Aryl hydrocarbon receptor (AhR) activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) dose-dependently shifts the gut microbiome consistent with the progression of steatosis to steatohepatitis with fibrosis

Mapping Intimacies ◽

10.1101/2021.11.02.466980 ◽

2021 ◽

Author(s):

Russell R Fling ◽

Tim Zacharewski

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Acid Metabolism ◽

Lactobacillus Species ◽

Bile Acid Metabolism ◽

Bile Salt Hydrolase ◽

Metagenomic Sequencing ◽

Secondary Bile Acid ◽

Alcoholic Fatty Liver ◽

Dose Dependent

Gut dysbiosis with disrupted enterohepatic bile acid metabolism is commonly associated with non-alcoholic fatty liver disease (NAFLD) and recapitulated in a NAFLD-phenotype elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. TCDD induces hepatic fat accumulation and increases levels of secondary bile acids including taurolithocholic acid and deoxycholic acid, microbial modified bile acids involved in host bile acid regulation signaling pathways. To investigate the effects of TCDD on the gut microbiota, cecum contents of male C57BL/6 mice orally gavaged with sesame oil vehicle or 0.3, 3, or 30 µg/kg TCDD were examined using shotgun metagenomic sequencing. Taxonomic analysis identified dose-dependent increases in Lactobacillus species (i.e., Lactobacillus reuteri). Increased species were also associated with dose-dependent increases in bile salt hydrolase sequences, responsible for deconjugation reactions in secondary bile acid metabolism. Increased L. reuteri levels were further associated with mevalonate-dependent isopentenyl diphosphate (IPP) biosynthesis and menaquinone biosynthesis genes. Analysis of gut microbiomes from cirrhosis patients identified increased abundance of these pathways as identified in the mouse cecum metagenomic analysis. These results extend the association of lactobacilli with the AhR/intestinal axis in NAFLD progression and highlight the similarities between TCDD-elicited phenotypes in mice to human NAFLD.

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Aryl Hydrocarbon Receptor (AhR) Activation by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Dose-Dependently Shifts the Gut Microbiome Consistent with the Progression of Non-Alcoholic Fatty Liver Disease

International Journal of Molecular Sciences ◽

10.3390/ijms222212431 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12431

Author(s):

Russell R. Fling ◽

Timothy R. Zacharewski

Keyword(s):

Liver Disease ◽

Bile Acid ◽

Fatty Liver ◽

Bile Acids ◽

Fatty Liver Disease ◽

Acid Metabolism ◽

Bile Acid Metabolism ◽

Alcoholic Fatty Liver ◽

Dose Dependent ◽

Alcoholic Fatty Liver Disease

Gut dysbiosis with disrupted enterohepatic bile acid metabolism is commonly associated with non-alcoholic fatty liver disease (NAFLD) and recapitulated in a NAFLD-phenotype elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. TCDD induces hepatic fat accumulation and increases levels of secondary bile acids, including taurolithocholic acid and deoxycholic acid (microbial modified bile acids involved in host bile acid regulation signaling pathways). To investigate the effects of TCDD on the gut microbiota, the cecum contents of male C57BL/6 mice orally gavaged with sesame oil vehicle or 0.3, 3, or 30 µg/kg TCDD were examined using shotgun metagenomic sequencing. Taxonomic analysis identified dose-dependent increases in Lactobacillus species (i.e., Lactobacillus reuteri). Increased species were also associated with dose-dependent increases in bile salt hydrolase sequences, responsible for deconjugation reactions in secondary bile acid metabolism. Increased L. reuteri levels were further associated with mevalonate-dependent isopentenyl diphosphate (IPP) biosynthesis and o-succinylbenzoate synthase, a menaquinone biosynthesis associated gene. Analysis of the gut microbiomes from cirrhosis patients identified an increased abundance of genes from the mevalonate-dependent IPP biosynthesis as well as several other menaquinone biosynthesis genes, including o-succinylbenzoate synthase. These results extend the association of lactobacilli with the AhR/intestinal axis in NAFLD progression and highlight the similarities between TCDD-elicited phenotypes in mice to human NAFLD.

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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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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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Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles

Journal of Clinical Medicine ◽

10.3390/jcm11010004 ◽

2021 ◽

Vol 11 (1) ◽

pp. 4

Author(s):

Boyan Zhang ◽

Folkert Kuipers ◽

Jan Freark de de Boer ◽

Jan Albert Kuivenhoven

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Acid Metabolism ◽

Ldl Cholesterol ◽

Farnesoid X Receptor ◽

New Drugs ◽

Bile Acid Metabolism ◽

Atherosclerotic Cardiovascular Disease ◽

Faecal Excretion ◽

Alcoholic Fatty Liver

New drugs targeting bile acid metabolism are currently being evaluated in clinical studies for their potential to treat cholestatic liver diseases, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Changes in bile acid metabolism, however, translate into an alteration of plasma cholesterol and triglyceride concentrations, which may also affect cardiovascular outcomes in such patients. This review attempts to gain insight into this matter and improve our understanding of the interactions between bile acid and lipid metabolism. Bile acid sequestrants (BAS), which bind bile acids in the intestine and promote their faecal excretion, have long been used in the clinic to reduce LDL cholesterol and, thereby, atherosclerotic cardiovascular disease (ASCVD) risk. However, BAS modestly but consistently increase plasma triglycerides, which is considered a causal risk factor for ASCVD. Like BAS, inhibitors of the apical sodium-dependent bile acid transporter (ASBTi’s) reduce intestinal bile acid absorption. ASBTi’s show effects that are quite similar to those obtained with BAS, which is anticipated when considering that accelerated faecal loss of bile acids is compensated by an increased hepatic synthesis of bile acids from cholesterol. Oppositely, treatment with farnesoid X receptor agonists, resulting in inhibition of bile acid synthesis, appears to be associated with increased LDL cholesterol. In conclusion, the increasing efforts to employ drugs that intervene in bile acid metabolism and signalling pathways for the treatment of metabolic diseases such as NAFLD warrants reinforcing interactions between the bile acid and lipid and lipoprotein research fields. This review may be considered as the first step in this process.

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A9 BACTERIAL BILE SALT HYDROLASE GENE ABUNDANCE IS ASSOCIATED WITH RORC GENE EXPRESSION IN INTESTINAL MUCOSA OF INFLAMMATORY DISEASE PATIENTS

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwz047.008 ◽

2020 ◽

Vol 3 (Supplement_1) ◽

pp. 11-12

Author(s):

C Hernandez-Rocha ◽

K Borowski ◽

W Turpin ◽

M Smith ◽

J Stempak ◽

...

Keyword(s):

Gene Expression ◽

Bile Acid ◽

Bile Acids ◽

Acid Metabolism ◽

Bile Acid Metabolism ◽

Bile Salt Hydrolase ◽

Host Gene Expression ◽

Biopsy Site ◽

Endoscopic Score

Abstract Background The role of gut microbes involved in bile acid metabolism and their impact on mucosal immune regulation is beginning to be appreciated. For instance, changes in microbial bile salt hydrolase (BSH) activity which deconjugates bile acids in the gastrointestinal tract of gnotobiotic mice, significantly alters gene expression patterns of immune-related genes in ileum. Moreover, bile acid dysmetabolism may participate in the chronic inflammation loop of Inflammatory bowel disease (IBD). Aims We carried out an integrated mucosal microbiome-transcriptome analysis to elucidate associations between microbial bile-acid metabolizing function and host gene expression. Methods Crohn’s disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU) patients were recruited prior to scheduled colonoscopy performed as part of clinical care. Only patients with non-inflamed mucosa defined as a segmental simple endoscopic score 0–2 in CD and a segmental Mayo endoscopic score of 0 in UC/IBDU were included in this analysis to minimize the effect of inflammation on gene expression. Biopsy samples were obtained from terminal ileum, ascending colon and sigmoid colon, and microbial DNA and human RNA was extracted. V4 region of 16S rRNA gene was sequenced and the relative abundance of bile acid-metabolizing genes was inferred using PICRUSt. RNA-seq was used to sequence total human RNA and a supervised transcript reduction analysis focus upon 65 genes previously associated with bile acid metabolism and IBD was utilized. Associations between microbiome clusters of orthologous groups (COGs), transcriptome, diagnosis (CD vs UC/IBDU), and biopsy site were analyzed using linear mixed-effects model with lmer4 function in R. An adjusted-p value after false discovery rate correction < 0.05 was considered significant. Results A total of 126 samples from 86 subjects were analyzed corresponding to 35 CD and 51 UC/IBDU. Mean age for the total cohort was 34.7 ± 11 years and 35 (40.6%) were females. There was a significant negative correlation between relative abundance of bacterial bsh genes (COG3049) and human RORC gene (p < 0.03). This association was independent of type of diagnosis and biopsy site. There was no association among other analyzed bacterial COGs and host genes. Conclusions Using an integrative microbiome-host transcriptome approach, our data provide new evidence linking microbial bile acid deconjugation (bsh genes) and host gene expression in the mucosal-luminal interface in quiescent IBD-affected tissue. Nuclear receptor RORC is pivotal in the differentiation and function of innate lymphoid cells and T-helper 17 cells. Modulation of this pathway by bile acids or gut bacteria involved in their metabolism could shed light on the immune role of bile acids in IBD patients. Funding Agencies CAG, CIHRNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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Abstract 49: The Transcriptional Repressor MafG Regulates Cholesterol Catabolism

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.49 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Thomas Q de Aguiar Vallim ◽

Elizabeth J Tarling ◽

Hannah Ahn ◽

Lee R Hagey ◽

Casey E Romanoski ◽

...

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Acid Metabolism ◽

Metabolic Diseases ◽

Cholesterol Metabolism ◽

Transcriptional Repressor ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Bile Acid Metabolism ◽

Biliary Bile Acid

Elevated circulating cholesterol levels is a major risk factor for cardiovascular diseases (CVD), and therefore understanding pathways that affect cholesterol metabolism are important for potential treatment of CVD. The major route for cholesterol excretion is through its catabolism to bile acids. Specific bile acids are also potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis ( Cyp7a1 , Cyp8b1 ) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway, and modifies the biliary bile acid composition. In contrast, MafG loss-of-function studies cause de-repression of the bile acid genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-Seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR. The identification of this pathway will likely have important implications in metabolic diseases.

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Identification of bile acids in the serum and urine in cholestasis. Evidence for 6α-hydroxylation of bile acids in man

Biochemical Journal ◽

10.1042/bj1540507 ◽

1976 ◽

Vol 154 (2) ◽

pp. 507-516 ◽

Cited By ~ 88

Author(s):

J A. Summerfield ◽

B H. Billing ◽

C H. L. Shackleton

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Acid Metabolism ◽

Gas Chromatography Mass Spectrometry ◽

Acid Mixture ◽

Bile Acid Metabolism ◽

Hyodeoxycholic Acid ◽

Normal Man ◽

Hyocholic Acid ◽

Sulphate Conjugate

In this qualitative study of the pattern of bile acid excretion in cholestasis, methods are described for the isolation of bile acids from large volumes of urine and plasma. The bile acids were subjected to a group separation and identified by combined gas chromatography-mass spectrometry. The techniques were developed to allow identification of the minor components of the bile acid mixture. Four bile acids that have not previously been described in human urine and plasma were detected, namely 3β, 7α-dihydroxy-5β-cholan-24-oic acid, 3α, 6α-dihydroxy-5β-cholan-24-oic acid (hyodeoxycholic acid), 3α, 6α, 7α-trihydroxy-5β-cholan-24-oic acid (hyocholic acid) and 3α, 7β, 12α-trihydroxy-5β-cholan-24-oic acid. In addition three C27 steroids were found; 26-hydroxycholesterol and a trihydroxy cholestane, probably 5 β-cholestane-3α, 7α, 26-triol were found in the sulphate fraction of plasma and urine. In the plasma sample, a sulphate conjugate of 24-hydroxycholesterol was found. The presence of these compounds probably reflects the existence of further pathways for bile acid metabolism. It is not yet known whether this is a consequence of the cholestasis or whether they are also present in normal man, at much lower concentrations.

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