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Inhibiting antibiotic-resistant Enterobacteriaceae by microbiota-mediated intracellular acidification.

ABSTRACT: Klebsiella pneumoniae, Escherichia coli, and other members of the Enterobacteriaceae family are common human pathogens that have acquired broad antibiotic resistance, rendering infection by some strains virtually untreatable. Enterobacteriaceae are intestinal residents, but generally represent <1% of the adult colonic microbiota. Antibiotic-mediated destruction of the microbiota enables Enterobacteriaceae to expand to high densities in the colon, markedly increasing the risk of bloodstream invasion, sepsis, and death. Here, we demonstrate that an antibiotic-naive microbiota suppresses growth of antibiotic-resistant clinical isolates of Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis by acidifying the proximal colon and triggering short chain fatty acid (SCFA)-mediated intracellular acidification. High concentrations of SCFAs and the acidic environment counter the competitive edge that O2 and NO3 respiration confer upon Enterobacteriaceae during expansion. Reestablishment of a microbiota that produces SCFAs enhances clearance of Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis from the intestinal lumen and represents a potential therapeutic approach to enhance clearance of antibiotic-resistant pathogens.

SUBMITTER: Sorbara MT

PROVIDER: S-EPMC6314524 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Inhibiting antibiotic-resistant Enterobacteriaceae by microbiota-mediated intracellular acidification.

Sorbara Matthew T MT Dubin Krista K Littmann Eric R ER Moody Thomas U TU Fontana Emily E Seok Ruth R Leiner Ingrid M IM Taur Ying Y Peled Jonathan U JU van den Brink Marcel R M MRM Litvak Yael Y Bäumler Andreas J AJ Chaubard Jean-Luc JL Pickard Amanda J AJ Cross Justin R JR Pamer Eric G EG

The Journal of experimental medicine 20181218 1

<i>Klebsiella pneumoniae</i>, <i>Escherichia coli</i>, and other members of the Enterobacteriaceae family are common human pathogens that have acquired broad antibiotic resistance, rendering infection by some strains virtually untreatable. Enterobacteriaceae are intestinal residents, but generally represent <1% of the adult colonic microbiota. Antibiotic-mediated destruction of the microbiota enables Enterobacteriaceae to expand to high densities in the colon, markedly increasing the risk of blo ...[more]

PMID: 30563917

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Project description:BackgroundThe human intestinal microbiome is a complex community that contributes to host health and disease. In addition to normal microbiota, pathogens like carbapenem-resistant Enterobacteriaceae may be asymptomatically present. When these bacteria are present at very low levels, they are often undetectable in hospital surveillance cultures, known as occult or subclinical colonization. Through the receipt of antibiotics, these subclinical pathogens can increase to sufficiently high levels to become detectable, in a process called outgrowth. However, little is known about the interaction between gut microbiota and Enterobacteriaceae during occult colonization and outgrowth.ResultsWe developed a clinically relevant mouse model for studying occult colonization. Conventional wild-type mice without antibiotic pre-treatment were exposed to Klebsiella pneumoniae but rapidly tested negative for colonization. This occult colonization was found to perturb the microbiome as detected by both 16S rRNA amplicon and shotgun metagenomic sequencing. Outgrowth of occult K. pneumoniae was induced either by a four-antibiotic cocktail or by individual receipt of ampicillin, vancomycin, or azithromycin, which all reduced overall microbial diversity. Notably, vancomycin was shown to trigger K. pneumoniae outgrowth in only a subset of exposed animals (outgrowth-susceptible). To identify factors that underlie outgrowth susceptibility, we analyzed microbiome-encoded gene functions and were able to classify outgrowth-susceptible microbiomes using pathways associated with mRNA stability. Lastly, an evolutionary approach illuminated the importance of xylose metabolism in K. pneumoniae colonization, supporting xylose abundance as a second susceptibility indicator. We showed that our model is generalizable to other pathogens, including carbapenem-resistant Escherichia coli and Enterobacter cloacae.ConclusionsOur modeling of occult colonization and outgrowth could help the development of strategies to mitigate the risk of subsequent infection and transmission in medical facilities and the wider community. This study suggests that microbiota mRNA and small-molecule metabolites may be used to predict outgrowth-susceptibility. Video Abstract.

Dataset Information

Inhibiting antibiotic-resistant Enterobacteriaceae by microbiota-mediated intracellular acidification.

Publications

Inhibiting antibiotic-resistant Enterobacteriaceae by microbiota-mediated intracellular acidification.

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