Inhibiting antibiotic-resistant Enterobacteriaceae by microbiota-mediated intracellular acidification

Matthew T. Sorbara, Krista Dubin, Eric R. Littmann, Thomas U. Moody, Emily Fontana, Ruth Seok, Ingrid M. Leiner, Ying Taur, Jonathan U. Peled, Marcel R.M. Van Den Brink, Yael Litvak, Andreas J Baumler, Jean Luc Chaubard, Amanda J. Pickard, Justin R. Cross, Eric G. Pamer

Research output: Contribution to journalArticle

25 Scopus citations

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 O 2 and NO 3 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.

Original languageEnglish (US)
Pages (from-to)84-98
Number of pages15
JournalJournal of Experimental Medicine
Volume216
Issue number1
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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