Abstract
Clostridioides difficile (formerly Clostridium difficile) infection (CDI) is one of the most common hospital-acquired infections, which is often triggered by a dysbiosed indigenous gut microbiota (e.g., upon antibiotic therapy). Symptoms can be as severe as life-threatening colitis. The current study assessed the antipathogenic potential of human milk oligosaccharides (HMOs), i.e., 2′-O-fucosyllactose (2′FL), lacto-N-neotetraose (LNnT), and a combination thereof (MIX), against C. difficile ATCC 9689 using in vitro gut models that allowed the evaluation of both direct and, upon microbiota modulation, indirect effects. During a first 48 h fecal batch study, dysbiosis and CDI were induced by dilution of the fecal inoculum. For each of the three donors tested, C. difficile levels strongly decreased (with >4 log CFU/mL) upon treatment with 2′FL, LNnT and MIX versus untreated blanks, coinciding with increased acetate/Bifidobacteriaceae levels. Interindividual differences among donors at an intermediate time point suggested that the antimicrobial effect was microbiota-mediated rather than being a direct effect of the HMOs. During a subsequent 11 week study with the PathogutTM model (specific application of the Simulator of the Human Intestinal Microbial Ecosystem (SHIME®)), dysbiosis and CDI were induced by clindamycin (CLI) treatment. Vancomycin (VNC) treatment cured CDI, but the further dysbiosis of the indigenous microbiota likely contributed to CDI recurrence. Upon co-supplementation with VNC, both 2′FL and MIX boosted microbial activity (acetate and to lesser extent propionate/butyrate). Moreover, 2′FL avoided CDI recurrence, potentially because of increased secondary bile acid production. Overall, while not elucidating the exact antipathogenic mechanisms-of-action, the current study highlights the potential of HMOs to combat CDI recurrence, help the gut microbial community recover after antibiotic treatment, and hence counteract the adverse effects of antibiotic therapies.
Highlights
Clostridioides difficile is a Gram-positive, spore-forming anaerobe [1] that is the causative agent of C. difficile infection (CDI)
The current study aimed to investigate the antipathogenic potential of human milk oligosaccharides (HMOs) against C. difficile using a combination of two in vitro models
These interindividual differences in C. difficile inhibition suggest that the antimicrobial effect of HMOs is likely not a direct effect of the HMOs as such, but rather an indirect effect via the modulation of the background microbiota
Summary
Clostridioides difficile is a Gram-positive, spore-forming anaerobe [1] that is the causative agent of C. difficile infection (CDI). As reviewed by Martin et al [2], the C. difficile infection cycle involves several steps: (i) CDI transmission via the fecal–oral route, (ii) germination of C. difficile spores in susceptible hosts, and (iii) toxin A/B production resulting in adverse effects on the colonic epithelium with consequences ranging from mild diarrhea to colonic perforation and death. A dysbiosis of the indigenous gut microbiota following antibiotic therapy is considered as a key factor for host susceptibility to CDI [3,4]. As a result of the high effectivity of intestinal microbiota transplantation (IMT), i.e., disease resolution in 92% of cases [7], there is a clear interplay between the gut microbiome and CDI. The underlying mechanisms by which the indigenous gut microbiota can inhibit CDI remain largely to be elucidated. There is a need for a further understanding of the mechanisms involved, which could provide a foundation for potential future microbiome-mediated therapies targeting CDI
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