Diarrhea | AAFP

  https://www.aafp.org/pubs/afp/issues/2005/0301/p921.html/1000

  C. difficile causes toxin-mediated colitis. Pathogenic strains of C. difficile produce two protein exotoxins: toxin A and toxin B. […] Toxin A activates macrophages and mast cells. Activation of these cells causes the production of inflammatory mediators, which leads to fluid secretion and increased mucosal permeability. […] Toxin B has little enterotoxic activity but is extremely cytotoxic in vitro. C. difficile toxins also cause leukocyte chemotaxis and the upregulation of cytokines and other inflammatory mediators. Consequently, there is a profound colonic inflammatory response, which is evidenced clinically by a high WBC count. […] As colitis worsens, focal ulcerations occur, and the accumulation of purulent and necrotic debris forms the typical pseudomembrane.

• #10 Clostridium difficile–Associated Diarrhea | AAFP

  https://www.aafp.org/pubs/afp/issues/2005/0301/p921.html/1000

  Clostridium difficile infection is responsible for approximately 3 million cases of diarrhea and colitis annually in the United States. […] Major predisposing factors for symptomatic C. difficile colitis include antibiotic therapy; advanced age; multiple, severe underlying diseases; and a faulty immune response to C. difficile toxins. […] The precipitating event for C. difficile colitis is disruption of the normal colonic microflora. This disruption usually is caused by broad-spectrum antibiotics, with clindamycin and broad-spectrum penicillins and cephalosporins most commonly implicated. […] After disruption of the colonic microflora, colonization of C. difficile generally occurs through the ingestion of heat-resistant spores, which convert to vegetative forms in the colon. […] The major host factors predisposing patients to the development of symptomatic C. difficile associated diarrhea include antibiotic therapy, advanced age, number and severity of underlying diseases, and faulty immune response to C. difficile toxins.

• #11 Clostridium difficile and PMC • LITFL • CCC Gastroenterology

  https://litfl.com/clostridium-difficile-enterocolitis-and-pseudomembranous-colitis/

  Clostridium difficile enterocolitis and pseudomembranous colitis (PMC) […] Mechanism […] antibiotic exposure – overgrowth of C. difficile – increased toxin production – mucosal damage – inflammation and necrosis.

• #12 Clostridioides Difficile Pathogenesis & Manifestation

  https://www.contagionlive.com/view/clostridioides-difficile-pathogenesis-and-manifestation

  Id like you to think about C diff [Clostridioides difficile] infection as a disease in general. I would characterize this as the original microbiome disease. What I mean by that is theres a very solid and clear link between the microbiome and C diff infection. Its been known since roughly 1978 that C diff infections were the most prominent of a class of infection called antibiotic-associated diarrhea. […] The normal microbiome in a healthy gut is like that diverse garden, it has many different colors, flavors, and functions that help the gut function well. But when you damage that through the use of antibiotics for another reason, then you reduce that ability to resist colonization by C diff. C diff very often then will come in and take over, proliferate, and cause serious infection. […] When C diff is able to proliferate in that damaged microbiome, or the damaged garden of the gut, it actually grows, proliferates, and takes over the environment. You had asked about virulence factorsat that point it expresses its primary virulence factors, which are called toxins A and B. Both toxins A and B will cause changes in the shape and function of intestinal epithelial cells. It damages the cells and causes loose injunctions in the intestinal epithelium, which leads to a variety of symptoms, ranging from mild to severe.

• #13 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.

• #14 About C. diff | C. diff | CDC

  https://www.cdc.gov/c-diff/about/index.html

  Healthy people don’t get infected often even if the spores reach their intestines. If your immune system is weak or you’ve recently taken antibiotics, you could get sick. Taking antibiotics can affect your microbiome, making you more susceptible to illnesses like C. diff infection. […] A healthy microbiome helps protect you from infection (like C. diff), but antibiotics disrupt your microbiome. Antibiotics that fight bacterial infections by killing bad germs can also get rid of the good germs living in the digestive tract that protect the body against infections. The effect of antibiotics can last as long as several months. If you come in contact with C. diff germs during this time, you can get sick. […] Treatment for C. diff infection usually involves taking a specific antibiotic such as vancomycin or fidaxomicin for at least 10 days. […] Some people get C. diff infection over and over again. […] For those with repeat infections, innovative treatments, including fecal microbiota transplants, have shown promising results.

• #14 About C. diff | C. diff | CDC

  https://www.cdc.gov/c-diff/about/index.html

  Clostridioides difficile [klosTRIDeOY-dees difuhSEEL], formerly known as Clostridium difficile and often called C. difficile or C. diff, is a bacterium (germ) that causes diarrhea and colitis. Colitis is an inflammation of the colon. […] C. diff infection is more common among patients in healthcare settings, such as hospitals and nursing homes. This is because many people carrying C. diff stay or get treated in those facilities. […] C. diff germs spread from person to person in poop, but the bacteria are often found in the environment. Finding C. diff germs in the home is not unusual, even when no one in the home has been ill with C. diff infection. […] When C. diff germs are outside the body, they become spores. These spores are an inactive form of the germ and have a protective coating allowing them to live for months or years on surfaces and in the soil. The germs become active again when you swallow these spores and they reach the intestines.

• #15 Clostridioides difficile infection – Wikipedia

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

  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. […] 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. […] 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. difficile biofilm formation. […] 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.

• #16 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. […] 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. […] The spore thus has a central role in the persistence of the organism in the environment, infection, recurrence and transmission of the disease. […] Spores are resistant to heat, oxygen and other environmental insults, including commonly used ethanol-based disinfectants.

• #16 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

  The use of antimicrobial agents and acquired resistances explains in part the emergence and spreading of epidemic strains of Clostridium difficile. […] The life cycle of C. difficile involves growth, spore formation and germination. […] Highly resistant spores produced by antibiotic-resistant/multiresistant strains may be one of the most serious challenges we face in what concerns the containment of C. difficile. […] C. difficile is an enteric pathogen that relies on the disturbance of the normal gut microbiota to expand in the gut and cause infection; individuals with a normal, balanced microbiota are usually resistant to infection by C. difficile. […] Disease symptoms range from mild diarrhoea and abdominal pain to life-threatening inflammatory lesions such as PMC, toxin megacolon or bowel perforation, and in severe cases sepsis and death.

• #17 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. […] 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. […] The spore thus has a central role in the persistence of the organism in the environment, infection, recurrence and transmission of the disease. […] Spores are resistant to heat, oxygen and other environmental insults, including commonly used ethanol-based disinfectants.

• #18 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

  To cause disease, the dormant C. difficile spores must germinate in the host gastrointestinal tract. […] C. difficile responds to unique germinants, such as bile salts. […] C. difficile can exploit specific metabolites that become more abundant in the mouse gut after antibiotic treatment, including the primary bile acid CA for germination, and carbon sources such as mannitol, fructose, sorbitol, raffinose and stachyose for growth. […] The link between toxin production and spore differentiation is also unclear. […] The link between the expression of tcdR and flagellar assembly, resulting from the D-type promoter in the tcdR-regulatory region, may also be viewed in this context.

• #19 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 is able to metabolise carbon dioxide, the amino acids proline, hydroxyproline, and ornithine, the cell membrane constituent ethanolamine, and the carbohydrates trehalose, cellobiose, sorbitol, and mucin degradation products as carbon and energy sources through multiple pathways. […] Persistence within the gut environment is also mediated by the by-products of metabolism through the production of p-cresol, which inhibit gut commensal species growth promoting dysbiosis. This review aims to explore and describe the various metabolic pathways of C. difficile, which facilitate its survival and pathogenesis within the colonised host gut.

• #20 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 purpose of this review is to highlight recent advances in our understanding of how the interplay between C. difficile, its host and the gut microbiota with respect to the availability and metabolism of certain nutrients is implicated in the pathogenesis of this important gut pathobiont. […] Stickland metabolism is of great importance in Clostridium species, and C. difficile is no exception. […] Proline and glycine are thought as the most important Stickland electron acceptors in C. difficile with D-proline being reduced to 5-aminovalerate by proline reductase (PR), and glycine reduced to acetyl phosphate by glycine reductase (GR). […] 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.

• #21 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 production of p-cresol as a by-product of p-HPA, and possibly tyrosine, metabolism governs C. difficile’s success within the gut environment by diminishing the numbers of gut commensal species that establish colonisation resistance towards it. […] Understanding the processes C. difficile uses to suppress growth of the gut microbiota is critical in order to fully understand its pathogenesis.

• #22 Clostridioides difficile – Wikipedia

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

  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. […] Additional virulence factors include an adhesion factor that mediates the binding to human colonic cells and a hyaluronidase. […] The bacterium also produces the chemical para-cresol, which inhibits the growth of other microbes in its vicinity and allows it to outcompete normal human gut flora. […] C. difficile secretes mucolytic enzymes like CWp84 to degrade the colonic mucosa. […] These spores are also capable of adhering to colon cells. […] Additionally, C. difficile is a motile bacterium that can switch between both the motile and sessile phases, a process regulated by cyclic-di-GMP. […] C. difficile can carry a broad spectrum of clinical manifestations, from being asymptomatic to severe colitis and death.

• #23 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

  CDI is mediated by the toxins TcdA and TcdB, which act to damage the gut epithelium leading to a breakdown in the gut barrier integrity. […] 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 possesses a large and mosaic genome, capable of metabolising a diverse range of nutrients for growth. […] Virulence of C. difficile also has an intimate relationship with nutrient availability as, upon nutrient limitation in the gut environment, C. difficile responds by producing toxins that liberate host-derived nutrients through cytotoxic activity and creation of a proinflammatory environment.

• #24 Targeting the Metabolic Basis of C. difficile’s Life Cycle

  https://asm.org/articles/2021/march/targeting-the-metabolic-basis-of-c-difficile-s-lif

  C. difficile is not picky when it comes to food, and can alter its metabolism depending on the nutrients present in its environment at a given time. However, there are some nutrients that are critical for efficient growth, including amino acids like proline, leucine and glycine. These substrates fuel Stickland metabolism, a set of amino acid fermentation reactions common in members of the Clostridium genus, in which electrons are transferred from one amino acid to another to produce adenosine triphosphate (ATP) and other molecular drivers of life. […] C. difficiles phase as a vegetative cell is marked by intestinal destruction. The pathogen releases up to 3 toxins that disrupt intestinal barrier integrity and promote inflammation. Interestingly, toxin production occurs not in the presence of specific nutritional or metabolic signals, but rather in the absence of such signals.

• #25 Harnessing the Immune System to Treat C diff Infection

  https://www.todaysgeriatricmedicine.com/archive/JF17p28.shtml

  Clostridium difficile (C diff) is a bacterial pathogen that was first identified as the cause of antibiotic-associated diarrhea in the late 1970s. Today, C diff causes an estimated 500,000 infections per year and has become the most common hospital-acquired infection in the United States. Patients typically become infected with C diff following antibiotic treatment, which disrupts the healthy bacteria found in the gut that are responsible for out-competing the pathogen and promoting beneficial immune responses. C diff spores are transmitted via the fecal-oral route and germinate into actively dividing bacteria upon reaching the intestine. This pathogen produces toxins that are primarily responsible for the symptoms of infection, as nontoxigenic strains are not associated with disease. Symptoms of C diff infection (CDI) range from mild diarrhea to life-threatening pseudomembranous colitis and toxic megacolon. Successful resolution of CDI involves generation of a protective immune response against the bacterium and its toxins, and recurrence has been associated with significantly lower levels of antitoxin antibodies. Indeed, the type and intensity of inflammation generated in response to C diff appear to be a crucial determinant of outcome, as recent studies show high levels of the inflammatory cytokines interleukin-8 and chemokine ligand 5 were better predictors of severe disease than C diff burden.

• #26 clostridium-difficile-infection-pathogenesis-and-clinical-findings | Calgary Guide

  https://calgaryguide.ucalgary.ca/clostridium-difficile-infection-pathogenesis-and-clinical-findings/c-diff-pathogenesis-and-clinical-findings-2022/

  Clostridium difficile (C. diff) Infection […] Release of C. diff toxin A and B inactivates Rho and Ras GTPases in colonic epithelial cells (colonocytes) (Rho and Ras GTPases control cytoskeletal dynamics and gene expression) […] Cytoskeletal disorganization and arrest of RNA synthesis causes necrosis of colonocytes and triggers host immune response […] Neutrophil chemotaxis and activation […] Inflammation of colon […] Disruption of tight junctions between colonocytes […] Release of fluid into intestinal lumen and inability of colon to reabsorb it […] Toxic megacolon […] Bowel perforation […] Bloody stool.

• #27 Biliary Tract Disorders, Gallbladder Disorders, & Gallstone Pancreatitis | ACG

  https://gi.org/topics/c-difficile-infection/

  Diarrhea is a frequent side effect of antibiotics, occurring 10–20% of the time. It usually gets better when the antibiotics are stopped. Clostridium difficile infection (CDI) is due to a toxin-producing bacteria that causes a more severe form of antibiotic associated diarrhea. The disease ranges from mild diarrhea to severe colon inflammation that can even be fatal. CDI usually occurs when people have taken antibiotics that change the normal colon bacteria allowing the C. difficile bacteria to grow and produce its toxins. […] C. difficile produces two main toxins – toxins A and B – that cause inflammation in the colon. […] Major risk factors are older age, weakened immune system, having other illnesses, and being in a hospital or a long-term care facility. […] Symptoms of CDI can vary. Diarrhea is the most common symptom; it is usually watery and, rarely, bloody, and may be associated with crampy abdominal pain.

• #28 Biliary Tract Disorders, Gallbladder Disorders, & Gallstone Pancreatitis | ACG

  https://gi.org/topics/c-difficile-infection/

  The diagnosis of C. difficile should be considered in patients with new and unexplained diarrhea occurring more than 3 times per day. […] Treatment for C. difficile is based on the severity of the infection. […] Severe infections are diagnosed based on laboratory data including elevated white blood cell count (>15,000) and worsening kidney function (Creatinine >1.5). […] Fulminant infections are defined by the presence of shock, low blood pressure, or toxic megacolon. […] While antibiotics are effective in treating most cases of CDI, the symptoms recur after the end of treatment in 10-20% of cases. […] Current recommendations for the treatment of recurrent CDI include a vancomycin taper over six to eight weeks or fidaxomicin for ten days. […] The most effective treatment, however, is fecal microbiota transplant (FMT). FMT is typically administered via colonoscopy where stool from a healthy donor is instilled into the colon of a patient with recurrent CDI. […] Wise antibiotic policies, by using narrow-spectrum agents when directed and avoiding unnecessary use of broad-spectrum antibiotics, are key in the prevention of CDI.

• #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. […] The overall suggestion from this study is that the substance P receptor is very important in the pathogenesis of inflammatory diarrhea. […] Further insight into the genetics of C difficile toxin A reveals that the main binding protein is gp96. In addition, it has been found that C difficile has potent stimulatory activity for the Nod1 gene, and mice who were homozygous knockouts for Nod1 had increased lethality to CDI despite similar levels of intestinal damage relative to control the mice. […] The implication of this study is that Nod1 regulates the susceptibility to C difficile. […] Ultimately, many of the genetic influences on CDI and the clinical course of C difficile colitis likely remain unknown. At this point, it is understood that subtle differences in the immune system may significantly influence the natural history of C difficile disease.

• #30 Updated Clinical Practice Guidelines for C difficile Infection in Adults

  https://www.uspharmacist.com/article/updated-clinical-practice-guidelines-for-c-difficile-infection-in-adults

  The main risk factors for development of CDI are exposure to the healthcare environment, advanced age (65 years or older), and exposure to antibiotics. Receipt of an antimicrobial agent is the most significant modifiable risk factor for initial or recurrent CDI. Although most antibiotics can disrupt normal intestinal gut flora, thereby creating an environment that enables growth and colonization of C difficile, carbapenems, clindamycin, fluoroquinolones, piperacillin-tazobactam, and third- and fourth-generation cephalosporins have been shown to confer the highest risk of infection. Patients are at highest risk for CDI during antimicrobial therapy and within the first month after its discontinuation, and they continue to be at risk for 3 months after completion of therapy. […] Recurrent CDI may occur after completion of treatment, and approximately 25% of patients with a first episode of CDI will have a recurrent infection. The risk of recurrence increases with the number of CDI episodes, with up to 45% of patients experiencing recurrent CDI after the second episode and more than 60% having a recurrence after three or more episodes.

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

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

  If a C. diff infection isn’t treated quickly, you could become dehydrated due to severe diarrhea. This loss of fluids might also affect your blood pressure, kidney function, and overall health. […] Pseudomembranous colitis. Caused by toxins produced by C. diff, this type of colitis attacks the cells of your intestinal lining, resulting in ulcers and plaques there. […] Toxic megacolon. Your colon dilates and can’t release gas or stool. This could cause it to swell and rupture. It can be life-threatening without emergency surgery. […] 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. […] C. diff is very contagious. Externally, C. diff is transmitted to your gut through your mouth. Many of us already have C. diff in our intestines that other, helpful bacteria keep in check. When antibiotics kill off these helpful bacteria, C. diff can take over in your gut.

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

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

  This review focuses on recent advances in understanding how TcdA, TcdB, and CDT interact with host cells, altering the cellular physiology and immune responses. We unravel their binding mechanisms to cellular receptors and manipulation of intracellular signaling pathways, shedding light on the intricate toxin–host dynamics. These toxins are pivotal in CDI pathogenesis, disrupting cell adhesion, and cytoskeletal rearrangements, and triggering pro-inflammatory responses and cell death. Moreover, this review provides a brief overview of potential toxin-based therapeutic strategies, presenting promising approaches for novel CDI treatments.

Zobacz więcej