Abstract
This study investigated the effect of carvacrol (CR), a phytophenolic compound on antibiotic-associated gut dysbiosis and C. difficile infection in a mouse model. Five to six-week-old C57BL/6 mice were randomly divided into seven treatment groups (challenge and control) of eight mice each. Mice were fed with irradiated feed supplemented with CR (0, 0.05, and 0.1%); the challenge groups were made susceptible to C. difficile by orally administering an antibiotic cocktail in water and an intra-peritoneal injection of clindamycin. Both challenge and control groups were infected with 105CFU/ml of hypervirulent C. difficile (ATCC 1870) spores or PBS, and observed for clinical signs for 10 days. Respective control groups for CR, antibiotics, and their combination were included for investigating their effect on mouse enteric microflora. Mouse body weight and clinical and diarrhea scores were recorded daily post infection. Fecal samples were collected for microbiome analysis using rRNA sequencing in MiSeq platform. Carvacrol supplementation significantly reduced the incidence of diarrhea and improved the clinical and diarrhea scores in mice (p < 0.05). Microbiome analysis revealed a significant increase in Proteobacteria and reduction in the abundance of protective bacterial flora in antibiotic-treated and C. difficile-infected mice compared to controls (p < 0.05). However, CR supplementation positively altered the microbiome composition, as revealed by an increased abundance of beneficial bacteria, including Firmicutes, and significantly reduced the proportion of detrimental flora such as Proteobacteria, without significantly affecting the gut microbiome diversity compared to control. Results suggest that CR could potentially be used to control gut dysbiosis and reduce C. difficile infection.
Highlights
Clostridium difficile infection is the major cause of antibiotic-associated diarrhea in hospital settings around the world (McFarland, 2008; Hookman and Barkin, 2009)
C. difficile infection has been associated with the use of antibiotics and gastric acid suppressing agents that result in gut dysbiosis (Bartlett, 1992; Kelly and LaMont, 1998; Dial et al, 2005)
In order to assess the prophylactic effect of CR against C. difficile associated diarrhea in mice (8 mice per treatment group), the animal diets were supplemented with CR at two different concentrations (0.05% and 0.1%) in feed prior to antibiotic treatment and subsequent C. difficile infection
Summary
Clostridium difficile infection is the major cause of antibiotic-associated diarrhea in hospital settings around the world (McFarland, 2008; Hookman and Barkin, 2009). Clostridium difficile toxins (A and B) are functionally glucosyl transferases, which inactivate the Rho family GTPases associated with Factin regulation, and cause disruption of the cytoskeleton and intestinal epithelial tight junctions (von Eichel-Streiber et al, 1999; Keel and Songer, 2006). This leads to a severe inflammatory response with the release of cytokines and leukotrienes, causing pseudomembrane formation and severe diarrhea (McDonald et al, 2006; Sunenshine and McDonald, 2006; Hookman and Barkin, 2009). Since gut dysbiosis is considered as the most important predisposing factor in CDAD, emerging and novel therapeutic approaches, including fecal microbiome transplantation (FMT) primarily aimed at restoration of the normal gut flora in CDAD patients are explored (Kassam et al, 2013)
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