Abstract
Clostridium (Clostridioides) difficile infection (CDI) is associated with dysbiosis. C. difficile has a characteristic propensity to persist and recur 1 to 4 weeks after treatment, but the mechanism is unknown. We hypothesized that C. difficile may persist by manipulating the intestinal microenvironment, thereby hampering gut microbiota reconstitution following antibiotic-mediated dysbiosis. By screening stools from CDI patients for unique markers, a metabolite identified to be indole by mass spectrometry and Fourier transform infrared spectroscopy was identified. The average fecal indole concentration detected in CDI patients (n = 216; mean, 1,684.0 ± 84.4 µM) was significantly higher than in stools of patients with non-C. difficile diarrhea (n = 204; mean, 762.8 ± 53.8 µM). Certain intestinal bacteria, but not C. difficile, produce indole, a potent antimicrobial antioxidant. Remarkably, C. difficile induced other indole-producing gut microbes to produce increasing amounts of indole. Furthermore, a C. difficile accessory gene regulator 1 quorum sensing system mutant cannot induce indole, but complementation of the mutant strain with the wild-type gene restored its ability to induce indole production. Indole tolerance assays indicated that the amount of indole required to inhibit growth of most gut-protective bacteria was within the range detected in the CDI stools. We think that a high indole level limits the growth of beneficial indole-sensitive bacteria in the colon and alters colonization resistance and this might allow C. difficile to proliferate and persist. Together, these results reveal a unique mechanism of C. difficile persistence and provide insight into complex interactions and chemical warfare among the gut microbiota. IMPORTANCE Clostridium difficile infection is the leading cause of hospital-acquired and antibiotic-associated diarrhea worldwide. C. difficile flourishes in the colon after the diversity of the beneficial and protective gut microbiota have been altered by antibiotic therapy. C. difficile tends to persist, as does dysbiosis, encouraging recurrence a few days to weeks after treatment, and this further complicates treatment options. Here, we show that C. difficile might persist by manipulating the indigenous microbiota to produce indole, a bioactive molecule that inhibits the growth and reconstitution of the protective gut microbiota during infection. This discovery may explain a unique strategy C. difficile uses to control other bacteria in the colon and provide insight into the complex interactions and chemical warfare among the gut microbiota.
Highlights
Clostridium (Clostridioides) difficile infection (CDI) is associated with dysbiosis
Based on these initial results, we questioned whether indole levels in diarrhea stools of C. difficile infection (CDI) patients would be different from stools of diarrhea patients without CDI
We demonstrate that C. difficile induces indole production in other indole-producing bacteria
Summary
Clostridium (Clostridioides) difficile infection (CDI) is associated with dysbiosis. C. difficile has a characteristic propensity to persist and recur 1 to 4 weeks after treatment, but the mechanism is unknown. We show that C. difficile might persist by manipulating the indigenous microbiota to produce indole, a bioactive molecule that inhibits the growth and reconstitution of the protective gut microbiota during infection. This discovery may explain a unique strategy C. difficile uses to control other bacteria in the colon and provide insight into the complex interactions and chemical warfare among the gut microbiota. While spore formation is important in CDI recurrence, we hypothesized that C. difficile may persist by direct manipulation of the intestinal microenvironment to hamper reconstitution of the gut microbiota following antibioticassociated dysbiosis. Indole-3-aldehyde and indole-3-propionic acid, are produced by the gut commensals Lactobacillus spp. [17] and Clostridium sporogenes [18], respectively
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