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JGM, Humans, Infant, Newborn, Klebsiella oxytoca, Enterotoxins, Enterocolitis, Pseudomembranous, Klebsiella Infections, Cytotoxins, Indoles

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mBio. 2022;13(1):e0375221.







This work was supported by funds from the Connecticut Children’s Department of Research (to A.P.M., M.C., and J.D.R.), the Connecticut Children’s Stevenson Fund for Microbiome Research (to A.P.M.), the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program—Investigator Initiated Research Award under award no. W81XWH-17-1-0479 (to S.M.), Czech Science Foundation grant 20-00449S (to Z.D.), the Austrian Science Fund (FWF) Molecular Metabolism (DOC 50 to E.L.Z.) and the DK Molecular Enzymology (W901 to E.L.Z.) and the BioTechMed Flagship “Secretome.”


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 differ- ential transcription of npsA and npsB, key genes involved in tilimycin biosynthesis. Indole also enhances conversion of tilimycin to tilivalline, an indole analog with reduced cytotox- icity. 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 inhib- ited tubulin-directed toxicity. Bacterial indole, therefore, acts in a multifunctional manner to mitigate cytotoxicity by Klebsiella spp.: suppression of toxin production, enhanced con- version of tilimycin to tilivalline, and activation of PXR.


This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.