Intestinal flora and bile acid interactions impact the progression of diabetic kidney disease.

In recent years, with the rapid development of omics technologies, researchers have shown that interactions between the intestinal flora and bile acids are closely related to the progression of diabetic kidney disease (DKD). By regulating bile acid metabolism and receptor expression, the intestinal flora affects host metabolism, impacts the immune system, and exacerbates kidney injury in DKD patients. To explore interactions among the gut flora, bile acids and DKD, as well as the related mechanisms, in depth, in this paper, we review the existing literature on correlations among the gut flora, bile acids and DKD. This review also summarizes the efficacy of bile acids and their receptors as well as traditional Chinese medicines in the treatment of DKD and highlights the unique advantages of bile acid receptors in DKD treatment. This paper is expected to reveal a new and important potential strategy for the clinical treatment of DKD.

Pulsatilla decoction alleviates DSS-induced UC by activating FXR-ASBT pathways to ameliorate disordered bile acids homeostasis.

Ethnopharmacological relevance: Pulsatilla decoction (PD) is a classical prescription for the treatment of ulcerative colitis. Previous studies have demonstrated that the therapeutic efficacy of PD is closely associated with the activation of Farnesoid X receptor (FXR). The activity of FXR is regulated by apical sodium-dependent bile acid transporter (ASBT), and the FXR-ASBT cascade reaction, centered around bile acid receptor FXR, plays a pivotal role in maintaining bile acid metabolic homeostasis to prevent the occurrence and progression of ulcerative colitis (UC). Aim of the study: To elucidate the underlying mechanism by which PD exerts its proteactive effects against Dextran Sulfate Sodium Salt (DSS)-induced ulcerative colitis, focusing on the modulation of FXR and ASBT. Materials and methods: To establish a model of acute ulcerative colitis, BALB/C mice were administered 3.5% DSS in their drinking water for consecutive 7 days. The disease activity index (DAI) was employed to evaluate the clinical symptoms exhibited by each group of mice. Goblet cell expression in colon tissue was assessed using glycogen schiff periodic acid-Schiff (PAS) and alcian blue staining techniques. Inflammatory cytokine expression in serum and colonic tissues was examined through enzyme-linked immunosorbent assay (ELISA). A PCR Array chip was utilized to screen 88 differential genes associated with the FXR-ASBT pathway in UC treatment with PD. Western blotting (WB) analysis was performed to detect protein expression levels of differentially expressed genes in mouse colon tissue. Results: The PD treatment effectively reduced the Disease Activity Index (DAI) score and mitigated colon histopathological damage, while also restoring weight and colon length. Furthermore, it significantly alleviated the severity of ulcerative colitis (UC), regulated inflammation, modulated goblet cell numbers, and restored bile acid balance. Additionally, a PCR Array analysis identified 21 differentially expressed genes involved in the FXR-ASBT pathway. Western blot results demonstrated significant restoration of FXR, GPBAR1, CYP7A1, and FGF15 protein expression levels following PD treatment; moreover, there was an observed tendency towards increased expression levels of ABCB11 and RXRα. Conclusion: The therapeutic efficacy of PD in UC mice is notable, potentially attributed to its modulation of bile acid homeostasis, enhancement of gut barrier function, and attenuation of intestinal inflammation.

Advances in the pathophysiology, diagnosis and management of chronic diarrhoea from bile acid malabsorption: a systematic review.

Bile acid malabsorption (BAM) is an important disorder of digestive pathophysiology as it generates chronic diarrhoea. This condition originates from intricate pathways involving bile acid synthesis and metabolism in the liver and gut, the composition of gut microbiota, enterohepatic circulation and key receptors as farnesoid X receptor (FXR), fibroblast growth factor receptor 4 (FGFR4), and the G-protein bile acid receptor-1 (GPBAR-1). Although symptoms can resemble those related to disorders of gut brain interaction, accurate diagnosis of BAM may greatly benefit the patient. The empiric diagnosis of BAM is primarily based on the clinical response to bile acid sequestrants. Specific tests including the 48-hour fecal bile acid test, serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19), and the 75Selenium HomotauroCholic Acid Test (SeHCAT) are not widely available. Nevertheless, lack of diagnostic standardization of BAM may account for poor recognition and delayed management. Beyond bile acid sequestrants, therapeutic approaches include the use of FXR agonists, FGF19 analogues, glucagon-like peptide-1 (GLP-1) receptor agonists, and microbiota modulation. These novel agents can best make their foray into the therapeutic armamentarium if BAM does not remain a diagnosis of exclusion. Ignoring BAM as a specific condition may continue to contribute to increased healthcare costs and reduced quality of life. Here, we aim to provide a comprehensive review of the pathophysiology, diagnosis, and management of BAM.

Genipin improves obesity through promoting bile secretion and changing bile acids composition in diet-induced obese rats.

OBJECTIVES: Bile acids (BAs), as signaling molecules to regulate metabolism, have received considerable attention. Genipin is an iridoid compound extracted from Fructus Gradeniae, which has been shown to relieve adiposity and metabolic syndrome. Here, we investigated the mechanism of genipin counteracting obesity and its relationship with BAs signals in diet-induced obese (DIO) rats. METHODS: The DIO rats were received intraperitoneal injections of genipin for 10 days. The body weight, visceral fat, lipid metabolism in the liver, thermogenic genes expressions in brown fat, BAs metabolism and signals, and key enzymes for BAs synthesis were determined. KEY FINDINGS: Genipin inhibited fat synthesis and promoted lipolysis in the liver, and upregulated thermogenic gene expressions in brown adipose tissue of DIO rats. Genipin increased bile flow rate and upregulated the expressions of aquaporin 8 and the transporters of BAs in liver. Furthermore, genipin changed BAs composition by promoting alternative pathways and inhibiting classical pathways for BAs synthesis and upregulated the expressions of bile acid receptors synchronously. CONCLUSIONS: These results suggest that genipin ameliorate obesity through BAs-mediated signaling pathways.

Bile acids and coronavirus disease 2019.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been significantly alleviated. However, long-term health effects and prevention strategy remain unresolved. Thus, it is essential to explore the pathophysiological mechanisms and intervention for SARS-CoV-2 infection. Emerging research indicates a link between COVID-19 and bile acids, traditionally known for facilitating dietary fat absorption. The bile acid ursodeoxycholic acid potentially protects against SARS-CoV-2 infection by inhibiting the farnesoid X receptor, a bile acid nuclear receptor. The activation of G-protein-coupled bile acid receptor, another membrane receptor for bile acids, has also been found to regulate the expression of angiotensin-converting enzyme 2, the receptor through which the virus enters human cells. Here, we review the latest basic and clinical evidence linking bile acids to SARS-CoV-2, and reveal their complicated pathophysiological mechanisms.

Gpbar-1/cAMP/PKA signaling mitigates macrophage-mediated acute cholestatic liver injury via antagonizing NLRP3-ASC inflammasome.

Acute cholestatic liver injury (ACLI) is a disease associated with bile duct obstruction that causes liver inflammation and apoptosis. Although G protein-coupled bile acid receptor1 (Gpbar-1) has diverse metabolic roles, its involvement in ACLI-associated immune activation remains unclear. Liver tissues and blood samples from 20 patients with ACLI and 20 healthy individuals were analyzed using biochemical tests, H&E staining, western blotting, and immunohistochemistry to verify liver damage and expression of Gpbar-1. The expression of Gpbar-1, cAMP/PKA signaling, and the NLRP3 inflammasome was tested in wild-type (WT) and Gpbar-1 knockdown (si-Gpbar-1) mice with ACLI induced by bile duct ligation (BDL) and in primary Kupffer cells (KCs) with or without Gpbar-1-siRNA. The results showed that total bile acids and Gpbar-1 expressions were elevated in patients with ACLI. Gpbar-1 knockdown significantly worsened BDL-induced acute hepatic damage, inflammation, and liver apoptosis in vivo. Knockdown of Gpbar-1 heightened KC sensitivity to lipopolysaccharide (LPS) stimulation. Gpbar-1 activation inhibited LPS-induced pro-inflammatory responses in normal KCs but not in Gpbar-1-knockdown KCs. Notably, NLRP3-ASC inflammasome expression was effectively enhanced by Gpbar-1 deficiency. Additionally, Gpbar-1 directly increased intracellular cAMP levels and PKA phosphorylation, thus disrupting the NLRP3-ASC inflammasome. The pro-inflammatory characteristic of Gpbar-1 deficiency was almost neutralized by the NLRP3 inhibitor CY-09. In vitro, M1 polarization was accelerated in LPS-stimulated Gpbar-1-knockdown KCs. Therapeutically, Gpbar-1 deficiency exacerbated BDL-induced ACLI, which could be rescued by inhibition of the NLRP3-ASC inflammasome. Our study reveal that Gpbar-1 may act as a novel immune-mediated regulator of ACLI by inhibiting the NLRP3-ASC inflammasome.

FXR Agonism with Bile Acid Mimetic Reduces Pre-Clinical Triple-Negative Breast Cancer Burden.

Bariatric surgery is associated with improved outcomes for several cancers, including breast cancer (BC), although the mechanisms mediating this protection are unknown. We hypothesized that elevated bile acid pools detected after bariatric surgery may be factors that contribute to improved BC outcomes. Patients with greater expression of the bile acid receptor FXR displayed improved survival in specific aggressive BC subtypes. FXR is a nuclear hormone receptor activated by primary bile acids. Therefore, we posited that activating FXR using an established FDA-approved agonist would induce anticancer effects. Using in vivo and in vitro approaches, we determined the anti-tumor potential of bile acid receptor agonism. Indeed, FXR agonism by the bile acid mimetic known commercially as Ocaliva ("OCA"), or Obeticholic acid (INT-747), significantly reduced BC progression and overall tumor burden in a pre-clinical model. The transcriptomic analysis of tumors in mice subjected to OCA treatment revealed differential gene expression patterns compared to vehicle controls. Notably, there was a significant down-regulation of the oncogenic transcription factor MAX (MYC-associated factor X), which interacts with the oncogene MYC. Gene set enrichment analysis (GSEA) further demonstrated a statistically significant downregulation of the Hallmark MYC-related gene set (MYC Target V1) following OCA treatment. In human and murine BC analyses in vitro, agonism of FXR significantly and dose-dependently inhibited proliferation, migration, and viability. In contrast, the synthetic agonism of another common bile acid receptor, the G protein-coupled bile acid receptor TGR5 (GPBAR1) which is mainly activated by secondary bile acids, failed to significantly alter cancer cell dynamics. In conclusion, agonism of FXR by primary bile acid memetic OCA yields potent anti-tumor effects potentially through inhibition of proliferation and migration and reduced cell viability. These findings suggest that FXR is a tumor suppressor gene with a high potential for use in personalized therapeutic strategies for individuals with BC.

Intrahepatic cholestasis of pregnancy: insights into pathogenesis and advances in omics studies.

Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-specific liver disease. It is characterized by pruritus, abnormal liver function and elevated total bile acid (TBA) levels, increasing the risk of maternal and fetal adverse outcomes. Its etiology remains poorly elucidated. Over the years, various omics techniques, including metabolomics, microbiome, genomics, etc., have emerged with the advancement of bioinformatics, providing a new direction for exploring the pathogenesis, diagnosis and treatment of ICP. In this review, we first summarize the role of bile acids and related components in the pathogenesis of ICP and then further illustrate the results of omics studies.

Defective Bile Acid Signaling Promotes Vascular Dysfunction, Supporting a Role for G-Protein Bile Acid Receptor 1/Farnesoid X Receptor Agonism and Statins in the Treatment of Nonalcoholic Fatty Liver Disease.

BACKGROUND: Patients with nonalcoholic fatty liver disease are at increased risk to develop atherosclerotic cardiovascular diseases. FXR and GPBAR1 are 2 bile acid-activated receptors exploited in the treatment of nonalcoholic fatty liver disease: whether dual GPBAR1/FXR agonists synergize with statins in the treatment of the liver and cardiovascular components of nonalcoholic fatty liver disease is unknown. METHODS AND RESULTS: Investigations of human aortic samples obtained from patients who underwent surgery for aortic aneurysms and Gpbar1-/-, Fxr-/-, and dual Gpbar1-/-Fxr-/- mice demonstrated that GPBAR1 and FXR are expressed in the aortic wall and regulate endothelial cell/macrophage interactions. The expression of GPBAR1 in the human endothelium correlated with the expression of inflammatory biomarkers. Mice lacking Fxr and Gpbar1-/-/Fxr-/- display hypotension and aortic inflammation, along with altered intestinal permeability that deteriorates with age, and severe dysbiosis, along with dysregulated bile acid synthesis. Vasomotor activities of aortic rings were altered by Gpbar1 and Fxr gene ablation. In apolipoprotein E-/- and wild-type mice, BAR502, a dual GPBAR1/FXR agonist, alone or in combination with atorvastatin, reduced cholesterol and low-density lipoprotein plasma levels, mitigated the development of liver steatosis and aortic plaque formation, and shifted the polarization of circulating leukocytes toward an anti-inflammatory phenotype. BAR502/atorvastatin reversed intestinal dysbiosis and dysregulated bile acid synthesis, promoting a shift of bile acid pool composition toward FXR antagonists and GPBAR1 agonists. CONCLUSIONS: FXR and GPBAR1 maintain intestinal, liver, and cardiovascular homeostasis, and their therapeutic targeting with a dual GPBAR1/FXR ligand and atorvastatin holds potential in the treatment of liver and cardiovascular components of nonalcoholic fatty liver disease.

Curcumin Compensates GLP-1 Deficiency via the Microbiota-Bile Acids Axis and Modulation in Functional Crosstalk between TGR5 and FXR in ob/ob Mice.

SCOPE: Glucagon-like peptide-1 (GLP-1) deficiency occurs in obesity-related pathologies due to defects in the intestinal lumen. And expanding the L-cell population has emerged as a promising avenue to elevate GLP-1 secretion to tackle metabolic disorders. Curcumin (Cur), the principal active component of spice turmeric, possesses well-established anti-obesity properties. To clarify, the study investigates whether Cur promotes GLP-1 secretion built upon the L-cell expansion. METHODS AND RESULTS: Cur (60 mg kg-1 ) is administered orally to male ob/ob mice for 8 weeks. Cur ameliorates obesity and impaires glucose tolerance through increasing energy expenditure in ob/ob mice, accompanied by the maintenance of crypt architecture and gut permeability. It refines the microbial structure and bile acid (BA) profiles, resulting in deoxycholic acid (DCA) accumulation by weakening the enrichment of Lactobacillus. Further analyses show radically different properties of Cur on the intestine function of TGR5 and FXR (i.e., activation and repression). Cur amplifies L-cell number to promote GLP-1 secretion in ob/ob mice. CONCLUSIONS: The findings suggest that Cur may act as a natural TGR5 agonist and FXR antagonist to improve obesity by enhancing GLP-1 release from L-cell expansion via the gut microbiota-BAs-TGR5/FXR axis, and it may serve as a promising therapeutic agent to compensate obesity-related metabolic disorders.

The Crosstalk between Gut Microbiota and Bile Acids Promotes the Development of Non-Alcoholic Fatty Liver Disease.

Recently the roles of gut microbiota are highly regarded in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The intestinal bacteria regulate the metabolism of bile acids depending on bile salt hydrolase (BSH), 7-dehydroxylation, hydroxysteroid dehydrogenase (HSDH), or amide conjugation reaction, thus exerting effects on NAFLD development through bile acid receptors such as farnesoid X receptor (FXR), Takeda G-protein-coupled bile acid protein 5 (TGR5), and vitamin D receptor (VDR), which modulate nutrient metabolism and insulin sensitivity via interacting with downstream molecules. Reversely, the composition of gut microbiota is also affected by the level of bile acids in turn. We summarize the mutual regulation between the specific bacteria and bile acids in NAFLD and the latest clinical research based on microbiota and bile acids, which facilitate the development of novel treatment modalities in NAFLD.

Bile Acids, Intestinal Barrier Dysfunction, and Related Diseases.

The intestinal barrier is a precisely regulated semi-permeable physiological structure that absorbs nutrients and protects the internal environment from infiltration of pathological molecules and microorganisms. Bile acids are small molecules synthesized from cholesterol in the liver, secreted into the duodenum, and transformed to secondary or tertiary bile acids by the gut microbiota. Bile acids interact with bile acid receptors (BARs) or gut microbiota, which plays a key role in maintaining the homeostasis of the intestinal barrier. In this review, we summarize and discuss the recent studies on bile acid disorder associated with intestinal barrier dysfunction and related diseases. We focus on the roles of bile acids, BARs, and gut microbiota in triggering intestinal barrier dysfunction. Insights for the future prevention and treatment of intestinal barrier dysfunction and related diseases are provided.

Effect of gut flora mediated-bile acid metabolism on intestinal immune microenvironment.

According to reports, gut microbiota and metabolites regulate the intestinal immune microenvironment. In recent years, an increasing number of studies reported that bile acids (BAs) of intestinal flora origin affect T helper cells and regulatory T cells (Treg cells). Th17 cells play a pro-inflammatory role and Treg cells usually act in an immunosuppressive role. In this review, we emphatically summarised the influence and corresponding mechanism of different configurations of lithocholic acid (LCA) and deoxycholic acid (DCA) on intestinal Th17 cells, Treg cells and intestinal immune microenvironment. The regulation of BAs receptors G protein-coupled bile acid receptor 1 (GPBAR1/TGR5) and farnesoid X receptor (FXR) on immune cells and intestinal environment are elaborated. Furthermore, the potential clinical applications above were also concluded in three aspects. The above will help researchers better understand the effects of gut flora on the intestinal immune microenvironment via BAs and contribute to the development of new targeted drugs.

Taurochenodeoxycholic acid reduces astrocytic neuroinflammation and alleviates experimental autoimmune encephalomyelitis in mice.

OBJECTIVE: Multiple sclerosis (MS) is an immune regulatory disease that affects the central nervous system (CNS). The main pathological features include demyelination and neurodegeneration, and the pathogenesis is associated with astrocytic neuroinflammation. Taurochenodeoxycholic acid (TCDCA) is one of the conjugated bile acids in animal bile, and it is not clear whether TCDCA could improve MS by inhibiting the activation of astrocytes. This study was aimed to evaluate the effects of TCDCA on experimental autoimmune encephalomyelitis (EAE)-a classical animal model of MS, and to probe its mechanism from the aspect of suppressing astrocytic neuroinflammation. It is expected to prompt the potential application of TCDCA for the treatment of MS. RESULTS: TCDCA effectively alleviated the progression of EAE and improved the impaired neurobehavior in mice. It mitigated the hyperactivation of astrocytes and down-regulated the mRNA expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 in the brain cortex. In the C6 astrocytic cell line induced by lipopolysaccharide (LPS), TCDCA treatment dose-dependently decreased the production of NO and the protein expression of iNOS and glial fibrillary acidic protein (GFAP). TCDCA consistently inhibited the mRNA expressions of COX2, iNOS and other inflammatory mediators. Furthermore, TCDCA decreased the protein expression of phosphorylated serine/threonine kinase (AKT), inhibitor of NFκB α (IκBα) and nuclear factor κB (NFκB). And TCDCA also inhibited the nuclear translocation of NFκB. Conversely, as an inhibitor of the G-protein coupled bile acid receptor Gpbar1 (TGR5), triamterene eliminated the effects of TCDCA in LPS-stimulated C6 cells. CONCLUSION: TCDCA improves the progress of EAE by inhibiting the astrocytic neuroinflammation, which might be exerted by the regulation of TGR5 mediated AKT/NFκB signaling pathway. These findings may prompt the potential application of TCDCA for MS therapy by suppressing astrocyte inflammation.

Blueberry extract alleviated lipopolysaccharide-induced inflammation responses in mice through activating the FXR/TGR5 signaling pathway and regulating gut microbiota.

BACKGROUND: Blueberry extract (BE) is rich in phenols, especially anthocyanins. Anthocyanins regulate the inflammatory response in mice and may be related to gut microbiota and bile acid receptors. The aim of the present study was to explore the effects of BE on the inflammatory response by regulating gut microbiota and bile acid receptors in mice administered Escherichia coli lipopolysaccharide (LPS). METHOD: Thirty male KM mice were randomly divided into three groups: CON (control diet) group; LPS (LPS stimulation) group; and LPS + BE (LPS stimulation, 5% BE intervention) group. RESULTS: our results showed that, compared with the LPS group, the addition of BE decreased the level of inflammatory factors in serum and tissues, inhibited the TLR4/MyD88 signaling pathway, protected the intestinal barrier and activated FXR/TGR5, which was related to gut microbiota (especially Akkermansia). The active component (e.g., cyanidin 3-O-glucoside, C3G) in BE may be an important factor in regulating gut microbiota. CONCLUSION: BE alleviated the inflammatory response mainly by activating bile acid receptor expression and regulating the gut microbiota; this effect may be related to the composition of bioactive substances in BE. © 2023 Society of Chemical Industry.

The role of bile acids in regulating glucose and lipid metabolism.

In recent years, bile acids (BAs) are increasingly being appreciated as signaling molecules beyond their involvement in bile formation and fat absorption. The farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5) are two dominating receptors through which BAs modulate glucose and lipid metabolism. FXR is highly expressed in the intestine and liver. GPBAR1 is highly expressed in the intestine. The present study reviews the metabolism and regulation of BAs, especially the effects of BAs on glucose and lipid metabolism by acting on FXR in the liver and intestine, and GPBAR1 in the intestine. Furthermore, it explains that fibroblast growth factor 15/19 (FGF15/19), ceramide, and glucagon like peptide-1 (GLP-1) are all involved in the signaling pathways by which BAs regulate glucose and lipid metabolism. This article aims to provide an overview of the molecular mechanisms by which BAs regulate glucose and lipid metabolism, and promote further scientific and clinical research on BAs.

The discovery of 12ß-methyl-17-epi-18-nor-bile acids as potent and selective TGR5 agonists.

Recent discoveries have demonstrated that the physiological function of bile acids extends to the regulation of diverse signaling processes through interactions with nuclear and G protein-coupled receptors, most notably the Farnesoid-X nuclear receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5). Targeting such signaling pathways pharmacologically, i.e. with bile acid-derived therapeutics, presents great potential for the treatment of various metabolic, inflammatory immune, liver, and neurodegenerative diseases. Here we report the discovery of two potent and selective TGR5 agonists (NZP196 and 917). These compounds are the taurine conjugates of 6α-ethyl-substituted 12ß-methyl-18-nor-bile acids with the side chain being located on the α-face of the steroid scaffold. The compounds emerged from a screening effort of a diverse library of 12ß-methyl-18-nor-bile acids that were synthesized from 12ß-methyl-18-nor-chenodeoxycholic acid and its C17-epimer. Upon testing for FXR activity, both compounds were found to be inactive, thus revealing selectivity for TGR5.

Deoxyschizandrin ameliorates obesity and non-alcoholic fatty liver disease: Involvement of dual Farnesyl X receptor/G protein-coupled bile acid receptor 1 activation and leptin sensitization.

Natural dual farnesyl X receptor (FXR)/G protein-coupled bile acid receptor 1 (TGR5) activators have received little attention in the management of metabolic diseases. Deoxyschizandrin (DS), a natural lignan, occurs in S. chinensis fruit and has potent hepatoprotective effects, whereas its protective roles and mechanisms against obesity and non-alcoholic fatty liver disease (NAFLD) are largely elusive. Here, we identified DS as a dual FXR/TGR5 agonist using luciferase reporter and cyclic adenosine monophosphate (cAMP) assays. DS was orally or intracerebroventricularly administrated to high-fat diet-induced obesity (DIO) mice, and methionine and choline-deficient L-amino acid diet (MCD diet)-induced non-alcoholic steatohepatitis to evaluate its protective effects. Exogenous leptin treatment was employed to investigate the sensitization effect of DS on leptin. The molecular mechanism of DS was explored by Western blot, quantitative real-time PCR analysis, and ELISA. The results showed that DS activated FXR/TGR5 signaling and effectively reduced NAFLD in DIO and MCD diet-fed mice. DS countered obesity in DIO mice by promoting anorexia and energy expenditure and reversing leptin resistance, involving both peripheral and central TGR5 activation and leptin sensitization. Our findings indicate that DS may be a novel therapeutic approach for alleviating obesity and NAFLD through regulating FXR and TGR5 activities and leptin signaling.

The essential roles of FXR in diet and age influenced metabolic changes and liver disease development: a multi-omics study.

BACKGROUND: Aging and diet are risks for metabolic diseases. Bile acid receptor farnesoid X receptor (FXR) knockout (KO) mice develop metabolic liver diseases that progress into cancer as they age, which is accelerated by Western diet (WD) intake. The current study uncovers the molecular signatures for diet and age-linked metabolic liver disease development in an FXR-dependent manner. METHODS: Wild-type (WT) and FXR KO male mice, either on a healthy control diet (CD) or a WD, were euthanized at the ages of 5, 10, or 15 months. Hepatic transcriptomics, liver, serum, and urine metabolomics as well as microbiota were profiled. RESULTS: WD intake facilitated hepatic aging in WT mice. In an FXR-dependent manner, increased inflammation and reduced oxidative phosphorylation were the primary pathways affected by WD and aging. FXR has a role in modulating inflammation and B cell-mediated humoral immunity which was enhanced by aging. Moreover, FXR dictated neuron differentiation, muscle contraction, and cytoskeleton organization in addition to metabolism. There were 654 transcripts commonly altered by diets, ages, and FXR KO, and 76 of them were differentially expressed in human hepatocellular carcinoma (HCC) and healthy livers. Urine metabolites differentiated dietary effects in both genotypes, and serum metabolites clearly separated ages irrespective of diets. Aging and FXR KO commonly affected amino acid metabolism and TCA cycle. Moreover, FXR is essential for colonization of age-related gut microbes. Integrated analyses uncovered metabolites and bacteria linked with hepatic transcripts affected by WD intake, aging, and FXR KO as well as related to HCC patient survival. CONCLUSION: FXR is a target to prevent diet or age-associated metabolic disease. The uncovered metabolites and microbes can be diagnostic markers for metabolic disease.

Bile acid-gut microbiota crosstalk in irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction with an increasing prevalence, and its precise aetiology remains unclear. Gut microbiota dysbiosis has been found to be associated with IBS pathogenesis. In addition, a high incidence of bile acid diarrhoea and disturbed bile acid metabolism has been observed in IBS patients. The abundant microorganisms inhabited in human gut have essential functions in bile acid biotransformation, and can immensely affect the size and constitution of bile acid pool. Meanwhile, the alterations of bile acid profile can inversely interfere with the gut microbiota. This review discussed the role of intricate correlations between bile acids and gut microbiota in IBS pathogenesis and delineated the possible molecular mechanisms, mainly the signalling induced by farnesoid X receptor and transmembrane G protein-coupled receptor 5. Besides, some biomarkers for identifying bile acid diarrhoea in IBS population were listed, assisting the diagnosis and classification of IBS. Moreover, it also assessed some therapeutic strategies for IBS that regulate the bile acid-gut microbiota axis, such as dietary modulation, probiotics/prebiotics, faecal microbiota transplantation, and antibiotics. Collectively, this article illustrated the relationship between bile acids and gut microbiota in IBS pathophysiology and might offer some novel therapeutic options for IBS.