Strain-Dependent Inhibition of Clostridioides difficile by Commensal Clostridia Carrying the Bile Acid-Inducible (bai) Operon
- 31 May 2020
- journal article
- research article
- Published by American Society for Microbiology in Journal of Bacteriology
- Vol. 202 (11)
- https://doi.org/10.1128/JB.00039-20
Abstract
Clostridioides difficile is one of the leading causes of antibiotic-associated diarrhea. Gut microbiota-derived secondary bile acids and commensal Clostridia that carry the bile acid-inducible (bai) operon are associated with protection from C. difficile infection (CDI), although the mechanism is not known. In this study, we hypothesized that commensal Clostridia are important for providing colonization resistance against C. difficile due to their ability to produce secondary bile acids, as well as potentially competing against C. difficile for similar nutrients. To test this hypothesis, we examined the abilities of four commensal Clostridia carrying the bai operon (Clostridium scindens VPI 12708, C. scindens ATCC 35704, Clostridium hiranonis, and Clostridium hylemonae) to convert cholate (CA) to deoxycholate (DCA) in vitro, and we determined whether the amount of DCA produced was sufficient to inhibit the growth of a clinically relevant C. difficile strain. We also investigated the competitive relationships between these commensals and C. difficile using an in vitro coculture system. We found that inhibition of C. difficile growth by commensal Clostridia supplemented with CA was strain dependent, correlated with the production of similar to 2 mM DCA, and increased the expression of bai operon genes. We also found that C. difficile was able to outcompete all four commensal Clostridia in an in vitro coculture system. These studies are instrumental in understanding the relationship between commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics. Future studies dissecting the regulation of the bai operon in vitro and in vivo and how this affects CDI will be important. IMPORTANCE Commensal Clostridia carrying the bai operon, such as C. scindens, have been associated with protection against CDI; however, the mechanism for this protection is unknown. Herein, we show four commensal Clostridia that carry the bai operon and affect C. difficile growth in a strain-dependent manner, with and without the addition of cholate. Inhibition of C. difficile by commensals correlated with the efficient conversion of cholate to deoxycholate, a secondary bile acid that inhibits C. difficile germination, growth, and toxin production. Competition studies also revealed that C. difficile was able to outcompete the commensals in an in vitro coculture system. These studies are instrumental in understanding the relationship between commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics.Keywords
Funding Information
- NIH (T32 GM008776, R35GM119438)
- HHS | NIH | National Institute of General Medical Sciences (R35GM119438)
This publication has 59 references indexed in Scilit:
- Treatment of First Recurrence of Clostridium difficile Infection: Fidaxomicin Versus VancomycinClinical Infectious Diseases, 2012
- Geneious Basic: An integrated and extendable desktop software platform for the organization and analysis of sequence dataBioinformatics, 2012
- Profound Alterations of Intestinal Microbiota following a Single Dose of Clindamycin Results in Sustained Susceptibility to Clostridium difficile-Induced ColitisInfection and Immunity, 2012
- BLAST Ring Image Generator (BRIG): simple prokaryote genome comparisonsBMC Genomics, 2011
- Chenodeoxycholate Is an Inhibitor of Clostridium difficile Spore GerminationJournal of Bacteriology, 2009
- Bile Salts and Glycine as Cogerminants for Clostridium difficile SporesJournal of Bacteriology, 2008
- Mechanism of Growth Inhibition by Free Bile Acids in Lactobacilli and BifidobacteriaJournal of Bacteriology, 2006
- Assignment of Eubacterium sp. VPI 12708 and related strains with high bile acid 7alpha-dehydroxylating activity to Clostridium scindens and proposal of Clostridium hylemonae sp. nov., isolated from human faeces.International Journal of Systematic and Evolutionary Microbiology, 2000
- Gapped BLAST and PSI-BLAST: a new generation of protein database search programsNucleic Acids Research, 1997
- The Amino Acid-fermenting ClostridiaJournal of General Microbiology, 1971