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Enterohepatic circulation of bile acids: anatomical overview. Primary bile acids (BA; indicated as green dots) are released into bile canaliculi and secreted into the duodenum, where they mediate absorption of nutrients, for example emulsification of lipids and fat‐soluble vitamins, and regulate signalling pathways in the gut‐liver axis. Metabolisation of BA by gut bacteria leads to the formation of secondary BAs. Most BAs undergo enterohepatic circulation: the highest proportion of BAs is reabsorbed in the ileum, transported into the portal circulation, and delivered back to the liver via the portal vein. After reuptake in hepatocytes, BAs are recycled and secreted into the bile, and again reach the gut, thus completing the enterohepatic cycle. Abbreviation: BA, bile acid
Source publication
Background
Bile acids are important endocrine modulators of intestinal and hepatic signalling cascades orchestrating critical pathophysiological processes in various liver diseases. Increasing knowledge on bile acid signalling has stimulated the development of synthetic ligands of nuclear bile acid receptors and other bile acid analogues.
Aim
This...
Citations
... Gut microbes metabolize primary BAs (cholic acid and chenodeoxycholic acid) via deconjugation, oxidation/epimerization, (7-a-) dehydroxylation, and esterification, pro-ducing secondary BAs and modulating the affinity of BAs for their receptors. [78][79][80] Deconjugation occurs via bile salt hydrolases (BSH) found in Firmicutes, Bacteroidetes and Actinobacteria, leading to better reabsorption of BAs and bacterial nutrition (source of sulfur, nitrogen and carbon). 81 The most important secondary BAs are ursodeoxycholic acid (UDCA), deoxycholic acid (DCA) and lithocholic acid (LCA). ...
... 74 BAs are necessary for nutrient absorption, although the effect depends on their concentration, hydrophilic/hydrophobic ratio, as BAs may also cause damage to the liver under certain circumstances. 80,86 The hydrophilic/hydrophobic ratio reflects the concentration of hydrophilic BAs, such as UDHA, and hydrophobic bile acids (BAs), including lithocholic acid (LCA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), taurine conjugated BAs, and so on. The more hydrophobic BA is, the more toxic effects it has, so hydrophilic and hydrophobic BAs should be balanced to maintain GI health. ...
... Cen Xie et al. were able to selectively inhibit intestinal FXR signaling by supplementing caffeic acid phenethyl ester (CAPE) to increase tauro-βmuricholic acid levels (an FXR inhibitor) in high-fat diet-fed mice to ameliorate glucose metabolism dysfunction and regulate hepatic glucose isomerization through the intestinal FXR-ceramide pathway [102]. The TGR5 receptor activation by bile acids can mediate critical signal transduction pathways such as nuclear factor-κB (NF-κB), protein kinase B (AKT), extracellular regulated protein kinases (ERK), and signal transducer and activator of transcription 3 (STAT3) [103]. Among them, the TGR5-AKT-mTORC and TGR5-AKT-ERK1/2 pathways are involved in regulating metabolism, alleviating insulin resistance, regulating hepatic lipid metabolism, and ameliorating metabolic disorders [104,105]. ...
Unhealthy lifestyles (high-fat diet, smoking, alcohol consumption, too little exercise, etc.) in the current society are prone to cause lipid metabolism disorders affecting the health of the organism and inducing the occurrence of diseases. Saponins, as biologically active substances present in plants, have lipid-lowering, inflammation-reducing, and anti-atherosclerotic effects. Saponins are thought to be involved in the regulation of lipid metabolism in the body; it suppresses the appetite and, thus, reduces energy intake by modulating pro-opiomelanocortin/Cocaine amphetamine regulated transcript (POMC/CART) neurons and neuropeptide Y/agouti-related peptide (NPY/AGRP) neurons in the hypothalamus, the appetite control center. Saponins directly activate the AMP-activated protein kinase (AMPK) signaling pathway and related transcriptional regulators such as peroxisome-proliferator-activated-receptors (PPAR), CCAAT/enhancer-binding proteins (C/EBP), and sterol-regulatory element binding proteins (SREBP) increase fatty acid oxidation and inhibit lipid synthesis. It also modulates gut–liver interactions to improve lipid metabolism by regulating gut microbes and their metabolites and derivatives—short-chain fatty acids (SCFAs), bile acids (BAs), trimethylamine (TMA), lipopolysaccharide (LPS), et al. This paper reviews the positive effects of different saponins on lipid metabolism disorders, suggesting that the gut–liver axis plays a crucial role in improving lipid metabolism processes and may be used as a therapeutic target to provide new strategies for treating lipid metabolism disorders.
... Bile acids are metabolized by gut bacteria-derived enzymes and have a profound effect on each other [34]. The conjugated bile acids are believed to indicate liver dysfunction in cirrhosis or chronic hepatitis [35]. In this study, the GHCA, TCDCA, GCA, and TCA levels in this positive subgroup were significantly higher than those in the negative controls (P<0.05, ...
... This multidirectional regulatory axis represents an interactive network between the central nervous system and the gastrointestinal tract, involving multiple systems, such as the nervous, endocrine, and immune systems. It operates through both top-down and bottom-up interactions to regulate mood and gastrointestinal functions [6,7]. Stress and adverse emotions activate the braingut-related bio-axis, and the CRH system can activate CRH-R1 thereby enhancing IgE-mediated allergic responses and triggering MCs degranulation in response to psychological stress [8]. ...
Aim of the study
To evaluate the therapeutic effect of SYNC in diarrhea irritable bowel syndrome (IBS-D) and explore its underlying mechanism through transcriptomic sequencing (RNA-Seq).
Materials and methods
A rat model of IBS-D was constructed to elucidate the effects of SYNC. Abdominal withdrawal reflex (AWR), fecal water content (FWC), and recording body weight were calculated to assess visceral sensitivity in rats. Histopathological changes in the colon and alterations in mast cell (MC) count were determined. Immunohistochemistry was employed to assess mast cell tryptase (MCT) expression in rat colons. Serum levels of corticotropin-releasing Hormone (CRH), interleukin-6 (IL-6), calcitonin gene-related peptide (CGRP), and 5-hydroxytryptamine (5-HT) were quantified using ELISA. RNA-Seq of colon tissue was performed, followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Western blot analysis was conducted to quantify the expression levels of key proteins in the Nr4a3 pathway in the colon and hypothalamus tissues of rats.
Results
SYNC alleviated visceral hypersensitivity and mood disorders in rats with IBS-D. Moreover, it was positively correlated with its dosage and the observed effects, such as the enhancement of the colon’s mucosal lining condition and reduction in the number and activation of MCs within the model group. SYNC reduced the expression levels of factors related to the brain-gut axis and inflammatory markers in the bloodstream. RNA-Seq analysis indicated that SYNC down-regulated the expression of Nr4a3 and PI3K. These SYNC-targeted genes primarily played roles in immune regulation and inflammatory responses, correlating with the modulation of Nr4a3 and the PI3K/AKT pathway. Western blot analysis further confirmed SYNC’s influence on inflammation-related MC activation by downregulating key proteins in the Nr4a3/PI3K pathway.
Conclusions
SYNC inhibited mast cell activation and attenuated visceral hypersensitivity in the colon tissues of IBS-D rats. These effects were mediated by the Nr4a3/PI3K signaling pathway.
... Bile acids are steroidal compounds derived from cholesterol that are critical for the digestion of dietary lipids. These endogenous compounds are fundamental in the regulation of multiple metabolic processes, including cholesterol and insulin homeostasis [64]. Bile acid concentrations within the gastrointestinal tract are tightly regulated by the cholehepatic shunt and enterohepatic recirculation pathways to maintain digestive homeostasis ( Figure 2) [18]. ...
A large percentage (~60%) of prescription drugs and new molecular entities are designed for oral delivery, which requires passage through a semi-impervious membrane bilayer in the gastrointestinal wall. Passage through this bilayer can be dependent on membrane transporters that regulate the absorption of nutrients or endogenous substrates. Several investigations have provided links between nutrient, endogenous substrate, or drug absorption and the activity of certain membrane transporters. This knowledge has been key in the development of new therapeutics that can alleviate various symptoms of select diseases, such as cholestasis and diabetes. Despite this progress, recent studies revealed potential clinical dangers of unintended altered nutrient or endogenous substrate disposition due to the drug-mediated disruption of intestinal transport activity. This review outlines reports of glucose, folate, thiamine, lactate, and bile acid (re)absorption changes and consequent adverse events as examples. Finally, the need to comprehensively expand research on intestinal transporter-mediated drug interactions to avoid the unwanted disruption of homeostasis and diminish therapeutic adverse events is highlighted.
... Farnesoid X receptor (FXR) is the most important endogenous receptor for bile acids (BA) and highly expressed in the liver and intestines [1]. FXR signaling modulates the synthesis and enterohepatic circulation of BAs, hepatic inflammation and fibrogenesis, and intestinal defence mechanisms protecting against bacterial translocation (BT) from the gut [2]. Activation of FXR in the intestines leads to the intestinal release of fibroblast growth factor-19 (FGF19), which is secreted into the portal vein and leads to suppression of hepatic BA synthesis, thus, acting as an important feedback mechanism [2]. ...
... FXR signaling modulates the synthesis and enterohepatic circulation of BAs, hepatic inflammation and fibrogenesis, and intestinal defence mechanisms protecting against bacterial translocation (BT) from the gut [2]. Activation of FXR in the intestines leads to the intestinal release of fibroblast growth factor-19 (FGF19), which is secreted into the portal vein and leads to suppression of hepatic BA synthesis, thus, acting as an important feedback mechanism [2]. ...
... Systemic BA exhibited a positive association with hepatic Figure S5). Based on conflicting data from studies whether the liver expresses FGF19 under pathological conditions [2], we evaluated hepatic FGF19 expression in liver biopsies. FGF19 mRNA was only detected in 57% (n = 28/49; n = 4 not analysed due to limited cDNA availability) of liver biopsies. ...
Background and aims
Experimental studies linked dysfunctional Farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling to liver disease. This study investigated key intersections of the FXR-FGF19 pathway along the gut–liver axis and their link to disease severity in patients with cirrhosis.
Methods
Patients with cirrhosis undergoing hepatic venous pressure gradient measurement (cohort-I n = 107, including n = 53 with concomitant liver biopsy; n = 5 healthy controls) or colonoscopy with ileum biopsy (cohort-II n = 37; n = 6 controls) were included. Hepatic and intestinal gene expression reflecting FXR activation and intestinal barrier integrity was assessed. Systemic bile acid (BA) and FGF19 levels were measured.
Results
Systemic BA and FGF19 levels correlated significantly ( r = 0.461; p < 0.001) and increased with cirrhosis severity. Hepatic SHP expression decreased in patients with cirrhosis (vs. controls; p < 0.001), indicating reduced FXR activation in the liver. Systemic FGF19 ( r = −0.512, p < 0.001) and BA ( r = −0.487, p < 0.001) levels correlated negatively with hepatic CYP7A1, but not SHP or CYP8B1 expression, suggesting impaired feedback signaling in the liver. In the ileum, expression of FXR, SHP and FGF19 decreased in patients with cirrhosis, and interestingly, intestinal FGF19 expression was not linked to systemic FGF19 levels. Intestinal zonula occludens-1, occludin, and alpha-5-defensin expression in the ileum correlated with SHP and decreased in patients with decompensated cirrhosis as compared to controls.
Conclusions
FXR-FGF19 signaling is dysregulated at essential molecular intersections along the gut–liver axis in patients with cirrhosis. Decreased FXR activation in the ileum mucosa was linked to reduced expression of intestinal barrier proteins. These human data call for further mechanistic research on interventions targeting the FXR-FGF19 pathway in patients with cirrhosis.
Clinical trial number: NCT03267615
Graphical abstract
Physiology of enterohepatic FXR-FGF19 signaling and its regulation in patients with advanced chronic liver disease (ACLD). (FXR) farnesoid X receptor; (FGF19) fibroblast growth factor 19; (BA) bile acids; (c/dACLD) compensated/decompensated advanced chronic liver disease; (FXR) farnesoid X receptor; (SHP) small heterodimer partner; (OST-α/-β) organic solute transporter subunit alpha/beta; (CYP7A1) cholesterol 7 alpha-hydroxylase; (NTCP) Na+-taurocholate cotransporting polypeptide; (CYP8B1) sterol 12-alpha-hydroxylase; (HVPG) hepatic venous pressure gradient; (TJ) tight junctions; (AMP) antimicrobial peptides; (ASBT) Apical Sodium Dependent Bile Acid Transporter; (ZO 1) zonula occludens-1; (OCLN) occluding; (DEFA5) alpha-5-defensin.
... FXR is highly expressed in both the intestines and the liver and is beneficial for intestinal barrier function and hepatic lipid metabolism. Currently, FXR agonists such as obeticholic acid are potential drugs for treating NAFLD and have entered the clinical trial phase (Simbrunner et al., 2021). Research has shown that berberine can alter the BA profile in NAFLD mice and increase FXR expression (Wang et al., 2021), suggesting that BAs could be one of the potential targets for DZF in regulating the gut-liver axis. ...
Introduction: Hepatic steatosis is a hepatic pathological change closely associated with metabolic disorders, commonly observed in various metabolic diseases such as metabolic syndrome (MetS), with a high global prevalence. Dai-Zong-Fang (DZF), a traditional Chinese herbal formula, is widely used in clinical treatment for MetS, exhibiting multifaceted effects in reducing obesity and regulating blood glucose and lipids. This study aims to explore the mechanism by which DZF modulates the gut microbiota and reduces hepatic steatosis based on the gut-liver axis.
Methods: This study utilized db/db mice as a disease model for drug intervention. Body weight and fasting blood glucose were monitored. Serum lipid and transaminase levels were measured. Insulin tolerance test was conducted to assess insulin sensitivity. Hematoxylin and eosin (HE) staining was employed to observe morphological changes in the liver and intestine. The degree of hepatic steatosis was evaluated through Oil Red O staining and hepatic lipid determination. Changes in gut microbiota were assessed using 16S rRNA gene sequencing. Serum lipopolysaccharide (LPS) levels were measured by ELISA. The expression levels of intestinal tight junction proteins, intestinal lipid absorption-related proteins, and key proteins in hepatic lipid metabolism were examined through Western blot and RT-qPCR.
Results: After DZF intervention, there was a decrease in body weight, alleviation of glucose and lipid metabolism disorders, reduction in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and mitigation of insulin resistance in mice. DZF significantly modulated the diversity of the gut microbiota, with a notable increase in the abundance of the Bacteroidetes phylum. PICRUSt indicated that DZF influenced various functions in gut microbiota, including carbohydrate and amino acid metabolism. Following DZF intervention, serum LPS levels decreased, intestinal pathological damage was reduced, and the expression of intestinal tight junction protein occludin was increased, while the expression of intestinal lipid absorption-related proteins cluster of differentiation 36 (CD36) and apolipoprotein B48 (ApoB48) were decreased. In the liver, DZF intervention resulted in a reduction in hepatic steatosis and lipid droplets, accompanied by a decrease fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1) and fatty acid transport protein 2 (FATP2). Conversely, there was an increase in the expression of the fatty acid oxidation-related enzyme carnitine palmitoyltransferase-1𝛂 (CPT-1𝛂).
Conclusion: DZF can regulate the structure and function of the intestinal microbiota in db/db mice. This ameliorates intestinal barrier damage and the detrimental effects of endotoxemia on hepatic metabolism. DZF not only inhibits intestinal lipid absorption but also improves hepatic lipid metabolism from various aspects, including de novo lipogenesis, fatty acid uptake, and fatty acid oxidation. This suggests that DZF may act on the liver and intestine as target organs, exerting its effects by improving the intestinal microbiota and related barrier and lipid absorption functions, ultimately ameliorating hepatic steatosis and enhancing overall glucose and lipid metabolism.
... The gDNA integrity was detected by 0.8% agarose electrophoresis, followed by nucleic acid concentration detection using PicoGreen fluorescent dye (Shanghai Haling Biological Technology Co., Ltd., Shanghai, China). PCR amplification of the full-length fragment of the 16S rDNA gene of the sample was performed by synthesizing specific (3,28), p = 0.0175) and AST (F (DFn, DFd) = 2.309 (3,28), p = 0.0981) in mouse serum using ELISA. C The release of pro-inflammatory cytokines IL-6 (F (DFn, DFd) = 4.631 (3,28), p = 0.0094), IFN-γ (F (DFn, DFd) = 5.038 (3,28), p = 0.0065), and TNF-α (F (DFn, DFd) = 1.701 (3,28), p = 0.1895) in mouse serum using ELISA. ...
... The gDNA integrity was detected by 0.8% agarose electrophoresis, followed by nucleic acid concentration detection using PicoGreen fluorescent dye (Shanghai Haling Biological Technology Co., Ltd., Shanghai, China). PCR amplification of the full-length fragment of the 16S rDNA gene of the sample was performed by synthesizing specific (3,28), p = 0.0175) and AST (F (DFn, DFd) = 2.309 (3,28), p = 0.0981) in mouse serum using ELISA. C The release of pro-inflammatory cytokines IL-6 (F (DFn, DFd) = 4.631 (3,28), p = 0.0094), IFN-γ (F (DFn, DFd) = 5.038 (3,28), p = 0.0065), and TNF-α (F (DFn, DFd) = 1.701 (3,28), p = 0.1895) in mouse serum using ELISA. ...
... PCR amplification of the full-length fragment of the 16S rDNA gene of the sample was performed by synthesizing specific (3,28), p = 0.0175) and AST (F (DFn, DFd) = 2.309 (3,28), p = 0.0981) in mouse serum using ELISA. C The release of pro-inflammatory cytokines IL-6 (F (DFn, DFd) = 4.631 (3,28), p = 0.0094), IFN-γ (F (DFn, DFd) = 5.038 (3,28), p = 0.0065), and TNF-α (F (DFn, DFd) = 1.701 (3,28), p = 0.1895) in mouse serum using ELISA. D The representative images of the livers. ...
Background
Dysbiosis of gut microbiota is frequent in liver cirrhosis (LC) patients, and splenectomy (SP) has been reported to improve LC. Herein, we report the effects of SP on gut microbiota, especially on Veillonella parvula, a Gram-negative coccus of the gastrointestinal tract, in LC mice, and the underlying mechanism.
Methods
LC mice models were induced by tail vein injection of concanavalin A (ConA), followed by SP. 16 s rRNA sequencing was conducted to analyze the effects of ConA induction and SP on mouse gut microbiota and the gene expression affected by gut microbiota. LC mice receiving SP were gavaged with Veillonella parvula. Likewise, hepatic stellate cells (HSC) and hepatocytes (HC) were induced with conditioned medium (CM) of Veillonella parvula.
Results
SP alleviated LC in mice by restoring gut barrier function and maintaining gut microbiota balance, with Veillonella as the key genus. The Veillonella parvula gavage on LC mice reversed the ameliorative effect of SP. The CM of Veillonella parvula promoted the activation of HSC and the release of IL-6, IL-1β, and TNF-α. Also, the CM of Veillonella parvula induced HC pyroptosis and the release of ALT and AST. Veillonella parvula represented an imbalance in the gut microbiota, thus enhancing gut-derived endotoxins in the liver with the main target being Tlr4/Nlrp3. Inhibition of Tlr4 blocked Veillonella parvula-induced HC damage, HSC activation, and subsequent LC progression.
Conclusion
SP-mediated gut microbiota regulation ameliorates ConA-related LC progression by inhibiting Tlr4/Nlrp3 in the liver.
... Among them, some microbial metabolites are called intestinal microbial derived signals, which play a key signal regulation role in the gut-liver axis. For example, the liver secretes bile acids into the intestine (Schneider, Albers and Trautwein 2018;Simbrunner, Trauner and Reiberger 2021). In addition to assisting digestion of fat-soluble nutrients in the diet, it can directly inhibit the growth of specific bacterial groups in the gut and indirectly stimulate the production of antimicrobials in the gut to regulate the gut microbiota, thereby playing a vital role in protecting the key components of the gut-liver axis and the formation of the gut microbiota. ...
An imbalance between energy consumption and energy expenditure causes obesity. It is characterized by increased adipose accumulation and accompanied by chronic low-grade inflammation. Many studies have suggested that the gut microbiota of the host mediates the relationship between high-fat diet consumption and the development of obesity. Diet and nutrition of the body are heavily influenced by gut microbiota. The alterations in the microbiota in the gut may have effects on the homeostasis of the host's energy levels, systemic inflammation, lipid metabolism, and insulin sensitivity. The liver is an important organ for fat metabolism and gut-liver axis play important role in the fat metabolism. Gut-liver axis is a bidirectional relationship between the gut and its microbiota and the liver. As essential plant components, lignans have been shown to have different biological functions. Accumulating evidences have suggested that lignans may have lipid-lowering properties. Lignans can regulate the level of the gut microbiota and their metabolites in the host, thereby affecting signaling pathways related to fat synthesis and metabolism. These signaling pathways can make a difference in inhibiting fat accumulation, accelerating energy metabolism, affecting appetite, and inhibiting chronic inflammation. It will provide the groundwork for future studies on the lipid-lowering impact of lignans and the creation of functional meals based on those findings.
... Thus, it is likely that microbial translocation might be, at least in part, linked to altered specific composition of gut microbiota, rather than related to gut barrier dysfunction after DAA therapy. Alternatively, these observations may be associated with the improvement of liver function following achieved SVR, which results in enhanced production of bile acids that could exert direct antimicrobial defense and ameliorate bacterial translocation via farnesoid X receptor (FXR) signaling 28 . ...
Long-term effect of Direct-acting antivirals (DAAs) on gut microbiota, short-chain fatty acids (SCFAs) and microbial translocation in patients with hepatitis C virus (HCV) infection who achieve sustained virological response (SVR) were limited. A longitudinal study of 50 patients with HCV monoinfection and 19 patients with HCV/HIV coinfection received DAAs were conducted. Fecal specimens collected at baseline and at week 72 after treatment completion (FUw72) were analyzed for 16S rRNA sequencing and the butyryl-CoA:acetateCoA transferase (BCoAT) gene expression using real-time PCR. Plasma lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) were quantified by ELISA assays. SVR rates in mono- and coinfected patients were comparable (94% vs. 100%). The improvement of gut dysbiosis and microbial translocation was found in responders but was not in non-responders. Among responders, significant restoration of alpha-diversity, BCoAT and LBP were observed in HCV patients with low-grade fibrosis (F0–F1), while HCV/HIV patients exhibited partial improvement at FUw72. I-FABP did not decline significantly in responders. Treatment induced microbiota changes with increasing abundance of SCFAs-producing bacteria, including Blautia, Fusicatenibacter, Subdoligranulum and Bifidobacterium. In conclusion, long-term effect of DAAs impacted the restoration of gut dysbiosis and microbial translocation. However, early initiation of DAAs required for an alteration of gut microbiota, enhanced SCFAs-producing bacteria, and could reduce HCV-related complications.
