Precision microbiome restoration of bile acid-mediated resistance to Clostridium difficile

By C. Buffie, V. Bucci, Richard R. Stein, Peter T. McKenney, Lilan Ling, Asia Gobourne, Daniel No, Hui Liu, Melissa A. Kinnebrew, A. Viale and 9 more. Nature, 2014

1,251 citations recorded by the source corpus.

The gastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute to health, including colonization resistance against intestinal pathogens. Many antibiotics destroy intestinal microbial communities and increase susceptibility to intestinal pathogens. Among these, Clostridium difficile, a major cause of antibiotic-induced diarrhoea, greatly increases morbidity and mortality in hospitalized patients. Which intestinal bacteria provide resistance to C. difficile infection and their in vivo inhibitory mechanisms remain unclear. Here we correlate loss of specific bacterial taxa with development of infection, by treating mice with different antibiotics that result in distinct microbiota changes and lead to varied susceptibility to C. difficile. Mathematical modelling augmented by analyses of the microbiota of hospitalized patients identifies resistance-associated bacteria common to mice and humans. Using these platforms, we determine that Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium, is associated with resistance to C. difficile infection and, upon administration, enhances resistance to infection in a secondary bile acid dependent fashion. Using a workflow involving mouse models, clinical studies, metagenomic analyses, and mathematical modelling, we identify a probiotic candidate that corrects a clinically relevant microbiome deficiency. These findings have implications for the rational design of targeted antimicrobials as well as microbiome-based diagnostics and therapeutics for individuals at risk of C. difficile infection.

Subfields: Gastroenterology, Infectious Diseases, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9209315f7ba053e1ec13a297a169c0d6602c86fe

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In Molecular Biology

1. H. Smidt
2. Ellen E. Blaak
3. Yang Xie
4. Nihal Hasan
5. J. Durack
6. S. Lynch
7. Hongyi Yang
8. John Penders

Citations in the corpus

• Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients (2017, methodology): “MSS has several advantages over the more commonly used 16S rRNA sequencing: 1) elimination of the PCR bias seen with 16S rRNA sequencing, where specific gut microbiota taxa can be either over- or underrepresented depending on the choice of primers and 16S rRNA variable region used for amplification ”
• Gut microbiome stability and resilience: elucidating the response to perturbations in order to modulate gut health (2020, background): “68 Antibiotics with strong and broad activity against anaerobes, such as ciprofloxacin and clindamycin, typically cause long-lasting effects on microbiota composition, for example with decrease in the relative abundance of Bifidobacterium in both treatments, as well as of Bacteroides in the…”
• The gut microbiome: Relationships with disease and opportunities for therapy (2018, background): “Germination and overgrowth of this pathogen are thought to be facilitated by a reduction of microbiota-derived secondary bile acid metabolites that inhibit spore germination (Buffie et al., 2015).”
• Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis (2015, neutral): “, 2011) and the severity of Clostridium difficile and Camphylobacter jejuni infections (Buffie et al., 2014; Malik-Kale et al., 2008).”
• Factors affecting the composition of the gut microbiota, and its modulation (2019, background): “difficile for essential nutrients (Buffie et al., 2015; Theriot et al., 2014), and this could prevent CDI.”