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Recent preclinical and observational cohort studies have implicated imbalances in gut microbiota composition as a contributor to atrial fibrillation (AF). The gut microbiota is a complex and dynamic ecosystem containing trillions of microorganisms, which produces bioactive metabolites influencing host health and disease development. In addition to host-specific determinants, lifestyle-related factors such as diet and drugs are important determinants of the gut microbiota composition. In this review, we discuss the evidence suggesting a potential bidirectional association between AF and gut microbiota, identifying gut microbiota-derived metabolites as possible regulators of the AF substrate. We summarize the effect of gut microbiota on the development and progression of AF risk-factors, including heart failure, hypertension, obesity and coronary artery disease. We also discuss the potential antiarrhythmic effects of pharmacological and diet-induced modifications of gut microbiota composition, which may modulate and prevent the progression to AF. Finally, we highlight important gaps in knowledge and areas requiring future investigation. Although data supporting a direct relationship between gut microbiota and AF are very limited at the present time, emerging preclinical and clinical research dealing with mechanistic interactions between gut microbiota and AF is important as it may lead to new insights into AF pathophysiology and the discovery of novel therapeutic targets for AF.

Recent preclinical and observational cohort studies have implicated imbalances in gut microbiota composition as a contributor to atrial fibrillation (AF). The gut microbiota is a complex and dynamic ecosystem containing trillions of microorganisms, which produces bioactive metabolites influencing host health and disease development. In addition to host-specific determinants, lifestyle-related factors such as diet and drugs are important determinants of the gut microbiota composition. In this review, we discuss the evidence suggesting a potential bidirectional association between AF and gut microbiota, identifying gut microbiota-derived metabolites as possible regulators of the AF substrate. We summarize the effect of gut microbiota on the development and progression of AF risk factors, including heart failure, hypertension, obesity, and coronary artery disease. We also discuss the potential anti-arrhythmic effects of pharmacological and diet-induced modifications of gut microbiota composition, which may modulate and prevent the progression to AF. Finally, we highlight important gaps in knowledge and areas requiring future investigation. Although data supporting a direct relationship between gut microbiota and AF are very limited at the present time, emerging preclinical and clinical research dealing with mechanistic interactions between gut microbiota and AF is important as it may lead to new insights into AF pathophysiology and the discovery of novel therapeutic targets for AF.

Chorioamnionitis can lead to inflammation and injury of the liver and gut, thereby predisposing patients to adverse outcomes such as necrotizing enterocolitis (NEC). In addition, intestinal bile acids (BAs) accumulation is causally linked to NEC development. Plant sterols are a promising intervention to prevent NEC development, considering their anti-inflammatory properties in the liver. Therefore, we investigated whether an intra-amniotic (IA) Ureaplasma parvum (UP) infection affected the liver and enterohepatic circulation (EHC) and evaluated whether an IA administered plant sterol mixture dissolved in &beta, cyclodextrin exerted prophylactic effects. An ovine chorioamnionitis model was used in which liver inflammation and the EHC were assessed following IA UP exposure in the presence or absence of IA prophylactic plant sterols (a mixture of &beta, sitosterol and campesterol dissolved in &beta, cyclodextrin (carrier)) or carrier alone. IA UP exposure caused an inflammatory reaction in the liver, histologically seen as clustered and conflated hepatic erythropoiesis in the parenchyma, which was partially prevented by IA administration of sterol + &beta, cyclodextrin, or &beta, cyclodextrin alone. In addition, IA administration of &beta, cyclodextrin prior to UP caused changes in the expression of several hepatic BAs transporters, without causing alterations in other aspects of the EHC. Thereby, the addition of plant sterols to the carrier &beta, cyclodextrin did not have additional effects.

Cholestasis comprises aetiologically heterogeneous conditions characterized by accumulation of bile acids in the liver that actively contribute to liver damage. Sirtuin 1 (SIRT1) regulates liver regeneration and bile acid metabolism by modulating farnesoid X receptor (FXR); we here investigate its role in cholestatic liver disease. We determined SIRT1 expression in livers from patients with cholestatic disease, in two experimental models of cholestasis, as well as in human and murine liver cells in response to bile acid loading. SIRT1-overexpressing (SIRToe) and hepatocyte-specific SIRT1-KO (knockout) mice (SIRThep-/-) were subjected to bile duct ligation (BDL) and were fed with a 0.1% DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine) diet to determine the biological relevance of SIRT1 during cholestasis. The effect of NorUDCA (24-norursodeoxycholic acid) was tested in BDL/SIRToe mice. We found that SIRT1 was highly expressed in livers from cholestatic patients, mice after BDL, and Mdr2 knockout mice (Mdr2(-/-)) animals. The detrimental effects of SIRT1 during cholestasis were validated in vivo and in vitro. SIRToe mice showed exacerbated parenchymal injury whereas SIRThep-/- mice evidenced a moderate improvement after BDL and 0.1% DDC feeding. Likewise, hepatocytes isolated from SIRToe mice showed increased apoptosis in response to bile acids, whereas a significant reduction was observed in SIRThep-/- hepatocytes. Importantly, the decrease, but not complete inhibition, of SIRT1 exerted by norUDCA treatment correlated with pronounced improvement in liver parenchyma in BDL/SIRToe mice. Interestingly, both SIRT1 overexpression and hepatocyte-specific SIRT1 depletion correlated with inhibition of FXR, whereas modulation of SIRT1 by NorUDCA associated with restored FXR signaling. Conclusion: SIRT1 expression is increased during human and murine cholestasis. Fine-tuning expression of SIRT1 is essential to protect the liver from cholestatic liver damage. Supported by the Biotechnology and Biological Sciences Research Council (BBSRC) by the BBSRC Institute Strategic Programme Gut Health and Food Safety and Gut Microbes and Health BBS/E/F/00044509 (to N.B.), the NRP Science Links Seed Corn Fund grant (to N.B., S.R.), Biotechnology and Biological Sciences Research Council (BBSRC) Doctoral Training Partnership programme (to N.B., A.T.), and Instituto de Salud Carlos III; FIS, PS12/00402 (to N.B. and M.V.R.). N.B. was funded by the BBSRC Institute Strategic Programme Gut Health and Food Safety BB/J004529/1, the Program Ramon y Cajal (Ministry of Economy and Competitiveness, Spain) and Ikerbaske foundation (Basque government, Spain). FIS PI12/00380, FIS PI15/01132, and Miguel Servet Program CON14/00129 cofinanced by "Fondo Europeo de Desarrollo Regional" (FEDER; to J.M.B.). Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C.), MINECO: SAF2014-54658-R, EITB Maratoia BIO15/CA/014 (to M.L.M.C.) Asociacion Espanola contra el Cancer. Ciberehd is funded by the Instituto de Salud Carlos III. Work produced with the support of a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (to M.V.R.). M.E. and M.G. were supported by the Camara de Comercio de Navarra.

Type I diabetes mellitus (T1DM) increases atherosclerotic cardiovascular disease; however, the underlying pathophysiology is still incompletely understood. We investigated whether experimental T1DM impacts HDL-mediated reverse cholesterol transport (RCT). C57BL/6J mice with alloxan-induced T1DM had higher plasma cholesterol levels (P

Biliary cholesterol secretion is a process important for 2 major disease complexes, atherosclerotic cardiovascular disease and cholesterol gallstone disease With respect to cardiovascular disease, biliary cholesterol secretion is regarded as the final step for the elimination of cholesterol originating from cholesterol laden macrophage foam cells in the vessel wall in a pathway named re verse cholesterol transport On the other hand, cholesterol hypersecretion into the bile is considered the main pathophysiological determinant of cholesterol gallstone formation This review summarizes current knowledge on the origins of cholesterol secreted into the bile as well as the relevant processes and transporters involved Next to the established ATP binding cassette (ABC) transporters mediating the biliary secretion of bile acids (ABCB11), phospholipids (ABCB4) and cholesterol (ABCG5/G8), special attention is given to emerging proteins that modulate or mediate biliary cholesterol secretion In this regard, the potential impact of the phosphatidylserine flippase ATPase class I type 8B member 1, the Niemann Pick C1 like protein 1 that mediates cholesterol absorption and the high density lipoprotein cholesterol uptake receptor, scavenger receptor class B type I, is discussed (C) 2010 Baishideng All rights reserved

High density lipoprotein cholesterol represents a major source of biliary cholesterol. Secretory phospholipase A(2) (sPLA(2)) is an acute phase enzyme mediating decreased plasma HDL cholesterol levels. Clinical studies reported a link between increased sPLA(2) expression and the presence of cholesterol gallstones. The aim of our study was to investigate whether the overexpression of human sPLA(2) in transgenic mice affects biliary cholesterol secretion and gallstone formation. Liver weight (P

Background & Aims: Reverse cholesterol transport (RCT) is defined as high-density lipoprotein (HDL)-mediated flux of excess cholesterol from peripheral cells to liver, followed by secretion into bile and disposal via the feces. Various steps of this pathway are controlled by the liver X receptor (LXR). We addressed the role of the intestine in LXR-dependent stimulation of fecal cholesterol excretion. Methods: To segregate biliary from intestine-derived cholesterol, wild-type and Mdr2 P-glycoprotein-deficient mice (Mdr2(-/-)), which are unable to secrete cholesterol into bile, were treated with the LXR agonist GW3965. Results: Treatment with GW3965 increased biliary cholesterol secretion by 74% in wild-type mice but had no effect in Mdr2(-/-) mice. LXR activation increased fecal neutral sterol excretion 2.1-fold in wild-type mice. Surprisingly, an identical increase was observed in Mdr2(-/-) mice. Fractional cholesterol absorption was reduced on LXR activation in both strains but was more pronounced in Mdr2(-/-) mice, coinciding with reduced Npc111 expression. Intestinal gene expression of ATPbinding cassette transporters (Abc) Abca1, Abcg1, Abcg5, and Abcg8 was strongly induced upon LXR activation in both strains, whereas expression of HMGCoA reductase, controlling cholesterol synthesis, remained unaffected. Additionally, LXR activation stimulated the excretion of plasma-derived [H-3]cholesterol into the fecal neutral sterol fraction in Mdr2(-/-) mice. Conclusions: Increased fecal cholesterol loss upon LXR activation is independent of biliary cholesterol secretion in mice. An important part of excess cholesterol is excreted directly via the intestine, supporting the existence of an alternative, quantitatively important route for cholesterol disposal.

The adenosine triphosphate (ATP)-binding cassette (ABC)-transporters ABCG5 and ABCG8 have been shown to mediate hepatic and intestinal excretion of cholesterol. In various (genetically modified) marine models, a strong relationship was found between hepatic expression of ABCG5/ABCG8 and biliary cholesterol content. Our study aimed to relate levels of hepatic expression of ABCG5 and ABCG8 to biliary excretion of cholesterol in man. From 24 patients who had received a liver transplant, bile samples were collected daily after transplantation over a 2-week period to determine biliary composition. Expression of ABCG5, ABCG8, MDR3, and BSEP was assessed by real-time polymerase chain reaction (PCR) in liver biopsy specimens collected before and after transplantation. Levels of hepatic ABCG5, ABCG8, and MDR3 messenger RNA (mRNA) were strongly correlated. After transplantation, the biliary secretion rate of cholesterol continuously increased, coinciding with gradual increases in bile salt and phospholipid secretion. In contrast, hepatic levels of ABCG5 and ABCG8 mRNA remained unchanged. Surprisingly, no correlation was found between the hepatic expression of ABCG5 and ABCG8 and rates of biliary cholesterol secretion, normalized for biliary phospholipid. secretion. As expected, the concentration of biliary phospholipids correlated well with MDR3 expression. In conclusion the strong relationship between ABCG5 and ABCG8 gene expression is consistent with the coordinate regulation of both genes, and in line with heterodimerization of both proteins into a functional transporter. Hepatic ABCG5/ABCG8 expression, at least during the early phase after transplantation, is not directly related to biliary cholesterol secretion in humans. This finding suggests the existence of alternative pathways for the hepatobiliary transport of cholesterol that are not controlled by ABCG5/ABCG8.

Transport processes for larger organic solutes at the canalicular membrane are mainly driven by members of the superfamily of ATP-binding cassette (ABC) transporters. The funct ions of these transporters range from bile component secretion to xenobiotica and phase II-conjugate export. The transcriptional control of the expression of their respective genes differs, and this may be to guarantee tissue specificity, effective response to stress, or changes in substrate concentrations. Inside the nucleus, the concentration of competing and specifically activated transcription factors determines the transcriptional activation in transporter gene expression. Some transcription factors function as sensors for metabolites (LXR, FXR, CAR, SREBP, PPARs), xenobiotics (PPARs, PXR), oxidative stress (NF-kappaB, AP-1), or DNA damage (p53). Changes in their nuclear concentrations and activity will influence the transcription rates of the respective target genes that contain specific responsive elements in their 5'-promoter/enhancer DNA sequences. Until now little was known about the transcriptional control of most ABC transporter proteins. However, due to the enormous progress in molecular biology, many tools have become recently available to study and understand the "battle inside the nucleus" with respect to hepatic transporter gene expression.

BACKGROUND/AIMS Apolipoprotein (apo)A-I(M) (ilano), is a molecular variant of apoA-I(wild-type), associated with dramatically low HDL-cholesterol levels, but no increased risk for cardiovascular disease. In view of the present uncertainties on the role of apoA-I in liver cholesterol removal by way of bile acids and neutral sterols, and of the greater capacity of apoA-I(M) (ilano) to remove arterial cholesterol, biliary sterol metabolism was evaluated in transgenic mice expressing apoA-I(M) (ilano). METHODS ApoA-I(M) (ilano) mice were fed a high-cholesterol/high-fat diet, and compared with human apoA-I(wild-type) mice. Plasma lipid levels, hepatic bile flow and composition, hepatic and intestinal cholesterol and bile acid content, and faecal sterol content were measured. Moreover, the expression of hepatic ABCA1, SR-B1 and that of hepatic and intestinal genes involved in bile acid metabolism were evaluated. RESULTS The dietary treatment led to a strong elevation in HDL-cholesterol levels in A-I(M) (ilano) mice, associated with an increased expression of hepatic ABCA1. ApoA-I(M) (ilano) mice showed lower cholesterol output from the liver compared with apoA-I(wild-type) mice, in the absence of liver sterol accumulation. Faecal excretion of neutral sterols and bile acids was similar in the two mouse lines. CONCLUSIONS In spite of a different response to the dietary challenge, with an increased ABCA1 expression and a lower hepatic cholesterol output in apoA-I(M) (ilano) mice, the net sterol excretion is comparable in the two transgenic lines.

Biliary cholesterol secretion is a process important for 2 major disease complexes, atherosclerotic cardiovascular disease and cholesterol gallstone disease With respect to cardiovascular disease, biliary cholesterol secretion is regarded as the final step for the elimination of cholesterol originating from cholesterol laden macrophage foam cells in the vessel wall in a pathway named re verse cholesterol transport On the other hand, cholesterol hypersecretion into the bile is considered the main pathophysiological determinant of cholesterol gallstone formation This review summarizes current knowledge on the origins of cholesterol secreted into the bile as well as the relevant processes and transporters involved Next to the established ATP binding cassette (ABC) transporters mediating the biliary secretion of bile acids (ABCB11), phospholipids (ABCB4) and cholesterol (ABCG5/G8), special attention is given to emerging proteins that modulate or mediate biliary cholesterol secretion In this regard, the potential impact of the phosphatidylserine flippase ATPase class I type 8B member 1, the Niemann Pick C1 like protein 1 that mediates cholesterol absorption and the high density lipoprotein cholesterol uptake receptor, scavenger receptor class B type I, is discussed (C) 2010 Baishideng All rights reserved

High density lipoprotein cholesterol represents a major source of biliary cholesterol. Secretory phospholipase A(2) (sPLA(2)) is an acute phase enzyme mediating decreased plasma HDL cholesterol levels. Clinical studies reported a link between increased sPLA(2) expression and the presence of cholesterol gallstones. The aim of our study was to investigate whether the overexpression of human sPLA(2) in transgenic mice affects biliary cholesterol secretion and gallstone formation. Liver weight (P

Background & Aims: Reverse cholesterol transport (RCT) is defined as high-density lipoprotein (HDL)-mediated flux of excess cholesterol from peripheral cells to liver, followed by secretion into bile and disposal via the feces. Various steps of this pathway are controlled by the liver X receptor (LXR). We addressed the role of the intestine in LXR-dependent stimulation of fecal cholesterol excretion. Methods: To segregate biliary from intestine-derived cholesterol, wild-type and Mdr2 P-glycoprotein-deficient mice (Mdr2(-/-)), which are unable to secrete cholesterol into bile, were treated with the LXR agonist GW3965. Results: Treatment with GW3965 increased biliary cholesterol secretion by 74% in wild-type mice but had no effect in Mdr2(-/-) mice. LXR activation increased fecal neutral sterol excretion 2.1-fold in wild-type mice. Surprisingly, an identical increase was observed in Mdr2(-/-) mice. Fractional cholesterol absorption was reduced on LXR activation in both strains but was more pronounced in Mdr2(-/-) mice, coinciding with reduced Npc111 expression. Intestinal gene expression of ATPbinding cassette transporters (Abc) Abca1, Abcg1, Abcg5, and Abcg8 was strongly induced upon LXR activation in both strains, whereas expression of HMGCoA reductase, controlling cholesterol synthesis, remained unaffected. Additionally, LXR activation stimulated the excretion of plasma-derived [H-3]cholesterol into the fecal neutral sterol fraction in Mdr2(-/-) mice. Conclusions: Increased fecal cholesterol loss upon LXR activation is independent of biliary cholesterol secretion in mice. An important part of excess cholesterol is excreted directly via the intestine, supporting the existence of an alternative, quantitatively important route for cholesterol disposal.

The intestinal microbiota has been implicated in insulin resistance, although evidence regarding causality in humans is scarce. We therefore studied the effect of lean donor (allogenic) versus own (autologous) fecal microbiota transplantation (FMT) to male recipients with the metabolic syndrome. Whereas we did not observe metabolic changes at 18 weeks after FMT, insulin sensitivity at 6 weeks after allogenic FMT was significantly improved, accompanied by altered microbiota composition. We also observed changes in plasma metabolites such as γ-aminobutyric acid and show that metabolic response upon allogenic FMT (defined as improved insulin sensitivity 6 weeks after FMT) is dependent on decreased fecal microbial diversity at baseline. In conclusion, the beneficial effects of lean donor FMT on glucose metabolism are associated with changes in intestinal microbiota and plasma metabolites and can be predicted based on baseline fecal microbiota composition. Kootte et al. show that fecal microbiota transplantation from lean donors to obese patients with metabolic syndrome improves insulin sensitivity, a transient effect associated with changes in microbiota composition and fasting plasma metabolites. Baseline fecal microbiota composition in recipients predicts the response to lean donor fecal microbiota transplantation.

Transport processes for larger organic solutes at the canalicular membrane are mainly driven by members of the superfamily of ATP-binding cassette (ABC) transporters. The functions of these transporters range from bile component secretion to xenobiotica and phase II-conjugate export. The transcriptional control of the expression of their respective genes differs, and this may be to guarantee tissue specificity, effective response to stress, or changes in substrate concentrations. Inside the nucleus, the concentration of competing and specifically activated transcription factors determines the transcriptional activation in transporter gene expression. Some transcription factors function as sensors for metabolites (LXR, FXR, CAR, SREBP, PPARs), xenobiotics (PPARs, PXR), oxidative stress (NF-kappa B, AP-1), or DNA damage (p53). Changes in their nuclear concentrations and activity will influence the transcription rates of the respective target genes that contain specific responsive elements in their 5'-promoter/enhancer DNA sequences. Until now little was known about the transcriptional control of most ABC transporter proteins. However, due to the enormous progress in molecular biology, many tools have become recently available to study and understand the "battle inside the nucleus" with respect to hepatic transporter gene expression.