Nextgeneration probiotics targeting Clostridium difficile through precursor-directed antimicrobial biosynthesis

Jennifer K. Spinler, Jennifer Auchtung, Aaron Brown, Prapaporn Boonma, Numan Oezguen, Caná L. Ross, Ruth Ann Luna, Jessica Runge, James Versalovic, Alex Peniche, Sara M. Dann, Robert A. Britton, Anthony Haag, Tor C. Savidge

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Integration of antibiotic and probiotic therapy has the potential to lessen the public health burden of antimicrobial-associated diseases. Clostridium difficile infection (CDI) represents an important example where the rational design of next-generation probiotics is being actively pursued to prevent disease recurrence. Because intrinsic resistance to clinically relevant antibiotics used to treat CDI (vancomycin, metronidazole, and fidaxomicin) is a desired trait in such probiotic species, we screened several bacteria and identified Lactobacillus reuteri to be a promising candidate for adjunct therapy. Human-derived L. reuteri bacteria convert glycerol to the broad-spectrum antimicrobial compound reuterin. When supplemented with glycerol, strains carrying the pocR gene locus were potent reuterin producers, with L. reuteri 17938 inhibiting C. difficile growth at a level on par with the level of growth inhibition by vancomycin. Targeted pocR mutations and complementation studies identified reuterin to be the precursor-induced antimicrobial agent. Pathophysiological relevance was demonstrated when the codelivery of L. reuteri with glycerol was effective against C. difficile colonization in complex human fecal microbial communities, whereas treatment with either glycerol or L. reuteri alone was ineffective. A global unbiased microbiome and metabolomics analysis independently confirmed that glycerol precursor delivery with L. reuteri elicited changes in the composition and function of the human microbial community that preferentially targets C. difficile outgrowth and toxicity, a finding consistent with glycerol fermentation and reuterin production. Antimicrobial resistance has thus been successfully exploited in the natural design of human microbiome evasion of C. difficile, and this method may provide a prototypic precursor-directed probiotic approach. Antibiotic resistance and substrate bioavailability may therefore represent critical new determinants of probiotic efficacy in clinical trials.

Original languageEnglish (US)
Article numbere00303-17
JournalInfection and immunity
Volume85
Issue number10
DOIs
StatePublished - 2017

Keywords

  • Antimicrobial resistance
  • Clostridium difficile
  • Lactobacillus reuteri
  • Next-generation probiotics
  • Reuterin

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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    Spinler, J. K., Auchtung, J., Brown, A., Boonma, P., Oezguen, N., Ross, C. L., Luna, R. A., Runge, J., Versalovic, J., Peniche, A., Dann, S. M., Britton, R. A., Haag, A., & Savidge, T. C. (2017). Nextgeneration probiotics targeting Clostridium difficile through precursor-directed antimicrobial biosynthesis. Infection and immunity, 85(10), [e00303-17]. https://doi.org/10.1128/IAI.00303-17