Bifidobacterium breve Protects the Intestinal Epithelium and Mitigates Inflammation in Colitis via Regulating the Gut Microbiota-Cholic Acid Pathway.

In this study, we aimed to explore the protective effects of Bifidobacterium in colitis mice and the potential mechanisms. Results showed that Bifidobacterium breve (B. breve) effectively colonized the intestinal tract and alleviated colitis symptoms by reducing the disease activity index. Moreover, B. breve mitigated intestinal epithelial cell damage, inhibited the pro-inflammatory factors, and upregulated tight junction (TJ)-proteins. Gut microbiota and metabolome analysis found that B. breve boosted bile acid-regulating genera (such as Bifidobacterium and Clostridium sensu stricto 1), which promoted bile acid deconjugation in the intestine. Notably, cholic acid (CA) was closely associated with the expression levels of inflammatory factors and TJ-proteins (p < 0.05). Our in vitro cell experiments further confirmed that CA (20.24 ± 4.53 pg/mL) contributed to the inhibition of lipopolysaccharide-induced tumor necrosis factor-α expression (49.32 ± 5.27 pg/mL) and enhanced the expression of TJ-proteins (Occludin and Claudin-1) and MUC2. This study suggested that B. breve could be a probiotic candidate for use in infant foods.

Loss of SLC27A5 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis via Unconjugated Cholic Acid.

Although the dysregulation of bile acid (BA) composition has been associated with fibrosis progression, its precise roles in liver fibrosis is poorly understood. This study demonstrates that solute carrier family 27 member 5 (SLC27A5), an enzyme involved in BAs metabolism, is substantially downregulated in the liver tissues of patients with cirrhosis and fibrosis mouse models. The downregulation of SLC27A5 depends on RUNX family transcription factor 2 (RUNX2), which serves as a transcriptional repressor. The findings reveal that experimental SLC27A5 knockout (Slc27a5-/- ) mice display spontaneous liver fibrosis after 24 months. The loss of SLC27A5 aggravates liver fibrosis induced by carbon tetrachloride (CCI4 ) and thioacetamide (TAA). Mechanistically, SLC27A5 deficiency results in the accumulation of unconjugated BA, particularly cholic acid (CA), in the liver. This accumulation leads to the activation of hepatic stellate cells (HSCs) by upregulated expression of early growth response protein 3 (EGR3). The re-expression of hepatic SLC27A5 by an adeno-associated virus or the reduction of CA levels in the liver using A4250, an apical sodium-dependent bile acid transporter (ASBT) inhibitor, ameliorates liver fibrosis in Slc27a5-/- mice. In conclusion, SLC27A5 deficiency in mice drives hepatic fibrosis through CA-induced activation of HSCs, highlighting its significant implications for liver fibrosis treatment.

Cholesterol (Blood lipid) lowering potential of Rosuvastatin chitosan nanoparticles for atherosclerosis: Preclinical study in rabbit model.

Atherosclerosis is the condition of narrowing of arteries due to plaque buildup on the artery walls. Aortic valve calcification (AVC) is one of the reasons of atherosclerosis which leads to narrowing at the opening of the aortic valve which is commonly referred as Aortic valve stenosis (AS). The Rosuvastatin-chitosan (ROS-chitosan) nanoparticles were prepared using ionotropic gelation method. Nanoparticulate formulation was optimized by 3 factor, 2 level full factorial design to find the effect of independent variables on particle size and percentage encapsulation efficiency. Particle size, encapsulation efficiency, scanning electron microscopy, in vitro drug release of nanoparticles was determined. The adult male rabbit of 4-5 months old were chosen for the study. Hypercholesterolemia was induced in experimental animals by administering diet with Cholesterol and Cholic acid (1.25 % and 0.5% respectively.) Blood lipid profile, interleukin 6 levels and histopathological study was performed. Rosuvastatin was found to be significantly effective in lowering the blood lipid levels. It helps to attenuate atherosclerosis as well as calcification of various valve tissues in experimental animals.

High Sensitivity to Cholic Acid-induced Colonic Tumorigenesis Makes Female PIRC Rats (F344/NTac-Apcam1137) a Suitable Model for Studying CRC-promoting Agents.

BACKGROUND/AIM: Rats of the adenomatous polyposis coli (Apc)-mutated female polyposis in rat (PIRC) (F344/NTac-Apcam1137) model exhibit a low level of intestinal tumorigenesis and are thus potentially exploitable as a model for identifying substances increasing colorectal cancer (CRC). MATERIALS AND METHODS: To test this possibility, we treated such rats with the bile acid (BA) cholic acid (CA) (0.3% w/w in the diet), known to promote CRC, and assessed tumorigenesis. RESULTS: Precancerous colonic lesions (mucin-depleted foci) and intestinal tumors were dramatically increased in CA-treated rats compared to controls (p<0.01). Colon mucosa proliferation was higher and apoptosis lower than those in controls. Expression of nuclear receptor 1h4 (Nr1h4) gene [encoding for BA receptor farnesoid X receptor (FXR)], organic solute transporter beta (Ostb) and fatty acid-binding protein 6 (Fabp6), FXR-dependent BA transporters, were dramatically down-regulated in CA-treated rats. CONCLUSION: CA-increased tumorigenesis in female PIRC rats, with mechanisms involving increased proliferation, reduced apoptosis and marked down-regulation of genes controlling BA homeostasis. Since BAs have been implicated in CRC, we suggest that female PIRC rats can be used to identify CRC-promoting agents.

Investigation of new acyloxy derivatives of cholic acid and their esters as drug absorption modifiers.

Skin penetration enhancers are used in the formulation of transdermal delivery systems for drugs that are otherwise not sufficiently skin-permeable. Intestinal absorption promoters/enhancers are used as excipients in oral formulations of poorly oral-bioavailable drugs. Series of fourteen acyloxy derivatives of 5ß-cholic acid as potential drug absorption modifiers was generated by multistep synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy methods. All the prepared compounds were analyzed using RP-TLC, and their lipophilicity (R(M)) was determined. The hydrophobicity (logP) and solubility (logS) of the studied compounds were also calculated using two commercially available programs. All the target compounds were tested for their in vitro transdermal penetration activity and as potential intestinal absorption enhancers. The anti-proliferative activity of all the final compounds was also assessed against the human cancer cell lines: T-lymphoblastic leukemia cell line and the breast adenocarcinoma cell line. Their cytotoxicity was also evaluated against the normal human skin fibroblast cells. Two compounds showed anti-proliferative effect on cancer cells without affecting the growth of normal cells, which should be promising in potential development of new drugs. Most of the target compounds showed minimal anti-proliferative activity (IC(50)>37 µM), indicating they would have low cytotoxicity when administered as chemical absorption modifiers. The relationships between the lipophilicity and the chemical structure of the studied compounds as well as the relationships between their chemical structure and enhancement effects are discussed in this article.

Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective long-term therapy.

BACKGROUND & AIMS: Oral bile acid replacement has been shown to be an effective therapy in primary bile acid synthesis defects, but to date there have been no reports of the long-term effects of this therapy. The aim of the study was to evaluate the long-term effectiveness and safety of cholic acid (CA) therapy. METHODS: Fifteen patients with either 3beta-hydroxy-Delta(5)-C(27)-steroid oxidoreductase (3beta-HSD) (n = 13) or Delta(4)-3-oxosteroid 5beta-reductase (Delta(4)-3-oxo-R) (n = 2) deficiency confirmed by mass spectrometry and gene sequencing received oral CA and were followed up prospectively. RESULTS: CA therapy was started at a median age of 3.9 years (range, 0.3-13.1 years). The median follow-up with treatment was 12.4 years (range, 5.6-15 years). The mean daily dose of CA was initially 13 mg/kg and was 6 mg/kg at last evaluation. During CA therapy, physical examination findings, laboratory test results, and findings on sonography normalized. Mass spectrometry analysis of urine showed that excretion of the atypical metabolites was reduced by 500-fold and 30-fold in 3beta-HSD and Delta(4)-3-oxo-R deficiency, respectively, and total urinary bile acid excretion decreased dramatically. Liver biopsies performed in 14 patients after at least 5 years of CA therapy showed marked improvement, especially in patients with the 3beta-HSD deficiency. CA was well tolerated with all children developing normally, including 2 women having 4 normal pregnancies during treatment. CONCLUSIONS: Oral CA therapy is a safe and effective long-term treatment of the most common primary bile acid synthesis defects.