Gut Dysbiosis and Abnormal Bile Acid Metabolism in Colitis-Associated Cancer

Background. Patients with prolonged inflammatory bowel disease (IBD) can develop into colorectal cancer (CRC), also called colitis-associated cancer (CAC). Studies have shown the association between gut dysbiosis, abnormal bile acid metabolism, and inflammation process. Here, we aimed to investigate these two factors in the CAC model. Methods. C57BL/6 mice were randomly allocated to two groups: azoxymethane/dextran sodium sulfate (AOM/DSS) and control. The AOM/DSS group received AOM injection followed by DSS drinking water. Intestinal inflammation, mucosal barrier, and bile acid receptors were determined by real-time PCR and immunohistochemistry. Fecal microbiome and bile acids were detected via 16S rRNA sequencing and liquid chromatography-mass spectrometry. Results. The AOM/DSS group exhibited severe mucosal barrier impairment, inflammatory response, and tumor formation. In the CAC model, the richness and biodiversity of gut microbiota were decreased, along with significant alteration of composition. The abundance of pathogens was increased, while the short-chain fatty acids producing bacteria were reduced. Interestingly, Clostridium XlV and Lactobacillus, which might be involved in the bile acid deconjugation, transformation, and desulfation, were significantly decreased. Accordingly, fecal bile acids were decreased, accompanied by reduced transformation of primary to secondary bile acids. Given bile acid receptors, the ileum farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) axis was downregulated, while Takeda G-protein receptor 5 (TGR5) was overexpressed in colonic tumor tissues. Conclusion. Gut dysbiosis might alter the metabolism of bile acids and promote CAC, which would provide a potential preventive strategy of CAC by regulating gut microbiota and bile acid metabolism.

Download Full-text

P054 Modulation of the Gut Microbiota-Farnesoid X Receptor Axis Improves Deoxycholic Acid-induced Intestinal Inflammation in Mice

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.183 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S161-S161

Author(s):

M Xu ◽

Y Shen ◽

M Cen

Keyword(s):

Bile Acid ◽

Gut Microbiota ◽

Intestinal Microbiota ◽

Acid Metabolism ◽

Deoxycholic Acid ◽

Intestinal Inflammation ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Gut Dysbiosis ◽

Rdna Sequencing

Abstract Background Inflammatory bowel disease (IBD) is associated with gut dysbiosis and dysregulation of bile acid metabolism. A high luminal content of deoxycholic acid (DCA) with consumption of a Westernized diet is implicated in the pathogenesis of IBD. The aim of the study is to explore the role of intestinal microbiota and bile acid metabolism in mice with DCA-induced intestinal inflammation. Methods 4-week-old wild-type C57BL mice were fed with AIN-93G (control diet), AIN-93G+0.2% DCA, AIN-93G+0.2% DCA+6 weeks of fexaramine (FXR agonist), or AIN-93G+0.2% DCA+antibiotic cocktail for 24 weeks. Histopathology, Western blotting, and qPCR were performed on the intestinal tissue. Fecal microbiota was analyzed by 16S rDNA sequencing. Fecal bile acid and short-chain fatty acid (SCFA) levels were analyzed by chromatography. Results Gut dysbiosis and enlarged bile acid pool were observed in DCA-treated mice, accompanied by a lower farnesoid X receptor (FXR) activity in the intestine. Administration of fexaramine mitigated DCA-induced intestinal injury, restored intestinal FXR activity, activated ﬁbroblast growth factor 15, and normalized bile acid metabolism. Furthermore, fexaramine administration increased the abundance of SCFA-producing bacteria. Depletion of the commensal microbiota with antibiotics decreased the diversity of the intestinal microbiota, attenuated bile acid synthesis, and reduced intestinal inflammation induced by DCA. Conclusion DCA induced-intestinal inflammation is associated with alterations of gut microbiota and bile acid proﬁles. Interventions targeting the gut microbiota-FXR signaling pathway may reduce DCA-induced intestinal disease.

Download Full-text

Intestinal bile acid receptors are key regulators of glucose homeostasis

Proceedings of The Nutrition Society ◽

10.1017/s0029665116002834 ◽

2017 ◽

Vol 76 (3) ◽

pp. 192-202 ◽

Cited By ~ 10

Author(s):

Mohamed-Sami Trabelsi ◽

Sophie Lestavel ◽

Bart Staels ◽

Xavier Collet

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Glucose Homeostasis ◽

Energy Homeostasis ◽

Acid Metabolism ◽

Dietary Lipid ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Metabolism Regulation ◽

Bile Acid Receptors

In addition to their well-known function as dietary lipid detergents, bile acids have emerged as important signalling molecules that regulate energy homeostasis. Recent studies have highlighted that disrupted bile acid metabolism is associated with metabolism disorders such as dyslipidaemia, intestinal chronic inflammatory diseases and obesity. In particular, type 2 diabetes (T2D) is associated with quantitative and qualitative modifications in bile acid metabolism. Bile acids bind and modulate the activity of transmembrane and nuclear receptors (NR). Among these receptors, the G-protein-coupled bile acid receptor 1 (TGR5) and the NR farnesoid X receptor (FXR) are implicated in the regulation of bile acid, lipid, glucose and energy homeostasis. The role of these receptors in the intestine in energy metabolism regulation has been recently highlighted. More precisely, recent studies have shown that FXR is important for glucose homeostasis in particular in metabolic disorders such as T2D and obesity. This review highlights the growing importance of the bile acid receptors TGR5 and FXR in the intestine as key regulators of glucose metabolism and their potential as therapeutic targets.

Download Full-text

Disease-Associated Changes in Bile Acid Profiles and Links to Altered Gut Microbiota

Digestive Diseases ◽

10.1159/000450907 ◽

2017 ◽

Vol 35 (3) ◽

pp. 169-177 ◽

Cited By ~ 36

Author(s):

Susan A. Joyce ◽

Cormac G.M. Gahan

Keyword(s):

Bile Acid ◽

Gut Microbiota ◽

Bile Acids ◽

Farnesoid X Receptor ◽

Gastrointestinal Microbiota ◽

Signalling Molecules ◽

Disease States ◽

Irritable Bowel ◽

Bile Acid Profiles ◽

Bile Acid Receptors

The gastrointestinal microbiota plays a central role in the host metabolism of bile acids through deconjugation and dehydroxylation reactions, which generate unconjugated free bile acids and secondary bile acids respectively. These microbially generated bile acids are particularly potent signalling molecules that interact with host bile acid receptors (including the farnesoid X receptor, vitamin D receptor and TGR5 receptor) to trigger cellular responses that play essential roles in host lipid metabolism, electrolyte transport and immune regulation. Perturbations of microbial populations in the gut can therefore profoundly alter bile acid profiles in the host to impact upon the digestive and signalling properties of bile acids in the human superorganism. A number of recent studies have clearly demonstrated the occurrence of microbial disturbances allied to alterations in host bile acid profiles that occur across a range of disease states. Intestinal diseases including irritable bowel syndrome, inflammatory bowel disease (IBD), short bowel syndrome and Clostridium difficile infection all exhibit concurrent alterations in the composition of the gut microbiota and changes to host bile acid profiles. Similarly, extraintestinal diseases and syndromes such as asthma and obesity may be linked to aberrant bile acid profiles in the host. Here, we focus upon recent studies that highlight the links between alterations to gut microbial communities and altered bile acid profiles across a range of diseases from asthma to IBD.

Download Full-text

Effects of Rhein on Bile Acid Homeostasis in Rats

BioMed Research International ◽

10.1155/2020/8827955 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Zhong Xian ◽

Jingzhuo Tian ◽

Lianmei Wang ◽

Yushi Zhang ◽

Jiayin Han ◽

...

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Acid Metabolism ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Edible Plant ◽

Clinical Dose ◽

Acid Accumulation ◽

Liver And Kidney ◽

Hepatic Transporters

Rhein, the active ingredient of rhubarb, a medicinal and edible plant, is widely used in clinical practice. However, the effects of repeated intake of rhein on liver function and bile acid metabolism are rarely reported. In this work, we investigated the alterations of 14 bile acids and hepatic transporters after rats were administered with rhein for 5 weeks. There was no obvious injury to the liver and kidney, and there were no significant changes in biochemical indicators. However, 1,000 mg/kg rhein increased the liver total bile acid (TBA) levels, especially taurine-conjugated bile acids (t-CBAs), inhibited the expression of farnesoid X receptor (FXR), small heterodimer partner (SHP), and bile salt export pump (BSEP) mRNA, and upregulated the expression of (cholesterol 7α-hydroxylase) CYP7A1 mRNA. Rhein close to the clinical dose (10 mg/kg and 30 mg/kg) reduced the amounts of TBAs, especially unconjugated bile acids (UCBAs), and elevated the expression of FXR and multidrug resistance-associated protein 3 (Mrp3) mRNA. These results denote that rhein is relatively safe to use at a reasonable dose and timing. 30 mg/kg rhein may promote bile acid transport and reduce bile acid accumulation by upregulating the expression of FXR mRNA and Mrp3 mRNA, potentially resulting in the decrease in serum UBCAs.

Download Full-text

The contribution of bile acid metabolism to the pathogenesis of Clostridioides difficile infection

Therapeutic Advances in Gastroenterology ◽

10.1177/17562848211017725 ◽

2021 ◽

Vol 14 ◽

pp. 175628482110177

Author(s):

Benjamin H. Mullish ◽

Jessica R. Allegretti

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Gut Microbiome ◽

Acid Metabolism ◽

Disease Process ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Clostridioides Difficile ◽

Gut Barrier Function ◽

Clostridioides Difficile Infection

Clostridioides difficile infection (CDI) remains a major global cause of gastrointestinal infection, with significant associated morbidity, mortality and impact upon healthcare system resources. Recent antibiotic use is a key risk factor for the condition, with the marked antibiotic-mediated perturbations in gut microbiome diversity and composition that underpin the pathogenesis of CDI being well-recognised. However, only relatively recently has further insight been gained into the specific mechanistic links between these gut microbiome changes and CDI, with alteration of gut microbial metabolites – in particular, bile acid metabolism – being a particular area of focus. A variety of in vitro, ex vivo, animal model and human studies have now demonstrated that loss of gut microbiome members with bile-metabolising capacity (including bile salt hydrolases, and 7-α-dehydroxylase) – with a resulting alteration of the gut bile acid milieu – contributes significantly to the disease process in CDI. More specifically, this microbiome disruption results in the enrichment of primary conjugated bile acids (including taurocholic acid, which promotes the germination of C. difficile spores) and loss of secondary bile acids (which inhibit the growth of C. difficile, and may bind to and limit activity of toxins produced by C. difficile). These bile acid changes are also associated with reduced activity of the farnesoid X receptor pathway, which may exacerbate C. difficile colitis throughout its impact upon gut barrier function and host immune/inflammatory response. Furthermore, a key mechanism of efficacy of faecal microbiota transplant (FMT) in treating recurrent CDI has been shown to be restoration of gut microbiome bile metabolising functionality; ensuring the presence of this functionality among defined microbial communities (and other ‘next generation’ FMT products) designed to treat CDI may be critical to their success.

Download Full-text

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.

Download Full-text

Dynamics of the enterohepatic circulation of bile acids in healthy humans

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00476.2020 ◽

2021 ◽

Author(s):

Frans Stellaard ◽

Dieter Lütjohann

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Acid Metabolism ◽

Enterohepatic Circulation ◽

Feedback Inhibition ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Healthy Humans

Regulation of bile acid metabolism is normally discussed as the regulation of bile acid synthesis, which serves to compensate for intestinal loss in order to maintain a constant pool size. After a meal, bile acids start cycling in the enterohepatic circulation. Farnesoid X receptor-dependent ileal and hepatic processes lead to negative feedback inhibition of bile acid synthesis. When the intestinal bile acid flux decreases, the inhibition of synthesis is released. The degree of inhibition of synthesis and the mechanism and degree of activation are still unknown. Moreover, in humans, a biphasic diurnal expression pattern of bile acid synthesis has been documented, indicating maximal synthesis around 3 pm and 9 pm. Quantitative data on the hourly synthesis schedule as compensation for intestinal loss are lacking. In this review, we describe the classical view on bile acid metabolism and present alternative concepts that are based on the overlooked feature that bile acids transit through the enterohepatic circulation very rapidly. A daily profile of the cycling and total bile acid pool sizes and potential controlled and uncontrolled mechanisms for synthesis are predicted. It remains to be elucidated by which mechanism clock genes interact with the Farnesoid X receptor-controlled regulation of bile acid synthesis. This mechanism could become an attractive target to enhance bile acid synthesis at night, when cholesterol synthesis is high, thus lowering serum LDL-cholesterol.

Download Full-text

Bile Acid Signaling in Neurodegenerative and Neurological Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms21175982 ◽

2020 ◽

Vol 21 (17) ◽

pp. 5982

Author(s):

Stephanie M. Grant ◽

Sharon DeMorrow

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Neurological Diseases ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Sphingosine 1 Phosphate ◽

The Central Nervous System ◽

Membrane Bound ◽

Bile Acid Receptors ◽

Cholestatic Diseases

Bile acids are commonly known as digestive agents for lipids. The mechanisms of bile acids in the gastrointestinal track during normal physiological conditions as well as hepatic and cholestatic diseases have been well studied. Bile acids additionally serve as ligands for signaling molecules such as nuclear receptor Farnesoid X receptor and membrane-bound receptors, Takeda G-protein-coupled bile acid receptor and sphingosine-1-phosphate receptor 2. Recent studies have shown that bile acid signaling may also have a prevalent role in the central nervous system. Some bile acids, such as tauroursodeoxycholic acid and ursodeoxycholic acid, have shown neuroprotective potential in experimental animal models and clinical studies of many neurological conditions. Alterations in bile acid metabolism have been discovered as potential biomarkers for prognosis tools as well as the expression of various bile acid receptors in multiple neurological ailments. This review explores the findings of recent studies highlighting bile acid-mediated therapies and bile acid-mediated signaling and the roles they play in neurodegenerative and neurological diseases.

Download Full-text

Circulating bile acids as a link between the gut microbiota and cardiovascular health: Impact of Prebiotics, probiotics and polyphenol-rich foods

Nutrition Research Reviews ◽

10.1017/s0954422421000081 ◽

2021 ◽

pp. 1-54

Author(s):

R.A.G. Pushpass ◽

S. Alzoufairi ◽

K.G. Jackson ◽

J.A. Lovegrove

Keyword(s):

Bile Acid ◽

Gut Microbiota ◽

Bile Acids ◽

Cardiovascular Health ◽

Acid Metabolism ◽

Cholesterol Metabolism ◽

Human Studies ◽

Bile Acid Metabolism ◽

Risk Markers ◽

Cvd Risk

Abstract Beneficial effects of probiotic, prebiotic and polyphenol-rich interventions on fasting lipid profiles have been reported, with changes in the gut microbiota composition believed to play an important role in lipid regulation. Primary bile acids, which are involved in the digestion of fats and cholesterol metabolism, can be converted by the gut microbiota to secondary bile acids, some species of which are less well reabsorbed and consequently may be excreted in the stool. This can lead to increased hepatic bile acid neo-synthesis, resulting in a net loss of circulating low density lipoprotein. Bile acids may therefore provide a link between the gut microbiota and cardiovascular health. This narrative review presents an overview of bile acid metabolism and the role of probiotics, prebiotics and polyphenol-rich foods in modulating circulating cardiovascular disease (CVD) risk markers and bile acids. Although findings from human studies are inconsistent, there is growing evidence for associations between these dietary components and improved lipid CVD risk markers, attributed to modulation of the gut microbiota and bile acid metabolism. These include increased bile acid neo-synthesis, due to bile sequestering action, bile salt metabolising activity and effects of short chain fatty acids generated through bacterial fermentation of fibres. Animal studies have demonstrated effects on the FXR/FGF-15 axis and hepatic genes involved in bile acid synthesis (CYP7A1) and cholesterol synthesis (SREBP and HMGR). Further human studies are needed to determine the relationship between diet and bile acid metabolism and whether circulating bile acids can be utilised as a potential CVD risk biomarker.

Download Full-text

Combined use of epigallocatechin-3-gallate (EGCG) and caffeine in low doses exhibits marked anti-obesity synergy through regulation of gut microbiota and bile acid metabolism

Food & Function ◽

10.1039/d0fo01768j ◽

2021 ◽

Author(s):

Ming-zhi Zhu ◽

Fang Zhou ◽

Jian Ouyang ◽

Qi-ye Wang ◽

Yi-long Li ◽

...

Keyword(s):

Bile Acid ◽

Synergistic Effect ◽

Gut Microbiota ◽

Acid Metabolism ◽

Bile Acid Metabolism ◽

Low Doses ◽

Combined Use

Combined use of epigallocatechin-3-gallate (EGCG) and caffeine in low doses exhibits marked anti-obesity synergy. The synergistic effect may be attributed to regulation of gut microbiota and BA metabolism.

Download Full-text