The Toxin-Producing Pathobiont Klebsiella oxytoca Is Not Associated with Flares of Inflammatory Bowel Diseases

Zollner‐Schwetz, Ines; Herzog, Kathrin; Feierl, Gebhard; Leitner, Eva; Schneditz, Georg; Sprenger, Hanna; Prattes, Juergen; Petritsch, Wolfgang; Wenzl, H; Kump, Patrizia; Gorkiewicz, Gregor; Zechner, Ellen L.; Högenauer, Christoph

doi:10.1007/s10620-015-3765-y

Cited by 16 publications

(7 citation statements)

References 33 publications

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“… 10 A single case report has described K. ocytoca complicating a diagnosis of CD, 11 while stool samples from 235 patients with IBD identified 11 (4.7%) harboring K. ocytoca , among which 2 strains were toxigenic. 12 …”

Section: Discussionmentioning

confidence: 99%

Enteric infections complicating ulcerative colitis

et al. 2018

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Enteric infections have previously been postulated to play a role in the pathogenesis of inflammatory bowel disease (IBD), however, little evidence exists in the etiologic role of specific enteric infections in the development of IBD. When encountered in the setting of IBD, enteric infections pose a clinical challenge in management given the competing treatment strategies for infectious conditions and autoimmune disorders. Here we present the case of a young male with enteric infections complicating a new diagnosis of IBD. Our patient's initial clinical presentation included diagnoses of Klebsiella oxytoca isolation and Clostridium difficile infection. Directed therapies to include withdrawal of antibiotics and fecal microbiota transplantation were performed without resolution of clinical symptoms. Given persistence of symptoms and active colitis, the patient was diagnosed with ulcerative colitis (UC), requiring treatments directed at severe UC to include cyclosporine therapy. The finding of multiple enteric infections in a newly presenting patient with IBD is an unexpected finding that has treatment implications.

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Section: Discussionmentioning

confidence: 99%

Enteric infections complicating ulcerative colitis

et al. 2018

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“…The PBD tilivalline (TV, 1 ), is produced by Klebsiella oxytoca [ 22 – 24 ], a human gut pathobiont [ 25 , 26 ]. Klebsiella oxytoca shifts from an anti-inflammatory commensal to a pro-inflammatory pathobiont during antibiotic treatment [ 27 , 28 ]. When antibiotic driven enterobacterial overgrowth occurs and 1 is produced in higher amounts by Klebsiella oxytoca , activation of mucosal immune cells leads to a damage of the intestinal epithelium [ 24 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…Klebsiella oxytoca shifts from an anti-inflammatory commensal to a pro-inflammatory pathobiont during antibiotic treatment [ 27 , 28 ]. When antibiotic driven enterobacterial overgrowth occurs and 1 is produced in higher amounts by Klebsiella oxytoca , activation of mucosal immune cells leads to a damage of the intestinal epithelium [ 24 , 27 ]. This in turn increases intestinal permeability and chronic activation of the immune system resulting the pathology of antibiotic associated hemorrhagic colitis (AAHC) [ 28 – 31 ].…”

Section: Introductionmentioning

confidence: 99%

The benzodiazepine-like natural product tilivalline is produced by the entomopathogenic bacterium Xenorhabdus eapokensis

Wolff

Bode

2018

PLoS ONE

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The pyrrolobenzodiazepine tilivalline (1) was originally identified in the human gut pathobiont Klebsiella oxytoca, the causative agent of antibiotic-associated hemorrhagic colitis. Here we show the identification of tilivalline and analogs thereof in the entomopathogenic bacterium Xenorhabdus eapokensis as well as the identification of its biosynthesis gene cluster encoding a bimodular non-ribosomal peptide synthetase. Heterologous expression of both genes in E. coli resulted in the production of 1 and from mutasynthesis and precursor directed biosynthesis 11 new tilivalline analogs were identified in X. eapokensis. These results allowed the prediction of the tilivalline biosynthesis being similar to that in K. oxytoca.

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“…K. oxytoca is a pathobiont of the intestinal microbiota that can produce TV cytotoxin ( Beaugerie et al, 2003 ; Högenauer et al, 2006 ; Zollner-Schwetz et al, 2015 ; Glabonjat et al, 2021 ). After penicillin treatment, alteration of the enteric microbiota occurs, and overgrowth of K. oxytoca is originated in the colon causing a severe dysbiosis ( Schneditz et al, 2014 ; Hajishengallis and Lamont, 2016 ; Dornisch et al, 2017 ; von Tesmar et al, 2018 ; Alexander et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

cAMP Receptor Protein Positively Regulates the Expression of Genes Involved in the Biosynthesis of Klebsiella oxytoca Tilivalline Cytotoxin

et al. 2021

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Klebsiella oxytoca is a resident of the human gut. However, certain K. oxytoca toxigenic strains exist that secrete the nonribosomal peptide tilivalline (TV) cytotoxin. TV is a pyrrolobenzodiazepine that causes antibiotic-associated hemorrhagic colitis (AAHC). The biosynthesis of TV is driven by enzymes encoded by the aroX and NRPS operons. In this study, we determined the effect of environmental signals such as carbon sources, osmolarity, and divalent cations on the transcription of both TV biosynthetic operons. Gene expression was enhanced when bacteria were cultivated in tryptone lactose broth. Glucose, high osmolarity, and depletion of calcium and magnesium diminished gene expression, whereas glycerol increased transcription of both TV biosynthetic operons. The cAMP receptor protein (CRP) is a major transcriptional regulator in bacteria that plays a key role in metabolic regulation. To investigate the role of CRP on the cytotoxicity of K. oxytoca, we compared levels of expression of TV biosynthetic operons and synthesis of TV in wild-type strain MIT 09-7231 and a Δcrp isogenic mutant. In summary, we found that CRP directly activates the transcription of the aroX and NRPS operons and that the absence of CRP reduced cytotoxicity of K. oxytoca on HeLa cells, due to a significant reduction in TV production. This study highlights the importance of the CRP protein in the regulation of virulence genes in enteric bacteria and broadens our knowledge on the regulatory mechanisms of the TV cytotoxin.

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The Toxin-Producing Pathobiont Klebsiella oxytoca Is Not Associated with Flares of Inflammatory Bowel Diseases

Abstract: Our data demonstrate that toxin (tilivalline)-producing K. oxytoca is not associated with IBD flares.

Cited by 16 publications

References 33 publications

Enteric infections complicating ulcerative colitis

Enteric infections complicating ulcerative colitis

The benzodiazepine-like natural product tilivalline is produced by the entomopathogenic bacterium Xenorhabdus eapokensis

cAMP Receptor Protein Positively Regulates the Expression of Genes Involved in the Biosynthesis of Klebsiella oxytoca Tilivalline Cytotoxin

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