Review Int Arch Allergy Immunol 2014;165:1–8 DOI: 10.1159/000366100

Published online: September 24, 2014

The Immunomodulatory Role of Bile Acids Sándor Sipka a Geza Bruckner b  

Division of Clinical Immunology, University of Debrecen, Debrecen, Hungary; b Division of Clinical Nutrition, University of Kentucky, Lexington, Ky., USA  


Key Words Bile acid · Endotoxin · Immune system · Inflammation

Abstract Enzymatic oxidation of cholesterol generates numerous distinct bile acids which function both as detergents that facilitate the digestion and absorption of dietary lipids and as hormones that activate five distinct receptors. Activation of these receptors alters gene expression in multiple tissues, leading to changes not only in bile acid metabolism but also in glucose homeostasis, lipid and lipoprotein metabolism, energy expenditure, intestinal motility, bacterial growth, inflammation, and in the liver-gut axis. This review focuses on the present knowledge regarding the physiologic and pathologic role of bile acids and their immunomodulatory role, with particular attention to bacterial lipopolysaccharides (endotoxins) and bile acid and immunological disorders. The specific role that bile acids play in the regulation of innate immunity, various systemic inflammations, inflammatory bowel diseases, allergy, psoriasis, cholestasis, obesity, metabolic syndrome, alcoholic liver disease, and colon cancer will be reviewed. © 2014 S. Karger AG, Basel

Pleiotropic Roles of Bile Acids in Metabolism

Bile acids are known to play critical roles in lipid metabolism. First, bile acids are essential for the formation of mixed micelles in the small intestine that facilitate the solubilization, digestion and absorption of long-chain dietary © 2014 S. Karger AG, Basel 1018–2438/14/1651–0001$39.50/0 E-Mail [email protected]

triglycerides and fat-soluble vitamins. Second, bile acids present in the gallbladder serve to solubilize cholesterol in biliary micelles, thus impairing cholesterol crystallization and gallstone formation. Third, bile salts induce bile flow from hepatocytes into the bile canaliculi and then into the gallbladder. Fourth, hepatic conversion of cholesterol to bile acids and the subsequent excretion of bile acids in the feces represent the major route for cholesterol excretion that is important in whole body sterol homeostasis. Bile is also thought to have a bacteriostatic function that maintains sterility in the biliary tree. Consistent with these roles, disruption of normal bile acid synthesis and metabolism is associated with cholestasis, gallstones, inflammation, malabsorption of lipids and fat-soluble vitamins, bacterial overgrowth in the small intestine, atherosclerosis, neurological diseases, and various inborn errors such as progressive familial intrahepatic cholestasis types I–III. It has been discovered that specific bile acids differentially activate 4 nuclear receptors, namely farnesoid X receptor (FXR), pregnane X receptor (PXR), constitutive androstane receptor, and vitamin D receptor (VDR); in addition, one G-protein-coupled receptor (TGR5) has identified bile acids as hormones that alter multiple metabolic pathways in many tissues [1].

Bile Acid Synthesis and the Enterohepatic Circulation

At least 17 enzymes are involved in the modification of the cholesterol steroid ring, cleavage of the side chain and subsequent conjugation with glycine or taurine to form primary bile salts. The classic or neutral bile acid Correspondence to: Dr. Sándor Sipka Division of Clinical Immunology, Institute of Internal Medicine University of Debrecen, Nagyerdei krt. 98 HU–4032 Debrecen (Hungary) E-Mail sipka @

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  3 HO

Deoxycholic acid









Primary bile acids


Secondary bile acids


Cholic acid


Deoxycholic acid


Chenodeoxycholic acid


į0XULFKROLF acid (rodents) DŽ0XULFKROLF acid (rodents)

Lithocholic acid Ursodeoxycholic acid

į įDŽ


Ǖ0XULFKROLF acid (rodents)


pathway is regulated by cholesterol 7α-hydroxylase, a cytochrome P450 enzyme that converts cholesterol to 7α-cholesterol. The latter intermediate is either converted to chenodeoxycholic acid or to cholic acid in roughly equal amounts. The alternative (or acidic) pathway is initiated by sterol 27-hydroxylase. Prior to secretion, bile acids are conjugated with taurine or glycine, a process that lowers their protein kinase A (PKA) and increases their solubility (hydrophilic character), thereby facilitating micelle formation in the acidic environment of the duodenum. However, unlike non-conjugated bile acids that can diffuse across membranes, bile salts require a transmembrane transporter to move them across membranes [2]. Bile salts, together with phospholipids and cholesterol, are passed into the gallbladder, where they are concentrated to form bile, which is composed of 85% water. The remaining solution is a complex mixture of bile salts (67%), phospholipids (22%) and cholesterol (4%), together with electrolytes, minerals and minor levels of proteins, plus bilirubin and biliverdin pigments, which give it a yellow-green or even orange-blue color [3]. Small amounts of mucus and secretory IgA may contribute to the bacteriostatic functions of bile [4]. As previously stated, bile salts and phospholipid micelles play a key role in solubilizing cholesterol in bile, thus preventing cholesterol crystallization and formation of cholesterol gallstones [5]. The presence of dietary fat in the duodenum causes the secretion of cholecystokinin from intestinal mucosa into the circulation, which in turn promotes contraction of smooth muscle cells of the gallbladder and relaxation of 2

Int Arch Allergy Immunol 2014;165:1–8 DOI: 10.1159/000366100

the sphincter of Oddi, thus allowing bile to enter the duodenum [6]. In the lumen, the bile salt-containing mixed micelles facilitate absorption of the fat-soluble vitamins A, D and E and the digestion of dietary lipids by pancreatic enzymes, prior to their absorption. The gallbladder itself is not essential, since rats, who lack gallbladder, and patients who have undergone cholecystectomy (removal of the gallbladder) are still able to absorb lipids from the diet as a result of direct secretion of bile into the duodenum. Following the secretion of bile salts into the duodenum, most (about 95%) are reabsorbed in the distal ileum via the apical sodium-dependent transporter. Other transport molecules facilitate the transport of bile salts across the enterocytes to the basolateral membrane where they are effluxed into the blood. However, a small percentage of bile salts escape resorption and are deconjugated by bacterial flora before being either absorbed or converted into secondary bile acids. Secondary bile acids may be absorbed by passive processes or excreted in the feces. The absorbed primary and secondary bile acids and salts are transported back to the liver where most, but not all, are actively transported into hepatocytes by various transporters (fig. 1) [7]. In humans, the bile acid pool contains about 2–4 g of bile acids. Recycling of bile acids/salts between the liver and intestine occurs 6–10 times each day and transports 20–40 g of bile acids. However, about 0.2–0.6 g of bile acids are excreted in the feces each day, an amount that must be replenished by de novo synthesis from cholesterol [3]. Hepatic recovery of bile acids from the portal Sipka/Bruckner

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Fig. 1. Types and synthesis of bile acids. From de Aguiar Vallim [1].

Table 1. Endogenous ligands of bile acid-activated receptors Receptor


Principal ligand

Additional ligands

Farneosid X receptor Pregnane X receptor Constitutive androstane receptor Vitamin D receptor Bile acid-activated GPCR



farnesol pregnenolone androstanes LCA>GLCA>CDCA linolenic acid and oleanolic acid

GPCR = G-protein-coupled transmembrane receptors; CDCA = chenodeoxycholic acid; DCA = deoxycholic acid; LCA = lithocholic acid; CA = cholic acid; GLCA = glycol-conjugated lithocholic acid; TLCA = taurine-conjugated lithocholic acid; UDCA = ursodeoxycholic acid. From Fiorucci et al. [11].

Table 2. Expression of bile acid receptors in cells of the human immune system


Monocytes/ macrophages

CD4+ cells

CD19+ cells

CD8+ cells

Dendritic cells


yes yes yes yes yes

yes yes yes yes no

yes yes yes yes no

yes yes yes yes no

not known not known not known yes not known

From Fiorucci et al. [11].

Bile Acid-Activated Receptors in Immunity and Inflammation

Clinical Observations on the Immunomodulatory Activity of Bile Acids Susceptibility to infectious complications observed in patients suffering from hepatobiliary diseases, e.g., priBile Acids and the Immune System

mary biliary cirrhosis with elevated serum concentrations of bile acids, suggest that bile acids are able to inhibit cellmediated immunity and macrophage activation [9–12]. In obstructive jaundice, the activity of Kupffer cells is depressed [13, 14], and deoxycholic and chenodeoxycholic acids exert inhibitory effects on the production of interleukin-1 (IL-1), IL-6 and tumor necrosis factor-α (TNF-α) in macrophages stimulated by bacterial lipopolysaccharide (LPS) [15]. Table 1 demonstrates the main characteristics of the 5 types of receptors activated by bile acids [11]. Table  2 shows the expression of bile acid receptors in cells of the human immune system [11]. Farneosid X Receptor FXR functions as a bile acid sensor in enterohepatic tissues, regulating many aspects of bile acid metabolism. A rise in intracellular bile acid concentrations in target tissues results in the transcriptional activation of these receptors. FXR ligands exert anti-inflammatory activities through their ability to antagonize other signaling pathways, in part through the interaction with other transcription factors, including activator protein 1, nuclear factor-κB (NF-κB) and signal transducers and activators of transcription 1. Activation of FXR represses the exInt Arch Allergy Immunol 2014;165:1–8 DOI: 10.1159/000366100


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vein is incomplete, which is the reason for the observed low plasma concentrations (2–10 μM). As might be expected, the concentrations of individual bile acids in the portal vein and systemic blood vary with food consumption, as resorption of bile acids is greatest in the postprandial period. The relatively high concentrations of bile acids in the tissues involved in the enterohepatic circulation (liver, bile ducts, gallbladder, and intestine) are sufficient to activate receptors present in these tissues. The hydrophilic or hydrophobic character of bile acid compared to cholic acid (CA) is reflected by the hydrophilic-hydrophobic index (HHI). Hydrophilic bile acids with HHI < CA, e.g., ursodeoxycholic acid, have a hepatoprotective effect, whereas bile acids with HHI > CA are hepatotoxic, e.g., lithocholic or deoxycholic. Primary versus secondary bile acids are more hydrophilic [8].

Bile Acid-Activated G-Protein-Coupled Receptor (TGR5/M-BAR/GP-BAR1 or BG37) The bile acid-activated G-protein-coupled receptor is a member of the rhodopsin-like subfamily of G-proteincoupled receptors localized at the plasma membrane but internalized into the cytoplasm in response to its activation. It is expressed at the highest level in the gallbladder, 4

Int Arch Allergy Immunol 2014;165:1–8 DOI: 10.1159/000366100

ileum and colon. Lung, spleen, kidney, stomach, jejunum, uterus, placenta, leukocytes, liver, Kupffer cells, white adipose tissue, and several brain areas express intermediate levels of these receptors, while low levels of expression have been detected in the liver, heart, skeletal muscle, and pancreas [25, 26]. TGR5 activation leads to cAMP production which activates PKA that in turn phosphorylates the cAMP response binding element in the target cells. The cAMP response binding element activates several target genes. An increase in cAMP in innate immune cells leads to downregulation of inflammatory cytokines such as TNF-α, IL-1β, IL-6 and IL-8; furthermore, bile acid PKA dependently induces a switch of the IL-10/IL-12 ratio and reduces the proinflammatory capability of human macrophages [27]. Therefore, TGR5 can be regarded as a novel pharmacological target in metabolic, inflammatory and neoplastic disorders. Pregnane X Receptor PXR suppresses the expression of NF-κB target genes, including prostaglandin-endoperoxide synthase 2, TNF-α, intercellular adhesion molecule 1, and the generation of interleukins and chemokines [28]. Consitutive Androsterone Receptor The consitutive androsterone receptor (CAR) is highly expressed in the liver and intestine and is a biosensor for endo- and xenobiotic compounds, e.g., bile acids, bilirubin and steroids. CAR mediates the induction of detoxifying enzymes during phenobarbital treatment [29]. CAR expression is controlled by the glucocorticoid receptor, and IL-1β downregulates CAR by the glucocorticoid receptor [30]. Vitamin D Receptor The vitamin D receptor is a vitamin D3 ligand-dependent transcription factor belonging to the superfamily of steroid/thyroid hormone receptors, associated with calcemic activities, calcium and phosphorus homeostasis and with the maintenance of bone density. It is also involved in the function of secondary bile acids [31, 32]. Cholestasis induces the release of proinflammatory cytokines and the expression of bile acid transporters and is regulated by both bile acid sensing receptors and cytokine signaling [33]. However, vitamin D3 has no regulatory activities on the network of bile acid metabolic genes but directly represses the production of proinflammatory cytokines [34]. Sipka/Bruckner

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pression of Toll-like receptor 4 (TLR4)-regulated genes, including proinflammatory cytokines, chemokines and their receptors. On the other hand, interferon-γ is a potent inhibitor of FXR expression in macrophages requiring signal transducers and activators of transcription 1 [16]. A reciprocal regulation exists between FXR and TLR (TLR2, TLR4, TLR5, TLR6) expression, while activation of intracellular TLR3, TLR7, TLR8, and TLR9 upregulates the expression of FXR [17]. FXR antagonizes NF-κB in hepatic inflammatory response [18]. In the repression of inflammatory response, genes take part in the conjugation of FXR with SUMO1 (small ubiquitin-like modifier), resulting in the SUMOylation of FXR [16]. Activation of FXR by bile acids has a protective role on intestinal epithelial cells against bacterial overgrowth and mucosal injury [16] and decreases the production of C-reactive protein [19], decreases inflammation and preserves the intestinal barrier in inflammatory bowel disease [20]. The absence of the FXR gene results in exacerbated liver injury [21] and a proinflammatory phenotype of mild to moderate intestinal inflammation and fibrosis, as well as in a predisposition to develop atherosclerosis [22]. These data suggest that the FXR agonists might have a role in treating inflammatory bowel diseases because they have an immunoregulatory activity that is independent from their regulatory activity on bile acid and lipid homeostasis [23]. Upon feeding, gallbladder contraction occurs, with release of bile acids into the intestine. In the ileum, bile acids are conserved via enterohepatic circulation by transport proteins; they are transported via the portal vein to the liver and reabsorbed by transport protein NTCP (Na-taurocholate cotransporter protein). In the liver, neosynthesis, conjugation and detoxification of bile acids occur. In the enterocyte, bile acid-dependent FXR activation results in the production/secretion of fibroblast growth factor 15/19. This hormone exerts negative feedback on hepatic bile salt neosynthesis and induces gallbladder dilatation, signaling the end of the fed state and the transition to the fasting state [23]. Choleretic agents like peppermint oil upregulate FXR mRNA levels and promote bile and bile secretion in rats [24].

Intestinal microbial organisms play an important role in bile acid metabolism, as they readily deconjugate and 7α-dehydroxylate primary bile salts that escape reabsorption in the distal ileum and convert them to secondary bile acids. However, secondary bile acids comprise only a small percent of the normal bile acid pool. Recent studies have shown that the microbiome affects not only the composition of the bile acid pool but also the expression of genes controlled by the bile acid-activated receptor FXR. For example, as compared to rats with a normal microflora, germ-free rats were shown to have reduced levels of bile acids in various tissues, an almost total loss of unconjugated and glycine-conjugated bile acids, a significant increase in taurine-conjugated bile salts, and changes in the hepatic expression of genes regulated by the bile acidresponsive nuclear receptor FXR [9]. Dietary components, e.g., fats, fibers, mucopolysaccharides, and oligosaccharides, can also affect the microbiome and the bile acid pool, as well as intestinal inflammation. For example, feeding milk-derived saturated fatty acids to mice specifically increased the taurocholate levels which provided a selective growth advantage for Bilophilia wadworthia, a sulphite-reducing pathobiont [10].

Bacterial LPS/Bacterial Endotoxin

A definitive feature of Gram-negative bacteria is the presence of an outer membrane, which is an asymmetrical bilayer with glycerophospholipids confined to the inner leaflet and LPS anchored to the outer leaflet. LPS is composed of three domains: (1) a glucosamine-based hydrophobic lipid moiety, designated as lipid A, (2) an oligosaccharide core attached to lipid A via ketodeoxyoctonic acid, and (3) an O-antigen, containing repeating saccharide units with different sizes depending on the bacterial species and strain. Lipid A is the endotoxic portion of LPS. For recognition of the LPS molecular structure by the hosts, conserved ‘microorganism-associated molecular pattern’- or ‘pathogen-associated molecular pattern’-specific elements have been selected during evolution [35, 36]. Derived from the gut Gram-negative bacteria, endotoxin continuously enters the blood in a ‘physiological manner’ through the intestinal epithelial cells and the vessels of vena portae, resulting in measurable plasma levels in every healthy human subject, ranging from 0.01 to 1.0 endotoxin units/ml [37, 38]. Bile Acids and the Immune System

Interactions between LPS Moieties and Macrophage Recognition Receptors Endotoxins are recognized and transferred sequentially by lipid-binding protein to CD14, then to the myeloid differentiation protein 2 (MD-2)/TLR4 complex. CD14, a coreceptor of LPS, exists in soluble form or as a protein anchored into the membrane. During acute infection and inflammation, concentrations of lipid-binding protein and soluble CD14 increase in plasma and extravascular fluids. LPS binds TLR4 and also interacts with the coreceptor MD-2. When LPS binds to MD-2, it initiates the dimerization of the MD-2/TLR4 complex to initiate the myeloid differentiation factor-88-dependent and -independent pathways resulting in inflammatory cytokines (TNF-α, IL-1β, IL-6, chemokines) and type I interferons by macrophages, monocytes and all types of CD14-bearing cells [36, 38, 39]. Endotoxin in Septic Shock The potent effect of bacterial endotoxin on the immune system was observed many decades ago [40]. The endotoxin (lipid A) component of LPS is regarded to be the main trigger for the activation of the proinflammatory cytokine genes [41] and is responsible for the lethality and multi-organ failure in septic shock [42]. The Role of Endotoxin in Gut and Liver Disease Chronic exposure to circulating endotoxin has been associated with obesity, diabetes and cardiovascular disease. Western-style meals (high-fat diet) invoke an acute postprandial elevation of endotoxin contributing to the pathogenesis of these diseases [43]. Some gut microbiota increase the intestinal permeability, resulting in elevated systemic levels of bacterial LPS, thereby inducing a lowgrade systemic inflammation with increased insulin resistance [44, 45]. The crucial role of LPS was verified also in alcoholic liver disease [36], in sepsis-associated cholestasis [46], inflammatory bowel diseases [47], primary biliary cirrhosis [48], and metabolic endotoxemia [49]. Endotoxin and Allergy Increased endotoxin concentrations were found in the house dust of farms compared to urban environments, suggesting a protective effect against the development of atopy [50], possibly by causing Th1 domination in the immune system [51, 52]. However, this protective effect of the farm environment may exist only in the early years of childhood [53]. In a mouse model, pulmonary endotoxin tolerance was found to be protective against cockroach allergen-induced asthma-like inflammation [52]. Int Arch Allergy Immunol 2014;165:1–8 DOI: 10.1159/000366100


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The Influence of Microbiome on Bile Acids

Obesity was found to be associated with the development of atopic dermatitis only in children. However, no clear association was found between obesity and the prevalence of allergic rhinitis or allergic conjunctivitis or increased sensitivity to food allergens [54].

being carried by the pollen molecule. These plant steroids can modify the allergenic potency of birch pollen [68, 69].

Bile Acids and Colon Cancer

Bile Acids in Allergy Prevention in Childhood

Bile acid production and bile flow are much lower in the first 4 years of life [65] and may explain the allergyprotective effect in early childhood of a farm milieu, which is rich in endotoxins. This idea was confirmed also by animal experiments, e.g., that microbial LPS treatment had a preventive effect on allergen-specific tolerance induction [66]. In a low bile acid gut milieu, a relatively higher amount of LPS can enter the blood from the gut to induce a Th1 domination in the immune system in this period of life [50, 51, 66]. Therefore, one can speculate that in a relatively sterile, low LPS urbanized environment, the reintroduction of a detoxified form of LPS would be an effective allergy prevention treatment [67]. Testing the crystal structure of the major birch pollen allergen Bet v 1, deoxycholate molecules were found 6

Int Arch Allergy Immunol 2014;165:1–8 DOI: 10.1159/000366100

Bile acids are essential in the maintenance of intestinal epithelium homeostasis by inducing programmed cell death, thereby propagating the renewal of the epithelium [70]. However, bile acids are potent endogenous etiologic agents in gastrointestinal cancer [71]. The hydrophilic ursodeoxycholic or low concentrations of hydrophobic bile acids can protect colonic cells against apoptosis induced by high concentrations of cytotoxic bile acids [72]. However, there is increasing evidence that the continuous exposure to certain hydrophobic bile acids, due to a fat-rich diet or pathological conditions, may induce oxidative DNA damage that, in turn, may lead to colorectal carcinogenesis. The hydrophobic bile acids cause genomic instability in colon carcinogenesis [72]. The downregulation of PXR [73] or the silencing of FXR expression [74] represents promising therapeutic options for the treatment of colon cancer.


Bile acids not only affect digestion, but also the regulation of innate immunity, various systemic inflammations like septic shock, inflammatory bowel diseases, allergy, psoriasis, and the gut-liver axis, e.g., cholestasis, obesity, metabolic syndrome, alcoholic liver disease, and colon cancer. The intent of this review is to encourage further research to unravel the delicate interrelationship between bile acids and the mechanisms involved in the development and treatment of these diseases.


1 de Aguiar Vallim TQ, Tarling EJ, Edwards PA: Pleiotropic roles of bile acids in metabolism. Cell Metab 2013;17:657–669. 2 Russel DW: The enzymes, regulation and genetics of bile acid synthesis and metabolism. Annu Rev Biochem 2003;72:137–174. 3 Dawson PA: Bile secretion and the enterohepatic circulation; in Feldman M, Friedman LS, Brandt LJ, Sleisenger MH (eds): Gastrointestinal and Liver Disease. Philadelphia, Saunders, 2010, vol 1, pp 1075–1088. 4 Sung JY, Costerton JW, Shaffer EA: Defense system in the biliary tract against bacterial infection. Dig Dis Sci 1992;37:689–969.


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Bile Acids Are Natural and Physiological Inhibitors of the Intestinal Absorption of Bacterial Endotoxins The first and early observation on the inhibitory effect of bile acids on the intestinal absorption of bacterial endotoxin was based on elegant experiments almost 3 decades ago [55]. It was later confirmed also by newer methods [56]. Physical investigations proved that the endotoxin-bile acid interaction is not governed by Coulomb forces, but rather by hydrophobic interactions [57]. Bertók [58] was the first to label bile acids as natural and physiological molecules with a ‘physicochemical host defense’ against endotoxins. In animal experiments, they prevented the lethality of an endotoxin shock by bile acid pretreatment [59], and in psoriatic patients, they found oral bile acid (dehydrocholic acid) treatment to reduce the symptoms of skin inflammation [60]; this finding was recently confirmed by others [61]. In the pathogenesis of chronic inflammation and autoimmune diseases, impaired production of bile acids may be one of the factors leading to the increased absorption of bacterial LPS [62, 63], thereby promoting systemic inflammation in the organism. In addition, there is a circulus vitiosus regulation of these processes, as an increase in LPS levels involves a decrease in bile acid excretion and bile flow [64] leading to further increased intestinal absorption of bacterial LPS.

Bile Acids and the Immune System













tein expression by FXR agonists. Biochem Biophys Res Commun 2009;379:476–479. Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooli W, Mutilli S, Klomp LW, Siersema PD, Schipper ME, Danese S, Penna G, Laverny G, Adorini L, Moschetta A, van Mil SW: Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 2011;60:463–472. Mencarelli A, Renga B, Migliorati M, Cipriani S, Distrutti E, Santucci L, Fiorucci S: The bile acid sensor farnesoid receptor is a modulator of liver immunity in a rodent model of acute hepatitis. J Immunol 2009;183:6657–6666. Hanniman EA, Lambert G, McCarthy TC, Sinal CJ: Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E deficient mice. J Lipid Res 2005;46: 2595–2604. Gadaleta RM, van Mil SWC, Oldenburg B, Siersema PD, Klomp LWJ, van Erpecum KJ: Bile acids and their nuclear receptor FXR: relevance for hepatobiliary and gastrointestinal disease. Biochim Biophys Acta 2010; 1801: 683–692. Zong L, Qu Y, Luo DX, Zhu ZY, Zhang S, Su Z, Shan JC, Gao XP, Lu LG: Preliminary experimental research on the mechanism of liver bile secretion stimulated by peppermint oil. J Dig Dis 2011;12:295–301. Keitel V, Donner M, Winandy S, Kubitz R, Haussinger D: Expression and function of bile acid receptor TGRT on Kupffer cells. Biophys Res Commun 2008;372:78–84. Stepanov V, Stankov K, Mikov M: The bile acid membrane receptor TGR5: a novel pharmacological target in metabolic, inflammatory and neoplastic disorders. J Recept Signal Transduct Res 2013;33:213–223. Haselow K, Bode JG, Wammers M, Ehlting C, Keitel V, Kleinebrecht L, Schupp AK, Haussinger D, Graf D: Bile acids PKA-dependently induce a switch of the IL-10/IL-12 ratio and reduce proinflammatory capability of human macrophages. J Leukoc Biol 2013; 94: 1253– 1264. Pascucussi JM, Gerbal-Chaloin S, PichardGarcia L, Daujat M, Fabre JM, Maurel P, Vilarem MJ: Interleukin 6 negatively regulates the expression of pregnane X receptor and constitutively activated receptor in primary human hepatocytes. Biochem Biophys Res Commun 2000;274:707–713. Inoue K, Borchers CH, Negishi M: Cohesin protein 3MC1 represses the nuclear receptor CAR mediated synergistic activation of a human P450 gene by xenobiotics. Biochem J 2006;398:125–133. Ray A, Prefontaine KE: Physical association and functional antagonism between p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor. Proc Natl Acad Sci USA 1994;91:752–756. Pinette KV, Yee YK, Amegadzie BY, Nagpal S: Vitamin D receptor as a drug discovery target. Mini Rev Med Chem 2003;3:193–204.

32 Gascon-Barré M, Demers C, Mirshani A, Néron S, Zalzal S, Nanci A: The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells. Hepatology 2003;35:126–131. 33 Alrefai WA, Gill RK: Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm Res 2007; 24:1803–1823. 34 Ogura M, Nishida S, Ishikawa M, Sakurai K, Shimizu M, Matsuo S, Amano S, Uno S, Makishima M: Vitamin D3 modulates the expression of bile acid regulatory genes and represses inflammation in bile duct-ligated mice. J Pharmacol Exp Ther 2009; 328: 564– 570. 35 Needham BD, Trent MS: Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis. Nat Rev Microbiol 2013; 11:467–481. 36 Szabo G, Bala S, Petrasek J, Gattu A: Gut-liver axis and sensing microbes. Dig Dis 2010; 28: 737–744. 37 Nádházi Z, Takáts A, Offenmüller K, Bertók L: Plasma endotoxin level of healthy donors. Acta Microbiol Immunhol Hung 2002; 49: 151–157. 38 Győrfy ZS, Duda E, Vizler CS: Interactions between LPS moieties and macrophage pattern recognition receptors. Vet Immunol Immunpathol 2013;152:28–36. 39 Landy M, Pillemer L: Elevation of properdin levels in mice following administration of bacterial lipopolysaccharides. J Exp Med 1956;103:823–830. 40 Ulich TR, Guo K, del Castillo J: Endotoxininduced cytokine gene expression in vivo. Expression of tumor necrosis factor mRNA in visceral organs under physiologic conditions and during endotoxinemia. Am J Pathol 1989; 143:11–14. 41 Morrison DC, Bucklin SE: Evidence for antibiotic-mediated endotoxin release as a contributing factor to lethality in experimental Gram-negative sepsis. Scand J Infect Dis Suppl 1996;101:3–8. 42 Sipka S, Seres T, Dinya Z, Szekanecz Z, Szentmiklósi J, Bodolay E, Szegedi G: Tumour necrosis factor-α and adenosine in endotoxin shock-related cardiovascular symptoms. Mediators Inflamm 1995; 4: 454–455. 43 Kelly CJ, Colgan SP, Frank DN: Of microbes and meals: the health consequences of dietary endotoxinemia. Nutr Clin Pract 2012;27:215– 225. 44 Blaut M, Klaus S: Intestinal microbiota and obesity. Handb Exp Pharmacol 2012; 209: 251–273. 45 Teixeira TF, Collado MC, Ferreira CL, Bressan J, Peluzio MdoC: Potential mechanism for the emerging link between obesity and increased intestinal permeability. Nutr Res 2012;32:637–647. 46 Kosters A, Karpen SJ: The role of inflammation in cholestasis: clinical and basic aspects. Semin Liver Dis 2010;30:186–194.

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5 Wang DQ, Cohen DE, Carey MC: Biliary lipids and cholesterol gallstone disease. J Lipid Res 2000;50(suppl):S406–S411. 6 Chandra R, Liddle RA: Cholecystokinin. Curr Opin Endocrinol Diabetes Obes 2007; 14: 63– 67. 7 Chiang JY: Bile acids: regulation of synthesis. J Lipid Res 2009;50:1965–1966. 8 Lamcharfi E, Cohen-Solal C, Parquet M, Lutton C, Dupré J, Meyer C: Determination of molecular associations of some hydrophobic and hydrophilic bile acids by infrared and Raman spectroscopy. Eur Biophys J 1997; 25: 285–291. 9 Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID, Sidaway JE, Nicholson JK, Holmes E: Systemic gut microbial modulation of bile acid modulation in host tissue compartments. Proc Natl Acad Sci USA 2011; 108(suppl 1):4523–4530. 10 Devkota S, Wang Y, Musch MW, Leone W, Fehlner-Peach, Nadimpali A, Antonopulos DA, Jabri B, Chang EB: Dietary fat-induced taurocholic acid promotes pathobiont expansion and colitis in II10–/–mice. Nature 2012; 487:104–108. 11 Fiorucci S, Cipriani S, Mencarelli A, Renga B, Distrutti E, Baldelli F: Counter-regulatory role of bile acid activated receptors in immunity and inflammation. Curr Mol Med 2010; 10:579–595. 12 Keane RM, Gadacz TR, Munster AM, Birmingham W, Winchurch RA: Impairment of human lymphocyte function by bile salts. Surgery 1984;95:439–443. 13 Kimmings AN, van Deventer SJ, Obertop H, Rauws EA, Gouma DJ: Inflammatory and immunologic effects of obstructive jaundice: pathogenesis and treatment. J Am Surg 1995; 18:567–581. 14 Drivas G, James O, Wardle N: Study of reticuloendothelial phagocyte capacity in patients with cholestasis. Brit Med J 1976; 1: 1568– 1569. 15 Calmus Y, Guechot J, Podevin P, Bonnefis MT, Giboudeau J, Poupon R: Differential effects of chemodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor alpha production by monocytes. Hepatology 1992;16:719–723. 16 Vavassori P, Mencarelli A, Renga B, Distrutti E, Fiorucci S: The bile acid receptor FXR is a modulator of intestinal innate immunity. J Immunol 2009;183:6251–6261. 17 Renga B, Mencarelli A, Cipriani S, D’Amore C, Carino A, Bruno A, Francisci D, Zampella A, Distrutti E, Fiorucci S: The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation. PLoS One 2013;8:e54472. 18 Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W: Farnesoid X receptor antagonizes nuclear factor kappa B in hepatic inflammatory response. Hepatology 2008;48: 1632–1643. 19 Zhang S, Liu Q, Wang J, Harnish C: Suppression of interleukin 6 induced C reactive pro-


56 Parlesak A, Schaeckeler S, Moser L, Bode C: Conjugated primary salts reduce permeability of endotoxin through intestinal epithelial cells and synergize with phosphatidylcholine in suppression of inflammatory cytokine production. Crit Care Med 2007;35:2367–2374. 57 Fukuoka S, Richter W, Howe J, Andra J, Rössle M, Alexander C, Gutsmann T, Brandenburg K: Biophysical investigations into the interactions of endotoxins with bile acids. Innate Immun 2011;18:307–317. 58 Bertók L: Bile acids in physico-chemical host defence. Pathophysiology 2004;11:139–145. 59 Bertók L: Role of endotoxins and bile acids in the pathogenesis of septic circulatory shock. Acta Chir Hung 1997;36:33–36. 60 Gyucsovics K, Bertók L: Pathophysiology of psoriasis: coping endotoxins with bile acid therapy. Pathophysiology 2003;10:57–61. 61 Itoh S, Kono M, Akimoto T: Psoriasis treated with ursodeoxycholic acid: three case reports. Clin Exp Dermatol 2007;32:398–400. 62 Dial E, Romero JJ, Villa X, Mercer DW, Lichtenberger LM: Lipopolysaccharide induced gastrointestinal injury in rats: role of surface hydrophobicity and bile salts. Shock 2002;17: 77–80. 63 Tlaskalova-Hogenova H, Steankova R, Hudcovic T, Tuckova L, Cukrowska B, LodinovaZadnikova R, Kozakova H, Rossmann P, Bartova J, Sokol D, Funda DP, Borovska D, Rehakova Z, Sinkora J, Hofman J, Drastich P, Kokesova A: Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunol Lett 2004;15:97–108. 64 Hojo M, Sano N, Takikawa H: Effects of lipopolysaccharide on the biliary excretion of bile acids and organic anions in rats. J Gastroenterol Hepatol 2003;18:815–821. 65 Huang CT, Rodriguez JT, Woodward WE, Nichols BL: Comparison of pattern of fecal bile acid and neutral sterol between children and adults. Am J Clin Nutr 1976; 29: 1196– 1203. 66 Gerhold K, Avagyan A, Reichert E, Blumchen K, Wahn U, Hamelmann E: Lipopolysaccharides modulate allergen specific immune regulation in a murine model of mucosal tolerance induction. Int Arch Allergy Immunol 2008;147:25–34.

Int Arch Allergy Immunol 2014;165:1–8 DOI: 10.1159/000366100

67 Brix S, Kjaer TM, Barkholt V, Frokiaer H: Lipopolysaccharide contamination of beta-lactoglobulin affects the immune response against intraperitoneally and orally administered antigen. Int Arch Allergy Immunol 2004;135:216–220. 68 Gajhede M, Osmark P, Flemming M, Poulsen M, Ipsen H, Larsen JN, Joost van Neerven RJ, Schou C, Lowenstein H, Spangfort MD: X ray and NMR structure of Bet v 1, the origin of birch pollen allergy. Nat Struct Biol 1996; 3: 1040–1045. 69 Markovic-Housley Z, Degano M, Lamba D, Roepenack-Lahaye E, Clemens S, Susani M, Ferreira F, Scheiner O, Breiteneder H: Crystal structure of a hypoallergenic isoform of the major birch pollen allergen Bet v 1 and its likely biological function as a plant steroid carrier. J Mol Biol 2003;325:123–133. 70 Barrasa JI, Olmo N, Lizarbe MA, Turnay J: Bile acids in the colon, from healthy to cytotoxic molecules. Toxicol In Vitro 2013; 27: 964–977. 71 Bernstein H, Bernstein C, Payne CM, Dvorak K: Bile acids as endogenous etiologic agents in gastrointestinal cancer. World J Gasroenterol 2009;15:3329–3340. 72 Payne CM, Crowley-Skillicorn C, Bernstein C, Holubec H, Moyer MP, Bernstein H: Hydrophobic bile acid induced micronuclei formation, mitotic perturbations, and decreases in spindle checkpoint proteins: relevance to genomic instability in colon carcinogenesis. Nutr Cancer 2010;62:825–840. 73 Koutsounas I, Patsouris E, Theocharis S: Pregnane X receptor and human malignancy. Histol Histopathol 2013;28:405–420. 74 Bailey AM, Zhan L, Maru D, Shureigi I, Pickering CR, Kiriakova G, Izzo J, He N, Wei C, Baladandayuthapani V, Liang H, Kopetz S, Powis G, Guo GL: FXR silencing in human colon cancer by DNA methylation and KRAS signalling. Am J Physiol Gastrointest Liver Physiol 2014;306:G48–G58.


Downloaded by: Selçuk Universitesi - 1/28/2015 7:59:07 AM

47 Caradonna L, Amati L, Magrone T, Pellegrino NM, Jirillo E, Caccavo D: Enteric bacteria, liopopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance. J Endotoxin Res 2000; 6: 205–214. 48 Sakisaka S, Koga H, Sasatomi K, Mimira Y, Kawaguchi T, Tanikawa K: Biliary secretion of endotoxin and pathogenesis of primary biliary cirrhosis. Yale J Biol Med 1997; 70: 403– 406. 49 Piya MK, Harte AL, McTernan PG: Metabolic endotoxaemia: is it more than just a gut feeling. Curr Opin Lipidol 2013;24:78–85. 50 von Mutius E, Braun-Fahrlander C, Schierl R, Riedler J, Ehlermann S, Maisch S, Waser M, Nowak D: Exposure to endotoxin or other bacterial components might protect against the development of atopy. Clin Exp Allergy 2000;30:1230–1234. 51 Gereda JE, Leung DY, Thatayatikom A, Streib JE, Price MR, Klinnert MD, Liu AH: Relation between house-dust endotoxin exposure type 1 T cell development, and allergen sensitisation in infants at high risk of asthma. Lancet 2000;355:1680–1683. 52 Natarajan S, Kim J, Bouchard J, Cruikshank W, Remick DG: Pulmonary endotoxin tolerance protects against cockroach allergen induced asthma-like inflammation in a mouse model. Int Arch Allergy Immunol 2012; 158: 120–130. 53 Illi S, Depner M, Genuneit J, Horak E, Loss G, Strunz-Lehner C, Büchele G, Boznanski A, Danielewicz H, Cullinan P, Heederik D, Braun-Fahrlander C, von Mutius E: Protection from childhood asthma and allergy in Alpine farm environments – the GABRIEL Advanced Studies. J Allergy Clin Immunol 2012; 129:1470–1477. 54 Baumann S, Lorentz A: Obesity – a promoter of allergy? Int Arch Allergy Immunol 2013; 162:205–213. 55 Kocsár LT, Bertók L, Várterész V: Effect of bile acids on the intestinal absorption of endotoxin in rats. J Bacteriol 1969;100:220–223.

The immunomodulatory role of bile acids.

Enzymatic oxidation of cholesterol generates numerous distinct bile acids which function both as detergents that facilitate the digestion and absorpti...
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