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Journal article
Bacterial Indole as a Multifunctional Regulator of Klebsiella oxytoca Complex Enterotoxicity
mBio, v 13(1), pp e0375221-e0375221
01 Jan 2022
PMID: 35073747
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Y Gastrointestinal microbes respond to biochemical metabolites that coordinate their behaviors. Here, we demonstrate that bacterial indole functions as a multifactorial mitigator of Klebsiella grimontii and Klebsiella oxytoca pathogenicity. These closely related microbes produce the enterotoxins tilimycin and tilivalline; cytotoxin-producing strains are the causative agent of antibiotic-associated hemorrhagic colitis and have been associated with necrotizing enterocolitis of premature infants. We demonstrate that carbohydrates induce cytotoxin synthesis while concurrently repressing indole biosynthesis. Conversely, indole represses cytotoxin production. In both cases, the alterations stemmed from differential transcription of npsA and npsB, key genes involved in tilimycin biosynthesis. Indole also enhances conversion of tilimycin to tilivalline, an indole analog with reduced cytotoxicity. In this context, we established that tilivalline, but not tilimycin, is a strong agonist of pregnane X receptor (PXR), a master regulator of xenobiotic detoxification and intestinal inflammation. Tilivalline binding upregulated PXR-responsive detoxifying genes and inhibited tubulin-directed toxicity. Bacterial indole, therefore, acts in a multifunctional manner to mitigate cytotoxicity by Klebsiella spp.: suppression of toxin production, enhanced conversion of tilimycin to tilivalline, and activation of PXR.
IMPORTANCE The human gut harbors a complex community of microbes, including several species and strains that could be commensals or pathogens depending on context. The specific environmental conditions under which a resident microbe changes its relationship with a host and adopts pathogenic behaviors, in many cases, remain poorly understood. Here, we describe a novel communication network involving the regulation of K. grimontii and K. oxytoca enterotoxicity. Bacterial indole was identified as a central modulator of these colitogenic microbes by suppressing bacterial toxin (tilimycin) synthesis and converting tilimycin to tilivalline while simultaneously activating a host receptor, PXR, as a means of mitigating tissue cytotoxicity. On the other hand, fermentable carbohydrates were found to inhibit indole biosynthesis and enhance toxin production. This integrated network involving microbial, host, and metabolic factors provides a contextual framework to better understand K. oxytoca complex pathogenicity.
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Details
- Title
- Bacterial Indole as a Multifunctional Regulator of Klebsiella oxytoca Complex Enterotoxicity
- Creators
- Nagender Ledala - University of Connecticut Health CenterMishika Malik - University of Connecticut Health CenterKarim Rezaul - University of Connecticut Health CenterSara Paveglio - University of Connecticut Health CenterAnthony Provatas - University of ConnecticutAaron Kiel - University of Connecticut Health CenterMelissa Caimano - University of Connecticut Health CenterYanjiao Zhou - University of Connecticut Health CenterJonathan Lindgren - University of Connecticut Health CenterKristyna Krasulova - Palacký University, OlomoucPeter Illes - Palacký University, OlomoucZdenek Dvorak - Palacký University, OlomoucSandhya Kortagere - Drexel UniversitySabine Kienesberger - BioTechMed-GrazAmar Cosic - BioTechMed-GrazLisa Poeltl - Karl Franzens Univ Graz, Inst Mol Biosci, BioTechMed Graz, Graz, AustriaEllen L. Zechner - BioTechMed-GrazSubho Ghosh - Albert Einstein College of MedicineSridhar Mani - Albert Einstein College of MedicineJustin D. Radolf - University of Connecticut Health CenterAdam P. Matson - University of Connecticut Health Center
- Publication Details
- mBio, v 13(1), pp e0375221-e0375221
- Publisher
- Amer Soc Microbiology
- Number of pages
- 19
- Grant note
- Connecticut Children's Stevenson Fund for Microbiome Research BioTechMed Flagship "Secretome" W81XWH-17-1-0479 / Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program-Investigator Initiated Research Award DOC 50 / Austrian Science Fund (FWF) W901 / DK Molecular Enzymology; Austrian Science Fund (FWF) Connecticut Children's Department of Research 20-00449S / Czech Science Foundation; Grant Agency of the Czech Republic
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000766822800003
- Scopus ID
- 2-s2.0-85125860383
- Other Identifier
- 991019167815804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Microbiology