Identification and Characterization of Major Bile Acid 7α-Dehydroxylating Bacteria in the Human Gut

Kim, Kyung Hyun; Park, Dongbin; Jia, Baolei; Baek, Ju Hye; Hahn, Yoonsoo; Jeon, Che‐Ok

doi:10.1128/msystems.00455-22

Cited by 22 publications

(23 citation statements)

References 78 publications

(101 reference statements)

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“…3a, 3b). Proteocatella sphenisci has also been reported to encode the bai polycistronic operon (22,46), and our demonstration that P. sphenisci harbors baiP indicate that secondary allo-bile acids may constitute part of the bile acid metabolome of penguin guano (Fig. 3b).…”

Section: Resultssupporting

confidence: 59%

“…Taken together, the close phylogenetic clustering of BaiJ with BaiP indicates that the baiJ gene may also encode a bile acid 5ɑ-reductase isoform ( Fig. 3a, 3b ) (22, 44, 45).…”

Section: Resultsmentioning

confidence: 72%

“…1 ), and CDCA and ursodeoxycholic acid (UDCA; 3ɑ-,7β-dihydroxy-5β-cholan-24-oic acid) to LCA has been elucidated over the past three decades in strains of Lachnoclostridum scindens (formerly Clostridium scindens ), Peptacetobacter hiranonis (formerly Clostridium hiranonis ), and Lachnoclostridum hylemonae (formerly Clostridium hylemonae ) (21). Discovery and characterization of bai genes has allowed recent studies to extend the species distribution of 7-dehydroxylating bacteria into new families within the Firmicutes through bioinformatics-based searches of metagenomic sequence databases (22, 23). Similarly, comparison of the distribution of bai genes between fecal metagenomes obtained from healthy and disease cohorts has also enabled the association of the abundance of bai genes with risk for adenomatous polyps (24) or colorectal cancer (25).…”

Section: Introductionmentioning

confidence: 99%

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Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes

Lee

Cowley

Wolf

et al. 2022

Preprint

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The gut microbiome of vertebrates is capable of numerous biotransformations of bile acids, which are responsible for intestinal lipid digestion and function as key nutrient-signaling molecules. The human liver produces bile acids from cholesterol predominantly in the A/B-trans orientation in which the sterol rings are kinked, as well as small quantities of A/B-cis oriented flat stereoisomers known as primary allo-bile acids. While the complex multi-step bile acid 7α-dehydroxylation pathway has been well-studied for conversion of kinked primary bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA) to deoxycholic acid (DCA) and lithocholic acid (LCA), respectively, the enzymatic basis for the formation of flat stereoisomers allo-deoxycholic acid (allo-DCA) and allo-lithocholic acid (allo-LCA) by Firmicutes has remained unsolved for three decades. Here, we present a novel mechanism by which Firmicutes generate the flat bile acids allo-DCA and allo-LCA. The BaiA1 was shown to catalyze the final reduction from 3-oxo-allo-DCA to allo-DCA and 3-oxo-allo-LCA to allo-LCA. Phylogenetic and metagenomic analyses of human stool samples indicate that BaiP and BaiJ are encoded only in Firmicutes and differ from membrane-associated bile acid 5α-reductases recently reported in Bacteroidetes that indirectly generate allo-LCA from 3-oxo-Δ4-LCA. We further map the distribution of baiP and baiJ among Firmicutes in human metagenomes, demonstrating an increased abundance of the two genes in colorectal cancer (CRC) patients relative to healthy individuals.

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Section: Resultssupporting

confidence: 59%

“…Taken together, the close phylogenetic clustering of BaiJ with BaiP indicates that the baiJ gene may also encode a bile acid 5ɑ-reductase isoform ( Fig. 3a, 3b ) (22, 44, 45).…”

Section: Resultsmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes

Lee

Cowley

Wolf

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Previous work established bai genes in P. hiranonis , 45 although the present data provide first indication that P. hiranonis has the potential to form secondary allo-bile acids ( Figure 3a, 3b ). P. sphenisci has also been reported to encode the bai polycistronic operon, 21 , 22 and our demonstration that P. sphenisci harbors baiP indicate that secondary allo-bile acids may constitute part of the bile acid metabolome of penguin guano ( Figure 3b ).…”

Section: Phylogenetic Analysis Of Baip Followed By Functional Assay R...mentioning

confidence: 57%

“… 20 Discovery and characterization of bai genes have allowed recent studies to extend the species distribution of 7-dehydroxylating bacteria into new families within the Firmicutes through bioinformatics-based searches of metagenomic sequence databases. 21 , 22 Similarly, comparison of the distribution of bai genes between fecal metagenomes obtained from healthy and disease cohorts has also enabled the association of the abundance of bai genes with risk for adenomatous polyps 23 or colorectal cancer. 24 This agrees with bile acid metabolomic studies that demonstrate increased fecal and serum DCA and LCA derivatives in subjects at high risk for CRC.…”

Section: Introductionmentioning

confidence: 99%

Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes

et al. 2022

View full text Add to dashboard Cite

The gut microbiome of vertebrates is capable of numerous biotransformations of bile acids, which are responsible for intestinal lipid digestion and function as key nutrient-signaling molecules. The human liver produces bile acids from cholesterol predominantly in the A/B- cis orientation in which the sterol rings are “kinked”, as well as small quantities of A/B- trans oriented “flat” stereoisomers known as “primary allo-bile acids”. While the complex multi-step bile acid 7α-dehydroxylation pathway has been well-studied for conversion of “kinked” primary bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA) to deoxycholic acid (DCA) and lithocholic acid (LCA), respectively, the enzymatic basis for the formation of “flat” stereoisomers allo-deoxycholic acid (allo-DCA) and allo-lithocholic acid (allo-LCA) by Firmicutes has remained unsolved for three decades. Here, we present a novel mechanism by which Firmicutes generate the ”flat” bile acids allo-DCA and allo-LCA. The BaiA1 was shown to catalyze the final reduction from 3-oxo-allo-DCA to allo-DCA and 3-oxo-allo-LCA to allo-LCA. Phylogenetic and metagenomic analyses of human stool samples indicate that BaiP and BaiJ are encoded only in Firmicutes and differ from membrane-associated bile acid 5α-reductases recently reported in Bacteroidetes that indirectly generate allo-LCA from 3-oxo-Δ 4 -LCA. We further map the distribution of baiP and baiJ among Firmicutes in human metagenomes, demonstrating an increased abundance of the two genes in colorectal cancer (CRC) patients relative to healthy individuals.

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Tacrolimus Pharmacokinetics is Associated with Gut Microbiota Diversity in Kidney Transplant Patients: Results from a Pilot Cross‐Sectional Study

Degraeve,

Bindels,

Haufroid

et al. 2023

Clin Pharma and Therapeutics

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Clinical use of tacrolimus, an essential immunosuppressant following transplantation, is complexified by its high pharmacokinetic variability. The gut microbiota gains growing interest but limited investigations have evaluated its contribution to tacrolimus pharmacokinetics. Here, we explore the associations between the gut microbiota composition and tacrolimus pharmacokinetics. In this pilot cross‐sectional study (Clinicaltrial.gov NCT04360031), we recruited 93 CYP3A5 non‐expressers stabilized kidney transplant patients. Gut microbiota composition was characterized by 16S rRNA gene sequencing, tacrolimus pharmacokinetic parameters were computed, and additional demographical and medical covariates were collected. Associations between pharmacokinetic parameters or diabetic status and the gut microbiota composition, as reflected by α‐ and β‐diversity metrics, were evaluated. Patients with higher tacrolimus AUC/(dose/kg) had higher bacterial richness, and tacrolimus pharmacokinetic parameters were associated with specific bacterial taxa (e.g., Bilophila) and amplicon sequence variant (ASV) (e.g., ASV 1508 and ASV 1982 [Veillonella/unclassified Sporomusaceae]; ASV 664 [unclassified Oscillospiraceae]). Building a multiple linear regression model showed that ASV 1508 (co‐abundant with ASV 1982) and ASV 664 explained respectively 16.0% and 4.6% of the inter‐individual variability in tacrolimus AUC/(dose/kg) in CYP3A5 non‐expressers patients, when adjusting for haematocrit and age. Anaerostipes relative abundance was decreased in diabetic patients. Altogether, this pilot study revealed unprecedented links between the gut microbiota composition and diversity and tacrolimus pharmacokinetics in stable kidney transplant patients. It supports the relevance of studying the gut microbiota as an important contributor to tacrolimus pharmacokinetic variability. Elucidating the causal relationship will offer new perspectives to predict tacrolimus inter‐ and intra‐pharmacokinetic variability.

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Identification and Characterization of Major Bile Acid 7α-Dehydroxylating Bacteria in the Human Gut

Cited by 22 publications

References 78 publications

Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes

Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes

Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes

Tacrolimus Pharmacokinetics is Associated with Gut Microbiota Diversity in Kidney Transplant Patients: Results from a Pilot Cross‐Sectional Study

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