In vitro and in vivo characterization of Clostridium scindens bile acid transformations

Abstract

The human gut hosts trillions of microorganisms that exert a profound influence on human biology. Gut bacteria communicate with their host by secreting small molecules that can signal to distant organs in the body. Bile acids are one class of these signaling molecules, synthesized by the host and chemically transformed by the gut microbiota. Among bile acid metabolizers, bile acid 7-dehydroxylating bacteria are commensals of particular importance as they carry out the 7-dehydroxylation of liver-derived primary bile acids to 7-dehydroxylated bile acids. The latter represents a major fraction of the secondary bile acid pool. The microbiology of this group of gut microorganisms is understudied and warrants more attention. Here, we detail the bile acid transformations carried out by the 7-dehydroxylating bacterium Clostridium scindens in vitro and in vivo. In vitro, C. scindens exhibits not only 7α-dehydroxylating capabilities but also, the ability to oxidize other hydroxyl groups and reduce ketone groups in primary and secondary bile acids. This study revealed 12-oxolithocholic acid as a major transient product in the 7α-dehydroxylation of cholic acid. Furthermore, the in vivo study included complementing a gnotobiotic mouse line (devoid of the ability to 7-dehydroxylate bile acids) with C. scindens and investigating its colonization dynamics and bile acid transformations. Using NanoSIMS (Nanoscale Secondary Ion Mass Spectrometry), we demonstrate that the large intestine constitutes a niche for C. scindens, where it efficiently 7-dehydroxylates cholic acid to deoxycholic acid. Overall, this work reveals a novel transient species during 7-dehydroxylation as well as provides direct evidence for the colonization and growth of 7-dehydroxylating bacteria in the large intestine.

Berberine alters gut microbial function through modulation of bile acids

“…Conversion of CDCA to a-and bmuricholic acid (MCA) was observed ( Figure S4), however little conversion of MCA to murideoxycholic acid (MDCA) and w-MCA was detected. This con rmed the mice in this study housed a microbial consortium of human bacteria, as only limited MDCA has been shown to be generated by the host [32], and human mixed fecal bacteria and bile acid 7a-dehydroxylating clostridia appear to be unable to metabolize MCA to MDCA and w-MCA [12,30,31].…”

Berberine alters gut microbial function through modulation of bile acids

“…Conversion of CDCA to α-and βmuricholic acid (MCA) was observed ( Figure S4); however, little conversion of MCA to murideoxycholic acid (MDCA) and ω-MCA was detected. This con rmed the mice in this study housed a microbial consortium of human bacteria, as human mixed fecal bacteria and bile acid 7α-dehydroxylating clostridia appear to be unable to metabolize MCA to MDCA and ω-MCA [11,[13][14][15]. Additionally, MDCA has been shown to be generated by the host [16].…”

Gut microbiome communication with bone marrow regulates susceptibility to amebiasis

“…This analysis also indicated enrichment of genes associated with CCAAT/enhancer-binding proteins, known to be important for GMP and neutrophil differentiation and expansion (refs. 30 , 31 and Supplemental Figure 3F ). Quantitative PCR of sorted marrow GMPs confirmed that significant changes in expression occurred in JMJD3 ( Supplemental Figure 3, C–E, G, J, and K ) and 2 CCAAT/enhancer-binding protein genes important in granulopoiesis ( 28 , 29 ), C/EBPA ( Supplemental Figure 3H ) and C/EBPB ( Supplemental Figure 3I ).…”