scholarly journals Prophylactic inhibition of colonization by Streptococcus pneumoniae with the secondary bile acid metabolite deoxycholic acid

2021 ◽  
Author(s):  
Jorge E. Vidal ◽  
Meagan N. Wier ◽  
Uriel Angulo-Zamudio ◽  
Erin McDevitt ◽  
Ana G Vidal ◽  
...  
Keyword(s):  
Bile Acid ◽  
Streptococcus Pneumoniae ◽  
Deoxycholic Acid ◽  
Ex Vivo ◽  
Post Inoculation ◽  
Acid Metabolite ◽  
Nasopharyngeal Colonization ◽  
Secondary Bile Acid ◽  
Human Bile

Streptococcus pneumoniae (Spn) colonizes the nasopharynx of children and the elderly but also kills millions worldwide yearly. The secondary bile acid metabolite, deoxycholic acid (DoC), affects the viability of human pathogens but also plays multiple roles in host physiology. We assessed in vitro the antimicrobial activity of DoC and investigated its potential to eradicate Spn colonization using an ex vivo model of human nasopharyngeal colonization and an in vivo mouse model of colonization. At a physiological concentration DoC (0.5 mg/ml; 1.27 mM) killed all tested Spn strains (N=48) two h post-inoculation. The ex-vivo model of nasopharyngeal colonization showed that DoC eradicated colonization by Spn strains as soon as 10 min post-exposure. The mechanism of action did not involve activation of autolysis since the autolysis-defective double mutants ΔlytAΔlytC and ΔspxBΔlctO were as susceptible to DoC as was the wild-type (WT). Oral streptococcal species (N=20), however, were not susceptible to DoC (0.5 mg/ml). Unlike trimethoprim, whose spontaneous resistance frequency (srF) for TIGR4 or EF3030 was ≥1x10-9, no spontaneous resistance was observed with DoC (srF≥1x10-12). Finally, the efficacy of DoC to eradicate Spn colonization was assessed in vivo using a topical route via intranasal (i.n.) administration and as a prophylactic treatment. Mice challenged with Spn EF3030 carried a median of 4.05x105 cfu/ml four days post-inoculation compared to 6.67x104 cfu/ml for mice treated with DoC. Mice in the prophylactic group had a ~99% reduction of the pneumococcal density (median, 2.61 x103 cfu/ml). Thus, DoC, an endogenous human bile salt, has therapeutic potential against Spn.

scholarly journals Prophylactic inhibition of colonization by Streptococcus pneumoniae with the secondary bile acid metabolite deoxycholic acid

2021 ◽  
Author(s):  
Jorge E. Vidal ◽  
Meagan N. Wier ◽  
Uriel Angulo-Zamudio ◽  
Erin McDevitt ◽  
Ana G. Jop Vidal ◽  
...  
Keyword(s):  
Bile Acid ◽  
Streptococcus Pneumoniae ◽  
Deoxycholic Acid ◽  
Therapeutic Potential ◽  
Post Inoculation ◽  
Acid Metabolite ◽  
Nasopharyngeal Colonization ◽  
Secondary Bile Acid ◽  
Human Bile

Streptococcus pneumoniae (Spn) colonizes the nasopharynx of children and the elderly but also kills millions worldwide yearly. The secondary bile acid metabolite, deoxycholic acid (DoC), affects the viability of human pathogens but also plays multiple roles in host physiology. We assessed in vitro the antimicrobial activity of DoC and investigated its potential to eradicate Spn colonization using a model of human nasopharyngeal colonization and an in vivo mouse model of colonization. At a physiological concentration DoC (0.5 mg/ml; 1.27 mM) killed all tested Spn strains (N=48) two hours post-inoculation. The model of nasopharyngeal colonization showed that DoC eradicated colonization by Spn strains as soon as 10 min post-exposure. The mechanism of action did not involve activation of autolysis since the autolysis-defective double mutants Δ lytA Δ lytC and ΔspxBΔlctO were as susceptible to DoC as was the wild-type (WT). Oral streptococcal species (N=20), however, were not susceptible to DoC (0.5 mg/ml). Unlike trimethoprim, whose spontaneous resistance frequency (srF) for TIGR4 or EF3030 was ≥1x10 −9 , no spontaneous resistance was observed with DoC (srF≥1x10- 12 ). Finally, the efficacy of DoC to eradicate Spn colonization was assessed in vivo using a topical route via intranasal (i.n.) administration and as a prophylactic treatment. Mice challenged with Spn EF3030 carried a median of 4.05x10 5 cfu/ml four days post-inoculation compared to 6.67x10 4 cfu/ml for mice treated with DoC. Mice in the prophylactic group had a ∼99% reduction of the pneumococcal density (median, 2.61 x10 3 cfu/ml). Thus, DoC, an endogenous human bile salt, has therapeutic potential against Spn.

In Vitro Metabolism of E2, G2: Novel Bile Acid-Coupling Camptothecin Analogues, in Rat Liver Microsomes

2021 ◽  
Vol 16 ◽  
Author(s):  
Xiangli Zhang ◽  
Qin Shen ◽  
Yi Wang ◽  
Leilei Zhou ◽  
Qi Weng ◽  
...  
Keyword(s):  
Bile Acid ◽  
Phase I ◽  
Rat Liver ◽  
Deoxycholic Acid ◽  
Liver Microsomes ◽  
Intrinsic Clearance ◽  
Rat Liver Microsomes ◽  
Camptothecin Analogues

Background: E2 (Camptothecin - 20 (S) - O- glycine - deoxycholic acid), and G2 (Camptothecin - 20 (S) - O - acetate - deoxycholic acid) are two novel bile acid-derived camptothecin analogues by introducing deoxycholic acid in 20-position of CPT(camptothecin) with greater anticancer activity and lower systematic toxicity in vivo. Objective: We aimed to investigate the metabolism of E2 and G2 by Rat Liver Microsomes (RLM). Methods: Phase Ⅰ and Phase Ⅱ metabolism of E2 and G2 in rat liver microsomes were performed respectively, and the mixed incubation of phase I and phase Ⅱ metabolism of E2 and G2 was also processed. Metabolites were identified by liquid chromatographic/mass spectrometry. Results: The results showed that phase I metabolism was the major biotransformation route for both E2 and G2. The isoenzyme involved in their metabolism had some difference. The intrinsic clearance of G2 was 174.7mL/min. mg protein, more than three times of that of E2 (51.3 mL/min . mg protein), indicating a greater metabolism stability of E2. 10 metabolites of E2 and 14 metabolites of G2 were detected, including phase I metabolites (mainly via hydroxylations and hydrolysis) and their further glucuronidation products. Conclusion: These findings suggested that E2 and G2 have similar biotransformation pathways except some difference in the hydrolysis ability of the ester bond and amino bond from the parent compounds, which may result in the diversity of their metabolism stability and responsible CYPs(Cytochrome P450 proteins).

scholarly journals An optimized probucol microencapsulated formulation integrating a secondary bile acid (deoxycholic acid) as a permeation enhancer

2014 ◽  
pp. 1673 ◽  
Author(s):  
Hani Al-Salami ◽  
Armin Mooranian ◽  
Rebecca Negrulj ◽  
Nigel Chen-Tan ◽  
Gerald Watts ◽  
...  
Keyword(s):  
Bile Acid ◽  
Deoxycholic Acid ◽  
Permeation Enhancer ◽  
Secondary Bile Acid

scholarly journals Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon

2017 ◽  
Vol 312 (6) ◽  
pp. G550-G558 ◽  
Author(s):  
Joseph B. J. Ward ◽  
Natalia K. Lajczak ◽  
Orlaith B. Kelly ◽  
Aoife M. O’Dwyer ◽  
Ashwini K. Giddam ◽  
...  
Keyword(s):  
Bile Acid ◽  
Ursodeoxycholic Acid ◽  
Inflammatory Responses ◽  
Lithocholic Acid ◽  
Primary Metabolite ◽  
Secondary Bile Acid ◽  
Colonic Inflammation ◽  
Anti Inflammatory

Inflammatory bowel diseases (IBD) comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile acid, ursodeoxycholic acid (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating IBD. We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6α-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic acid (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-α, IL-6, Il-1β, and IFN-γ) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography-mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile acid. Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic inflammation and suggest that microbial metabolism of UDCA is necessary for the full expression of its protective actions. NEW & NOTEWORTHY On the basis of its cytoprotective and anti-inflammatory actions, the secondary bile acid ursodeoxycholic acid (UDCA) has well-established uses in both traditional and Western medicine. We identify a new role for the primary metabolite of UDCA, lithocholic acid, as a potent inhibitor of intestinal inflammatory responses, and we present data to suggest that microbial metabolism of UDCA is necessary for the full expression of its protective effects against colonic inflammation.

scholarly journals Multiple Consecutive Lavage Samplings Reveal Greater Burden of Disease and Provide Direct Access to the Nontypeable Haemophilus influenzae Biofilm in Experimental Otitis Media

2007 ◽  
Vol 75 (8) ◽  
pp. 4158-4172 ◽  
Author(s):  
Magali Leroy ◽  
Howard Cabral ◽  
Marisol Figueira ◽  
Valérie Bouchet ◽  
Heather Huot ◽  
...  
Keyword(s):  
Gene Expression ◽  
Haemophilus Influenzae ◽  
Otitis Media ◽  
Vaccine Development ◽  
Ex Vivo ◽  
Direct Analysis ◽  
Direct Access ◽  
Nontypeable Haemophilus Influenzae ◽  
Nasopharyngeal Colonization

ABSTRACT The typically recovered quantity of nontypeable Haemophilus influenzae (NTHi) bacteria in an ex vivo middle ear (ME) aspirate from the chinchilla model of experimental otitis media is insufficient for direct analysis of gene expression by microarray or of lipopolysaccharide glycoforms by mass spectrometry. This prompted us to investigate a strategy of multiple consecutive lavage samplings to increase ex vivo bacterial recovery. As multiple consecutive lavage samples significantly increased the total number of bacterial CFU collected during nasopharyngeal colonization or ME infection, this led us to evaluate whether bacteria sequentially acquired from consecutive lavages were similar. Comparative observation of complete ex vivo sample series by microscopy initially revealed ME inflammatory fluid consisting solely of planktonic-phase NTHi. In contrast, subsequent lavage samplings of the same infected ear revealed the existence of bacteria in two additional growth states, filamentous and biofilm encased. Gene expression analysis of such ex vivo samples was in accord with different bacterial growth phases in sequential lavage specimens. The existence of morphologically distinct NTHi subpopulations with varying levels of gene expression indicates that the pooling of specimens requires caution until methods for their separation are developed. This study based on multiple consecutive lavages is consistent with prior reports that NTHi forms a biofilm in vivo, describes the means to directly acquire ex vivo biofilm samples without sacrificing the animal, and has broad applicability for a study of mucosal infections. Moreover, this approach revealed that the actual burden of bacteria in experimental otitis media is significantly greater than was previously reported. Such findings may have direct implications for antibiotic treatment and vaccine development against NTHi.

scholarly journals Microbial metabolite deoxycholic acid controlsClostridium perfringens-induced chicken necrotic enteritis through attenuating cyclooxygenase signaling

2018 ◽  
Author(s):  
Hong Wang ◽  
Juan D. Latorre ◽  
Mohit Bansal ◽  
Mussie Abraha ◽  
Bilal Al-Rubaye ◽  
...  
Keyword(s):  
Bile Acid ◽  
Inflammatory Response ◽  
Inflammatory Mediators ◽  
Cell Apoptosis ◽  
Deoxycholic Acid ◽  
Intestinal Inflammation ◽  
Metabolic Product ◽  
Intestinal Cell ◽  
Necrotic Enteritis ◽  
Secondary Bile Acid

AbstractClostridium perfringens-induced necrotic enteritis (NE) has reemerged as a prevalent chicken disease worldwide due to reduced usage of prophylactic antibiotics. The lack of antimicrobial alternative strategies to control NE is mainly due to limited insight into the disease pathogenesis. The aim of this study is to investigate the role of microbiota metabolic product secondary bile acid deoxycholic acid (DCA) on preventing NE.C. perfringensgrowth was inhibited by 82.8% in 50 μM DCA Tryptic Soy Broth. SequentialEimeria maximaandC. perfringenschallenges induced acute NE showed as severe intestinal inflammation and body weight (BW) loss in broiler chickens, while 1.5 g/kg DCA diet dramatically reduced the disease. At the cellular level, DCA alleviated NE-associated ileal epithelial death and reduced lamina propria cell apoptosis. Interestingly, DCA reducedC. perfringensinvasion into ileum without altering the bacterial ileal luminal colonization. Molecular analysis showed that DCA reduced inflammatory mediators ofInfγ,Litaf, andMmp9mRNA accumulation in ileal tissue. Mechanism studies revealed thatC. perfringensinduced elevated expression of inflammatory mediators ofInfγ,Litaf,Mmp9,andPtgs2(Cyclooxygenase- 2 (COX-2) gene) in chicken splenocytes. Blocking COX signaling by pharmacological inhibitor aspirin attenuated INFγ-induced inflammatory response in the splenocytes. Consistent with thein vitroassay, chickens fed 0.12 g/kg aspirin diet protected the birds against NE-induced ileal inflammation, intestinal cell apoptosis, and BW loss. In conclusion, microbial metabolic product DCA prevents NE-induced ileal inflammation and BW loss through attenuating inflammatory response. These novel findings offer new strategies againstC. perfringens-induced diseases.Significance StatementWidespread antimicrobial resistance has become a serious challenge to both agricultural and healthcare industries. Withdrawing antimicrobials without effective alternatives exacerbates chicken productivity loss at billions of dollars every year, caused by intestinal diseases, such as coccidiosis-andC. perfringens-induced necrotic enteritis. This study revealed that microbial metabolic product secondary bile acid DCA preventsC. perfringens-induced intestinal disease in chickens through modulating inflammatory COX signaling pathways. Therefore, microbiome and its downstream targets of host inflammatory responses could be used to control NE. These findings have opened new avenues for developing novel antimicrobial free alternatives to prevent or treatC. perfringens-induced diseases.

scholarly journals Bile acid bio-nanoencapsulation improved drug targeted-delivery and pharmacological effects via cellular flux: 6-months diabetes preclinical study

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Armin Mooranian ◽  
Susbin Raj Wagle ◽  
Bozica Kovacevic ◽  
Ryu Takechi ◽  
John Mamo ◽  
...  
Keyword(s):  
Bile Acid ◽  
Targeted Delivery ◽  
Oral Delivery ◽  
Ex Vivo ◽  
Biological Effects ◽  
Protective Effects ◽  
Β Cells ◽  
Positive Effects ◽  
Anti Inflammatory

AbstractThe antilipidemic drug, probucol (PB), has demonstrated potential applications in Type 2 diabetes (T2D) through its protective effects on pancreatic β-cells. PB has poor solubility and bioavailability, and despite attempts to improve its oral delivery, none has shown dramatic improvements in absorption or antidiabetic effects. Preliminary data has shown potential benefits from bile acid co-encapsulation with PB. One bile acid has shown best potential improvement of PB oral delivery (ursodeoxycholic acid, UDCA). This study aimed to examine PB and UDCA microcapsules (with UDCA microcapsules serving as control) in terms of the microcapsules’ morphology, biological effects ex vivo, and their hypoglycemic and antilipidemic and anti-inflammatory effects in vivo. PBUDCA and UDCA microcapsules were examined in vitro (formulation studies), ex vivo and in vivo. PBUDCA microcapsules exerted positive effects on β-cells viability at hyperglycemic state, and brought about hypoglycemic and anti-inflammatory effects on the prediabetic mice. In conclusion, PBUDCA co-encapsulation have showed beneficial therapeutic impact of dual antioxidant-bile acid effects in diabetes treatment.

scholarly journals Development of a Covalent Inhibitor of Gut Bacterial Bile Salt Hydrolases

2019 ◽  
Author(s):  
Arijit A. Adhikari ◽  
Tom C. Seegar ◽  
Scott B. Ficarro ◽  
Megan D. McCurry ◽  
Deepti Ramachandran ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Salt ◽  
Bile Acids ◽  
Unmet Need ◽  
Cysteine Residue ◽  
Gut Bacteria ◽  
Bile Salt Hydrolase ◽  
Secondary Bile Acid ◽  
Bsh Activity

AbstractBile salt hydrolase (BSH) enzymes are widely expressed by human gut bacteria and catalyze the gateway reaction leading to secondary bile acid formation. Bile acids regulate key metabolic and immune processes by binding to host receptors. There is an unmet need for a potent tool to inhibit BSHs across all gut bacteria in order to study the effects of bile acids on host physiology. Here, we report the development of a covalent pan-inhibitor of gut bacterial BSH. From a rationally designed candidate library, we identified a lead compound bearing an alpha-fluoromethyl ketone warhead that modifies BSH at the catalytic cysteine residue. Strikingly, this inhibitor abolished BSH activity in conventional mouse feces. Mice gavaged with a single dose of this compound displayed decreased BSH activity and decreased deconjugated bile acid levels in feces. Our studies demonstrate the potential of a covalent BSH inhibitor to modulate bile acid composition in vivo.

Deoxycholic Acid Activates and Sensitizes Vagal Nociceptive Afferent C-fibers in Guinea Pig Esophagus

2021 ◽  
Author(s):  
Xiaoyun Yu ◽  
Youtian Hu ◽  
Mingwei Yu ◽  
Bradley J Undem ◽  
Shaoyong Yu
Keyword(s):  
Bile Acid ◽  
Deoxycholic Acid ◽  
Ex Vivo ◽  
Acid Reflux ◽  
Proton Pump Inhibitor Therapy ◽  
Patch Clamp Recording ◽  
C Fibers ◽  
Subsequent Response ◽  
C Fiber ◽  
Inward Currents

Bile acid reflux in the esophagus plays a role in the pathogenesis of certain esophageal disorders where it can induce esophageal pain and heartburn. The present study aimed to determine whether bile acid, deoxycholic acid (DCA), directly activates and sensitizes esophageal vagal nociceptive afferent C-fiber subtypes. DCA-elicited effects on vagal nodose and jugular neurons were studied by calcium imaging. Its effects on esophageal-labeled nodose and jugular neurons were then determined by patch-clamp recording. At nodose and jugular C-fiber nerve endings in the esophagus, DCA-evoked action potentials (APs) were compared by extra-cellular single-unit recordings in ex vivo esophageal-vagal preparations. DCA application induced calcium influxes in nodose and jugular neurons and elicited inward currents in esophageal-labeled nodose and jugular neurons. In the presence of DCA, the current densities elicited by capsaicin were enhanced in those labeled neurons. Consistently, DCA perfusion at nerve terminals in the esophagus evoked APs in about 50% of esophageal nodose and jugular C-fibers. In DCA-sensitive C-fibers, DCA perfusion also sensitized the fibers such that the subsequent response to capsaicin was amplified. Collectively, these results provide new evidence that DCA directly activates and sensitizes nociceptive nodose and jugular C-fibers in the esophagus. Such activation and sensitization effects may contribute to bile acid-induced esophageal nociceptive symptoms that are refractory to proton-pump inhibitor therapy.

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