Abstract
ABSTRACT Susceptibility of patients to antibiotic-associated C. difficile disease is intimately associated with specific changes to gut microbiome composition. In particular, loss of microbes that modify bile salt acids (BSA) play a central role; primary bile acids stimulate spore germination whilst secondary bile acids limit C. difficile vegetative growth. To determine the relative contribution of bile salt (BS) metabolism on C. difficile disease severity, we treated mice with three combinations of antibiotics prior to infection. Mice given clindamycin alone became colonized but displayed no tissue pathology while severe disease, exemplified by weight loss and inflammatory tissue damage occurred in animals given a combination of five antibiotics and clindamycin. Animals given only the five antibiotic cocktails showed only transient colonization and no disease. C. difficile colonization was associated with a reduction in bacterial diversity, an inability to amplify bile salt hydrolase (BSH) sequences from fecal DNA and a relative increase in primary bile acids (pBA) in cecal lavages from infected mice. Further, the link between BSA modification and the microbiome was confirmed by the isolation of strains of Lactobacillus murinus that modified primary bile acids in vitro, thus preventing C. difficile germination. Interestingly, BSH activity did not correlate with disease severity which appeared linked to alternations in mucin, which may indirectly lead to increased exposure of the epithelial surface to inflammatory signals. These data confirm the role of microbial metabolic activity in protection of the gut and highlights the need for greater understanding the function of bacterial communities in disease prevention.
Highlights
Clostridiodes difficile is a disease of the gut microbiome with onset associated with the use of antibiotics[1] that reduce bacterial diversity within the colon
These animals were subsequently orally challenged with 1 × 105 C. difficile B-I7 spores and animals monitored for changes in behavior, appearance, and weight loss; animals showing a drop in weight of greater than 15% were culled
The transition to the mouse from the hamster has been achieved through the identification of antibiotic regimens that allow for the study of both colonization and disease.[15,29]
Summary
Clostridiodes difficile is a disease of the gut microbiome with onset associated with the use of antibiotics[1] that reduce bacterial diversity within the colon. It is the leading cause of antibiotic-associated diarrhea (AAD) and the main cause of pseudomembranous colitis (PMC).[2] Further, a significant number of patients suffer relapsing disease[3,4,5] following cessation of antibiotics (metronidazole and vancomycin) used in treatment Such episodes reflect persistent disruption of the microbiota, creating an environment in which the pathogen can flourish.[6,7] restoration of microbiota diversity has become the focus for new treatments including fecal microbiota transplantation (FMT),[8,9] defined bacterial therapies[10,11,12] and more recently sterile fecal filtrate transfer (FFT).[13] these approaches frequently restore microbial diversity within the niche and eliminate disease, the long-term consequences of using undefined microbial therapies on long-term health, is not yet clear. Several groups have shown that specified cocktails of bacterial species may be sufficient to limit disease, at least in mice[11,15] and whilst knowledge of the identity of key players is increasing,[11] for such therapies to be successful and safe, it is important
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