Su1880 – Secondary Bile Acids Protect Against Intestinal Inflammation Via Bile Acid Tgr5 Receptor

Children with nonalcoholic fatty liver disease (NAFLD) display an altered gut microbiota compared with healthy children. However, little is known about the fecal bile acid profiles and their association with gut microbiota dysbiosis in pediatric NAFLD. A total of 68 children were enrolled in this study, including 32 NAFLD patients and 36 healthy children. Fecal samples were collected and analyzed by metagenomic sequencing to determine the changes in the gut microbiota of children with NAFLD, and an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) system was used to quantify the concentrations of primary and secondary bile acids. The associations between the gut microbiota and concentrations of primary and secondary bile acids in the fecal samples were then analyzed. We found that children with NAFLD exhibited reduced levels of secondary bile acids and alterations in bile acid biotransforming-related bacteria in the feces. Notably, the decrease in Eubacterium and Ruminococcaceae bacteria, which express bile salt hydrolase and 7α-dehydroxylase, was significantly positively correlated with the level of fecal lithocholic acid (LCA). However, the level of fecal LCA was negatively associated with the abundance of the potential pathogen Escherichia coli that was enriched in children with NAFLD. Pediatric NAFLD is characterized by an altered profile of gut microbiota and fecal bile acids. This study demonstrates that the disease-associated gut microbiota is linked with decreased concentrations of secondary bile acids in the feces. The disease-associated gut microbiota likely inhibits the conversion of primary to secondary bile acids.

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TGR5 signaling mitigates parenteral nutrition-associated liver disease

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00216.2019 ◽

2020 ◽

Vol 318 (2) ◽

pp. G322-G335

Author(s):

Kent A. Willis ◽

Charles K. Gomes ◽

Prahlad Rao ◽

Dejan Micic ◽

E. Richard Moran ◽

...

Keyword(s):

Liver Disease ◽

Bile Acid ◽

Parenteral Nutrition ◽

Bile Acids ◽

G Protein ◽

Prolonged Exposure ◽

Serum Bile Acid ◽

Immune Functions ◽

Protein Receptor ◽

Secondary Bile Acids

Bile acid receptors regulate the metabolic and immune functions of circulating enterohepatic bile acids. This process is disrupted by administration of parenteral nutrition (PN), which may induce progressive hepatic injury for unclear reasons, especially in the newborn, leading to PN-associated liver disease. To explore the role of bile acid signaling on neonatal hepatic function, we initially observed that Takeda G protein receptor 5 (TGR5)-specific bile acids were negatively correlated with worsening clinical disease markers in the plasma of human newborns with prolonged PN exposure. To test our resulting hypothesis that TGR5 regulates critical liver functions to PN exposure, we used TGR5 receptor deficient mice (TGR5−/−). We observed PN significantly increased liver weight, cholestasis, and serum hepatic stress enzymes in TGR5−/− mice compared with controls. Mechanistically, PN reduced bile acid synthesis genes in TGR5−/−. Serum bile acid composition revealed that PN increased unconjugated primary bile acids and secondary bile acids in TGR5−/− mice, while increasing conjugated primary bile acid levels in TGR5-competent mice. Simultaneously, PN elevated hepatic IL-6 expression and infiltrating macrophages in TGR5−/− mice. However, the gut microbiota of TGR5−/− mice compared with WT mice following PN administration displayed highly elevated levels of Bacteroides and Parabacteroides, and possibly responsible for the elevated levels of secondary bile acids in TGR5−/− animals. Intestinal bile acid transporters expression was unchanged. Collectively, this suggests TGR5 signaling specifically regulates fundamental aspects of liver bile acid homeostasis during exposure to PN. Loss of TGR5 is associated with biochemical evidence of cholestasis in both humans and mice on PN. NEW & NOTEWORTHY Parenteral nutrition is associated with deleterious metabolic outcomes in patients with prolonged exposure. Here, we demonstrate that accelerated cholestasis and parental nutrition-associated liver disease (PNALD) may be associated with deficiency of Takeda G protein receptor 5 (TGR5) signaling. The microbiome is responsible for production of secondary bile acids that signal through TGR5. Therefore, collectively, these data support the hypothesis that a lack of established microbiome in early life or under prolonged parenteral nutrition may underpin disease development and PNALD.

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Ursodeoxycholic Acid and Its Taurine- or Glycine-Conjugated Species Reduce Colitogenic Dysbiosis and Equally Suppress Experimental Colitis in Mice

Applied and Environmental Microbiology ◽

10.1128/aem.02766-16 ◽

2017 ◽

Vol 83 (7) ◽

Cited By ~ 25

Author(s):

Lien Van den Bossche ◽

Pieter Hindryckx ◽

Lindsey Devisscher ◽

Sarah Devriese ◽

Sophie Van Welden ◽

...

Keyword(s):

Community Structure ◽

Bile Acid ◽

Bile Acids ◽

Experimental Colitis ◽

Acid Therapy ◽

Content Type ◽

Bile Acid Therapy ◽

Inflammatory Bowel ◽

The Impact ◽

Secondary Bile Acids

ABSTRACT The promising results seen in studies of secondary bile acids in experimental colitis suggest that they may represent an attractive and safe class of drugs for the treatment of inflammatory bowel diseases (IBD). However, the exact mechanism by which bile acid therapy confers protection from colitogenesis is currently unknown. Since the gut microbiota plays a crucial role in the pathogenesis of IBD, and exogenous bile acid administration may affect the community structure of the microbiota, we examined the impact of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine or glycine conjugates on the fecal microbial community structure during experimental colitis. Daily oral administration of UDCA, tauroursodeoxycholic acid (TUDCA), or glycoursodeoxycholic acid (GUDCA) equally lowered the severity of dextran sodium sulfate-induced colitis in mice, as evidenced by reduced body weight loss, colonic shortening, and expression of inflammatory cytokines. Illumina sequencing demonstrated that bile acid therapy during colitis did not restore fecal bacterial richness and diversity. However, bile acid therapy normalized the colitis-associated increased ratio of Firmicutes to Bacteroidetes. Interestingly, administration of bile acids prevented the loss of Clostridium cluster XIVa and increased the abundance of Akkermansia muciniphila, bacterial species known to be particularly decreased in IBD patients. We conclude that UDCA, which is an FDA-approved drug for cholestatic liver disorders, could be an attractive treatment option to reduce dysbiosis and ameliorate inflammation in human IBD. IMPORTANCE Secondary bile acids are emerging as attractive candidates for the treatment of inflammatory bowel disease. Although bile acids may affect the intestinal microbial community structure, which significantly contributes to the course of these inflammatory disorders, the impact of bile acid therapy on the fecal microbiota during colitis has not yet been considered. Here, we studied the alterations in the fecal microbial abundance in colitic mice following the administration of secondary bile acids. Our results show that secondary bile acids reduce the severity of colitis and ameliorate colitis-associated fecal dysbiosis at the phylum level. This study indicates that secondary bile acids might act as a safe and effective drug for inflammatory bowel disease.

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Impact of Bacterial Metabolites on Gut Barrier Function and Host Immunity: A Focus on Bacterial Metabolism and Its Relevance for Intestinal Inflammation

Frontiers in Immunology ◽

10.3389/fimmu.2021.658354 ◽

2021 ◽

Vol 12 ◽

Author(s):

Naschla Gasaly ◽

Paul de Vos ◽

Marcela A. Hermoso

Keyword(s):

Celiac Disease ◽

Immune Responses ◽

Bile Acids ◽

Barrier Function ◽

Intestinal Inflammation ◽

Microbial Interactions ◽

Gut Barrier Function ◽

Gut Immunity ◽

Tryptophan Catabolites ◽

Secondary Bile Acids

The diverse and dynamic microbial community of the human gastrointestinal tract plays a vital role in health, with gut microbiota supporting the development and function of the gut immune barrier. Crosstalk between microbiota-gut epithelium and the gut immune system determine the individual health status, and any crosstalk disturbance may lead to chronic intestinal conditions, such as inflammatory bowel diseases (IBD) and celiac disease. Microbiota-derived metabolites are crucial mediators of host-microbial interactions. Some beneficially affect host physiology such as short-chain fatty acids (SCFAs) and secondary bile acids. Also, tryptophan catabolites determine immune responses, such as through binding to the aryl hydrocarbon receptor (AhR). AhR is abundantly present at mucosal surfaces and when activated enhances intestinal epithelial barrier function as well as regulatory immune responses. Exogenous diet-derived indoles (tryptophan) are a major source of endogenous AhR ligand precursors and together with SCFAs and secondary bile acids regulate inflammation by lowering stress in epithelium and gut immunity, and in IBD, AhR expression is downregulated together with tryptophan metabolites. Here, we present an overview of host microbiota-epithelium- gut immunity crosstalk and review how microbial-derived metabolites contribute to host immune homeostasis. Also, we discuss the therapeutic potential of bacterial catabolites for IBD and celiac disease and how essential dietary components such as dietary fibers and bacterial tryptophan catabolites may contribute to intestinal and systemic homeostasis.

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In Vitro Interactions of Dietary Fibre Enriched Food Ingredients with Primary and Secondary Bile Acids

Nutrients ◽

10.3390/nu11061424 ◽

2019 ◽

Vol 11 (6) ◽

pp. 1424 ◽

Cited By ~ 16

Author(s):

Susanne Naumann ◽

Ute Schweiggert-Weisz ◽

Julia Eglmeier ◽

Dirk Haller ◽

Peter Eisner

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Dietary Fibre ◽

In Vitro Digestion ◽

Food Ingredients ◽

Bile Acid Pool Size ◽

As Adsorption ◽

Secondary Bile Acids ◽

In Vitro Interactions

Dietary fibres are reported to interact with bile acids, preventing their reabsorption and promoting their excretion into the colon. We used a method based on in vitro digestion, dialysis, and kinetic analysis to investigate how dietary fibre enriched food ingredients affect the release of primary and secondary bile acids as related to viscosity and adsorption. As the main bile acids abundant in humans interactions with glyco- and tauroconjugated cholic acid, chenodesoxycholic acid and desoxycholic acid were analysed. Viscous interactions were detected for apple, barley, citrus, lupin, pea, and potato derived ingredients, which slowed the bile acid release rate by up to 80%. Adsorptive interactions of up to 4.7 μmol/100 mg DM were significant in barley, oat, lupin, and maize preparations. As adsorption directly correlated to the hydrophobicity of the bile acids the hypothesis of a hydrophobic linkage between bile acids and dietary fibre is supported. Delayed diffusion in viscous fibre matrices was further associated with the micellar properties of the bile acids. As our results indicate changes in the bile acid pool size and composition due to interactions with dietary fibre rich ingredients, the presented method and results could add to recent fields of bile acid research.

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The role of secondary bile acids in neoplastic development in the oesophagus

Biochemical Society Transactions ◽

10.1042/bst0380337 ◽

2010 ◽

Vol 38 (2) ◽

pp. 337-342 ◽

Cited By ~ 18

Author(s):

James Cronin ◽

Lisa Williams ◽

Elizabeth McAdam ◽

Zak Eltahir ◽

Paul Griffiths ◽

...

Keyword(s):

Dna Damage ◽

Bile Acid ◽

Bile Acids ◽

Association Studies ◽

Nuclear Factor Κb ◽

Dna Damaging Agents ◽

Pkc Protein Kinase C ◽

Oxide Synthase ◽

Secondary Bile Acids

Bile acids have been demonstrated, through the use of animal models and clinical association studies, to play a role in neoplastic development in Barrett's metaplasia. How specific bile acids promote neoplasia is as yet unknown, as are the exact identities of the important bile acid subtypes. The combination of bile subtype with appropriate pH is critical, as pH alters bile acid activity enormously. Hence glycine-conjugated bile acids are involved in neoplastic development at acidic pH (pH ~4), and unconjugated bile acids are involved in neoplastic development at more neutral pH (~6). Bile acids (at the appropriate pH) are potent DNA-damaging agents, due to the induction of ROS (reactive oxygen species), which are mainly induced by bile-induced damage to mitochondrial membranes, allowing leakage of ROS into the cytosol. These ROS also induce pro-survival signalling pathways [e.g. via PKC (protein kinase C)-dependent NF-κB (nuclear factor κB) activity]. Interestingly, NOS (nitric oxide synthase), through induction of NO may exacerbate this NF-κB activity and form a positive-feedback loop to amplify the activation of NF-κB by deoxycholic acid in particular. This combination of induced DNA damage and cell survival by bile acids is of major importance in neoplasia. Antioxidants and the tertiary bile acid UDCA (ursodeoxycholic acid) can block bile-induced DNA damage and bile-induced NF-κB activity, and should be considered in chemopreventative strategies.

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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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Differential effects of calcium ions and calcium phosphate on cytotoxicity of bile acids

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1991.260.1.g142 ◽

1991 ◽

Vol 260 (1) ◽

pp. G142-G147 ◽

Cited By ~ 3

Author(s):

R. Van der Meer ◽

D. S. Termont ◽

H. T. De Vries

Keyword(s):

Bile Acid ◽

Calcium Phosphate ◽

Bile Acids ◽

Colonic Mucosa ◽

Molecular Mechanisms ◽

Epithelial Proliferation ◽

Cytotoxic Potential ◽

Glycine Conjugate ◽

Taurine Conjugate ◽

Secondary Bile Acids

Unconjugated secondary bile acids can promote colon cancer by damaging colonic mucosa and consequently increasing epithelial proliferation. It has been proposed that dietary calcium inactivates intestinal bile acids either by a Ca2(+)-dependent precipitation or by binding to insoluble calcium phosphate (CaPi). We studied the molecular mechanisms of these opposing hypotheses by using hemolysis of erythrocytes as a model parameter for cytotoxicity. Washed human erythrocytes were incubated for 15 min with buffered media (pH 7.4) containing increasing amounts of different bile acids. Deconjugation and 7 alpha-dehydroxylation of mixtures of glycine- or taurine-conjugated cholate and chenodeoxycholate drastically increased their cytotoxicity. Parallel measurements, using a fluorescent micellar probe, indicated that micellar aggregation is a prerequisite for this bile acid-induced lysis. Ca2+ concentrations up to 15 mM did not precipitate bile acids but stimulated cytotoxicity of both deoxycholate (DC) and its glycine conjugate (GDC). Cytotoxicity of the taurine conjugate (TDC) was stimulated to a much lesser extent. Increasing amounts of CaPi precipitated micellar DC and GDC, but not TDC, and consequently inhibited only cytotoxicity of the former two. These findings indicate that 1) hydrophobicity and micellar aggregation are important determinants of bile acid-induced cytotoxicity that explain the high cytotoxic potential of secondary bile acids in colon, and 2) cytotoxicity of bile acids is stimulated by free Ca2+ and inhibited by CaPi. This inhibition is due to binding of carboxylic (including secondary) bile acids to CaPi.

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Bile Acid 7α-Dehydroxylating Gut Bacteria Secrete Antibiotics that Inhibit Clostridium difficile: Role of Secondary Bile Acids

Cell Chemical Biology ◽

10.1016/j.chembiol.2018.10.003 ◽

2019 ◽

Vol 26 (1) ◽

pp. 27-34.e4 ◽

Cited By ~ 37

Author(s):

Jason D. Kang ◽

Christopher J. Myers ◽

Spencer C. Harris ◽

Genta Kakiyama ◽

In-Kyoung Lee ◽

...

Keyword(s):

Bile Acid ◽

Clostridium Difficile ◽

Bile Acids ◽

Gut Bacteria ◽

Secondary Bile Acids

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Microbiota transplantation restores normal fecal bile acid composition in recurrentClostridium difficileinfection

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00282.2013 ◽

2014 ◽

Vol 306 (4) ◽

pp. G310-G319 ◽

Cited By ~ 210

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.

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