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 language | American English |
|---|---|
| Pages (from-to) | 84-98 |
| Number of pages | 15 |
| Journal | Journal of Experimental Medicine |
| Volume | 216 |
| Issue number | 1 |
| DOIs | |
| State | Published - 1 Jan 2019 |
| Externally published | Yes |
Bibliographical note
Funding Information:M.T. Sorbara is supported by a Canadian Institute of Health Research Fellowship (FRN#152527). E.G. Pamer has received funding from National Institutes of Health grants R01 AI042135, AI095706, U01 AI124275, and P30 CA008748.
Funding Information:
The pKD46-arr-3 plasmid was a gift from Dr. L. Chen (Rutgers New Jersey Medical School, Newark, NJ). The pGFPRO1 plasmid was a gift from Dr. J.L. Slonczewski (Kenyon College, Gambier, OH). M.T. Sorbara is supported by a Canadian Institute of Health Research Fellowship (FRN#152527). E.G. Pamer has received funding from National Institutes of Health grants R01 AI042135, AI095706, U01 AI124275, and P30 CA008748. J.U. Peled receives research support and licensing fees from Seres Therapeutics. M.R.M. van den Brink has received speaker honoraria from Flagship Ventures, Novartis, Evelo, Jazz Pharmaceuticals, Therakos, Amgen, Merck & Co. Inc., and Acute Leukemia Forum; is an advisor for and receives research support and licensing fees from Seres Therapeutics; receives licensing fees from Juno Therapeutics; and serves on the DKMS Medical Council Board. E.G. Pamer has received speaker honoraria from Bristol Myers Squibb, Celgene, Seres Therapeutics, MedIm-mune, Novartis, and Ferring Pharmaceuticals and is an inventor on patent application no. WPO2015179437A1, entitled “Methods and compositions for reducing Clostridium difficile infection,” and no. WO2017091753A1, entitled “Methods and compositions for reducing vancomycin-resistant enterococci infection or colonization,” and holds patents that receive royalties from Seres Therapeutics. The authors declare no further competing financial interests.
Publisher Copyright:
© 2018 Sorbara et al.