Microbiota transplantation restores normal fecal bile acid composition in recurrentClostridium difficileinfection

Fecal microbiota transplantation (FMT) has emerged as a highly effective therapy for refractory, recurrent Clostridium difficile infection (CDI), which develops following antibiotic treatments. Intestinal microbiota play a critical role in the metabolism of bile acids in the colon, which in turn have major effects on the lifecycle of C. difficile bacteria. We hypothesized that fecal bile acid composition is altered in patients with recurrent CDI and that FMT results in its normalization. General metabolomics and targeted bile acid analyses were performed on fecal extracts from patients with recurrent CDI treated with FMT and their donors. In addition, 16S rRNA gene sequencing was used to determine the bacterial composition of pre- and post-FMT fecal samples. Taxonomic bacterial composition of fecal samples from FMT recipients showed rapid change and became similar to the donor after the procedure. Pre-FMT fecal samples contained high concentrations of primary bile acids and bile salts, while secondary bile acids were nearly undetectable. In contrast, post-FMT fecal samples contained mostly secondary bile acids, as did non-CDI donor samples. Therefore, our analysis showed that FMT resulted in normalization of fecal bacterial community structure and metabolic composition. Importantly, metabolism of bile salts and primary bile acids to secondary bile acids is disrupted in patients with recurrent CDI, and FMT corrects this abnormality. Since individual bile salts and bile acids have pro-germinant and inhibitory activities, the changes suggest that correction of bile acid metabolism is likely a major mechanism by which FMT results in a cure and prevents recurrence of CDI.

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Temporal Fluctuations of Gut Microbiota and Bile Acid Metabolism in Critically Ill Children

10.21203/rs.3.rs-647124/v1 ◽

2021 ◽

Author(s):

Iain Robert Louis Kean ◽

Josef Wagner ◽

Anisha Wijeyesekera ◽

Marcus de Goffau ◽

Sarah Thurston ◽

...

Keyword(s):

Bile Acid ◽

Critical Illness ◽

Gut Microbiota ◽

Bile Acids ◽

Critically Ill ◽

Critically Ill Children ◽

Bile Acid Metabolism ◽

Rrna Gene ◽

Secondary Bile Acid ◽

Secondary Bile Acids

Abstract Background: Critical illness frequently requires the use of broad-spectrum antimicrobials to treat life-threatening infection. The resulting impact on microbiome diversity is profound, influencing gastrointestinal fermentation endpoints, host immune response and metabolic activity including the conversion of primary bile acids to secondary bile acids. We previously observed reduced fermentation capacity in the gut microbiota of critically ill children upon hospital admission, but the functional recovery trajectory of the paediatric gut microbiome during critical illness has not been well defined. Here, we longitudinally studied the intestinal microbiome and faecal bile acid profile of critically ill children during hospitalisation in a paediatric intensive care unit (PICU). The composition of the microbiome was determined by sequencing of the 16s rRNA gene, and bile acids were measured from faecal water by liquid chromatography hyphenated to mass spectrometry. Results: In comparison to admission faecal samples, members of Clostridium cluster XIVa and Lachnospiraceae recovered during the late-acute phase (days 8-10) of hospitalisation. Patients with infections had a lower proportion of Lachnospiraceae in their gut microbiota than control microbiota and patients with admitting diagnoses. The proportion of Recovery Associated Bacteria (RAB) was observed to decline with the length of PICU admission. Additionally, the proportions of RAB were reduced in those with systemic infection, respiratory failure, and undergoing surgery. Notably, Clostridioides were positively associated with the secondary bile acid deoxycholic acid, which we hypothesised to driven by secondary bile acid induced sporulation; the ratio of primary to secondary bile acids demonstrated recovery during critical illness. Conclusion: The recovery of secondary bile acids occurs quickly after intervention for critical illness. Bile acid recovery may be induced by the Lachnospiraceae , the composition of which shifts during critical illness. Our data suggest that gut health and early gut microbiota recovery can be assessed by readily quantifiable faecal bile acid profiles.

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Intestinal microbes affect bile acid metabolism involved in gallstone formation

10.21203/rs.2.17353/v1 ◽

2019 ◽

Author(s):

Qiang Wang ◽

Chenjun Hao ◽

Wenchao Yao ◽

Defu Zhu ◽

Haifeng Lu ◽

...

Keyword(s):

Bile Acid ◽

Gut Microbiota ◽

Bile Acids ◽

16S Rrna Gene Sequencing ◽

Bile Acid Metabolism ◽

Rrna Gene ◽

Intestinal Microbes ◽

Rrna Gene Sequencing ◽

Free Bile Acids ◽

Secondary Bile Acids

Abstract Background: The gut microbiota participates in the metabolism of substances and energy, promotes the development and maturation of the immune system, forms the mucosal barrier, and protects the host from pathogen attacks. Although the pathogenesis of cholesterol gallstones is still not clear, studies have suggested that gut microbiota dysbiosis plays an important role in their formation. Methods: Microbial DNA from faeces of normal control patients and those of patients with calculi was subjected to 16S rRNA gene sequencing to detect gene expression changes in intestinal microbes. ELISA kits were used to measure free bile acids, secondary bile acids and coprostanol according to the manufacturer’s instructions. The relationship between flora and their metabolites was then analysed. Results: In the gallstone group, the diversity of intestinal bacteria and the abundances of certain phylogroups were significantly decreased (p<0.05), especially Firmicutes (p<0.05), the largest phylum represented by the gut microbiota. This study found an increase in free bile acids (p<0.001) and secondary bile acids (p<0.01) in the enterohepatic circulation. Bile salt hydrolase activity was not related to the abundances of BSH-active bacteria. 7a-dehydroxylating gut bacteria were significantly increased (p<0.01), whereas cholesterol-lowering bacteria were significantly reduced (p<0.05). The Ruminococcus gnavus group could be used as a biomarker to distinguish the gallstone group from the control group. Conclusion: Substantial changes in the intestinal flora of patients with gallstones were observed, which affect cholesterol and bile acid metabolism and can lead to gallstones. Keywords: Gut microbiota, Gallstone, Bile acid, BSH, 16S rRNA gene sequencing

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The Gut Microbiota-Bile Acids-TGR5 Axis Mediates Eucommia ulmoides Leaf Extract Alleviation of Injury to Colonic Epithelium Integrity

Frontiers in Microbiology ◽

10.3389/fmicb.2021.727681 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhenya Zhai ◽

Kai-Min Niu ◽

Yichun Liu ◽

Chong Lin ◽

Xin Wu

Keyword(s):

Bile Acid ◽

Mrna Expression ◽

Bile Acids ◽

Intestinal Microbiota ◽

Cell Model ◽

16S Rrna Gene Sequencing ◽

Bile Acid Metabolism ◽

Rrna Gene ◽

Therapeutic Effects ◽

Eucommia Ulmoides

Eucommia ulmoides leaves (EL) are rich in phenolic acids and flavonoids, showing enhancing intestinal health effects. The intestinal microbiota-bile acid axis plays important roles in the occurrence and recovery of inflammatory bowel disease (IBD). However, whether EL extract (ELE) has regulatory effects on the intestinal microbiota, bile acid metabolism, and IBD is still unclear. To fill this gap, 2% dextran sulfate sodium (DSS)-induced mild IBD in a C57BL/6J mouse model that was treated with 200 or 400 mg/kg (intake dose/body weight) ELE was used. Oral ELE supplementation alleviated DSS-induced shortening of colon and colonic epithelial injury. Compared with the DSS group, ELE supplementation significantly decreased Toll-like receptor 4 (TLR4) and interlukin-6 (IL-6) and increased occludin and claudin-1 mRNA expression level in the colon (p < 0.05). Combined 16S rRNA gene sequencing and targeted metabolomic analyses demonstrated that ELE significantly improved the diversity and richness of the intestinal microbiota, decreased the abundance of Bacteroidaceae, and increased Akkermansiaceae and Ruminococcaceae abundance (p < 0.05) compared with DSS-induced IBD mice. Moreover, ELE significantly increased the serum contents of deoxycholic acid (DCA) and tauroursodeoxycholic acid (TUDCA), which were highly positively correlated with Akkermansia and unidentified_Ruminococccaceae relative to the DSS group. We then found that ELE increased Takeda G-protein coupled receptor 5 (TGR5), claudin-1, and occludin mRNA expression levels in the colon. In the Caco-2 cell model, we confirmed that activation of TGR5 improved the reduction in transepithelial electoral resistance (TEER) and decreased the permeability of FITC-dextran on monolayer cells induced by LPS (p < 0.05). siRNA interference assays showed that the decrease in TGR5 expression led to the decrease in TEER, an increase in FITC-dextran permeability, and a decrease in claudin-1 protein expression in Caco-2 cells. In summary, ELE alleviated IBD by influencing the intestinal microbiota structure and composition of bile acids, which in turn activated the colonic TGR5 gene expression in the colon and promoted the expression of tight junction proteins. These findings provide new insight for using ELE as a functional food with adjuvant therapeutic effects in IBD.

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The Microbiome in Functional Gastrointestinal Disorders Is Characterized by Bacteria and Genes Involved in Carbohydrate and Bile Acid Metabolism (OR23-01-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz040.or23-01-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Wayne Young ◽

Caterina Carco ◽

Jane Mullaney ◽

Paul Maclean ◽

Paul Cotter ◽

...

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Acid Metabolism ◽

Functional Gastrointestinal Disorders ◽

Functional Constipation ◽

Reference Database ◽

Bile Acid Metabolism ◽

Metagenomic Sequencing ◽

Fecal Samples ◽

Wide Range

Abstract Objectives Irritable Bowel Syndrome (IBS) is a functional gastrointestinal (GI) disorder featuring chronic or recurrent abdominal discomfort, usually with changes in GI habit. To improve our understanding of links between the microbiome and IBS, and how these links can be manipulated through diet, we undertook shotgun metagenomic sequencing of fecal samples from a case-control study. Methods Fecal samples from 172 individuals were analyzed by shotgun sequencing using the Illumina NextSeq platform. Of these, 77 were classified as controls, 16 were constipation-predominant IBS (IBS-C), 39 were diarrhea-predominant IBS (IBS-D), 29 were diagnosed with functional constipation (FC), and 11 had functional diarrhea (FD). Taxonomic classifications were determined using Metaxa2 and the SILVA 128 database. Gene functions were assigned by alignment of sequences against a protein reference database using DIAMOND. Mean relative abundance of bacterial taxa and functional genes were compared using permutation ANOVA. Ethical approval was obtained from the University of Otago Human Ethics Committee (Health) (Reference H16/094). Results Bacterial genera that discriminated case-controls (P < 0.05) from those with constipation (IBS-C + FC) and diarrhea (IBS-D + FD) included Megasphaera (increased in those with constipation), Blautia (increased in those with diarrhea), and Bilophila (increased in both constipation and diarrhea groups). Megasphaera and Blautia include bacteria that are bile-resistant and produce butyrate, possessing a wide range of Carbohydrate-Active enzymes. Bilophila are sulfite-reducing bacteria that are able to utilize bile-acids. Associated with these taxonomic differences, a wide range of genes involved in carbohydrate, energy, and amino acid metabolism differed significantly (P < 0.05), including some involved in taurine and glycine metabolism. Bile acids are conjugated with taurine or glycine in the liver, and these amino acids are removed by the action of members of the GI microbiota. Conclusions Results from our study suggest carbohydrate and bile acid metabolism by the GI microbiome may be important distinguishing characteristics in functional GI disorders. Funding Sources Funded by the New Zealand National Science Challenge High-Value Nutrition program.

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Identification of unique bile acid-metabolizing bacteria from the microbiome of centenarians

10.21203/rs.3.rs-115113/v1 ◽

2020 ◽

Author(s):

Kenya Honda ◽

Yuko Sato ◽

Koji Atarashi ◽

Damian Plichta ◽

Yasumichi Arai ◽

...

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Lithocholic Acid ◽

Multidrug Resistant ◽

Bile Acid Metabolism ◽

Critical Determinant ◽

Secondary Bile Acid ◽

Clostridioides Difficile ◽

Vancomycin Resistant ◽

Secondary Bile Acids

Abstract Centenarians, or individuals who have lived more than a century, represent the ultimate model of successful longevity associated with decreased susceptibility to ageing-associated illness and chronic inflammation. The gut microbiota is considered to be a critical determinant of human health and longevity. Here we show that centenarians (average 107 yo) have a distinct gut microbiome enriched in microbes capable of generating unique secondary bile acids, including iso-, 3-oxo-, and isoallo-lithocholic acid (LCA), as compared to elderly (85-89 yo) and young (21-55 yo) controls. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from a centenarian’s faecal microbiota, we identified Parabacteroides merdae and Odoribacteraceae strains as effective producers of isoalloLCA. Furthermore, we generated and tested mutant strains of P. merdae to show that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3βHSDH) were responsible for isoalloLCA production. This secondary bile acid derivative exerted the most potent antimicrobial effects among the tested bile acid compounds against gram-positive (but not gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and vancomycin-resistant Enterococcus faecium. These findings suggest that specific bile acid metabolism may be involved in reducing the risk of pathobiont infection, thereby potentially contributing to longevity.

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Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions

10.1101/782987 ◽

2019 ◽

Author(s):

Priyanka Baloni ◽

Cory C. Funk ◽

Jingwen Yan ◽

James T. Yurkovich ◽

Alexandra Kueider-Paisley ◽

...

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Metabolic Networks ◽

Cholesterol Metabolism ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Bile Acid Metabolism ◽

Post Mortem Brain ◽

The Brain ◽

Secondary Bile Acids

AbstractAlzheimer’s disease (AD) is the leading cause of dementia, with metabolic dysfunction seen years before the emergence of clinical symptoms. Increasing evidence suggests a role for primary and secondary bile acids, the end-product of cholesterol metabolism, influencing pathophysiology in AD. In this study, we analyzed transcriptomes from 2114 post-mortem brain samples from three independent cohorts and identified that the genes involved in alternative bile acid synthesis pathway was expressed in brain compared to the classical pathway. These results were supported by targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals. We reconstructed brain region-specific metabolic networks using data from three independent cohorts to assess the role of bile acid metabolism in AD pathophysiology. Our metabolic network analysis suggested that taurine transport, bile acid synthesis and cholesterol metabolism differed in AD and cognitively normal individuals. Using the brain transcriptional regulatory network, we identified putative transcription factors regulating these metabolic genes and influencing altered metabolism in AD. Intriguingly, we find bile acids from the brain metabolomics whose synthesis cannot be explained by enzymes we find in the brain, suggesting they may originate from an external source such as the gut microbiome. These findings motivate further research into bile acid metabolism and transport in AD to elucidate their possible connection to cognitive decline.

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Intestinal flora imbalance affects bile acid metabolism and is associated with gallstone formation

10.21203/rs.2.17353/v2 ◽

2020 ◽

Author(s):

Qiang Wang ◽

Chenjun Hao ◽

Wenchao Yao ◽

Defu Zhu ◽

Haifeng Lu ◽

...

Keyword(s):

Bile Acid ◽

Gut Microbiota ◽

Bile Acids ◽

Intestinal Flora ◽

Gallstone Formation ◽

Control Group ◽

Bile Acid Metabolism ◽

Intestinal Microbes ◽

Free Bile Acids ◽

Secondary Bile Acids

Abstract Background: The gut microbiota participates in the metabolism of substances and energy, promotes the development and maturation of the immune system, forms the mucosal barrier, and protects the host from pathogen attacks. Although the pathogenesis of cholesterol gallstones is still not clear, studies have suggested that gut microbiota dysbiosis plays an important role in their formation. Methods: Microbial DNA from faeces of normal control patients and those of patients with calculi was subjected to 16S rRNA gene sequencing to detect gene expression changes in intestinal microbes. ELISA kits were used to measure free bile acids, secondary bile acids and coprostanol according to the manufacturer’s instructions. The relationship between flora and their metabolites was then analysed. Results: In the gallstone group, the diversity of intestinal bacteria and the abundances of certain phylogroups were significantly decreased (p<0.05), especially Firmicutes (p<0.05), the largest phylum represented by the gut microbiota. This study found an increase in free bile acids (p<0.001) and secondary bile acids (p<0.01) in the enterohepatic circulation. Bile salt hydrolase activity was not related to the abundances of BSH-active bacteria. 7a-dehydroxylating gut bacteria were significantly increased (p<0.01), whereas cholesterol-lowering bacteria were significantly reduced (p<0.05). The Ruminococcus gnavus group could be used as a biomarker to distinguish the gallstone group from the control group. Conclusion: We conclude that intestinal flora imbalance affects bile acid and cholesterol metabolism and is associated with gallstone formation.

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The influence of probiotics on individual fecal secondary bile acid levels: a two-case study of schizophrenic patients receiving an atypical antipsychotic drug

Functional Foods in Health and Disease ◽

10.31989/ffhd.v7i11.384 ◽

2017 ◽

Vol 7 (11) ◽

pp. 849

Author(s):

Yosuke Saito ◽

Hiroyuki Nishimiya ◽

Yasue Kondo ◽

Toyoaki Sagae

Keyword(s):

Bile Acid ◽

Bile Salt ◽

Bile Acids ◽

Acid Metabolism ◽

Bile Acid Metabolism ◽

Bile Salt Hydrolase ◽

Atypical Antipsychotic Drug ◽

Secondary Bile Acid ◽

Secondary Bile Acids ◽

Bsh Activity

Background: Probiotics is used as a promising approach in the prevention and treatment of hypercholesterolemia. Modification of bile acid metabolism through the deconjugation of bile salts by microbial bile salt hydrolase (BSH) is considered to be the core mechanism of the hypocholesterolemic effects of probiotics. Nevertheless, BSH activity is reported to be detrimental to the human host due to the generation of toxic secondary bile acids. Thus, the influence of probiotic intake on bile acid metabolism needs to be elucidated. We analyzed the bile acid levels and microbiota in human fecal samples after probiotic supplementation to assess the influence of probiotic intake on fecal bile acid levels. Two patients hospitalized for schizophrenia and dyslipidemia, receiving an atypical antipsychotic drug, were enrolled in this study (Subjects A and B). Both subjects received Lactobacillus rhamnosus GG (LGG) for 4 weeks, and no probiotics for the following 4 weeks. Fecal samples were collected at baseline and after 4 and 8 weeks.Results: Conjugated bile acids may be modified by indigenous intestinal bacteria into unconjugated bile acids and secondary bile acids through deconjugation reactions by BSH activity and the subsequent 7a-dehydroxylation pathway, respectively. In the fecal microbiota from Subject A, the relative abundance of Bifidobacterium increased after LGG supplementation (30%–49%). Most Bifidobacterium and Lactobacillus strains that colonize mammalian intestines may report BSH activity, and in general bifidobacteria reveals a higher BSH activity than lactobacilli. The fecal unconjugated bile acid and secondary bile acid levels in Subject A increased after the LGG supplementation (0.36–1.79 and 1.82–16.19 mmol/g respectively). Although the LGG supplementation appears to promote bile acid deconjugation, most of the unconjugated bile acids in Subject A appear to have been modified into secondary bile acids. Alternatively, in Subject B there were no significant changes throughout the study.Conclusion: We observed a significant increase in the fecal secondary bile acid levels after probiotic administration in one of our cases. Further studies are needed to elucidate the factors affecting 7a-dehydroxylation of bile acids to confirm the safety of using probiotics.Keywords: bile salt hydrolase; BSH; dihydroxylation; Bifidobacterium

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Intestinal flora imbalance affects bile acid metabolism and is associated with gallstone formation.

10.21203/rs.2.17353/v3 ◽

2020 ◽

Author(s):

Qiang Wang ◽

Chenjun Hao ◽

Wenchao Yao ◽

Defu Zhu ◽

Haifeng Lu ◽

...

Keyword(s):

Bile Acid ◽

Gut Microbiota ◽

Bile Acids ◽

Intestinal Flora ◽

16S Rrna Gene Sequencing ◽

Gallstone Formation ◽

Rrna Gene ◽

Rrna Gene Sequencing ◽

Free Bile Acids ◽

Secondary Bile Acids

Abstract Background: The gut microbiota participates in the metabolism of substances and energy, promotes the development and maturation of the immune system, forms the mucosal barrier, and protects the host from pathogen attacks. Although the pathogenesis of cholesterol gallstones is still not clear, studies have suggested that gut microbiota dysbiosis plays an important role in their formation. Methods: Microbial DNA from faeces of normal control patients and those of patients with calculi was subjected to 16S rRNA gene sequencing to detect gene expression changes in intestinal microbes. ELISA kits were used to measure free bile acids, secondary bile acids and coprostanol according to the manufacturer’s instructions. The relationship between flora and their metabolites was then analysed. Results: In the gallstone group, the diversity of intestinal bacteria and the abundances of certain phylogroups were significantly decreased (p<0.05), especially Firmicutes (p<0.05), the largest phylum represented by the gut microbiota. This study found an increase in free bile acids (p<0.001) and secondary bile acids (p<0.01) in the enterohepatic circulation. Bile salt hydrolase activity was not related to the abundances of BSH-active bacteria. 7a-dehydroxylating gut bacteria were significantly increased (p<0.01), whereas cholesterol-lowering bacteria were significantly reduced (p<0.05). The Ruminococcus gnavus group could be used as a biomarker to distinguish the gallstone group from the control group. Conclusion: We conclude that intestinal flora imbalance affects bile acid and cholesterol metabolism and is associated with gallstone formation. Keywords: Gut microbiota, Gallstone, Bile acid, BSH, 16S rRNA gene sequencing

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