Microorganisms

18 pages, 3125 KiB

Open AccessArticle

Bile Acid Sequestrant, Sevelamer Ameliorates Hepatic Fibrosis with Reduced Overload of Endogenous Lipopolysaccharide in Experimental Nonalcoholic Steatohepatitis

by Yuki Tsuji, Kosuke Kaji, Mitsuteru Kitade, Daisuke Kaya, Koh Kitagawa, Takahiro Ozutsumi, Yukihisa Fujinaga, Hiroaki Takaya, Hideto Kawaratani, Tadashi Namisaki, Kei Moriya, Takemi Akahane and Hitoshi Yoshiji

Microorganisms 2020, 8(6), 925; https://doi.org/10.3390/microorganisms8060925 - 19 Jun 2020

Cited by 19 | Viewed by 3686

Abstract

Despite the use of various pharmacotherapeutic strategies, fibrosis due to nonalcoholic steatohepatitis (NASH) remains an unsatisfied clinical issue. We investigated the effect of sevelamer, a hydrophilic bile acid sequestrant, on hepatic fibrosis in a murine NASH model. Male C57BL/6J mice were fed a [...] Read more.

Despite the use of various pharmacotherapeutic strategies, fibrosis due to nonalcoholic steatohepatitis (NASH) remains an unsatisfied clinical issue. We investigated the effect of sevelamer, a hydrophilic bile acid sequestrant, on hepatic fibrosis in a murine NASH model. Male C57BL/6J mice were fed a choline-deficient, L-amino acid-defined, high-fat (CDHF) diet for 12 weeks with or without orally administered sevelamer hydrochloride (2% per diet weight). Histological and biochemical analyses revealed that sevelamer prevented hepatic steatosis, macrophage infiltration, and pericellular fibrosis in CDHF-fed mice. Sevelamer reduced the portal levels of total bile acid and inhibited both hepatic and intestinal farnesoid X receptor activation. Gut microbiome analysis demonstrated that sevelamer improved a lower α-diversity and prevented decreases in Lactobacillaceae and Clostridiaceae as well as increases in Desulfovibrionaceae and Enterobacteriaceae in the CDHF-fed mice. Additionally, sevelamer bound to lipopolysaccharide (LPS) in the intestinal lumen and promoted its fecal excretion. Consequently, the sevelamer treatment restored the tight intestinal junction proteins and reduced the portal LPS levels, leading to the suppression of hepatic toll-like receptor 4 signaling pathway. Furthermore, sevelamer inhibited the LPS-mediated induction of fibrogenic activity in human hepatic stellate cells in vitro. Collectively, sevelamer inhibited the development of murine steatohepatitis by reducing hepatic LPS overload. Full article

(This article belongs to the Special Issue Microbial Impact on Cholesterol and Bile Acid Metabolism)

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24 pages, 2623 KiB

Open AccessReview

Microbial Hydroxysteroid Dehydrogenases: From Alpha to Omega

by Heidi L. Doden and Jason M. Ridlon

Microorganisms 2021, 9(3), 469; https://doi.org/10.3390/microorganisms9030469 - 24 Feb 2021

Cited by 47 | Viewed by 5785

Abstract

Bile acids (BAs) and glucocorticoids are steroid hormones derived from cholesterol that are important signaling molecules in humans and other vertebrates. Hydroxysteroid dehydrogenases (HSDHs) are encoded both by the host and by their resident gut microbiota, and they reversibly convert steroid hydroxyl groups [...] Read more.

Bile acids (BAs) and glucocorticoids are steroid hormones derived from cholesterol that are important signaling molecules in humans and other vertebrates. Hydroxysteroid dehydrogenases (HSDHs) are encoded both by the host and by their resident gut microbiota, and they reversibly convert steroid hydroxyl groups to keto groups. Pairs of HSDHs can reversibly epimerize steroids from α-hydroxy conformations to β-hydroxy, or β-hydroxy to ω-hydroxy in the case of ω-muricholic acid. These reactions often result in products with drastically different physicochemical properties than their precursors, which can result in steroids being activators or inhibitors of host receptors, can affect solubility in fecal water, and can modulate toxicity. Microbial HSDHs modulate sterols associated with diseases such as colorectal cancer, liver cancer, prostate cancer, and polycystic ovary syndrome. Although the role of microbial HSDHs is not yet fully elucidated, they may have therapeutic potential as steroid pool modulators or druggable targets in the future. In this review, we explore metabolism of BAs and glucocorticoids with a focus on biotransformation by microbial HSDHs. Full article

(This article belongs to the Special Issue Microbial Impact on Cholesterol and Bile Acid Metabolism)

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17 pages, 15038 KiB

Open AccessReview

Functional and Phylogenetic Diversity of BSH and PVA Enzymes

by Jack W. Daly, Stephen J. Keely and Cormac G. M. Gahan

Microorganisms 2021, 9(4), 732; https://doi.org/10.3390/microorganisms9040732 - 31 Mar 2021

Cited by 24 | Viewed by 5329

Abstract

Bile salt hydrolase (BSH) and penicillin V acylase (PVA) are related enzymes that are classified as choloylglycine hydrolases (CGH). BSH enzymes have attracted significant interest for their ability to modulate the composition of the bile acid pool, alter bile acid signaling events mediated [...] Read more.

Bile salt hydrolase (BSH) and penicillin V acylase (PVA) are related enzymes that are classified as choloylglycine hydrolases (CGH). BSH enzymes have attracted significant interest for their ability to modulate the composition of the bile acid pool, alter bile acid signaling events mediated by the host bile acid receptors FXR and TGR5 and influence cholesterol homeostasis in the host, while PVA enzymes have been widely utilised in an industrial capacity in the production of semi-synthetic antibiotics. The similarities between BSH and PVA enzymes suggest common evolution of these enzymes and shared mechanisms for substrate binding and catalysis. Here, we compare BSH and PVA through analysis of the distribution, phylogeny and biochemistry of these microbial enzymes. The development of new annotation approaches based upon functional enzyme analyses and the potential implications of BSH enzymes for host health are discussed. Full article

(This article belongs to the Special Issue Microbial Impact on Cholesterol and Bile Acid Metabolism)

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16 pages, 3675 KiB

Open AccessArticle

Identifying a Novel Bile Salt Hydrolase from the Keystone Gut Bacterium Christensenella minuta

by Guillaume Déjean, Héloïse Tudela, Lisa Bruno, Déborah Kissi, Georges Rawadi and Sandrine P. Claus

Microorganisms 2021, 9(6), 1252; https://doi.org/10.3390/microorganisms9061252 - 9 Jun 2021

Cited by 21 | Viewed by 4665

Abstract

Christensenella minuta are human gut dwelling bacteria that have been proposed as key members of the gut microbiome, regulating energy balance and adiposity of their host. We formerly identified that a novel strain of C. minuta (strain DSM33407) boosted microbiota diversity and stimulated [...] Read more.

Christensenella minuta are human gut dwelling bacteria that have been proposed as key members of the gut microbiome, regulating energy balance and adiposity of their host. We formerly identified that a novel strain of C. minuta (strain DSM33407) boosted microbiota diversity and stimulated deconjugation of the primary bile acid taurocholic acid in human samples. However, there is no description of a bile salt hydrolase (BSH) protein carried in the genome of C. minuta. Here, we identified and cloned a protein from C. minuta’s genome that carries a potent BSH activity, which preferentially deconjugates glycine-conjugated bile acids. We then retrieved 14,319 putative BSH sequences from the NCBI database and filtered them using the UHGP database to collect a total of 6701 sequences that were used to build the most comprehensive phylogenetic tree of BSH-related enzymes identified in the human microbiome so far. This phylogenetic tree revealed that C. minuta’s BSH amino acid sequence clusters away from others with a threshold of 70% identity. This is therefore the first description of C. minuta’s BSH protein, which may be involved in its unique role within the human gut microbial ecosystem. Full article

(This article belongs to the Special Issue Microbial Impact on Cholesterol and Bile Acid Metabolism)

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28 pages, 2248 KiB

Open AccessReview

Degradation of Bile Acids by Soil and Water Bacteria

by Franziska Maria Feller, Johannes Holert, Onur Yücel and Bodo Philipp

Microorganisms 2021, 9(8), 1759; https://doi.org/10.3390/microorganisms9081759 - 17 Aug 2021

Cited by 15 | Viewed by 4345

Abstract

Bile acids are surface-active steroid compounds with a C₅ carboxylic side chain at the steroid nucleus. They are produced by vertebrates, mainly functioning as emulsifiers for lipophilic nutrients, as signaling compounds, and as an antimicrobial barrier in the duodenum. Upon excretion into [...] Read more.

Bile acids are surface-active steroid compounds with a C₅ carboxylic side chain at the steroid nucleus. They are produced by vertebrates, mainly functioning as emulsifiers for lipophilic nutrients, as signaling compounds, and as an antimicrobial barrier in the duodenum. Upon excretion into soil and water, bile acids serve as carbon- and energy-rich growth substrates for diverse heterotrophic bacteria. Metabolic pathways for the degradation of bile acids are predominantly studied in individual strains of the genera Pseudomonas, Comamonas, Sphingobium, Azoarcus, and Rhodococcus. Bile acid degradation is initiated by oxidative reactions of the steroid skeleton at ring A and degradation of the carboxylic side chain before the steroid nucleus is broken down into central metabolic intermediates for biomass and energy production. This review summarizes the current biochemical and genetic knowledge on aerobic and anaerobic degradation of bile acids by soil and water bacteria. In addition, ecological and applied aspects are addressed, including resistance mechanisms against the toxic effects of bile acids. Full article

(This article belongs to the Special Issue Microbial Impact on Cholesterol and Bile Acid Metabolism)

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19 pages, 846 KiB

Open AccessReview

Cholesterol-to-Coprostanol Conversion by the Gut Microbiota: What We Know, Suspect, and Ignore

by Catherine Juste and Philippe Gérard

Microorganisms 2021, 9(9), 1881; https://doi.org/10.3390/microorganisms9091881 - 5 Sep 2021

Cited by 51 | Viewed by 7480

Abstract

Every day, up to 1 g of cholesterol, composed of the unabsorbed dietary cholesterol, the biliary cholesterol secretion, and cholesterol of cells sloughed from the intestinal epithelium, enters the colon. All cholesterol arriving in the large intestine can be metabolized by the colonic [...] Read more.

Every day, up to 1 g of cholesterol, composed of the unabsorbed dietary cholesterol, the biliary cholesterol secretion, and cholesterol of cells sloughed from the intestinal epithelium, enters the colon. All cholesterol arriving in the large intestine can be metabolized by the colonic bacteria. Cholesterol is mainly converted into coprostanol, a non-absorbable sterol that is excreted in the feces. Interestingly, cholesterol-to-coprostanol conversion in human populations is variable, with a majority of high converters and a minority of low or inefficient converters. Two major pathways have been proposed, one involving the direct stereospecific reduction of the Δ5 double bond direct while the indirect pathway involves the intermediate formation of 4-cholelesten-3-one and coprostanone. Despite the fact that intestinal cholesterol conversion was discovered more than a century ago, only a few cholesterol-to-coprostanol-converting bacterial strains have been isolated and characterized. Moreover, the responsible genes were mainly unknown until recently. Interestingly, cholesterol-to-coprostanol conversion is highly regulated by the diet. Finally, this gut bacterial metabolism has been linked to health and disease, and recent evidence suggests it could contribute to lower blood cholesterol and cardiovascular risks. Full article

(This article belongs to the Special Issue Microbial Impact on Cholesterol and Bile Acid Metabolism)

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20 pages, 1370 KiB

Open AccessArticle

Functional Characterisation of Bile Metagenome: Study of Metagenomic Dark Matter

by Carlos Sabater, Natalia Molinero, Manuel Ferrer, Carmen María García Bernardo, Susana Delgado and Abelardo Margolles

Microorganisms 2021, 9(11), 2201; https://doi.org/10.3390/microorganisms9112201 - 21 Oct 2021

Cited by 2 | Viewed by 2133

Abstract

Gallbladder metagenome involves a wide range of unidentified sequences comprising the so-called metagenomic dark matter. Therefore, this study aimed to characterise three gallbladder metagenomes and a fosmid library with an emphasis on metagenomic dark matter fraction. For this purpose, a novel data analysis [...] Read more.

Gallbladder metagenome involves a wide range of unidentified sequences comprising the so-called metagenomic dark matter. Therefore, this study aimed to characterise three gallbladder metagenomes and a fosmid library with an emphasis on metagenomic dark matter fraction. For this purpose, a novel data analysis strategy based on the combination of remote homology and molecular modelling has been proposed. According to the results obtained, several protein functional domains were annotated in the metagenomic dark matter fraction including acetyltransferases, outer membrane transporter proteins, membrane assembly factors, DNA repair and recombination proteins and response regulator phosphatases. In addition, one deacetylase involved in mycothiol biosynthesis was found in the metagenomic dark matter fraction of the fosmid library. This enzyme may exert a protective effect in Actinobacteria against bile components exposure, in agreement with the presence of multiple antibiotic and multidrug resistance genes. Potential mechanisms of action of this novel deacetylase were elucidated by molecular simulations, highlighting the role of histidine and aspartic acid residues. Computational pipelines presented in this work may be of special interest to discover novel microbial enzymes which had not been previously characterised. Full article

(This article belongs to the Special Issue Microbial Impact on Cholesterol and Bile Acid Metabolism)

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17 pages, 1432 KiB

Open AccessReview

Physiological Role of Bile Acids Modified by the Gut Microbiome

by Yoshimitsu Kiriyama and Hiromi Nochi

Microorganisms 2022, 10(1), 68; https://doi.org/10.3390/microorganisms10010068 - 30 Dec 2021

Cited by 45 | Viewed by 5138

Abstract

Bile acids (BAs) are produced from cholesterol in the liver and are termed primary BAs. Primary BAs are conjugated with glycine and taurine in the liver and then released into the intestine via the gallbladder. After the deconjugation of glycine or taurine by [...] Read more.

Bile acids (BAs) are produced from cholesterol in the liver and are termed primary BAs. Primary BAs are conjugated with glycine and taurine in the liver and then released into the intestine via the gallbladder. After the deconjugation of glycine or taurine by the gut microbiome, primary BAs are converted into secondary BAs by the gut microbiome through modifications such as dehydroxylation, oxidation, and epimerization. Most BAs in the intestine are reabsorbed and transported to the liver, where both primary and secondary BAs are conjugated with glycine or taurine and rereleased into the intestine. Thus, unconjugated primary Bas, as well as conjugated and unconjugated secondary BAs, have been modified by the gut microbiome. Some of the BAs reabsorbed from the intestine spill into the systemic circulation, where they bind to a variety of nuclear and cell-surface receptors in tissues, whereas some of the BAs are not reabsorbed and bind to receptors in the terminal ileum. BAs play crucial roles in the physiological regulation of various tissues. Furthermore, various factors, such as diet, age, and antibiotics influence BA composition. Here, we review recent findings regarding the physiological roles of BAs modified by the gut microbiome in the metabolic, immune, and nervous systems. Full article

(This article belongs to the Special Issue Microbial Impact on Cholesterol and Bile Acid Metabolism)

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3 pages, 184 KiB

Open AccessEditorial

Special Issue: Microbial Impact on Cholesterol and Bile Acid Metabolism

by Jason M. Ridlon

Microorganisms 2022, 10(2), 477; https://doi.org/10.3390/microorganisms10020477 - 21 Feb 2022

Cited by 2 | Viewed by 1908

Abstract

An important current focus in microbiome science is the biotransformation and degradation of cholesterol, steroids, and bile acids [...] Full article

(This article belongs to the Special Issue Microbial Impact on Cholesterol and Bile Acid Metabolism)

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