Inhibiting antibiotic-resistant Enterobacteriaceae by microbiota-mediated intracellular acidification
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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.
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Enterobacteriaceae expansion in the gut significantly increases the risk of bloodstream invasion, sepsis, and death.
“Moreover, Enterobacteriaceae expansion in the gut significantly increases the risk of bloodstream invasion, sepsis, and death (28).”
From Sepsis-Induced Gut Dysbiosis Mediates the Susceptibility to Sepsis-Associated Encephalopathy in Mice (2022) · cites this paper as [28]
Nonionized SCFAs can diffuse across the bacterial membrane and into the cytoplasm, where they dissociate into their ionized forms, lowering the intracellular pH and inhibiting the growth of susceptible bacteria, including antibiotic-resistant Enterobacteriaceae.
“For example, nonionized SCFAs can diffuse across the bacterial membrane and into the cytoplasm, where they dissociate into their ionized forms, lowering the intracellular pH and inhibiting the growth of susceptible bacteria, including antibiotic-resistant Enterobacteriaceae [37].”
From Role of the gut microbiota in nutrient competition and protection against intestinal pathogen colonization (2023) · cites this paper as [37]
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“Moreover, Enterobacteriaceae expansion in the gut significantly increases the risk of bloodstream invasion, sepsis, and death (28).”
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- Authors
- Sorbara, M. T., Dubin, K., Littmann, E. R., Moody, T. U., Fontana, E., Seok, R., Leiner, I. M., Taur, Y., Peled, J. U., van den Brink, M. R. M., Litvak, Y., Bäumler, A. J., Chaubard, J.-L., Pickard, A. J., Cross, J. R., & Pamer, E. G.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 4
- University of California, Davis (US)
- Corresponding author
- Sorbara, Matthew T.
- Pamer, Eric G.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2018-12-18
- Volume
- 216
- Issue
- 1
- Pages
- 84-98
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC6314524
- OpenAlex
- W2904430902
- Cited by
- 259
- References
- 46
- Citations by year
- 2026: 36 · 2025: 40 · 2024: 48 · 2023: 34 · 2022: 26 · 2021: 38 · 2020: 25 · 2019: 11
- FWCI
- 6.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- Canadian Institute of Health Research (FRN#152527)
- National Institutes of Health (R01 AI042135, AI095706, U01 AI124275, P30 CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
- Keywords
- Klebsiella pneumoniae, Escherichia coli, Proteus mirabilis, gut microbiota, short-chain fatty acids, intracellular acidification, antibiotic-induced microbiota depletion, bacterial clearance, sepsis, nitrate respiration, oxygen respiration
- MeSH terms
- Gastrointestinal Microbiome, Animals, Colon, Enterobacteriaceae, Enterobacteriaceae Infections, Fatty Acids, Female, Humans, Hydrogen-Ion Concentration, Male, Drug Resistance, Bacterial, Mice
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