scholarly journals Association between Pre-Diagnostic Serum Bile Acids and Hepatocellular Carcinoma: The Singapore Chinese Health Study

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2648
Author(s):  
Claire E. Thomas ◽  
Hung N. Luu ◽  
Renwei Wang ◽  
Guoxiang Xie ◽  
Jennifer Adams-Haduch ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Bile Acid ◽  
Bile Acids ◽  
Chenodeoxycholic Acid ◽  
Conditional Logistic Regression ◽  
Health Study ◽  
Bile Acid Metabolism ◽  
Increased Risk ◽  
Singapore Chinese ◽  
Secondary Bile Acids

Hepatocellular carcinoma (HCC) is a commonly diagnosed malignancy with poor prognosis. Rising incidence of HCC may be due to rising prevalence of metabolic dysfunction-associated fatty liver disease, where altered bile acid metabolism may be implicated in HCC development. Thirty-five bile acids were quantified using ultra-performance liquid chromatography triple-quadrupole mass spectrometry assays in pre-diagnostic serum of 100 HCC cases and 100 matched controls from the Singapore Chinese Health Study. Conditional logistic regression was used to assess associations for bile acid levels with risk of HCC. Conjugated primary bile acids were significantly elevated whereas the ratios of secondary bile acids over primary bile acids were significantly lower in HCC cases than controls. The respective odds ratios and 95% confidence intervals of HCC were 6.09 (1.75–21.21) for highest vs. lowest tertile of cholic acid species and 30.11 (5.88–154.31) for chenodeoxycholic acid species. Doubling ratio of taurine-over glycine-conjugated chenodeoxycholic acid was associated significantly with 40% increased risk of HCC whereas doubling ratio of secondary over primary bile acid species was associated with 30–40% reduced risk of HCC. In conclusion, elevated primary bile acids and taurine over glycine-conjugated ratios were strongly associated with HCC risk whereas the ratios of secondary bile acids over primary bile acids were inversely associated with HCC risk.

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

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.

scholarly journals Microbiota transplantation restores normal fecal bile acid composition in recurrentClostridium difficileinfection

2014 ◽  
Vol 306 (4) ◽  
pp. G310-G319 ◽  
Author(s):  
Alexa R. Weingarden ◽  
Chi Chen ◽  
Aleh Bobr ◽  
Dan Yao ◽  
Yuwei Lu ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Composition ◽  
Bile Salts ◽  
Bile Acid Metabolism ◽  
Rrna Gene ◽  
Fecal Bile Acid ◽  
Bacterial Composition ◽  
Fecal Samples ◽  
Secondary Bile Acids

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.

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

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.

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

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.

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

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.

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

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

scholarly journals Clostridium scindensATCC 35704: Integration of Nutritional Requirements, the Complete Genome Sequence, and Global Transcriptional Responses to Bile Acids

2019 ◽  
Vol 85 (7) ◽  
Author(s):  
Saravanan Devendran ◽  
Rachana Shrestha ◽  
João M. P. Alves ◽  
Patricia G. Wolf ◽  
Lindsey Ly ◽  
...  
Keyword(s):  
Bile Acid ◽  
Amino Acid ◽  
Bile Acids ◽  
Cholic Acid ◽  
Acid Metabolism ◽  
Deoxycholic Acid ◽  
Nutritional Requirements ◽  
Bile Acid Metabolism ◽  
Content Type ◽  
Secondary Bile Acids

ABSTRACTIn the human gut,Clostridium scindensATCC 35704 is a predominant bacterium and one of the major bile acid 7α-dehydroxylating anaerobes. While this organism is well-studied relative to bile acid metabolism, little is known about the basic nutrition and physiology ofC. scindensATCC 35704. To determine the amino acid and vitamin requirements ofC. scindens, the leave-one-out (one amino acid group or vitamin) technique was used to eliminate the nonessential amino acids and vitamins. With this approach, the amino acid tryptophan and three vitamins (riboflavin, pantothenate, and pyridoxal) were found to be required for the growth ofC. scindens. In the newly developed defined medium,C. scindensfermented glucose mainly to ethanol, acetate, formate, and H2.The genome ofC. scindensATCC 35704 was completed through PacBio sequencing. Pathway analysis of the genome sequence coupled with transcriptome sequencing (RNA-Seq) under defined culture conditions revealed consistency with the growth requirements and end products of glucose metabolism. Induction with bile acids revealed complex and differential responses to cholic acid and deoxycholic acid, including the expression of potentially novel bile acid-inducible genes involved in cholic acid metabolism. Responses to toxic deoxycholic acid included expression of genes predicted to be involved in DNA repair, oxidative stress, cell wall maintenance/metabolism, chaperone synthesis, and downregulation of one-third of the genome. These analyses provide valuable insight into the overall biology ofC. scindenswhich may be important in treatment of disease associated with increased colonic secondary bile acids.IMPORTANCEC. scindensis one of a few identified gut bacterial species capable of converting host cholic acid into disease-associated secondary bile acids such as deoxycholic acid. The current work represents an important advance in understanding the nutritional requirements and response to bile acids of the medically important human gut bacterium,C. scindensATCC 35704. A defined medium has been developed which will further the understanding of bile acid metabolism in the context of growth substrates, cofactors, and other metabolites in the vertebrate gut. Analysis of the complete genome supports the nutritional requirements reported here. Genome-wide transcriptomic analysis of gene expression in the presence of cholic acid and deoxycholic acid provides a unique insight into the complex response ofC. scindensATCC 35704 to primary and secondary bile acids. Also revealed are genes with the potential to function in bile acid transport and metabolism.

scholarly journals Intestinal microbes affect bile acid metabolism involved in gallstone formation

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

scholarly journals Impaired absorption of cholesterol and bile acids in patients with an ileoanal anastomosis

Gut ◽  
1997 ◽  
Vol 41 (6) ◽  
pp. 771-777 ◽  
Author(s):  
K Hakala ◽  
M Vuoristo ◽  
P Luukkonen ◽  
H J Järvinen ◽  
T A Miettinen
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Metabolism ◽  
Saturation Index ◽  
Low Density Lipoprotein ◽  
Ileoanal Anastomosis ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Bile Acid Metabolism ◽  
Secondary Bile Acids

Background—No data exist on cholesterol absorption in patients with an ileoanal anastomosis (IAA).Aims—To study cholesterol absorption and its effects on cholesterol and bile acid metabolism in patients with an IAA.Patients and methods—Cholesterol absorption, and serum, biliary, and faecal lipids were studied in 24 patients with an IAA and 20 controls.Results—Fractional cholesterol absorption was significantly lower in the patients (36% versus 47% in controls). Surprisingly, the calculated intestinal influx of endogenous cholesterol was reduced so that the absolute absorption of cholesterol was decreased; elimination of cholesterol as faecal neutral steroids remained normal. Thus, the slightly increased cholesterol synthesis was mainly due to increased faecal bile acid excretion, which, in turn, was associated with reduced absorption and biliary secretion of bile acids. Serum total and low density lipoprotein (LDL) cholesterol and LDL triglycerides were lower in the patients. Molar percentage and saturation index of biliary cholesterol were slightly higher in patients with an IAA. Proportions of secondary bile acids in bile and faeces were diminished, and faecal unidentified bile acids were higher in patients.Conclusions—Cholesterol absorption is significantly impaired in patients with an IAA, and is closely related to changes in serum and biliary lipids observed in these patients.

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