Microbiota-derived genotoxin tilimycin generates colonic stem cell mutations

Pöltl, Lisa; Kitsera, Maksym; Raffl, Sandra; Schild, Stefan; Ćosić, Amar; Kienesberger, Sabine; Unterhauser, Katrin; Raber, Georg; Lembacher-Fadum, Christian; Breinbauer, Rolf; Gorkiewicz, Gregor; Sebastián, Carlos; Höefler, Gerald; Zechner, Ellen L.

doi:10.1016/j.celrep.2023.112199

Cited by 8 publications

(7 citation statements)

References 51 publications

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“…5e,f). TM causes DNA breakage in eukaryotic cells and several bacterial species 32,34,35 . To assess how S. Typhimurium responds to TM, we first performed scanning electron microscopy of the bacteria observing a significant toxin-dependent elongation in a subset of S. Typhimurium cells (Extended Data Fig.…”

Section: K Oxytoca Toxin Production Is Essential For the Inhibitionmentioning

confidence: 99%

“…til + KoSC strains have been identified as causative agents of a rare condition called antibiotic-associated haemorrhagic colitis [28][29][30] and were also associated with enterocolitis in premature infants 24,31 . In contrast to their well-described effects on mammalian cells [32][33][34] , the impact on the microbial community remained understudied. Notably, TM, but not TV, also exerts antimicrobial activity against a range of bacteria and promotes mutational evolution in co-resident opportunistic pathogens such as K. pneumoniae and E. coli 35 .…”

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confidence: 99%

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Klebsiella oxytoca inhibits Salmonella infection through multiple microbiota-context-dependent mechanisms

Osbelt,

Almási,

Wende

et al. 2024

Nat Microbiol

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The Klebsiella oxytoca species complex is part of the human microbiome, especially during infancy and childhood. K. oxytoca species complex strains can produce enterotoxins, namely, tilimycin and tilivalline, while also contributing to colonization resistance (CR). The relationship between these seemingly contradictory roles is not well understood. Here, by coupling ex vivo assays with CRISPR-mutagenesis and various mouse models, we show that K. oxytoca provides CR against Salmonella Typhimurium. In vitro, the antimicrobial activity against various Salmonella strains depended on tilimycin production and was induced by various simple carbohydrates. In vivo, CR against Salmonella depended on toxin production in germ-free mice, while it was largely toxin-independent in mice with residual microbiota. This was linked to the relative levels of toxin-inducing carbohydrates in vivo. Finally, dulcitol utilization was essential for toxin-independent CR in gnotobiotic mice. Together, this demonstrates that nutrient availability is key to both toxin-dependent and substrate-driven competition between K. oxytoca and Salmonella.

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Section: K Oxytoca Toxin Production Is Essential For the Inhibitionmentioning

confidence: 99%

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confidence: 99%

Klebsiella oxytoca inhibits Salmonella infection through multiple microbiota-context-dependent mechanisms

Osbelt,

Almási,

Wende

et al. 2024

Nat Microbiol

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“…These metabolites are causative agents of antibiotic-associated haemorrhagic colitis (AAHC; diffuse mucosal oedema, haemorrhagic erosions, bloody diarrhoea), with disease caused by the overgrowth of cytotoxin-producing strains secondary to the use of antibiotics [ 70 , 71 ]. A recent study in mice has demonstrated the DNA-alkylating metabolite TM causes the accumulation of mutations in cycling intestinal stem cells within weeks of a single K. oxytoca overgrowth, driving somatic changes that could hypothetically contribute to disease susceptibility in some preterm infants who are subject to transient ‘blooms’ of TM-producing bacteria in their gut [ 72 ]. We have identified strains of K. grimontii in the faecal microbiota of preterm infants that encode the BGC, along with metagenome-assembled genomes of K. michiganensis and K. oxytoca recovered from faecal samples of preterm infants [ 8 , 12 ].…”

Section: Virulence Of Klebsiella Spp and Cytotoxicitymentioning

confidence: 99%

“…Healthy infants (weeks 0–8 of life) in an Austrian cohort had a carriage rate of K. oxytoca sensu lato of 49–73%, with PCR-based assays leading to higher rates of detection than cultivation work; ∼50% of recovered isolates were cytotoxic, though it was noted that not all npsAB -positive strains produced cytotoxin as assessed by MTT and chemical analyses [ 74 ]. A recent study examined a published metagenomic dataset [ 75 ] derived from 829 faecal samples from 571 full-term infants born in the U.K. for the presence of K. oxytoca complex bacteria [ 72 ]. At days 7 and 21 of life, 76/504 (15%) and 74/325 (23%) samples, respectively, harboured toxigenic Klebsiella spp.…”

Section: Virulence Of Klebsiella Spp and Cytotoxicitymentioning

confidence: 99%

“…Of the complex-positive samples, 46/76 encoded the minimal til locus (BGC) at day 7 (in order of species prevalence: K. grimontii , n = 34/37; K. michiganensis , n = 4/25; K. oxytoca , n = 6/11; K. pasteurii , n = 2/3), with prevalence of each BGC-positive species increasing between days 7 and 21 of life (from 9.1 to 12.6%, n = 41/74). Across all BGC-positive samples, the relative abundance of BGC-encoding bacteria was high (range 0.92–94.1%, median 12.6%) [ 72 ]. No robust data are available for the gut carriage of K. oxytoca sensu lato (cytotoxic or otherwise) by preterm infants.…”

Section: Virulence Of Klebsiella Spp and Cytotoxicitymentioning

confidence: 99%

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The role of Klebsiella populations in preterm infants

McCartney

Hoyles

2023

Biochemical Society Transactions

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The preterm infant microbiota is dominated by Enterobacteriaceae (Escherichia, Klebsiella or Enterobacter spp.), Enterococcus and Staphylococcus spp. Recent work has demonstrated the development of this microbiota is predictable and driven by simple microbe–microbe interactions. Because of their systemic immaturity, including an underdeveloped immune system, preterm infants are susceptible to a range of infections. Numerous retrospective studies have examined the association of the preterm gut microbiota with diseases such as necrotizing enterocolitis (NEC), early-onset sepsis and late-onset sepsis. To date, no single bacterium has been associated with infection in these infants, but a Klebsiella/Enterococcus-dominated faecal microbiota is associated with an increased risk of developing NEC. Staphylococci aid and enterococci inhibit establishment/maintenance of gastrointestinal Klebsiella populations in preterm infants, though the mechanisms underlying these interactions are poorly understood. Klebsiella spp. recovered from healthy and sick preterm infants display similar antimicrobial resistance and virulence profiles, giving no clues as to why some infants develop potentially life-threatening diseases while others do not. The identification of cytotoxin-producing Klebsiella oxytoca sensu lato in the gut microbiota of some preterm infants has led to the suggestion that these bacteria may contribute to NEC in a subset of neonates. This mini review highlights current knowledge on Klebsiella spp. contributing to the preterm gut microbiota and provides insights into areas of research that warrant further attention.

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Microbiome in Colonic Carcinogenesis

Sun

Xia

2023

Comprehensive Physiology

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Microbiomes include bacteria, viruses, fungi, and other microbes. The microbiome modulates numerous aspects of host physiology and is critical in the pathophysiology of diseases, including colon cancer. Although gut bacterial pathogenesis has become an emerging area in colon cancer, the multi-kingdom aspect of microbiome has yet to be explored. Similar to the bacterial component of the microbiome, the virome contains certain makeup that varies between individuals. In the current review, we introduce the concepts of microbiome and microbiota, research history, methods for modern microbiome studies, and recent progress of mechanisms responsible for microbiome and virome in colon cancer. Furthermore, we discuss our understanding of microbial metabolites in the disease development and therapy of colon cancer. Finally, the gut microbiota can affect the efficacy and toxicity of cancer therapy. We discuss the challenges and future perspectives in microbiome and colon cancer. Exploring and understanding the mechanisms of microbiome will provide insights into effective approaches in potential prevention of treatment of colon cancer.

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Microbiota-derived genotoxin tilimycin generates colonic stem cell mutations

Cited by 8 publications

References 51 publications

Klebsiella oxytoca inhibits Salmonella infection through multiple microbiota-context-dependent mechanisms

Klebsiella oxytoca inhibits Salmonella infection through multiple microbiota-context-dependent mechanisms

The role of Klebsiella populations in preterm infants

Microbiome in Colonic Carcinogenesis

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