Gut microbiota promotes cholesterol gallstone formation by modulating bile acid composition and biliary cholesterol secretion

AbstractCholesterol gallstone disease is a worldwide common disease. Cholesterol supersaturation in gallbladder bile is the prerequisite for its pathogenesis, while the mechanism is not completely understood. In this study, we find enrichment of gut microbiota (especially Desulfovibrionales) in patients with gallstone disease. Fecal transplantation of gut microbiota from gallstone patients to gallstone-resistant strain of mice can induce gallstone formation. Carrying Desulfovibrionales is associated with enhanced cecal secondary bile acids production and increase of bile acid hydrophobicity facilitating intestinal cholesterol absorption. Meanwhile, the metabolic product of Desulfovibrionales, H2S increase and is shown to induce hepatic FXR and inhibit CYP7A1 expression. Mice carrying Desulfovibrionales present induction of hepatic expression of cholesterol transporters Abcg5/g8 to promote biliary secretion of cholesterol as well. Our study demonstrates the role of gut microbiota, Desulfovibrionales, as an environmental regulator contributing to gallstone formation through its influence on bile acid and cholesterol metabolism.

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Molecular Mechanisms Underlying the Link between Nuclear Receptor Function and Cholesterol Gallstone Formation

Journal of Lipids ◽

10.1155/2012/547643 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Mary Carmen Vázquez ◽

Attilio Rigotti ◽

Silvana Zanlungo

Keyword(s):

Nuclear Receptors ◽

Nuclear Receptor ◽

Molecular Mechanisms ◽

Cholesterol Metabolism ◽

Cholesterol Gallstone ◽

Gallstone Disease ◽

Gallstone Formation ◽

Receptor Function ◽

Prevalent Disease ◽

Bile Cholesterol

Cholesterol gallstone disease is highly prevalent in western countries, particularly in women and some specific ethnic groups. The formation of water-insoluble cholesterol crystals is due to a misbalance between the three major lipids present in the bile: cholesterol, bile salts, and phospholipids. Many proteins implicated in biliary lipid secretion in the liver are regulated by several transcription factors, including nuclear receptors LXR and FXR. Human and murine genetic, physiological, pathophysiological, and pharmacological evidence is consistent with the relevance of these nuclear receptors in gallstone formation. In addition, there is emerging data that also suggests a role for estrogen receptor ESR1 in abnormal cholesterol metabolism leading to gallstone disease. A better comprehension of the role of nuclear receptor function in gallstone formation may help to design new and more effective therapeutic strategies for this highly prevalent disease condition.

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Single Cell RNA-Sequencing Reveals a Murine Gallbladder Cell Transcriptome Atlas During the Process of Cholesterol Gallstone Formation

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.714271 ◽

2021 ◽

Vol 9 ◽

Author(s):

Jingjia Liang ◽

Wentao Shao ◽

Qian Liu ◽

Qifan Lu ◽

Aihua Gu ◽

...

Keyword(s):

Single Cell ◽

Rna Sequencing ◽

Cholesterol Gallstone ◽

Gallstone Disease ◽

Gallstone Formation ◽

Cellular Heterogeneity ◽

Common Disease ◽

Molecular Events ◽

Single Cell Rna Sequencing ◽

Cell Transcriptome

Gallstone disease is a worldwide common disease. However, the knowledge concerning the gallbladder in the pathogenesis of cholesterol gallstone formation remains limited. In this study, using single-cell RNA sequencing (scRNA-seq) to obtain the transcriptome of gallbladder cells, we showed cellular heterogeneity and transcriptomic dynamics in murine gallbladder cells during the process of lithogenesis. Our results indicated gallbladder walls were subjected to remodeling during the process of lithogenesis. The major molecular events that happened included proliferation of epithelial cells, infiltration of immune-cells, activation of angiogenesis, and extracellular matrix modulation. Furthermore, we observed partial reversal of gallbladder cell transcriptomes by ursodeoxycholic acid treatment. This work thus provides novel and integral knowledges on the cellular changes during lithogenesis, which is of great significance to the understanding of pathogenesis and treatment of cholesterol gallstone.

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Effect of different varieties of pectin and guar gum on plasma, hepatic and biliary lipids and cholesterol gallstone formation in hamsters fed on high-cholesterol diets

British Journal Of Nutrition ◽

10.1079/bjn19980077 ◽

1998 ◽

Vol 79 (5) ◽

pp. 463-471 ◽

Cited By ~ 17

Author(s):

Elke A. Trautwein ◽

Angelika Kunath-Rau ◽

Helmut F. Erbersdobler

Keyword(s):

Bile Acid ◽

Guar Gum ◽

Plasma Lipids ◽

Cholesterol Metabolism ◽

Cholesterol Gallstone ◽

Plasma Cholesterol ◽

Gallstone Formation ◽

Hamster Model ◽

Biliary Lipids ◽

Faecal Weight

The effect of high- (hePE) and low- (lePE) esterification pectin and high- (hvGG) and low-(lvGG) viscosity guar gum on plasma, hepatic and biliary lipids and on prevention of cholesterol gallstones was investigated in male golden Syrian hamsters (Mesocricetus auratus). Hamsters were fed on cholesterol-rich (4g/kg), gallstone-inducing diets for 6 weeks. The diets were supplemented with 80g hePE, lePE, hvGG or lvGG/kg or 80g additional cellulose/kg. No significant differences in plasma total cholesterol and triacylglycerol concentrations between hvGG and lvGG and the gallstone-inducing or cellulose-enriched diets were observed. The hePE diet produced a 16% (non-significant) reduction in total plasma cholesterol but significantly decreased the plasma triacylglycerol level by 45%. The lePE diet caused only minor changes in plasma lipids. Hepatic cholesterol concentrations were significantly higher in hamsters fed on hvGG, lvGG, hePE or lePE primarily due to the accumulation of esterified cholesterol. Supersaturated bile samples, with lithogenic indices ranging from 1.6 to 2.0, were determined with all diets. The hePE and lePE diets slightly altered the bile acid profile by increasing glycocholic acid and decreasing taurochenodeoxycholic acid concentrations resulting in a higher cholic: chenodeoxycholic acid ratio. Cholesterol gallstone formation was not substantially inhibited by the two varieties of pectin and guar gum. The hvGG, lvGG, hePE and lePE diets did not alter faecal weight and caused only minor increases in faecal bile acid excretion. In general, the present findings demonstrate that dietary pectins and guar gums had only minor effects on cholesterol metabolism and did not prevent cholesterol gallstone formation in this hamster model. Possible explanations for this lack of a distinct response to pectin and guar gum are discussed.

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Circadian Rhythm Disruption Influenced Hepatic Lipid Metabolism, Gut Microbiota and Promoted Cholesterol Gallstone Formation in Mice

Frontiers in Endocrinology ◽

10.3389/fendo.2021.723918 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chuanqi He ◽

Weiyi Shen ◽

Chaobo Chen ◽

Qihan Wang ◽

Qifan Lu ◽

...

Keyword(s):

Circadian Rhythm ◽

Lipid Metabolism ◽

Bile Acid ◽

Gut Microbiota ◽

Cholesterol Metabolism ◽

Gallstone Formation ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Lithogenic Diet ◽

Circadian Expression

BackgroundHepatic lipid metabolism regulates biliary composition and influences the formation of cholesterol gallstones. The genes Hmgcr and Cyp7a1, which encode key liver enzymes, are regulated by circadian rhythm-related transcription factors. We aimed to investigate the effect of circadian rhythm disruption on hepatic cholesterol and bile acid metabolism and the incidence of cholesterol stone formation.MethodsAdult male C57BL/6J mice were fed either a lithogenic diet (LD) only during the sleep phase (time-restricted lithogenic diet feeding, TRF) or an LD ad libitum (non-time-restricted lithogenic diet feeding, nTRF) for 4 weeks. Food consumption, body mass gain, and the incidence of gallstones were assessed. Circulating metabolic parameters, lipid accumulation in the liver, the circadian expression of hepatic clock and metabolic genes, and the gut microbiota were analyzed.ResultsTRF caused a dysregulation of the circadian rhythm in the mice, characterized by significant differences in the circadian expression patterns of clock-related genes. In TRF mice, the circadian rhythms in the expression of genes involved in bile acid and cholesterol metabolism were disrupted, as was the circadian rhythm of the gut microbiota. These changes were associated with high biliary cholesterol content, which promoted gallstone formation in the TRF mice.ConclusionDisordered circadian rhythm is associated with abnormal hepatic bile acid and cholesterol metabolism in mice, which promotes gallstone formation.

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Hepatic cholesterol metabolism in cholesterol gallstone disease

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)42070-x ◽

1991 ◽

Vol 32 (3) ◽

pp. 469-475

Author(s):

E Reihnér ◽

B Angelin ◽

I Björkhem ◽

K Einarsson

Keyword(s):

Cholesterol Metabolism ◽

Cholesterol Gallstone ◽

Gallstone Disease ◽

Hepatic Cholesterol

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Quantitative trait loci mapping for cholesterol gallstones in AKR/J and C57L/J strains of mice

Physiological Genomics ◽

10.1152/physiolgenomics.2000.4.1.59 ◽

2000 ◽

Vol 4 (1) ◽

pp. 59-65 ◽

Cited By ~ 58

Author(s):

BEVERLY PAIGEN ◽

NICHOLAS J. SCHORK ◽

KAREN L. SVENSON ◽

YIN-CHAI CHEAH ◽

JIAN-LONG MU ◽

...

Keyword(s):

Quantitative Trait ◽

Congenic Strain ◽

Cholesterol Gallstone ◽

Gallstone Disease ◽

Gallstone Formation ◽

Quantitative Trait Loci Mapping ◽

Cholesterol Gallstones ◽

Lithogenic Diet ◽

The Difference ◽

Trait Locus

Quantitative trait locus (QTL) mapping was used to locate genes that determine the difference in cholesterol gallstone disease between the gallstone-susceptible strain C57L/J and the gallstone-resistant strain AKR/J. Gallstone weight was determined in 231 male (AKR × C57L) F1× AKR backcross mice fed a lithogenic diet containing 1% cholesterol, 0.5% cholic acid, and 15% butterfat for 8 wk. Mice having no stones and mice having the largest stones were genotyped at ∼20-cM intervals to find the loci determining cholesterol gallstone formation. The major locus, Lith1, mapped near D2Mit56 and was confirmed by constructing a congenic strain, AK.L- Lith1s. Another locus, Lith2, mapped near D19Mit58 and was also confirmed by constructing a congenic strain AK.L- Lith2s. Other suggestive, but not statistically significant, loci mapped to chromosomes 6, 7, 8, 10, and X. The identification of these Lith genes will elucidate the pathophysiology of cholesterol gallstone formation.

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The Role of Diet in the Pathogenesis of Cholesterol Gallstones

Current Medicinal Chemistry ◽

10.2174/0929867324666170530080636 ◽

2019 ◽

Vol 26 (19) ◽

pp. 3620-3638 ◽

Cited By ~ 7

Author(s):

Agostino Di Ciaula ◽

Gabriella Garruti ◽

Gema Frühbeck ◽

Maria De Angelis ◽

Ornella de Bari ◽

...

Keyword(s):

Vitamin C ◽

Fast Food ◽

Cholesterol Gallstone ◽

Gallstone Disease ◽

Gallstone Formation ◽

Protective Role ◽

Cholesterol Homeostasis ◽

Major Health Problem ◽

Cholesterol Gallstones ◽

Beneficial Effects

: Cholesterol gallstone disease is a major health problem in Westernized countries and depends on a complex interplay between genetic factors, lifestyle and diet, acting on specific pathogenic mechanisms. Overweigh, obesity, dyslipidemia, insulin resistance and altered cholesterol homeostasis have been linked to increased gallstone occurrence, and several studies point to a number of specific nutrients as risk- or protective factors with respect to gallstone formation in humans. There is a rising interest in the identification of common and modifiable dietetic factors that put the patients at risk of gallstones or that are able to prevent gallstone formation and growth. In particular, dietary models characterized by increased energy intake with highly refined sugars and sweet foods, high fructose intake, low fiber contents, high fat, consumption of fast food and low vitamin C intake increase the risk of gallstone formation. On the other hand, high intake of monounsaturated fats and fiber, olive oil and fish (ω-3 fatty acids) consumption, vegetable protein intake, fruit, coffee, moderate alcohol consumption and vitamin C supplementation exert a protective role. : The effect of some confounding factors (e.g., physical activity) cannot be ruled out, but general recommendations about the multiple beneficial effects of diet on cholesterol gallstones must be kept in mind, in particular in groups at high risk of gallstone formation.

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Coordinate Regulation of Cholesterol and Bile Acid Metabolism by the Clock Modifier Nobiletin in Metabolically Challenged Old Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20174281 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4281 ◽

Cited By ~ 13

Author(s):

Kazunari Nohara ◽

Travis Nemkov ◽

Angelo D’Alessandro ◽

Seung-Hee Yoo ◽

Zheng Chen

Keyword(s):

Bile Acid ◽

Cholesterol Metabolism ◽

Orphan Receptor ◽

Regulatory Function ◽

Bile Acid Metabolism ◽

16S Sequencing ◽

Hepatic Expression ◽

Cholesterol Levels ◽

Age Related

Cholesterol and bile acid (BA) homeostasis plays a central role in systemic metabolism. Accumulating evidence suggests a key regulatory function of the circadian clock, our biological timer, in lipid metabolism, particularly cholesterol and bile acid flux. Previously, we showed that Nobiletin (NOB), a natural compound targeting the ROR (Retinoic acid receptor-related orphan receptor) nuclear receptors in the circadian oscillator, strongly protects lipid homeostasis, including normal serum cholesterol levels in high-fat (HF) fed mice at both young and old ages. In this study, we further examined the role of NOB in cholesterol metabolism in HF-fed aged mice, and found that NOB lowered the serum LDL/VLDL cholesterol levels and consequently the LDL/HDL ratio. BA levels in the serum were markedly reduced in the HF.NOB group, and examination of additional hepatic markers further indicate a protective role of NOB in the liver. At the molecular level, whereas HF feeding downregulated hepatic expression of several ROR target genes involved in bile acid synthesis, NOB treatment (HF.NOB) was able to rescue it. In accordance, fecal BA excretion was enhanced by NOB, and microbial 16S sequencing revealed alteration of several taxa known to be involved in secondary BA production in the gut. Together, these results demonstrate concerted effects of the clock-modulating compound NOB in cholesterol and BA metabolism, suggesting pharmacological manipulation of the clock as a novel therapeutic strategy against metabolic disorders and age-related decline.

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