The human bile salt sodium deoxycholate induces metabolic and cell envelope changes in Salmonella Typhi leading to bile resistance

2022 ◽  
Vol 71 (1) ◽  
Author(s):  
Isaac B. Olivar-Casique ◽  
Liliana Medina-Aparicio ◽  
Selena Mayo ◽  
Yitzel Gama-Martínez ◽  
Javier E. Rebollar-Flores ◽  
...  
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Cell Envelope ◽  
Sodium Deoxycholate ◽  
Salmonella Typhi ◽  
Metabolic Adaptation ◽  
Human Bile ◽  
Content Type ◽  
Genetic Elements ◽  
Bile Resistance

Introduction. Salmonella enterica serovar Typhi (S. Typhi) is the etiological agent of typhoid fever. To establish an infection in the human host, this pathogen must survive the presence of bile salts in the gut and gallbladder. Hypothesis. S. Typhi uses multiple genetic elements to resist the presence of human bile. Aims. To determine the genetic elements that S. Typhi utilizes to tolerate the human bile salt sodium deoxycholate. Methodology. A collection of S. Typhi mutant strains was evaluated for their ability to growth in the presence of sodium deoxycholate and ox-bile. Additionally, transcriptomic and proteomic responses elicited by sodium deoxycholate on S. Typhi cultures were also analysed. Results. Multiple transcriptional factors and some of their dependent genes involved in central metabolism, as well as in cell envelope, are required for deoxycholate resistance. Conclusion. These findings suggest that metabolic adaptation to bile is focused on enhancing energy production to sustain synthesis of cell envelope components exposed to damage by bile salts.

How does bile salt penetration affect the self-assembled architecture of pluronic P123 micelles? – light scattering and spectroscopic investigations

2015 ◽  
Vol 17 (30) ◽  
pp. 19977-19990 ◽  
Author(s):  
Arpita Roy ◽  
Niloy Kundu ◽  
Debasis Banik ◽  
Jagannath Kuchlyan ◽  
Nilmoni Sarkar
Keyword(s):  
Light Scattering ◽  
Bile Salt ◽  
Bile Salts ◽  
Triblock Copolymer ◽  
Sodium Taurocholate ◽  
Sodium Deoxycholate ◽  
The Self ◽  
Spectroscopic Investigations ◽  
Pluronic P123 ◽  
Supramolecular Aggregate

The triblock copolymer of the type (PEO)20–(PPO)70–(PEO)20 (P123) forms a mixed supramolecular aggregate with different bile salts, sodium deoxycholate (NaDC) and sodium taurocholate (NaTC), having different hydrophobicity.

scholarly journals Molecular basis of bile-salt- and iron-induced enterohaemorrhagic E. coli resistance to cationic antimicrobial peptides

Microbiology ◽  
2020 ◽  
Vol 166 (12) ◽  
pp. 1149-1159
Author(s):  
Chhatra B. Kunwar ◽  
Sarah Birstonas ◽  
Joseph B. McPhee ◽  
Debora Barnett Foster
Keyword(s):  
Gastrointestinal Tract ◽  
Bile Salt ◽  
Bile Salts ◽  
Type Species ◽  
Two Component System ◽  
Component System ◽  
Content Type ◽  
Link Type ◽  
Two Component ◽  
Mild Acid

Colonization of the gastrointestinal tract by enterohaemorrhagic Escherichia coli (EHEC) is critically dependent on its ability to sense and respond to various microenvironments within the host. EHEC exposure to physiologically relevant levels of bile salts upregulates the two-component system, pmrAB, and the arnBCADTEF operon, resulting in lipopolysaccharide modification and increased resistance to the cationic antimicrobial peptide, polymyxin B (PMB). A similar pmrAB- and arn-dependent PMB resistance has been observed in Salmonella enterica in the presence of ferric iron. Limiting magnesium levels and mild acid can also induce Salmonella resistance to PMB through another two-component system, PhoPQ and the connector protein, PmrD. This study aims to evaluate the relative contributions of a bile-salt mix (BSM), iron, limiting magnesium as well as the roles of pmrAB, phoPQ and pmrD to EHEC’s resistance to PMB. Killing assays show that EHEC treatment with the BSM or iron under excess magnesium and neutral pH conditions induces a pmrAB-dependent, phoP-independent PMB resistance. By contrast, exposure to limiting magnesium triggers a pmrB-, phoP- and pmrD-dependent PMB resistance. The iron-induced PMB resistance is independent of phoP and pmrD under limiting magnesium conditions while the bile-salt-induced PMB resistance is independent of pmrD only under non-PhoP-inducing conditions. GFP-pmrD transcriptional reporter studies reveal that the limiting magnesium enhances pmrD expression, which is repressed upon additional exposure to either BSM or iron. Our results also show that exposure to mild acid enhances PMB resistance in a pmrD-independent manner and GFP reporter results confirm minimal expression of pmrD at this pH regardless of the magnesium level. This study provides novel insights into how EHEC differentially employs PmrAB, PhoPQ and PmrD to monitor and respond to bile salts, iron, acidic pH and magnesium typically encountered within the gastrointestinal tract in order to modulate its survival against cationic antimicrobial peptides.

Comparison of In Vitro Binding of Bile Salt by Pectins from Various Sources

2012 ◽  
Vol 506 ◽  
pp. 274-277 ◽  
Author(s):  
K. Cheewatanakornkool ◽  
A. Chaidedgumjorn ◽  
U. Sotanaphun ◽  
S. Limsirichaikul ◽  
C. Wessapan ◽  
...  
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Serum Cholesterol Level ◽  
Sodium Deoxycholate ◽  
Sodium Cholate ◽  
Experimental Animals ◽  
Hypocholesterolemic Action ◽  
Acid Reaction ◽  
Layer Chromatography

Binding of bile salts by dietary fiber is believed to promote their excretion and hence to reduce the serum cholesterol level in man and experimental animals. In this study, the binding efficiency of soluble pectin from various sources, i.e., apple, citrus and pomelo, was examined. Sodium deoxycholate and sodium cholate hydrate were used as a model to represent bile salt in human body. The binding efficiency was assayed by acid reaction, thin layer chromatography (TLC) and enzyme cycling method. The results demonstrated that enzyme cycling method was the most suitable for assaying the in-vitro binding of bile salts while the TLC was not very sensitive, i.e., low amount of bile salts cannot be detected by TLC. Excess pectin from binding test could also interfere the acid reaction method even though the centrifugation was used to remove the excess pectin. When the concentration of pectin was increased, the binding efficiency with sodium deoxycholate increased. However, at 1% w/w of pectin, the binding efficiency decreased. The exception is for pomelo pectin in which the binding efficiency increased when the pectin concentration increased. With sodium cholate hydrate, only slight difference in binding efficiency was observed for all types and concentrations of pectin. The results indicate that the ability to bind bile salts of pectin might be responsible for its hypocholesterolemic action observed in experimental animals and humans.

scholarly journals Bile Salt Hydrolase of Bifidobacterium longum—Biochemical and Genetic Characterization

2000 ◽  
Vol 66 (6) ◽  
pp. 2502-2512 ◽  
Author(s):  
Hiroshi Tanaka ◽  
Honoo Hashiba ◽  
Jan Kok ◽  
Igor Mierau
Keyword(s):  
Molecular Weight ◽  
Amino Acid ◽  
Bile Salt ◽  
Bile Salts ◽  
Bifidobacterium Longum ◽  
Bacillus Sphaericus ◽  
Site Directed Mutagenesis ◽  
Bile Salt Hydrolase ◽  
Ph Optimum ◽  
Human Bile

ABSTRACT A bile salt hydrolase (BSH) was isolated from Bifidobacterium longum SBT2928, purified, and characterized. Furthermore, we describe for the first time cloning and analysis of the gene encoding BSH (bsh) in a member of the genusBifidobacterium. The enzyme has a native molecular weight of 125,000 to 130,000 and a subunit molecular weight of 35,024, as determined from the deduced amino acid sequence, indicating that the enzyme is a tetramer. The pH optimum of B. longum BSH is between 5 and 7, and the temperature optimum is 40°C. The enzyme is strongly inhibited by thiol enzyme inhibitors, indicating that a Cys residue is likely to be involved in the catalytic reaction. The BSH ofB. longum can hydrolyze all six major human bile salts and at least two animal bile salts. A slight preference for glycine-conjugated bile acids was detected based on both the specificity and the Km values. The nucleotide sequence of bsh was determined and used for homology studies, transcript analysis, and construction and analysis of various mutants. The levels of homology with BSH of other bacteria and with penicillin V acylase (PVA) of Bacillus sphaericus were high. On the basis of the similarity of BSH and PVA, whose crystal structure has been elucidated, BSH can be classified as an N-terminal nucleophile hydrolase with Cys as the N-terminal amino acid. This classification was confirmed by the fact that a Cys1Ala exchange by site-directed mutagenesis resulted in an inactive protein. Reverse transcription-PCR experiments revealed that bsh is part of an operon containing at least two genes, bsh andglnE (GlnE is glutamine synthetase adenylyltransferase). Two UV-induced BSH-negative mutants and one spontaneous BSH-negative mutant were isolated from B. longum SBT2928 cultures and characterized. These mutants had point mutations that inactivatedbsh by premature termination, frameshift, or amino acid exchange.

scholarly journals Calcium Enhances Bile Salt-Dependent Virulence Activation in Vibrio cholerae

2016 ◽  
Vol 85 (1) ◽  
Author(s):  
Amanda J. Hay ◽  
Menghua Yang ◽  
Xiaoyun Xia ◽  
Zhi Liu ◽  
Justin Hammons ◽  
...  
Keyword(s):  
Bile Salt ◽  
Vibrio Cholerae ◽  
Bile Salts ◽  
Diarrheal Disease ◽  
Content Type ◽  
Inner Membrane Protein ◽  
Virulence Regulator ◽  
Host Signals

ABSTRACT Vibrio cholerae is the causative bacteria of the diarrheal disease cholera, but it also persists in aquatic environments, where it displays an expression profile that is distinct from that during infection. Upon entry into the host, a tightly regulated circuit coordinates the induction of two major virulence factors: cholera toxin and a toxin-coregulated pilus (TCP). It has been shown that a set of bile salts, including taurocholate, serve as host signals to activate V. cholerae virulence through inducing the activity of the transmembrane virulence regulator TcpP. In this study, we investigated the role of calcium, an abundant mental ion in the gut, in the regulation of virulence. We show that whereas Ca2+ alone does not affect virulence, Ca2+ enhances bile salt-dependent virulence activation for V. cholerae. The induction of TCP by murine intestinal contents is counteracted when Ca2+ is depleted by the high-affinity calcium chelator EGTA, suggesting that the calcium present in the gut is a relevant signal for V. cholerae virulence induction in vivo. We further show that Ca2+ enhances virulence by promoting bile salt-induced TcpP-TcpP interaction. Moreover, fluorescence recovery after photobleaching (FRAP) analysis demonstrated that exposure to bile salts and Ca2+ together decreases the recovery rate for fluorescently labeled TcpP, but not for another inner membrane protein (TatA). Together, these data support a model in which physiological levels of Ca2+ may result in altered bile salt-induced TcpP protein movement and activity, ultimately leading to an increased expression of virulence.

Bile-salt-mediated induction of antimicrobial and bile resistance in Salmonella typhimurium

Microbiology ◽  
2004 ◽  
Vol 150 (4) ◽  
pp. 775-783 ◽  
Author(s):  
A. M. Prouty ◽  
I. E. Brodsky ◽  
S. Falkow ◽  
J. S. Gunn
Keyword(s):  
Salmonella Typhimurium ◽  
Bile Salt ◽  
Dna Microarray ◽  
Bile Salts ◽  
Efflux Pump ◽  
Resistance Phenotype ◽  
Ionic Detergent ◽  
Bile Resistance ◽  
Sublethal Concentrations

By DNA microarray, the Salmonella typhimurium marRAB operon was identified as being bile-activated. Transcriptional assays confirm that marRAB is activated in the presence of bile and that this response is concentration-dependent. The bile salt deoxycholate is alone able to activate transcription, while there was no response in the presence of other bile salts tested or a non-ionic detergent. Deoxycholate is able to interact with MarR and interfere with its ability to bind to the mar operator. In addition, incubation of salmonellae in the presence of sublethal concentrations of bile is able to enhance resistance to chloramphenicol and bile, by means of both mar-dependent and mar-independent pathways. To further characterize putative marRAB-regulated genes that may be important for the resistance phenotype, acrAB, which encodes an efflux pump, was analysed. In S. typhimurium, acrAB is required for bile resistance, but while transcription of acrAB is activated by bile, this activation is independent of marRAB, as well as Rob, RpoS or PhoP–PhoQ. These data suggest that bile interacts with salmonellae to increase resistance to bile and other antimicrobials and that this can occur by marRAB- and acrAB-dependent pathways that function independently with respect to bile activation.

scholarly journals Draft Genome Sequence of a New Methanobacterium Strain Potentially Resistant to Bile Salts, Isolated from Deer Feces

2020 ◽  
Vol 9 (32) ◽  
Author(s):  
Heleen T. Ouboter ◽  
Stefanie Berger ◽  
Erbil Güngör ◽  
Mike S. M. Jetten ◽  
Cornelia U. Welte
Keyword(s):  
Salt Tolerance ◽  
Bile Salt ◽  
Genome Sequence ◽  
Bile Salts ◽  
Draft Genome ◽  
Draft Genome Sequence ◽  
Bile Salt Hydrolase ◽  
High Quality ◽  
Content Type ◽  
Hydrogenotrophic Methanogen

ABSTRACT We present the high-quality draft genome of Methanobacterium subterraneum DF, a hydrogenotrophic methanogen that was isolated from deer feces. This organism has potentially been overlooked in previous studies. Interestingly, its genome encoded bile salt hydrolase, a crucial enzyme for bile salt tolerance that is found in gut organisms.

scholarly journals Nanosized Liposomes Containing Bile Salt: A Vesicular Nanocarrier for Enhancing Oral Bioavailability of BCS Class III Drug

2017 ◽  
Vol 20 ◽  
pp. 305 ◽  
Author(s):  
Mosab Arafat ◽  
Cathrin Kirchhoefer ◽  
Momir Mikov ◽  
Muhammad Sarfraz ◽  
Raimar Löbenberg
Keyword(s):  
Bile Salt ◽  
Oral Bioavailability ◽  
Bile Salts ◽  
Structural Integrity ◽  
Sodium Deoxycholate ◽  
Gastric Fluid ◽  
Simulated Gastric Fluid ◽  
Class Iii ◽  
Simulated Intestinal Fluid ◽  
Fed State

PURPOSE: Liposomes have been studied as a colloidal carrier in drug delivery systems, especially for oral administration. However, their low structural integrity in the gut is still a major shortcoming. Membrane disruptive effects of physiological bile salts in the small intestine result in premature drug release prior to intestinal absorption. Thus, we analyzed the stabilizing effect of sodium deoxycholate when incorporated into nano-sized liposomes. METHOD: Cefotaxime-loaded liposomes were prepared with different sodium deoxycholate concentrations (3.75- 30 mM) by rotary film evaporation followed by nano-size reduction. The physical integrity of liposomes was evaluated by monitoring cefotaxime leakage, particle sizes in different simulated physiological media. The oral bioavailability and pharmacokinetics of cefotaxime was assessed in rats (n = 6 per group) after single dose of drug-encapsulated in liposomes containing bile salt, drug in conventional liposomes, and cefotaxime solution (oral and intravenous). RESULTS: Simulated gastric fluid with low pH showed less effect on the stability of liposomes in comparison to media containing physiological bile salts.  Liposomes containing 15 mM sodium deoxycholate were most stable in size and retained the majority of encapsulated cefotaxime even in fed state of simulated intestinal fluid being the most destructive media. Pharmacokinetics data showed an increase in Cmax and AUC0-inf in the following order: cefotaxime solution < conventional liposomes < liposomes made with bile salts. The total oral bioavailability of cefotaxime in liposomes containing bile salt was found to be 5-times higher compared to cefotaxime solution and twice as much as in conventional liposomes. CONCLUSION: Incorporation of bile salts, initially used as membrane permeation enhancer, also acted as a stabilizer against physiological bile salts. The nano-sized liposomes containing sodium deoxycholate were able to reduce the leakage of encapsulated cefotaxime in the gut due to the improved vesicle stability and to enhance the oral bioavailability of acid-labile drugs up to 5-fold. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Glycochenodeoxycholate Promotes Liver Fibrosis in Mice with Hepatocellular Cholestasis

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 281 ◽  
Author(s):  
Simon Hohenester ◽  
Veronika Kanitz ◽  
Andreas E. Kremer ◽  
Coen C. Paulusma ◽  
Ralf Wimmer ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Bile Salt ◽  
Bile Salts ◽  
Collagen Deposition ◽  
Human Bile ◽  
Hepatic Expression ◽  
Cell Accumulation ◽  
Hepatocellular Cholestasis ◽  
Specific Contribution

Hydrophobic bile salts are considered to promote liver fibrosis in cholestasis. However, evidence for this widely accepted hypothesis remains scarce. In established animal models of cholestasis, e.g., by Mdr2 knockout, cholestasis and fibrosis are both secondary to biliary damage. Therefore, to test the specific contribution of accumulating bile salts to liver fibrosis in cholestatic disease, we applied the unique model of inducible hepatocellular cholestasis in cholate-fed Atp8b1G308V/G308V mice. Glycochenodeoxycholate (GCDCA) was supplemented to humanize the murine bile salt pool, as confirmed by HPLC. Biomarkers of cholestasis and liver fibrosis were quantified. Hepatic stellate cells (HSC) isolated from wild-type mice were stimulated with bile salts. Proliferation, cell accumulation, and collagen deposition of HSC were determined. In cholestatic Atp8b1G308V/G308V mice, increased hepatic expression of αSMA and collagen1a mRNA and excess hepatic collagen deposition indicated development of liver fibrosis only upon GCDCA supplementation. In vitro, numbers of myofibroblasts and deposition of collagen were increased after incubation with hydrophobic but not hydrophilic bile salts, and associated with EGFR and MEK1/2 activation. We concluded that chronic hepatocellular cholestasis alone, independently of biliary damage, induces liver fibrosis in mice in presence of the human bile salt GCDCA. Bile salts may have direct pro-fibrotic effects on HSC, putatively involving EGFR and MEK1/2 signaling.

scholarly journals The Campylobacter jejuni Response Regulator, CbrR, Modulates Sodium Deoxycholate Resistance and Chicken Colonization

2005 ◽  
Vol 187 (11) ◽  
pp. 3662-3670 ◽  
Author(s):  
Brian H. Raphael ◽  
Sonia Pereira ◽  
Gary A. Flom ◽  
Qijing Zhang ◽  
Julian M. Ketley ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Histidine Kinase ◽  
Bile Salts ◽  
Type Strain ◽  
Target Genes ◽  
Wild Type Strain ◽  
Response Regulator ◽  
Sodium Deoxycholate ◽  
Wild Type ◽  
Bile Resistance

ABSTRACT Two-component regulatory systems play a major role in the physiological response of bacteria to environmental stimuli. Such systems are composed of a sensor histidine kinase and a response regulator whose ultimate function is to affect the expression of target genes. Response regulator mutants of Campylobacter jejuni strain F38011 were screened for sensitivity to sodium deoxycholate. A mutation in Cj0643, which encodes a response regulator with no obvious cognate histidine kinase, resulted in an absence of growth on plates containing a subinhibitory concentration of sodium deoxcholate (1%, wt/vol). In broth cultures containing 0.05% (wt/vol) sodium deoxycholate, growth of the mutant was significantly inhibited compared to growth of the C. jejuni F38011 wild-type strain. Complementation of the C. jejuni cbrR mutant in trans restored growth in both broth and plate cultures supplemented with sodium deoxycholate. Based on the phenotype displayed by its mutation, we designated the gene corresponding to Cj0643 as cbrR (Campylobacter bile resistance regulator). While the MICs of a variety of bile salts and other detergents for the C. jejuni cbrR mutant were lower, no difference was noted in its sensitivity to antibiotics or osmolarity. Finally, chicken colonization studies demonstrated that the C. jejuni cbrR mutant had a reduced ability to colonize compared to the wild-type strain. These data support previous findings that bile resistance contributes to colonization of chickens and establish that the response regulator, CbrR, modulates resistance to bile salts in C. jejuni.

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