Bile Salts

Vibrio parahaemolyticus and Escherichia coli have expanded their pathogenicity and transmission range, developed resistance to various antibiotics and have the ability to form biofilms, posing a serious challenge to the clinical application of traditional antibiotics. To address this crisis of antibiotic resistance, the urgent need for natural, alternative or adjunctive strategies has become paramount. Bile salts exhibit potential value as a natural antimicrobial agent. The aim of this study was to explore the potential of bile salts as an antibiotic adjuvant to reduce the amount of antibiotics used and thus antibiotic resistance, and to provide new strategies for the treatment of infections. The fractional inhibitory concentration index (FICI) of bile salts with antibiotics was determined, with the combination with gentamicin (GEN) exhibited the most efficient synergistic antibacterial effects. Additionally, this combination significantly inhibited biofilm formation (83.76% and 60.98%) and reduced the production of extracellular polysaccharides and proteins. Further investigation demonstrated that this combination notably induced leakage of intracellular enzymes (e.g. alkaline phosphatase and β-galactosidase), and resulted in an elevation of the intracellular reactive oxygen species (ROS) levels. This phenomenon could be ascribed to the fact that bile salts significantly increased the membrane permeability, thus facilitating the penetration of GEN into bacterial cells. Therefore, the combination of bile salts and GEN triggered severe intracellular oxidative damage and irreversible cell membrane disruption, ultimately leading to bacterial death. The synergistic effect between bile salts and GEN offers a promising strategy for the treatment of foodborne pathogens. © 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

OBJECTIVES: Edaravone (EDR) is an effective neuroprotective agent in various neurological diseases; however, its use is restricted due to poor oral absorption. Bile salts are known for improving solubility and inhibiting drug crystallization in supersaturated conditions of the gastrointestinal tract (GIT). In our previous work, we prepared coamorphous dispersion (COAM) of EDR with sodium taurocholate (NaTC) using spray drying. The optimized EDR COAM exhibited superior in vitro performance compared to plain EDR. EDR is well absorbed in fasted-over-fed conditions. METHODS: The present work, we conducted a pharmacokinetic study for EDR and EDR COAM in fasted and fed conditions to check effect of food on its oral absorption. The LC-MS/MS-based method was developed and validated to determine the amount of EDR in plasma. RESULTS: The results suggested that EDR COAM did not show a significant difference in Cmax (P=0.3544) and AUC (P=0.1696) of fasted and fed states. On the other hand, plain EDR showed 2-fold and 3-fold reduced Cmax (P<0.0001) and AUC (P=0.0094) in the fed condition, respectively. The Cmax and AUC of EDR COAM were improved in fasted (AUC: 2.56-fold) and fed states (AUC: 5.74-fold) than plain EDR, suggesting better oral absorption of COAM than crystalline EDR without having the effect of food. CONCLUSIONS: The unique structural attributes of NaTC had the potential to inhibit the recrystallization of EDR in GIT, while concurrently reducing the impact of food on the oral absorption of EDR.

In this work, we set out to better understand how the permeation enhancer sodium caprate (C10) influences the intestinal absorption of macromolecules. FITC-dextran 4000 (FD4) was selected as a model compound and formulated with 50-300 mM C10. Absorption was studied after bolus instillation of liquid formulation to the duodenum of anesthetized rats and intravenously as a reference, whereafter plasma samples were taken and analyzed for FD4 content. It was found that the AUC and Cmax of FD4 increased with increasing C10 concentration. Higher C10 concentrations were associated with an increased and extended absorption but also increased epithelial damage. Depending on the C10 concentration, the intestinal epithelium showed significant recovery already at 60-120 min after administration. At the highest studied C10 concentrations (100 and 300 mM), the absorption of FD4 was not affected by the colloidal structures of C10, with similar absorption obtained when C10 was administered as micelles (pH 8.5) and as vesicles (pH 6.5). In contrast, the FD4 absorption was lower when C10 was administered at 50 mM formulated as micelles as compared to vesicles. Intestinal dilution of C10 and FD4 revealed a trend of decreasing FD4 absorption with increasing intestinal dilution. However, the effect was smaller than that of altering the total administered C10 dose. Absorption was similar when the formulations were prepared in simulated intestinal fluids containing mixed micelles of bile salts and phospholipids and in simple buffer solution. The findings in this study suggest that in order to optimally enhance the absorption of macromolecules, high (≥100 mM) initial intestinal C10 concentrations are likely needed and that both the concentration and total dose of C10 are important parameters.

Effective therapeutic options are urgently needed to tackle antibiotic resistance. Furazolidone (FZ), vancomycin (VAN), and sodium deoxycholate (DOC) show promise as their combination can synergistically inhibit the growth of, and kill, multidrug-resistant Gram-negative bacteria that are classified as critical priority by the World Health Organization. Here, we investigated the mechanisms of action and synergy of this drug combination using a transcriptomics approach in the model bacterium Escherichia coli. We show that FZ and DOC elicit highly similar gene perturbations indicative of iron starvation, decreased respiration and metabolism, and translational stress. In contrast, VAN induced envelope stress responses, in agreement with its known role in peptidoglycan synthesis inhibition. FZ induces the SOS response consistent with its DNA-damaging effects, but we demonstrate that using FZ in combination with the other two compounds enables lower dosages and largely mitigates its mutagenic effects. Based on the gene expression changes identified, we propose a synergy mechanism where the combined effects of FZ, VAN, and DOC amplify damage to Gram-negative bacteria while simultaneously suppressing antibiotic resistance mechanisms. IMPORTANCE Synergistic antibiotic combinations are a promising alternative strategy for developing effective therapies for multidrug-resistant bacterial infections. The synergistic combination of the existing antibiotics nitrofurans and vancomycin with sodium deoxycholate shows promise in inhibiting and killing multidrug-resistant Gram-negative bacteria. We examined the mechanism of action and synergy of these three antibacterials and proposed a mechanistic basis for their synergy. Our results highlight much-needed mechanistic information necessary to advance this combination as a potential therapy.

Cannabidiol (CBD) is a hydrophobic non-psychoactive compound with therapeutic characteristics. Animal and human studies have shown its poor oral bioavailability in vivo, and the impact of consuming lipid-soluble CBD with and without food on gut bioaccessibility has not been explored. The purpose of this research was to study the bioaccessibility of CBD after a three-phase upper digestion experiment with and without food, and to test lipase activity with different substrate concentrations. Our results showed that lipase enzyme activity and fatty acid absorption increased in the presence of bile salts, which may also contribute to an increase in CBD bioaccessibility. The food matrix used was a mixture of olive oil and baby food. Overall, the fed-state digestion revealed significantly higher micellarization efficiency for CBD (14.15 ± 0.6% for 10 mg and 22.67 ± 2.1% for 100 mg CBD ingested) than the fasted state digestion of CBD (0.65 ± 0.7% for 10 mg and 0.14 ± 0.1% for 100 mg CBD ingested). The increase in bioaccessibility of CBD with food could be explained by the fact that micelle formation from hydrolyzed lipids aid in bioaccessibility of hydrophobic molecules. In conclusion, the bioaccessibility of CBD depends on the food matrix and the presence of lipase and bile salts.

Physiologically based pharmacokinetic (PBPK) modeling is routinely used to study drug-drug interactions, replace some dedicated clinical studies, and inform product labeling. More recently, there has been increased application of PBPK models in the oral absorption field around drug product quality. Given the success of the models to characterize absorption of several orally administered drug products, a question arises whether PBPK could be used in a clinical setting to model food-drug interactions and thus streamline food effect assessments. Multiple publications have reported food effect predictions and comparisons with clinical data, primarily focusing on 2 food effect mechanisms: slowing down of gastric emptying and luminal solubilization by bile salts. Based on the available literature, this commentary proposes a workflow that PBPK model could be used to streamline food effect assessment during clinical development for different Biopharmaceutics Classification System classes. © 2020, The American College of Clinical Pharmacology.

Erratum in AAPS J. 2020 Nov 26;23(1):6. doi: 10.1208/s12248-020-00535-z. The effect of food on pharmacokinetic properties of drugs is a commonly observed occurrence affecting about 40% of orally administered drugs. Within the pharmaceutical industry, significant resources are invested to predict and characterize a clinically relevant food effect. Here, the predictive performance of physiologically based pharmacokinetic (PBPK) food effect models was assessed via de novo mechanistic absorption models for 30 compounds using controlled, pre-defined in vitro, and modeling methodology. Compounds for which absorption was known to be limited by intestinal transporters were excluded in this analysis. A decision tree for model verification and optimization was followed, leading to high, moderate, or low food effect prediction confidence. High (within 0.8- to 1.25-fold) to moderate confidence (within 0.5- to 2-fold) was achieved for most of the compounds (15 and 8, respectively). While for 7 compounds, prediction confidence was found to be low (> 2-fold). There was no clear difference in prediction success for positive or negative food effects and no clear relationship to the BCS category of tested drug molecules. However, an association could be demonstrated when the food effect was mainly related to changes in the gastrointestinal luminal fluids or physiology, including fluid volume, motility, pH, micellar entrapment, and bile salts. Considering these findings, it is recommended that appropriately verified mechanistic PBPK modeling can be leveraged with high to moderate confidence as a key approach to predicting potential food effect, especially related to mechanisms highlighted here.

ETHNOPHARMACOLOGICAL RELEVANCE: Bile traditionally was used in wound healing, having erodent, antioxidant and antimicrobial potential. Acinetobacter baumannii is a frequent etiological agent of wound infections, exhibiting high level of resistance to conventional antibiotics. AIM OF THE STUDY: To determine the effect of selected bile acid sodium salts and their 3-dehydro (i.e. 3-oxo) derivatives, as well as their combinations with commercial antibiotics against A. baumanniia, to confirm bile ethnopharmacological application in wound healing from aspect of microbiology. MATERIALS AND METHODS: The sensitivity of reference and multidrug resistant (MDR) A. baumannii strains to bile salts, their derivatives and conventional antibiotics were examined by a microtiter plate method. The interaction of bile salts/derivatives and antibiotics was examined by a checkerboard method and time kill curve method. The interaction of bile salts with ciprofloxacin in terms of micelles formation was examined by DOSY NMR technique. RESULTS: The bile salts sodium deoxycholate (Na-DCA) and sodium chenodeoxycholate (Na-CDCA), as well as their derivatives sodium 3-dehydro-deoxycholate (Na-3DH-DCA) and sodium 3-dehydro-chenodeoxycholate (Na-3DH-CDCA), potentiate antibiotic activity and resensitize A. baumannii. The bile salts and their derivatives enhance A. baumannii sensitivity to antibiotics, particularly those that should penetrate cell to exhibit activity. The sodium salts of bile acid derivatives, namely Na-3DH-DCA and Na-3DH-CDCA, showed synergy against both reference and MDR strain in combination with ciprofloxacin or gentamicin, while synergy with gentamicin was obtained in all combinations, regardless of bile salt type and bacterial strains. The synergy with Na-3DH-CDCA was further confirmed by the time-kill curve method, as bacterial number decreased after 12 h. NMR experiment revealed that this bile salt derivative and ciprofloxacin form co-aggregates when bile salts concentration was higher than critical micelle concentrations (CMC), which indicate the possibility that bile salts enhance ciprofloxacin cell penetration by membrane destabilization, contributing to the synergy. C

Renal impairment (RI) is known to influence the pharmacokinetics of nonrenally eliminated drugs, although the mechanism and clinical impact is poorly understood. We assessed the impact of RI and single dose oral rifampin (RIF) on the pharmacokinetics of CYP3A, OATP1B, P-gp, and BCRP substrates using a microdose cocktail and OATP1B endogenous biomarkers. RI alone had no impact on midazolam (MDZ), maximum plasma concentration (Cmax ), and area under the curve (AUC), but a progressive increase in AUC with RI severity for dabigatran (DABI), and up to ~2-fold higher AUC for pitavastatin (PTV), rosuvastatin (RSV), and atorvastatin (ATV) for all degrees of RI was observed. RIF did not impact MDZ, had a progressively smaller DABI drug-drug interaction (DDI) with increasing RI severity, a similar 3.1-fold to 4.4-fold increase in PTV and RSV AUC in healthy volunteers and patients with RI, and a diminishing DDI with RI severity from 6.1-fold to 4.7-fold for ATV. Endogenous biomarkers of OATP1B (bilirubin, coproporphyrin I/III, and sulfated bile salts) were generally not impacted by RI, and RIF effects on these biomarkers in RI were comparable or larger than those in healthy volunteers. The lack of a trend with RI severity of PTV and several OATP1B biomarkers, suggests that mechanisms beyond RI directly impacting OATP1B activity could also be considered. The DABI, RSV, and ATV data suggest an impact of RI on intestinal P-gp, and potentially BCRP activity. Therefore, DDI data from healthy volunteers may represent a worst-case scenario for clinically derisking P-gp and BCRP substrates in the setting of RI. © 2020 Merck Sharp & Dohme Corp. Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.

Existing in vitro dissolution or permeation models to predict food effect are mainly based on Pharmacopeias' compendial media, which specify such variables as pH, bile salts, lipolytic enzymes, and phospholipids content. However, the viscosity of food in the gastrointestinal (GI) tract is not taken into account, although it can affect both the dissolution of the oral solid dosage form and absorption of the released drug. Here, a new in vitro dissolution absorption system (IDAS2) is utilized, which comprises a dissolution apparatus USP2 (DISTEK) equipped with specially constructed permeability chambers containing Caco-2 monolayers, thereby allowing dissolution and transepithelial absorption to be ascertained simultaneously. The IDAS2 was used to evaluate the effect of medium viscosity on both the dissolution of oral solid dosage forms and absorption of released drugs. Such information, which is not ordinarily determined in dissolution and permeation studies, will be helpful to the formulators developing robust oral dosage forms. Commercially available solid dosage forms of ten model drugs from across all BCS classifications were used in this evaluation: metoprolol, minoxidil, and propranolol from BCS class 1; carbamazepine, ketoprofen, and simvastatin from BCS class 2; atenolol and ranitidine from BCS class 3; and acetazolamide and saquinavir from BCS class 4. The study revealed the applicability of IDAS2 as a tool for in vitro screening of dissolution and absorption of intact oral solid products to predict food viscosity effect. The most profound viscosity effect on dissolution and absorption was observed of solid dosage forms for the BCS class 2 compounds carbamazepine and simvastatin. A higher medium viscosity significantly slowed down the dissolution rate of tested BSC class 4 compounds acetazolamide and saquinavir, without significant effect on their absorption. The solid dosage forms least affected by the viscosity of the medium tested were the BCS class 1 compounds minoxidil and propranolol.

Bile salts are biosurfactants released into the intestinal lumen which play an important role in the solubilisation of fats and certain drugs. Their concentrations vary along the gastrointestinal tract (GIT). This is significant for implementation in physiologically based pharmacokinetic (PBPK) modelling to mechanistically capture drug absorption. The aims of this meta-analysis were to collate all appropriate data on intestinal bile salt concentrations in healthy adults across all GIT segments in fasted and fed states for the purpose of PBPK modelling. Terms relating to bile composition were searched in PubMed and Google Scholar from inception to May 2024. Selected studies included aspirated intestinal fluid collected via gastric tubes or colonoscopy. Results showed high variability across studies and a time-dependency for the fed state. Data were rich for the duodenum, which showed a two-fold increase for the fed state versus the fasted state within multiple studies. Peaks and troughs in bile salt concentrations along the GIT were observed for both fasted and fed states, likely due to segmental water absorption differences. The highest between subject variability was observed for the duodenum in the fasted and fed state and the fed proximal jejunum, distal ileum, and colon. The findings from this meta-analysis can be used for the purpose of PBPK modelling to capture segmental drug solubilisation and absorption in fasted and fed states. However, data are lacking under different fed conditions, especially following low-fat meals, so the impact of different fat content associated with different meals on bile salt concentrations cannot be discerned. © 2025. Crown.

BACKGROUND: Given the high prevalence of gestational diabetes mellitus and its significant impact on maternal and neonatal health, identifying reliable biomarkers for prediction and diagnosis is essential. The increased incidence of gestational diabetes mellitus among patients with intrahepatic cholestasis of pregnancy suggests a possible association between serum total bile acid levels and gestational diabetes mellitus. This study evaluated the relationship between total bile acid levels and gestational diabetes mellitus incidence. METHODS: A systematic search was performed on February 19, 2024, for studies examining the association between total bile acid levels and gestational diabetes mellitus incidence in both the general pregnant population and patients diagnosed with intrahepatic cholestasis of pregnancy. Meta-analyses were conducted to compare pooled total bile acid levels between patients with and without gestational diabetes mellitus, as well as to assess gestational diabetes mellitus prevalence in patients with mild (10 ≤ total bile acid < 40 µmol/L) vs. moderate-to-severe intrahepatic cholestasis of pregnancy (total bile acid ≥ 40 µmol/L). RESULTS: 15 observational studies involving 7,238 pregnant women were systematically reviewed. Our meta-analysis found significantly higher serum total bile acid levels in women diagnosed with gestational diabetes mellitus compared to controls in the general population (Hedge's g = 0.29 [0.03,0.54]). However, subgroup analysis indicated that total bile acid levels were only significantly higher in patients measured earlier in pregnancy, before the gestational diabetes mellitus diagnosis, compared to healthy controls (Hedge's g = 0.48 [0.33,0.64]), while no significant difference in total bile acid levels was observed when measurements were taken after the gestational diabetes mellitus diagnosis (Hedge's g = 0.00 [-0.26,0.27]). Additionally, we found that the prevalence of gestational diabetes mellitus was significantly lower in patients with mild intrahepatic cholestasis of pregnancy compared to those with moderate-to-severe intrahepatic cholestasis of pregnancy (Log odds ratio=-0.56 [-0.95,-0.17]). CONCLUSIONS: Th

13. Colorectal Dis. 2024 Feb;26(2):243-257. doi: 10.1111/codi.16837. Epub 2024 Jan 4. Influence of the bile acid/microbiota axis in ileal surgery: a systematic review. Senanayake T(1)(2)(3)(4), Makanyengo S(1)(2)(3)(4), Hoedt EC(1)(3)(4), Goggins B(1)(3)(4), Smith SR(2)(3), Keely S(1)(3)(4). A

Breast milk is tailored for optimal growth in all infants; however, in some infants, it is related to a unique phenomenon referred to as breast milk jaundice (BMJ). BMJ is a type of prolonged unconjugated hyperbilirubinemia that is often late onset in otherwise healthy-appearing newborns, and its occurrence might be related to breast milk itself. This review aims to systematically evaluate evidence regarding breast milk composition and the development of BMJ in healthy neonates. PubMed, Scopus and Embase were searched up to 13 February 2023 with key search terms, including neonates, hyperbilirubinemia, and breastfeeding. A total of 678 unique studies were identified and 12 were ultimately included in the systematic review with narrative synthesis. These included studies covered both nutritional compositions (e.g., fats and proteins) and bioactive factors (e.g., enzymes and growth factors) of breast milk and formally assessed the difference in the concentration (or presence) of various endogenous components of breast milk collected from mothers of BMJ infants and healthy infants. The results were inconsistent and inconclusive for most of the substances of interest, and there was only a single study available (e.g., total energy and mineral content, bile salts and cytokines); conflicting or even contradictory results arose when there were two or more studies on the subject matter (e.g., fats and free fatty acids contents and epidermal growth factor). The etiology of BMJ is likely multifactorial, and no single constituent of breast milk could explain all the BMJ cases observed. Further well-designed studies are warranted to investigate the complex interaction between maternal physiology, the breast milk system and infant physiology before this field could be progressed to uncover the etiology of BMJ.

The bile salt export pump (BSEP/ABCB11) is located on the apical membrane and mediates the secretion of bile salts from hepatocytes into the bile. BSEP-mediated bile salt efflux is the rate-limiting step of bile salt secretion and the main driving force of bile flow. BSEP drives and maintains the enterohepatic circulation of bile salts. In recent years, research efforts have been focused on understanding the physiological and pathological functions and regulatory mechanisms of BSEP. These studies elucidated the roles of farnesoid X receptor (FXR), AMP-activated protein kinase (AMPK), liver receptor homolog-1(LRH-1) and nuclear factor erythroid 2-related factor 2 (Nrf-2) in BSEP expression and discovered some regulatory factors which participate in its post-transcriptional regulation. A series of liver diseases have also been shown to be related to BSEP expression and dysfunction, such as cholestasis, drug-induced liver injury, and gallstones. Here, we systematically review and summarize recent literature on BSEP structure, physiological functions, regulatory mechanisms, and related diseases.

OBJECTIVES: To investigate the existing published evidence supporting the role of laryngopharyngeal reflux (LPR) in the development of the select nonfunctional laryngeal diseases of laryngotracheal stenosis, granuloma, leukoplakia, and laryngeal infections. DATA SOURCES: PubMed, Cochrane Library, and Scopus. REVIEW METHODS: A systematic review was performed by 3 independent investigators for studies providing information about the prevalence and role of LPR in the development of laryngotracheal stenosis, granuloma, leukoplakia, and laryngeal infections. Diagnostic criteria and clinical outcome evaluation of included studies were analyzed with PRISMA criteria. RESULTS: Of the 64 relevant publications, 27 clinical and 4 basic science studies were included. Ten studies used objective reliable examinations for LPR diagnosis (eg, dual- or triple-probe or oropharyngeal pH monitoring, multichannel intraluminal impedance-pH monitoring, or pepsin detection). According to the bias analysis and the results of studies, the association between LPR and laryngotracheal stenosis, leukoplakia, laryngeal papillomatosis, or vocal fold granuloma remains poorly demonstrated. There is a notable heterogeneity among included studies regarding their inclusion criteria, diagnostic methods, and clinical outcome evaluation. Although some experimental findings support the involvement of bile salts and other gastroduodenal proteins active in alkaline pH, no included clinical studies assessed the role of nonacid and mixed reflux through multichannel intraluminal impedance-pH monitoring. CONCLUSION: The involvement of LPR in the development of leukoplakia, laryngotracheal stenosis, vocal fold granuloma, and laryngeal papillomatosis is currently not demonstrated. The potential relationship between LPR and these select nonfunctional laryngeal diseases must be confirmed through future clinical and experimental studies considering acid, nonacid, and mixed LPR.

In vivo studies have shown cyclic bile salt (BS) outputs during fasting whereas higher amounts have been observed in fed states. This leads to fluctuations of intestinal BS concentrations ([BS]) that can affect the rate and extent of absorption of lipophilic drugs in particular. However, most PBPK models use fixed values of [BS] in fasted and fed states albeit with different values in different regions of the GI tract. During fasting, there is a relationship between gallbladder volume (GBV) and the phase of the Interdigestive Migrating Motor Complex cycle (IMMCc), showing cyclic GBV changes with periodic filling and emptying. This relationship is also affected by the origin of the IMMCc (antral or duodenal). In fed states, meta-analysis indicated that GB residual volume (% of fasting maximum) was 46.4 ± 27%CV and 30.7 ± 48%CV for low- and high-fat meals, respectively. The corresponding values for the duration of the emptying phase were for low fat meals 0.72h ± 1%CV and for high fat meals 1.17h ± 37%CV. The model, the Advanced Dynamic Bile Salt Model (ADBSM), was built bottom-up and its parameters were not fitted against in vivo measurements of [BS]. It involved update of the dynamic luminal fluid volumes model based on meta-analysis of available imaging data. The ADBSM is incorporated into the Simcyp (v18r2) PBPK simulator. The model predictivity was good (within 1.25-fold error for 11/20 of the clinical studies) and was assessed against clinical studies of luminal [BS] that provide only the type of meal (i.e., low- or high-fat), the timing of the meal and/or water intake events, and the number and age range of the study participants. The model is also an important component of models capturing enterohepatic recirculation of drug and metabolite. Further work is required to validate the current model and compare to simpler models with respect to drug absorption, especially of the lipophilic compounds.

AIM: To investigate the association between cholecystectomy and gastro-intestinal tract (GIT) cancers. METHODS: We conducted a systematic review according to the PRISMA guidelines. A MEDLINE search was performed with predefined search criteria for English Language articles on the association between cholecystectomy and GIT cancers. Additional articles were retrieved by manual search of references. All relevant articles were accessed in full text. Data on study type; cases; controls; country; effect estimate; adjustments for confounders and quality of publication were extracted. The quality of the publications were scored by adherence to the STROBE checklist. The data for each part of the GIT were presented in separate tables. RESULTS: Seventy-five studies and 5 meta-analyses satisfied the predefined criteria for inclusion and were included in this review. There were inconsistent reports and no strong evidence of an association between cholecystectomy and cancers of the oesophagus (Adenocarcinoma), pancreas, small bowel and right-sided colon cancers. In squamous cancer of the oesophagus, cancers of the stomach, liver, bile ducts, small bowel and left sided colon cancers, good quality studies suggested a lack of association with cholecystectomy. Equally, distal colon and rectal cancers were found not to be associated with cholecystectomy. Several mechanisms for carcinogenesis/promotion of carcinogensis have been proposed. These have focused on a role for bile salts in carcinogenesis with several potential mutagenic molecular events and gut metabolic hormones signaling cell proliferation or initiation of carcinogenesis. CONCLUSION: This is a comprehensive review of the association between GIT cancers and cholecystectomy. This review found no clear association between cholecystectomy and GIT cancers.

BACKGROUND: Barrett's esophagus (BE) is a premalignant condition caused by chronic gastroesophageal reflux. BE patients have an increased risk of developing esophageal adenocarcinoma (EAC). As many aspects of this condition are still unknown, there is a need for in vitro models to study BE development. AIM: To review the literature on cell lines and incubation conditions for studying BE development. METHODS: A literature search was performed using PubMed, EMBASE and the Cochrane library, combining the words esophagus, cell line, culture, Barrett's, bile, acid, exposure, reflux and adenocarcinoma. RESULTS: A wide range of cell lines and incubation conditions to study BE development have been reported. The most commonly used cell lines are derived from epithelium from patients with BE or EAC. A 25-minute incubation with 200 μM bile salts induced cell proliferation and Akt phosphorylation. However, increased CDX2 and MUC2 expression was only observed with longer incubations or higher bile salt concentrations. Two-hundred μM bile at pH 6 showed a higher toxicity to EAC cells than the same concentration at pH 7. Multiple 5-minute exposures with 200 μM bile at pH 4 or pH 7 increased CK8/18 and COX2 in BE epithelial cells. CONCLUSIONS: Two-hundred μM conjugated primary or secondary bile salts at pH 4 for multiple short exposures is able to induce BE specific factors in BE cell lines. In SQ and EAC cell lines; however, higher concentrations of secondary bile salts for 8 h are needed to induce BE specific molecules. Due to the high variability in reported methods, it is difficult to determine the most effective in vitro setup for studying the development of BE.

For local lung conditions and diseases, pulmonary drug delivery has been widely used for more than 50 years now. A more recent trend involves the pulmonary route as a systemic drug-delivery target. Advantages such as avoidance of the gastrointestinal environment, different enzyme content compared with the intestine, and avoidance of first-pass metabolism make the lung an alternative route for the systemic delivery of actives. However, the lung offers barriers to absorption such as a surfactant layer, epithelial surface lining fluid, epithelial monolayer, interstitium and basement membrane, and capillary endothelium. Many delivery strategies have been developed in order to overcome these limitations. The use of surfactants is one of these approaches and their role in enhancing pulmonary drug delivery is reviewed in this article. A systematic review of the literature relating to the effect of surfactants on formulations for pulmonary delivery was conducted. Specifically, research reporting enhancement of in vivo performance was focused on. The effect of the addition of surfactants such as phospholipids, bile salts, non-ionic, fatty acids, and liposomes as phospholipid-containing carriers on the enhancement of therapeutic outcomes of drugs for pulmonary delivery was compiled. The main use attributed to surfactants in pulmonary drug delivery is as absorption enhancers by mechanisms of action not yet fully understood. Furthermore, surfactants have been used to improve the delivery of inhaled drugs in various additional strategies discussed herein.