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.