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Ethanolamine is a valuable nutrient source that impacts Clostridium difficile pathogenesis.

ABSTRACT: Clostridium (Clostridioides) difficile is a gastrointestinal pathogen that colonizes the intestinal tract of mammals and can cause severe diarrheal disease. Although C. difficile growth is confined to the intestinal tract, our understanding of the specific metabolites and host factors that are important for the growth of the bacterium is limited. In other enteric pathogens, the membrane-derived metabolite, ethanolamine (EA), is utilized as a nutrient source and can function as a signal to initiate the production of virulence factors. In this study, we investigated the effects of ethanolamine and the role of the predicted ethanolamine gene cluster (CD1907-CD1925) on C. difficile growth. Using targeted mutagenesis, we disrupted genes within the eut cluster and assessed their roles in ethanolamine utilization, and the impact of eut disruption on the outcome of infection in a hamster model of disease. Our results indicate that the eut gene cluster is required for the growth of C. difficile on ethanolamine as a primary nutrient source. Further, the inability to utilize ethanolamine resulted in greater virulence and a shorter time to morbidity in the animal model. Overall, these data suggest that ethanolamine is an important nutrient source within the host and that, in contrast to other intestinal pathogens, the metabolism of ethanolamine by C. difficile can delay the onset of disease.

SUBMITTER: Nawrocki KL

PROVIDER: S-EPMC5903940 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Ethanolamine is a valuable nutrient source that impacts Clostridium difficile pathogenesis.

Nawrocki Kathryn L KL Wetzel Daniela D Jones Joshua B JB Woods Emily C EC McBride Shonna M SM

Environmental microbiology 20180209 4

Clostridium (Clostridioides) difficile is a gastrointestinal pathogen that colonizes the intestinal tract of mammals and can cause severe diarrheal disease. Although C. difficile growth is confined to the intestinal tract, our understanding of the specific metabolites and host factors that are important for the growth of the bacterium is limited. In other enteric pathogens, the membrane-derived metabolite, ethanolamine (EA), is utilized as a nutrient source and can function as a signal to initia ...[more]

PMID: 29349925

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Project description:Clostridium difficile is the largest single cause of hospital-acquired infection in the United States. A major risk factor for Clostridium difficile infection (CDI) is prior exposure to antibiotics, as they disrupt the gut bacterial community which protects from C. difficile colonization. Multiple antibiotic classes have been associated with CDI susceptibility, many leading to distinct community structures stemming from variation in bacterial targets of action. These community structures present separate metabolic challenges to C. difficile. Therefore, we hypothesized that the pathogen adapts its physiology to the nutrients within different gut environments. Utilizing an in vivo CDI model, we demonstrated that C. difficile highly colonized ceca of mice pretreated with any of three antibiotics from distinct classes. Levels of C. difficile spore formation and toxin activity varied between animals based on the antibiotic pretreatment. These physiologic processes in C. difficile are partially regulated by environmental nutrient concentrations. To investigate metabolic responses of the bacterium in vivo, we performed transcriptomic analysis of C. difficile from ceca of infected mice across pretreatments. This revealed heterogeneous expression in numerous catabolic pathways for diverse growth substrates. To assess which resources C. difficile exploited, we developed a genome-scale metabolic model with a transcriptome-enabled metabolite scoring algorithm integrating network architecture. This platform identified nutrients that C. difficile used preferentially between pretreatments, which were validated through untargeted mass spectrometry of each microbiome. Our results supported the hypothesis that C. difficile inhabits alternative nutrient niches across cecal microbiomes with increased preference for nitrogen-containing carbon sources, particularly Stickland fermentation substrates and host-derived glycans. IMPORTANCE Infection by the bacterium Clostridium difficile causes an inflammatory diarrheal disease which can become life threatening and has grown to be the most prevalent nosocomial infection. Susceptibility to C. difficile infection is strongly associated with previous antibiotic treatment, which disrupts the gut microbiota and reduces its ability to prevent colonization. In this study, we demonstrated that C. difficile altered pathogenesis between hosts pretreated with antibiotics from separate classes and exploited different nutrient sources across these environments. Our metabolite score calculation also provides a platform to study nutrient requirements of pathogens during an infection. Our results suggest that C. difficile colonization resistance is mediated by multiple groups of bacteria competing for several subsets of nutrients and could explain why total reintroduction of competitors through fecal microbial transplant currently is the most effective treatment for recurrent CDI. This work could ultimately contribute to the identification of targeted, context-dependent measures that prevent or reduce C. difficile colonization, including pre- and probiotic therapies.

Project description:BackgroundClostridium difficile is a major identifiable and treatable cause of antibiotic-associated diarrhea. Poor nutritional status contributes to mortality through weakened host defenses against various pathogens. The primary goal of this study was to assess the contribution of a reduced protein diet to the outcomes of C. difficile infection in a murine model.MethodsC57BL/6 mice were fed a traditional house chow or a defined diet with either 20% protein or 2% protein and infected with C. difficile strain VPI10463. Animals were monitored for disease severity, clostridial shedding and fecal toxin levels. Select intestinal microbiota were measured in stool and C. difficile growth and toxin production were quantified ex vivo in intestinal contents from untreated or antibiotic-treated mice fed with the different diets.ResultsC. difficile infected mice fed with defined diets, particularly (and unexpectedly) with protein deficient diet, had increased survival, decreased weight loss, and decreased overall disease severity. C. difficile shedding and toxin in the stool of the traditional diet group was increased compared with either defined diet 1 day post infection. Mice fed with traditional diet had an increased intestinal Firmicutes to Bacteroidetes ratio following antibiotic exposure compared with either a 2% or 20% protein defined nutrient diet. Ex vivo inoculation of cecal contents from antibiotic-treated mice showed decreased toxin production and C. difficile growth in both defined diets compared with a traditional diet.ConclusionsLow protein diets, and defined nutrient diets in general, were found to be protective against CDI in mice. Associated diet-induced alterations in intestinal microbiota may influence colonization resistance and clostridial toxin production in a defined nutrient diet compared to a traditional diet, leading to increased survival. However, mechanisms which led to survival differences between 2% and 20% protein defined nutrient diets need to be further elucidated.

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Ethanolamine is a valuable nutrient source that impacts Clostridium difficile pathogenesis.

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Ethanolamine is a valuable nutrient source that impacts Clostridium difficile pathogenesis.

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