Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis

Significance The human gut microbiota is a complex community of microbes with enormous metabolic potential. Recognition of the significance of bacterial metabolites in mediating host interactions and the impact of perturbations of this ecosystem on human health has increased dramatically. Antibiotic...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2014-09, Vol.111 (36), p.13181-13186
Main Authors: Schneditz, Georg, Rentner, Jana, Roier, Sandro, Pletz, Jakob, Herzog, Kathrin A. T., Bücker, Roland, Troeger, Hanno, Schild, Stefan, Weber, Hansjörg, Breinbauer, Rolf, Gorkiewicz, Gregor, Högenauer, Christoph, Zechner, Ellen L.
Format: Article
Language:English
Subjects:
Actinobacteria - metabolism
Animals
Anti-Bacterial Agents - adverse effects
Antibiotics
Apoptosis
Apoptosis - drug effects
Benzodiazepinones - toxicity
Biological Sciences
Caspase 3 - metabolism
Colitis
Colitis - chemically induced
Colitis - pathology
Cytotoxins
Cytotoxins - toxicity
Enterotoxins - toxicity
Epithelial cells
Epithelial Cells - drug effects
Epithelial Cells - microbiology
Epithelial Cells - pathology
Humans
Infections
Inflammatory bowel disease
Klebsiella oxytoca
Klebsiella oxytoca - genetics
Metabolic diseases
Mice, Inbred C57BL
Microbiota
Molecular Sequence Data
Multigene Family
Pathogenesis
Penicillins - pharmacology
Peptide Synthases - metabolism
Peptides
Peptides - toxicity
Ribosomes
Toxicity
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Summary:Significance The human gut microbiota is a complex community of microbes with enormous metabolic potential. Recognition of the significance of bacterial metabolites in mediating host interactions and the impact of perturbations of this ecosystem on human health has increased dramatically. Antibiotic therapy eliminates not only pathogens but also some of the commensal enteric microbiota, sometimes leading to inflammation and diarrhea. Understanding how microbial imbalance actually causes disease is challenging. This study reveals how a gut resident is able to cause colitis during penicillin therapy. We show that a pyrrolobenzodiazepine metabolite produced by Klebsiella oxytoca directly damages the intestinal epithelium and disrupts its protective barrier function. The enterotoxicity of tilivalline provides a mechanism for antibiotic-induced colitis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1403274111