Dataset Information

Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection.

ABSTRACT: Antibiotics can have significant and long-lasting effects on the gastrointestinal tract microbiota, reducing colonization resistance against pathogens including Clostridium difficile. Here we show that antibiotic treatment induces substantial changes in the gut microbial community and in the metabolome of mice susceptible to C. difficile infection. Levels of secondary bile acids, glucose, free fatty acids and dipeptides decrease, whereas those of primary bile acids and sugar alcohols increase, reflecting the modified metabolic activity of the altered gut microbiome. In vitro and ex vivo analyses demonstrate that C. difficile can exploit specific metabolites that become more abundant in the mouse gut after antibiotics, including the primary bile acid taurocholate for germination, and carbon sources such as mannitol, fructose, sorbitol, raffinose and stachyose for growth. Our results indicate that antibiotic-mediated alteration of the gut microbiome converts the global metabolic profile to one that favours C. difficile germination and growth.

SUBMITTER: Theriot CM

PROVIDER: S-EPMC3950275 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection.

Theriot Casey M CM Koenigsknecht Mark J MJ Carlson Paul E PE Hatton Gabrielle E GE Nelson Adam M AM Li Bo B Huffnagle Gary B GB Z Li Jun J Young Vincent B VB

Nature communications 20140101

Antibiotics can have significant and long-lasting effects on the gastrointestinal tract microbiota, reducing colonization resistance against pathogens including Clostridium difficile. Here we show that antibiotic treatment induces substantial changes in the gut microbial community and in the metabolome of mice susceptible to C. difficile infection. Levels of secondary bile acids, glucose, free fatty acids and dipeptides decrease, whereas those of primary bile acids and sugar alcohols increase, r ...[more]

PMID: 24445449

Similar Datasets

Project description:Antibiotics alter the gut microbiota and decrease resistance to Clostridium difficile colonization; however, the mechanisms driving colonization resistance are not well understood. Loss of resistance to C. difficile colonization due to antibiotic treatment is associated with alterations in the gut metabolome, specifically, with increases in levels of nutrients that C. difficile can utilize for growth in vitro. To define the nutrients that C. difficile requires for colonization and pathogenesis in vivo, we used a combination of mass spectrometry and RNA sequencing (RNA Seq) to model the gut metabolome and C. difficile transcriptome throughout an acute infection in a mouse model at the following time points: 0, 12, 24, and 30 h. We also performed multivariate-based integration of the omics data to define the signatures that were most important throughout colonization and infection. Here we show that amino acids, in particular, proline and branched-chain amino acids, and carbohydrates decrease in abundance over time in the mouse cecum and that C. difficile gene expression is consistent with their utilization in vivo. This was also reinforced by the multivariate-based integration of the omics data where we were able to discriminate the metabolites and transcripts that support C. difficile physiology between the different time points throughout colonization and infection. This report illustrates how important the availability of amino acids and other nutrients is for the initial stages of C. difficile colonization and progression of disease. Future studies identifying the source of the nutrients and engineering bacteria capable of outcompeting C. difficile in the gut will be important for developing new targeted bacterial therapeutics. IMPORTANCE Clostridium difficile is a bacterial pathogen of global significance that is a major cause of antibiotic-associated diarrhea. Antibiotics deplete the indigenous gut microbiota and change the metabolic environment in the gut to one favoring C. difficile growth. Here we used metabolomics and transcriptomics to define the gut environment after antibiotics and during the initial stages of C. difficile colonization and infection. We show that amino acids, in particular, proline and branched-chain amino acids, and carbohydrates decrease in abundance over time and that C. difficile gene expression is consistent with their utilization by the bacterium in vivo. We employed an integrated approach to analyze the metabolome and transcriptome to identify associations between metabolites and transcripts. This highlighted the importance of key nutrients in the early stages of colonization, and the data provide a rationale for the development of therapies based on the use of bacteria that specifically compete for nutrients that are essential for C. difficile colonization and disease.

Project description:Clostridium difficile is currently the leading cause of nosocomial infection. Antibiotics remain the first-line therapy for C. difficile-associated diseases (CDAD), despite the risks of resistance promotion and further gut microbiota perturbation. Notably, the abundance of Bacteroides fragilis was reported to be significantly decreased in CDAD patients. This study aimed to clarify the prophylactic effects of B. fragilis strain ZY-312 in a mouse model of C. difficile infection (CDI). The CDI mouse model was successfully created using C. difficile strain VPI 10463 spores, as confirmed by lethal diarrhea (12.5% survival rate), serious gut barrier disruption, and microbiota disruption. CDI model mice prophylactically treated with B. fragilis exhibited significantly higher survival rates (100% in low dosage group, 87.5% in high dosage group) and improved clinical manifestations. Histopathological analysis of colon and cecum tissue samples revealed an intact gut barrier with strong ZO-1 and Muc-2 expression. The bacterial diversity and relative abundance of gut microbiota were significantly improved. Interestingly, the relative abundance of Akkermansia muciniphila was positively correlated with B. fragilis treatment. In vitro experiments showed that B. fragilis inhibited C. difficile adherence, and attenuated the decrease in CDI-induced transepithelial electrical resistance, ZO-1 and MUC-2 loss, and apoptosis, suggesting that B. fragilis protected against CDI possibly by resisting pathogen colonization and improving gut barrier integrity and functions. In summary, B. fragilis exerted protective effects on a CDI mouse model by modulating gut microbiota and alleviating barrier destruction, thereby relieving epithelial stress and pathogenic colitis triggered by C. difficile. This study provides an alternative preventative measure for CDI and lays the foundations for further investigations of the relationships among opportunistic pathogens, commensal microbiota, and the gut barrier.

Dataset Information

Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection.

Publications

Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets