ABSTRACT: Clostridioides difficile infection (CDI) is a common infectious disease that is mainly caused by antibiotics.
Infectious diarrhea triggered by Clostridioides (previously known as Clostridium) difficile accounts for a large part of antibiotic-associated diarrhea (AAD), causing serious health hazards and considerable economic losses worldwide. C. difficile is generally recognized as a conditional pathogen in the gut, and most strains cannot cause infection except in special cases, such as during dysbiosis in gut homeostasis induced by antibiotics. The ingestion of antibiotics kills most gut microbes that can defend against C. difficile and causes the destruction of the intestinal mucosa and immune system. C. difficile survives during antibiotic intervention due to their spores. These recalcitrant spores can withstand multiple antibiotics; subsequently, they germinate and transform into vegetative cells again when suitable conditions manifest. Finally, without competitors, these regenerated C. difficile strains flourish in the gut, secrete toxins and cause infection.
Death and money
Infectious disease caused by C. difficile is one of the most common infectious diseases worldwide, resulting in serious harm to public health. In 2011, the US Centers for Disease Control and Prevention (CDC) evaluated 453,000 cases related to CDI and found that this infection killed 29,300 patients that year, accompanied by a heavy burden of 5.4 billion dollars. In Europe, a report from the European Center for Disease Prevention and Control (ECDC) indicated that therewere 124,000 CDI cases and 14,000 deaths annually.
The main reason behind this trend of increased CDI incidence is likely due to the broader utilization of antibiotics, especially in developing countries. The overuse of antibiotics is a severe public health issue. It has not only brought a huge medical cost but has allowed drug-resistant bacteria, including C. difficile, to flourish.
However, clinical data indicated that the morbidity of CDI in older C. difficile carriers reaches a high level. This result might be associated with many factors, such as the degeneration of the immune system and the fragile gut microbioma in elderly individuals, which provide the opportunity for C. difficile to expand.
Strong link between C. difficile and antibiotic diarrhea was confirmed, and the emergence of pseudomembranous colitis aroused wide attention. Pseudomembranous colitis is the most severe symptom induced by C. difficile. After antibiotic therapy, C. difficile releases toxins (TcdA and TcdB) in the gut.
The genetic material of C. difficile consists of an 4.3 Mb circular chromosome, and most of C. difficile can secrete two kinds of synergistic toxin proteins, enterotoxin A (TcdA, 308 kDa) and cytotoxin B (TcdB, 270 kDa), under suitable conditions. TcdA and TcdB can destroy intestinal epithelial cells and subsequently induce inflammatory and tissue damage. These two toxins are encoded and controlled by tcdA and tcdB, which are located in the pathogenicity determinant locus PaLoc (19.6 kb). In addition, the other three genes (tcdC, tcdD, and tcdE) in this area are associated with the production of toxin proteins. tcdC is a negative regulator of toxin expression, whereas tcdD is a positive regulator. The role of tcdE is to release toxin proteins from C. difficile cells. Recently, Cdt, a new type of binary toxin, has emerged, and this toxin is controlled by the cdtA and cdtB genes outside the PaLoc; only some high virulence strains, such as RT 027, can secrete it. C. difficile has resistance to various harsh environments due to its spores, and these spores can form when C. difficile stays in undernourished or special conditions. Spores have strong resistance against high temperatures, oxygen, and even high concentrations of ethanol and thus cannot be killed easily. These spores can germinate and become vegetative cells when they are in a suitable environment and subsequently form pathogenic strains, produce toxin proteins, and induce tissue damage and infection again.
Using antibiotics, on the one hand, can cure diseases; on the other hand, it can cause permanent damage to some inherent microorganisms.
Generally, C. difficile, as a kind of resident bacteria in the gut, does not cause nfection, and most C. difficile carriers have no symptoms due to the protection of the normal gut microbiota and intestinal immune system. However, the infection only occurs under certain conditions, such as the destruction of certain intestinal microorganisms induced by antibiotics, chemotherapy, proton pump inhibitors, antacids or antimotility drugs. Some antibiotic treatments kill many beneficial microorganisms and stimulate the overgrowth of C. difficile. These C. difficile strains flourish in the gut without competitors and secrete massive amounts of toxin, followed by intestinal infections and inflammation, which is called CDI. After intake of the antibiotics, most inherent bacteria and fungi are destroyed, and their corresponding niches are vacated; Vast numbers of spores are produced by C. difficile in the antibiotic-induced environment, and these spores can germinate into vegetative cells and strains again in suitable conditions; and (3) these pathogenic strains invade and occupy vacant niches and then indiscriminately grow and secrete toxin proteins (TcdA and TcdB), eventually causing inflammation and intestinal cell damage.
Disadvantages of antibiotics
Overall, the use of antibiotics leads to the emergence of resistant strains, body injury, dysbacteriosis and other complications. Multidrug-resistant strains are a considerable threat to public health on a global scale, and most of them are difficult to address with conventional drugs, including multidrug-resistant C. difficile strains.
Destruction of the normal gut microbiota is a serious consequence induced by antibiotics. The richness and diversity of the gut microbiota decrease after taking antibiotics, especially for some beneficial microorganisms, such as Lactobacillus rhamnosus. Their populations sharply drop, followed by the vacation of niches; subsequently, several resistant and opportunistic pathogens, such as C. difficile, invade and occupy these niches and flourish in the gut, causing further disorder in the microbiota, affecting the immune and metabolic functions of the body, and eventually causing diseases. C. difficile strains are resistant to many antibiotics due to their spores, and these spores can germinate and develop into C. difficile strains again under suitable conditions. Destruction of the gut microbiota, especially the damage to beneficial bacteria induced by antibiotics, involves the following two aspects: one is the direct inhibitory or bactericidal effects of antibiotics themselves against gut bacteria, and the other is the production of some special substances derived from C. difficile that can be activated or enhanced by antibiotics. These special substances are conducive to the survival and expansion of C. difficile.
Antibiotics can destroy beneficial microorganisms in the gut, such as Bacteroides thetaiotaomicron and Bifidobacterium breve. These two bacteria induce the expression of C-type lectin, followed by regeneration of islet-derived protein III c (REGIII c). REGIII c targets grampositive bacteria and inhibits their growth. Similarly, gut bacteria such as Clostridium scindens and Clostridium sordellii secrete tryptophan-derived antibiotics, which inhibit the division and proliferation of C. difficile. These results suggest that some gut bacteria that antagonize C. difficile can be killed easily in an antibioticinduced environment; subsequently, the levels of their antibacterial secretions decrease.
Antibiotics weaken the diversity of the gut microbiota and create favorable conditions to promote C. difficile growth.
New therapies can effectively treat CDI without affecting normal physiological function. Recently, a variety of emerging non-antibiotic treatments have attracted wide attention. Specifically, probiotics, engineered microorganisms, bacteriophages, diet, natural active substances, nanoparticles, and compounds are examples of non-antibiotic therapies.
Probiotics are generally defined as a kind of living microorganism that reach the intestine in an active state when given in sufficient doses and thus exert positive health effects in humans, such as the modulation of the intestinal microbiota and the activation of the immune system.
Historically, they have flourished in the food field; however, increasing evidence suggests that they also play critical roles in the area of biomedicine, especially in the prevention and treatment of infectious diseases.
Diet has a considerable effect on the composition of the gut microbiota.
A growing number of studies have suggested that there is a close relationship among diet, the gut microbiota and immune responses.
Natural active substances
Natural active substances refer to some natural active molecules that are derived from a variety of natural products, such as plants or animals.
Several studies have shown that natural plants have the potential to protect against C. difficile.
Information was taken from the recently published study in the journal – Critical Reviews in Clinical Laboratory Sciences :
Jingpeng Yang & Hong Yang (2019): Non-antibiotic therapy for Clostridioidesdifficile infection: A review, Critical Reviews in Clinical Laboratory Sciences, DOI: 10.1080/10408363.2019.1648377
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