Antibiotic-Induced Alterations of the Gut Microbiota Alter Secondary Bile Acid Production and Allow for Clostridium difficile Spore Germination and Outgrowth in the Large Intestine

Abstract

Antibiotics alter the gastrointestinal microbiota, allowing for Clostridium difficile infection, which is a significant public health problem. Changes in the structure of the gut microbiota alter the metabolome, specifically the production of secondary bile acids. Specific bile acids are able to initiate C. difficile spore germination and also inhibit C. difficile growth in vitro, although no study to date has defined physiologically relevant bile acids in the gastrointestinal tract. In this study, we define the bile acids C. difficile spores encounter in the small and large intestines before and after various antibiotic treatments. Antibiotics that alter the gut microbiota and deplete secondary bile acid production allow C. difficile colonization, representing a mechanism of colonization resistance. Multiple secondary bile acids in the large intestine were able to inhibit C. difficile spore germination and growth at physiological concentrations and represent new targets to combat C. difficile in the large intestine.

Community dynamics drive punctuated engraftment of the fecal microbiome following transplantation using freeze-dried, encapsulated fecal microbiota

“…12 In mouse models, antibiotic disruption of the colonic microbiota resulted in higher proportions of primary bile acids relative to secondary bile acids and this shift was correlated with greater colony formation from spores ex vivo. 19,20 Stepwise changes in the microbiota are potentially related to changes in bile acid metabolism that correspond with the delayed expansion of Bacteroidetes. The abundances of bile-acid metabolizing Firmicutes, including Clostridium XIVa, Blautia, and Clostridium XI, 21 were found to engraft quickly, and likely contributed to inhibition of C. difficile through the production of secondary bile acids.…”

The role of the microbiome in human health and disease: an introduction for clinicians

“…19 Some of these molecular species promote the germination of C difficile spores whereas others inhibit the growth of the vegetative form of the organism. [67][68][69] This understanding of molecular mechanism has led to the exploration of novel treatments. For example, because the pathogenesis of C difficile infection, and in particular recurrent infection, is associated with a loss of normal microbial diversity and function, microbiota replacement therapy including fecal microbiota transplantation is an active area of interest.…”

“…Multiple studies show that the intestinal microbiota of patients with IBD is distinct from that of people without IBD. [59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78] Studies of IBD were some of the first studies of disease that extensively used culture independent characterization of the intestinal microbiota to show an association between disease and an altered microbial community. Early studies used both 16S based sequencing methods and fluorescent in situ hybridization to show that the community structure found in patients with disease was distinct from that of controls.…”

Structural and functional features of small intestine mucous depending on quantitative and qualitative microbiota composition

“…При повному зникненні з пристінкового біотопу анаеробних представників родів Propionibacterium та Bacteroides на один-два порядки зростає кількість цукролітичних анаеробів Bifidobacterium та Lactobacillus. З літератур-них джерел відомо, що збільшення концен-трації облігатно-анаеробних цукролітичних бактерій у тонкій кишці може спонукати до передчасної декон'югації жовчних кислот і втрати їх з калом, утворення гідроокислів жирних і жовчних кислот [19]. В свою чергу надлишок жовчних кислот у товстій кишці посилює її моторику, викликає діарею та стеаторею, а їх дефіцит у тонкій кишці приз-водить до порушення всмоктування жиророз-чинних вітамінів і розвитку жовчнокам'яної хвороби .…”