Abstract
Disruption of the human gut microbiota by antibiotics can lead to Clostridium difficile (CD)-associated diarrhea. CD overgrowth and elevated CD toxins result in gut inflammation. Herein, we report that a gut symbiont, Bacteroides thetaiotaomicron (BT), suppressed CD toxin production. The suppressive components are present in BT culture supernatant and are both heat- and proteinase K-resistant. Transposon-based mutagenesis indicated that the polysaccharide metabolism of BT is involved in the inhibitory effect. Among the genes identified, we focus on the methylerythritol 4-phosphate pathway gene gcpE, which supplies the isoprenoid backbone to produce the undecaprenyl phosphate lipid carrier that transports oligosaccharides across the membrane. Polysaccharide fractions prepared from the BT culture suppressed CD toxin production in vitro; the inhibitory effect of polysaccharide fractions was reduced in the gcpE mutant (ΔgcpE). The inhibitory effect of BT-derived polysaccharide fraction was abrogated by lysozyme treatment, indicating that cellwall-associated glycans are attributable to the inhibitory effect. BT-derived polysaccharide fraction did not affect CD toxin gene expression or intracellular toxin levels. An autolysis assay showed that CD cell autolysis was suppressed by BT-derived polysaccharide fraction, but the effect was reduced with that of ΔgcpE. These results indicate that cell wall-associated glycans of BT suppress CD toxin release by inhibiting cell autolysis.
Highlights
Clostridium difficile (CD) is a Gram-positive, spore-forming, rod-shaped anaerobe
We examined the effect of Bacteroides spp. on the toxigenicity of CD and found that B. thetaiotaomicron suppressed CD toxin production
We first examined the effect of Bacteroides species on CD toxin production
Summary
Clostridium difficile (CD) is a Gram-positive, spore-forming, rod-shaped anaerobe. CD is a leading cause of nosocomial infectious diarrhea, especially in elderly patients at hospitals and nursing homes [1]. The human gut harbors diverse and numerous microbes that deeply associate with host physiology This ecosystem provides beneficial effects to the host such as energy extraction from otherwise indigestible dietary polysaccharides, gut immune system maturation, and colonization resistance to enteric pathogens. Antibiotic treatment compromises gut microbiota function and is recognized as the most important risk factor for CDAD [20]. The reduced colonization resistance caused by antibiotic therapy allows CD to overgrow, which increases the toxin level in the gut. The therapeutic efficacy of FMT has been reported at over 90% [26], indicating that restoration of the gut microbiota function is essential for remission from recurrent CDAD. It has been reported that the related species B. fragilis prevents CD infection by facilitating the restoration of gut barrier function and microbiota composition [29]. We report how this gut symbiont affects the toxin production of CD
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