Dataset Information

Functional Intestinal Bile Acid 7?-Dehydroxylation by Clostridium scindens Associated with Protection from Clostridium difficile Infection in a Gnotobiotic Mouse Model.

ABSTRACT: Bile acids, important mediators of lipid absorption, also act as hormone-like regulators and as antimicrobial molecules. In all these functions their potency is modulated by a variety of chemical modifications catalyzed by bacteria of the healthy gut microbiota, generating a complex variety of secondary bile acids. Intestinal commensal organisms are well-adapted to normal concentrations of bile acids in the gut. In contrast, physiological concentrations of the various intestinal bile acid species play an important role in the resistance to intestinal colonization by pathogens such as Clostridium difficile. Antibiotic therapy can perturb the gut microbiota and thereby impair the production of protective secondary bile acids. The most important bile acid transformation is 7?-dehydroxylation, producing deoxycholic acid (DCA) and lithocholic acid (LCA). The enzymatic pathway carrying out 7?-dehydroxylation is restricted to a narrow phylogenetic group of commensal bacteria, the best-characterized of which is Clostridium scindens. Like many other intestinal commensal species, 7-dehydroxylating bacteria are understudied in vivo. Conventional animals contain variable and uncharacterized indigenous 7?-dehydroxylating organisms that cannot be selectively removed, making controlled colonization with a specific strain in the context of an undisturbed microbiota unfeasible. In the present study, we used a recently established, standardized gnotobiotic mouse model that is stably associated with a simplified murine 12-species "oligo-mouse microbiota" (Oligo-MM¹²). It is representative of the major murine intestinal bacterial phyla, but is deficient for 7?-dehydroxylation. We find that the Oligo-MM¹² consortium carries out bile acid deconjugation, a prerequisite for 7?-dehydroxylation, and confers no resistance to C. difficile infection (CDI). Amendment of Oligo-MM¹² with C. scindens normalized the large intestinal bile acid composition by reconstituting 7?-dehydroxylation. These changes had only minor effects on the composition of the native Oligo-MM¹², but significantly decreased early large intestinal C. difficile colonization and pathogenesis. The delayed pathogenesis of C. difficile in C. scindens-colonized mice was associated with breakdown of cecal microbial bile acid transformation.

SUBMITTER: Studer N

PROVIDER: S-EPMC5168579 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

Functional Intestinal Bile Acid 7α-Dehydroxylation by <i>Clostridium scindens</i> Associated with Protection from <i>Clostridium difficile</i> Infection in a Gnotobiotic Mouse Model.

Studer Nicolas N Desharnais Lyne L Beutler Markus M Brugiroux Sandrine S Terrazos Miguel A MA Menin Laure L Schürch Christian M CM McCoy Kathy D KD Kuehne Sarah A SA Minton Nigel P NP Stecher Bärbel B Bernier-Latmani Rizlan R Hapfelmeier Siegfried S

Frontiers in cellular and infection microbiology 20161220

Bile acids, important mediators of lipid absorption, also act as hormone-like regulators and as antimicrobial molecules. In all these functions their potency is modulated by a variety of chemical modifications catalyzed by bacteria of the healthy gut microbiota, generating a complex variety of secondary bile acids. Intestinal commensal organisms are well-adapted to normal concentrations of bile acids in the gut. In contrast, physiological concentrations of the various intestinal bile acid specie ...[more]

PMID: 28066726

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Project description:Clostridioides difficile infection (CDI) is a major health concern and one of the leading causes of hospital-acquired diarrhea in many countries. C. difficile infection is challenging to treat as C. difficile is resistant to multiple antibiotics. Alternative solutions are needed as conventional treatment with broad-spectrum antibiotics often leads to recurrent CDI. Recent studies have shown that specific microbiota-based therapeutics such as bile acids (BAs) are promising approaches to treat CDI. Clostridium scindens encodes the bile acid-induced (bai) operon that carries out 7-alpha-dehydroxylation of liver-derived primary BAs to secondary BAs. This biotransformation is thought to increase the antibacterial effects of BAs on C. difficile. Here, we used an automated multistage fermentor to study the antibacterial actions of C. scindens and BAs on C. difficile in the presence/absence of a gut microbial community derived from healthy human donor fecal microbiota. We observed that C. scindens inhibited C. difficile growth when the medium was supplemented with primary BAs. Transcriptomic analysis indicated upregulation of C. scindens bai operon and suppressed expression of C. difficile exotoxins that mediate CDI. We also observed BA-independent antibacterial activity of the secretome from C. scindens cultured overnight in a medium without supplementary primary BAs, which suppressed growth and exotoxin expression in C. difficile mono-culture. Further investigation of the molecular basis of our observation could lead to a more specific treatment for CDI than current approaches. IMPORTANCE There is an urgent need for new approaches to replace the available treatment options against Clostridioides difficile infection (CDI). Our novel work reports a bile acid-independent reduction of C. difficile growth and virulence gene expression by the secretome of Clostridium scindens. This potential treatment combined with other antimicrobial strategies could facilitate the development of alternative therapies in anticipation of CDI and in turn reduce the risk of antimicrobial resistance.

Dataset Information

Functional Intestinal Bile Acid 7?-Dehydroxylation by Clostridium scindens Associated with Protection from Clostridium difficile Infection in a Gnotobiotic Mouse Model.

Publications

Functional Intestinal Bile Acid 7α-Dehydroxylation by <i>Clostridium scindens</i> Associated with Protection from <i>Clostridium difficile</i> Infection in a Gnotobiotic Mouse Model.

Similar Datasets

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