A Short Review on Obeticholic Acid: An Effective Modulator of Farnesoid X Receptor.

Farnesoid X receptor (FXR) was identified as an orphan nuclear receptor resembling the steroid receptor in the late '90s. Activation of FXR is a crucial step in many physiological functions of the liver. A vital role of FXR is impacting the amount of bile acids in the hepatocytes, which it performs by reducing bile acid synthesis, stimulating the bile salt export pump, and inhibiting its enterohepatic circulation, thus protecting the hepatocytes against the toxic accumulation of bile acids. Furthermore, FXR mediates bile acid biotransformation in the intestine, liver regeneration, glucose hemostasis, and lipid metabolism. In this review, we first discuss the mechanisms of the disparate pleiotropic actions of FXR agonists. We then delve into the pharmacokinetics of Obeticholic acid (OCA), the first-in-class selective, potent FXR agonist. We additionally discuss the clinical journey of OCA in humans, its current evidence in various human diseases, and its plausible roles in the future.

Longitudinal outcomes of obeticholic acid therapy in ursodiol-nonresponsive primary biliary cholangitis: Stratifying the impact of add-on fibrates in real-world practice.

BACKGROUND: Suboptimal response to ursodeoxycholic acid occurs in 40% of primary biliary cholangitis (PBC) patients, affecting survival. Achieving a deep response (normalisation of alkaline phosphatase [ALP] and bilirubin ≤0.6 upper limit of normal) improves survival. Yet, the long-term effectiveness of second-line treatments remains uncertain. AIMS: To evaluate the long-term effectiveness of obeticholic acid (OCA) ± fibrates. Focusing on biochemical response (ALP ≤1.67 times the upper limit of normal, with a decrease of at least 15% from baseline and normal bilirubin levels), normalisation of ALP, deep response and biochemical remission (deep response plus aminotransferase normalisation). METHODS: We conducted a longitudinal, observational, multicentre study involving ursodeoxyccholic acid non-responsive PBC patients (Paris-II criteria) from Spain and Portugal who received OCA ± fibrates. RESULTS: Of 255 patients, median follow-up was 35.1 months (IQR: 20.2-53). The biochemical response in the whole cohort was 47.2%, 61.4% and 68.6% at 12, 24 and 36 months. GLOBE-PBC and 5-year UK-PBC scores improved (p < 0.001). Triple therapy (ursodeoxycholic acid plus OCA plus fibrates) had significantly higher response rates than dual therapy (p = 0.001), including ALP normalisation, deep response and biochemical remission (p < 0.001). In multivariate analysis, triple therapy remained independently associated with biochemical response (p = 0.024), alkaline phosphatase normalisation, deep response and biochemical remission (p < 0.001). Adverse effects occurred in 41.2% of cases, leading to 18.8% discontinuing OCA. Out of 55 patients with cirrhosis, 12 developed decompensation. All with baseline portal hypertension. CONCLUSION: Triple therapy was superior in achieving therapeutic goals in UDCA-nonresponsive PBC. Decompensation was linked to pre-existing portal hypertension.

Obeticholic acid attenuates the intestinal barrier disruption in a rat model of short bowel syndrome.

BACKGROUND: Short bowel syndrome (SBS) features nutrients malabsorption and impaired intestinal barrier. Patients with SBS are prone to sepsis, intestinal flora dysbiosis and intestinal failure associated liver disease. Protecting intestinal barrier and preventing complications are potential strategies for SBS treatment. This study aims to investigate the effects of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), have on intestinal barrier and ecological environment in SBS. METHODS AND RESULTS: Through testing the small intestine and serum samples of patients with SBS, impaired intestinal barrier was verified, as evidenced by reduced expressions of intestinal tight junction proteins (TJPs), increased levels of apoptosis and epithelial cell damage. The intestinal expressions of FXR and related downstream molecules were decreased in SBS patients. Then, global FXR activator OCA was used to further dissect the potential role of the FXR in a rat model of SBS. Low expressions of FXR-related molecules were observed on the small intestine of SBS rats, along with increased proinflammatory factors and damaged barrier function. Furthermore, SBS rats possessed significantly decreased body weight and elevated death rate. Supplementation with OCA mitigated the damaged intestinal barrier and increased proinflammatory factors in SBS rats, accompanied by activated FXR-related molecules. Using 16S rDNA sequencing, the regulatory role of OCA on gut microbiota in SBS rats was witnessed. LPS stimulation to Caco-2 cells induced apoptosis and overexpression of proinflammatory factors in vitro. OCA incubation of LPS-pretreated Caco-2 cells activated FXR-related molecules, increased the expressions of TJPs, ameliorated apoptosis and inhibited overexpression of proinflammatory factors. CONCLUSIONS: OCA supplementation could effectively ameliorate the intestinal barrier disruption and inhibit overexpression of proinflammatory factors in a rat model of SBS and LPS-pretreated Caco-2 cells. As a selective activator of FXR, OCA might realize its protective function through FXR activation.

Biotransformation of chenodeoxycholic acid by human intestinal fungi and the agonistic effects on FXR.

Bile acids play a vital role in modulating host metabolism, with chenodeoxycholic acid (CDCA) standing out as a primary bile acid that naturally activates farnesoid X receptor (FXR). In this study, we investigated the microbial transformations of CDCA by seven human intestinal fungal species. Our findings revealed that hydroxylation and dehydrogenation were the most prevalent metabolic pathways. Incubation of CDCA with Rhizopus microspores (PT2906) afforded eight undescribed compounds (6-13) alongside five known analogs (1-5) which were elucidated by HRESI-MS and NMR data. Notably, compounds 8, 12 and 13 exhibited an inhibitory effect on FXR in contrast to the FXR activation observed with CDCA in vitro assays. This study shone a light on the diverse transformations of CDCA by intestinal fungi, unveiling potential modulators of FXR activity with implications for host metabolism.

Unique bile acid profiles in the bile ducts of patients with primary sclerosing cholangitis.

BACKGROUND: The relationship between primary sclerosing cholangitis (PSC) and biliary bile acids (BAs) remains unclear. Although a few studies have compared PSC biliary BAs with other diseases, they did not exclude the influence of cholestasis, which affects the composition of BAs. We compared biliary BAs and microbiota among patients with PSC, controls without cholestasis, and controls with cholestasis, based on the hypothesis that alterations in BAs underlie the pathophysiology of PSC. METHODS: Bile samples were obtained using endoscopic retrograde cholangiopancreatography from patients with PSC (n = 14), non-hepato-pancreato-biliary patients without cholestasis (n = 15), and patients with cholestasis (n = 13). RESULTS: The BA profiles showed that patients with PSC and cholestasis controls had significantly lower secondary BAs than non-cholestasis controls, as expected, whereas the ratio of cholic acid/chenodeoxycholic acid in patients with PSC was significantly lower despite cholestasis, and the ratio of (cholic acid + deoxycholic acid)/(chenodeoxycholic acid + lithocholic acid) in patients with PSC was significantly lower than that in the controls with or without cholestasis. The BA ratio in the bile of patients with PSC showed a similar trend in the serum. Moreover, there were correlations between the alteration of BAs and clinical data that differed from those of the cholestasis controls. Biliary microbiota did not differ among the groups. CONCLUSIONS: Patients with PSC showed characteristic biliary and serum BA compositions that were different from those in other groups. These findings suggest that the BA synthesis system in patients with PSC differs from that in controls and patients with other cholestatic diseases. Our approach to assessing BAs provides insights into the pathophysiology of PSC.

Increased hepatoprotective effects of the novel farnesoid X receptor agonist INT-787 versus obeticholic acid in a mouse model of nonalcoholic steatohepatitis.

The nuclear farnesoid X receptor (FXR), a master regulator of bile acid and metabolic homeostasis, is a key target for treatment of nonalcoholic steatohepatitis (NASH). This study compared efficacy of FXR agonists obeticholic acid (OCA) and INT-787 by liver histopathology, plasma biomarkers of liver damage, and hepatic gene expression profiles in the Amylin liver NASH (AMLN) diet-induced and biopsy-confirmed Lepob/ob mouse model of NASH. Lepob/ob mice were fed the AMLN diet for 12 weeks before liver biopsy and subsequent treatment with vehicle, OCA, or INT-787 for 8 weeks. Hepatic steatosis, inflammation, and fibrosis (liver lipids, galectin-3, and collagen 1a1 [Col1a1], respectively), as well as plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, were assessed. Hepatic gene expression was assessed in Lepob/ob mice that were fed the AMLN diet for 14 weeks then treated with vehicle, OCA, or INT-787 for 2 weeks. INT-787, which is equipotent to OCA but more hydrophilic, significantly reduced liver lipids, galectin-3, and Col1a1 compared with vehicle, and to a greater extent than OCA. INT-787 significantly reduced plasma ALT and AST levels, whereas OCA did not. INT-787 modulated a substantially greater number of genes associated with FXR signaling, lipid metabolism, and stellate cell activation relative to OCA in hepatic tissue. These findings demonstrate greater efficacy of INT-787 treatment compared with OCA in improving liver histopathology, decreasing liver enzyme levels, and enhancing gene regulation, suggesting superior clinical potential of INT-787 for the treatment of NASH and other chronic liver diseases.

Comparative analysis of proteomic adaptations in Enterococcus faecalis and Enterococcus faecium after long term bile acid exposure.

BACKGROUND: All gastrointestinal pathogens, including Enterococcus faecalis and Enterococcus faecium, undergo adaptation processes during colonization and infection. In this study, we investigated by data-independent acquisition mass spectrometry (DIA-MS) two crucial adaptations of these two Enterococcus species at the proteome level. Firstly, we examined the adjustments to cope with bile acid concentrations at 0.05% that the pathogens encounter during a potential gallbladder infection. Therefore, we chose the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) as well as the secondary bile acid deoxycholic acid (DCA), as these are the most prominent bile acids. Secondly, we investigated the adaptations from an aerobic to a microaerophilic environment, as encountered after oral-fecal infection, in the absence and presence of deoxycholic acid (DCA). RESULTS: Our findings showed similarities, but also species-specific variations in the response to the different bile acids. Both Enterococcus species showed an IC50 in the range of 0.01- 0.023% for DCA and CDCA in growth experiments and both species were resistant towards 0.05% CA. DCA and CDCA had a strong effect on down-expression of proteins involved in translation, transcription and replication in E. faecalis (424 down-expressed proteins with DCA, 376 down-expressed proteins with CDCA) and in E. faecium (362 down-expressed proteins with DCA, 391 down-expressed proteins with CDCA). Proteins commonly significantly altered in their expression in all bile acid treated samples were identified for both species and represent a "general bile acid response". Among these, various subunits of a V-type ATPase, different ABC-transporters, multi-drug transporters and proteins related to cell wall biogenesis were up-expressed in both species and thus seem to play an essential role in bile acid resistance. Most of the differentially expressed proteins were also identified when E. faecalis was incubated with low levels of DCA at microaerophilic conditions instead of aerobic conditions, indicating that adaptations to bile acids and to a microaerophilic atmosphere can occur simultaneously. CONCLUSIONS: Overall, these findings provide a detailed insight into the proteomic stress response of two Enterococcus species and help to understand the resistance potential and the stress-coping mechanisms of these important gastrointestinal bacteria.

Cerebrotendinous xanthomatosis with tremor as the main manifestation: A case report.

INTRODUCTION: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid metabolism disorder. It is caused by a defect in the sterol-27-hydroxylase gene, leading to the deposition of cholesteryl and bile alcohol in large amounts, causing a variety of clinical manifestations; however, tremor as the main manifestation of CTX has not been reported. PATIENTS CONCERNS AND CLINICAL FINDINGS: Herein, we report a 27-year-old woman, who developed head and body tremors at the age of 12 years. Many hospitals misdiagnosed her condition as idiopathic tremor and Parkinson disease, with a poor curative effect. PRIMARY DIAGNOSIS AND INTERVENTION: We diagnosed her with CTX and treated with chenodeoxycholic acid and clonazepam. CONCLUSION: The patient's condition considerably improved. This case could help avoid misdiagnosis and mistreatment in clinical practice.

CDCS-TCM: A framework based on complex network theory to analyze the causality and dynamic correlation of substances in the metabolic process of traditional Chinese medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine, with the feature of synergistic effects of multi-component, multi-pathway and multi-target, plays an important role in the treatment of cancer, cardiovascular and cerebrovascular diseases, etc. However, chemical components in traditional Chinese medicine are complex and most of the pharmacological mechanisms remain unclear, especially the relationships of chemical components change during the metabolic process. AIM OF STUDY: Our aim is to provide a method based on complex network theory to analyze the causality and dynamic correlation of substances in the metabolic process of traditional Chinese medicine. MATERIALS AND METHODS: We proposed a framework named CDCS-TCM to analyze the causality and dynamic correlation between substances in the metabolic process of traditional Chinese medicine. Our method mainly consists two parts. The first part is to discover the local and global causality by the causality network. The second part is to investigate the dynamic correlations and identify the essential substance by dynamic substance correlation network. RESULTS: We developed a CDCS-TCM method to analyze the causality and dynamic correlation of substances. Using the XiangDan Injection for ischemic stroke as an example, we have identified the important substances in the metabolic process including substance pairs with strong causality and the dynamic changes of the core effector substance clusters. CONCLUSION: The proposed framework will be useful for exploring the correlations of active ingredients in traditional Chinese medicine more effectively and will provide a new perspective for the elucidation of drug action mechanisms and the new drug discovery.

BaiJ and BaiB are key enzymes in the chenodeoxycholic acid 7α-dehydroxylation pathway in the gut microbe Clostridium scindens ATCC 35704.

Bile acid transformation is a common gut microbiome activity that produces secondary bile acids, some of which are important for human health. One such process, 7α-dehydroxylation, converts the primary bile acids, cholic acid and chenodeoxycholic acid, to deoxycholic acid and lithocholic acid, respectively. This transformation requires a number of enzymes, generally encoded in a bile acid-inducible (bai) operon and consists of multiple steps. Some 7α-dehydroxylating bacteria also harbor additional genes that encode enzymes with potential roles in this pathway, but little is known about their functions. Here, we purified 11 enzymes originating either from the bai operon or encoded at other locations in the genome of Clostridium scindens strain ATCC 35704. Enzyme activity was probed in vitro under anoxic conditions to characterize the biochemical pathway of chenodeoxycholic acid 7α-dehydroxylation. We found that more than one combination of enzymes can support the process and that a set of five enzymes, including BaiJ that is encoded outside the bai operon, is sufficient to achieve the transformation. We found that BaiJ, an oxidoreductase, exhibits an activity that is not harbored by the homologous enzyme from another C. scindens strain. Furthermore, ligation of bile acids to coenzyme A (CoA) was shown to impact the product of the transformation. These results point to differences in the 7α-dehydroxylation pathway among microorganisms and the crucial role of CoA ligation in the process.

Comparative Efficacy of Drug Interventions on NAFLD Over 24 Weeks: A Traditional and Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD), currently referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), affects approximately 38% of the world's population, yet no pharmacological therapies have been approved for treatment. We conducted a traditional and network meta-analysis to comprehensively assess the effectiveness of drug regimens on NAFLD, and continued to use the old terminology for consistency. METHODS: Randomized, placebo-controlled trials (RCTs) investigating drug therapy in an adult population diagnosed with NAFLD with or without diabetes mellitus were included. We assessed the quality of RCTs via the Risk of Bias 2 (ROB 2) tool. When I2 < 50%, we chose a random-effects model, otherwise a fixed-effects model was selected. A random effects model was applied in the network meta-analysis. The odds ratio (OR), weighted mean difference (WMD) or standard mean difference (SMD) with 95% confidence interval (CI) were used for outcome evaluation. The primary endpoint was the resolution of nonalcoholic steatohepatitis (NASH) without the worsening of liver fibrosis. Other endpoints included histological findings and metabolic changes. The PROSPERO Registration ID was CRD42023404309. RESULTS: Thiazolidinediones (TZDs), vitamin E plus pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists and fibroblast growth factor-21 (FGF-21) analogue had a higher surface under the cumulative ranking curve (SUCRA = 76.6, 73.0, 72.0 and 71.6) regarding NASH resolution. Improvement of liver fibrosis stage (≥ 1) was observed with obeticholic acid 25 mg/day (OR 2.01, 95% CI 1.35-2.98), lanifibranor 1200 mg/day (OR 2.39, 95% CI 1.19-4.82) and silymarin (OR 4.54, 95% CI 1.18-17.43) in traditional meta-analysis. CONCLUSIONS: The results of the comprehensive analysis suggested hypoglycemic drug therapy as an effective intervention for NAFLD, with or without diabetes mellitus. A prioritized selection of TZDs, vitamin E plus pioglitazone, GLP-1 receptor agonists and FGF-21 analogue may be considered for NASH resolution. Obeticholic acid, lanifibranor and silymarin could be considered for the improvement of liver fibrosis. Each medication was relatively safe compared with placebo.

The obeticholic acid can positively regulate the cancerous behavior of MCF7 breast cancer cell line.

BACKGROUND: The diagnosis and treatment processes of cancer are among the main challenges of medical science in recent decades. The use of different therapeutic agents is one of the most common methods frequently utilized for cancer treatment. Accumulating evidence points to a potential effect of Obeticholic acid (OCA), a specific ligand for farnesoid X receptor, on the regulation of cancer-associated pathways. In spite of tremendous efforts to introduce OCA into the clinical setting, there is a great deal of uncertainty about its impact on breast cancer treatment. This study was performed to evaluate the effects of OCA on breast cancer. METHODS AND RESULTS: In this experiment, the MCF-7 (Michigan Cancer Foundation-7) cell line was treated with 0.1 µM OCA, and cancerous characteristics of the MCF-7 cell line was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2 H-tetrazolium bromide) assay, gelatin zymography, western blot, Real-time PCR, flow cytometry, and ELISA techniques. The results indicated that OCA increased the rate of apoptosis and the expression levels of PPARα (Peroxisome proliferator-activated receptor alpha) and TIMP-1 (tissue inhibitor of metalloproteinase-1) genes in this cell line, while it reduced the mRNA levels of MMP7 (matrix metalloproteinase 7) and Bcl-2 (B-cell lymphoma 2) genes, as well as the protein levels of the active form of AKT (protein kinase B), Erk1/2 (extracellular signal-regulated kinase 1/2) and STAT3 (Signal transducers and activators of transcription-3). Also, OCA decreased the activity of MMP9, while it increased the secretion of VEGF-A (vascular endothelial growth factor-A). CONCLUSIONS: It seems that OCA can exert anti-cancer effects on the MCF-7 cells by reducing growth, proliferation, migration, invasion, and regulation of the expression of genes involved in cancer-associated pathways. However, it should be noted that further studies are warranted to establish this concept, especially the increase of VEGF-A can be considered a challenge for the results of this study.

The effect and safety of obeticholic acid for patients with nonalcoholic steatohepatitis: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) is one of the primary causes of chronic liver disease worldwide. Obeticholic acid (OCA), a potent farnesoid X nuclear receptor activator, has shown promise for treating NASH-related fibrosis due to its anti-fibrotic effects. This study aimed to examine the efficacy of OCA for patients with NASH as well as to investigate its impact on dyslipidemia. METHOD: A search of databases including PubMed, Embase, and Cochrane Library from January 1, 2010, to November 1, 2022, was conducted to identify systematic reviews of randomized controlled trials involving NASH patients. Inclusion criteria comprised randomized controlled trials that specifically addressed NASH as diagnosed through magnetic resonance imaging, computed tomography, or histology. The results were then categorized, with consideration given to both biochemical and histological outcomes. RESULT: Five NASH studies were ultimately selected for further analysis. In terms of biochemical indicators, patients receiving OCA treatment showed improvements in alanine transaminase (mean difference: -19.48, 95% confidence interval [CI]: -24.39 to 14.58; P < .05) and aspartate aminotransferase (mean difference: -9.22, 95% CI: -12.70 to 5.74; P < .05). As for histological improvement, OCA treatment reduced fibrosis (odds ratio [OR]: 1.95, 95% CI: 1.47-2.59; P = .001) and steatosis (OR: 1.95, 95% CI: 1.47-2.59; P = .001). No significant differences were observed regarding adverse events (1.44, 95% CI: 0.57-3.62; P > .001). Regarding dyslipidemia, mean differences between total cholesterol and low-density lipoprotein were found to be high (0.33, 95% CI: 0.01-0.64, P < .05; 0.39, 95% CI: 0.04-0.73, P < .05). In the case of pruritus, OCA achieved a high OR (3.22, 95% CI: 2.22-4.74) compared with placebo. CONCLUSION: OCA also reduced several liver test markers compared to placebo, including the biochemical indicators alanine transaminase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase, and improved hepatocellular ballooning, fibrosis, steatosis, and lobular inflammation. Although the incidence of adverse events did not significantly differ between OCA and placebo groups among NASH patients, OCA treatment was found to elevate total cholesterol and low-density lipoprotein levels, and the reported severity of pruritus increased with higher doses of OCA.

The function of the gut microbiota-bile acid-TGR5 axis in diarrhea-predominant irritable bowel syndrome.

Imbalanced gut microbiota (GM) and abnormal fecal bile acid (BA) are thought to be the key factors for diarrhea-predominant irritable bowel syndrome (IBS-D), but the underlying mechanism remains unclear. Herein, we explore the influence of the GM-BA-Takeda G-protein-coupled receptor 5 (TGR5) axis on IBS-D. Twenty-five IBS-D patients and fifteen healthy controls were recruited to perform BA-related metabolic and metagenomic analyses. Further, the microbiota-humanized IBS-D rat model was established by fecal microbial transplantation (FMT) to investigate the GM-BA-TGR5 axis effects on the colonic barrier and visceral hypersensitivity (VH) in IBS-D. Finally, we used chenodeoxycholic acid (CDCA), an important BA screened out by metabolome, to evaluate whether it affected diarrhea and VH via the TGR5 pathway. Clinical research showed that GM associated with bile salt hydrolase (BSH) activity such as Bacteroides ovatus was markedly reduced in the GM of IBS-D, accompanied by elevated total and primary BA levels. Moreover, we found that CDCA not only was increased as the most important primary BA in IBS-D patients but also could induce VH through upregulating TGR5 in the colon and ileum of normal rats. TGR5 inhibitor could reverse the phenotype, depression-like behaviors, pathological change, and level of fecal BSH in a microbiota-humanized IBS-D rat model. Our findings proved that human-associated FMT could successfully induce the IBS-D rat model, and the imbalanced GM-BA-TGR5 axis may promote colonic mucosal barrier dysfunction and enhance VH in IBS-D. IMPORTANCE: Visceral hypersensitivity and intestinal mucosal barrier damage are important factors that cause abnormal brain-gut interaction in diarrhea-predominant irritable bowel syndrome (IBS-D). Recently, it was found that the imbalance of the gut microbiota-bile acid axis is closely related to them. Therefore, understanding the structure and function of the gut microbiota and bile acids and the underlying mechanisms by which they shape visceral hypersensitivity and mucosal barrier damage in IBS-D is critical. An examination of intestinal feces from IBS-D patients revealed that alterations in gut microbiota and bile acid metabolism underlie IBS-D and symptom onset. We also expanded beyond existing knowledge of well-studied gut microbiota and bile acid and found that Bacteroides ovatus and chenodeoxycholic acid may be potential bacteria and bile acid involved in the pathogenesis of IBS-D. Moreover, our data integration reveals the influence of the microbiota-bile acid-TGR5 axis on barrier function and visceral hypersensitivity.

Chenodeoxycholic acid (CDCA) treatment during pregnancy in women with cerebrotendinous xanthomatosis (CTX): Lessons learned from 19 pregnancies.

PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder. Biallelic pathogenic variants in CYP27A1, encoding for sterol 27-hydroxylase, impair cholic acid (CA) and chenodeoxycholic acid (CDCA) synthesis and lead to accumulation of cholestanol and C27 bile alcohols. Treatment with CDCA decreases the accumulation of these harmful metabolites and slows disease progression. Currently, CDCA is contraindicated for use during pregnancy based on animal studies that showed that high-dose CDCA may cause fetal harm when administered to pregnant animals. Data regarding the safety of CDCA treatment in humans are lacking. METHODS: We present a case series of 19 pregnancies in 9 women with CTX who either received CDCA treatment throughout pregnancy or did not. RESULTS: In 11 pregnancies where mothers continued CDCA treatment, no complications were reported, and newborns were born at or near full term, with normal birth weight and Apgar scores. In 8 pregnancies where mothers did not receive CDCA, 2 newborns experienced elevated bilirubin soon after birth. One woman who stopped treatment during her pregnancy deteriorated neurologically while off treatment. CONCLUSION: The data we present support the benefit of continued CDCA treatment in pregnant women with CTX for both the affected women and their offspring.

Safety, pharmacokinetics and pharmacodynamics of obeticholic acid in subjects with fibrosis or cirrhosis from NASH.

BACKGROUND & AIMS: Fibrosis stage is a strong predictor of nonalcoholic steatohepatitis (NASH) outcomes. Two blinded studies evaluated the pharmacokinetics, pharmacodynamics and safety of obeticholic acid (OCA) in subjects with staged NASH fibrosis or cirrhosis. METHODS: Study 747-117 randomized 51 subjects with NASH (fibrosis stages F1-F4) to daily placebo, OCA 10 or OCA 25 mg (1:2:2) for 85 days. Study 747-118 randomized 24 subjects with NASH cirrhosis (F4; Child-Pugh [CP]-A) and normal liver control subjects matched for similar body weight to daily OCA 10 or OCA 25 mg (1:1) for 28 days. Individual and combined study data were analysed. RESULTS: No severe or serious adverse events (AEs) or AEs leading to discontinuation or death occurred. Pruritus was the most frequent AE. Plasma OCA exposure (dose-normalized area under the curve) increased with fibrosis stage but was a relatively poor predictor of hepatic OCA exposure (primary site of action), which remained constant across fibrosis stages F1-F3 and increased 1.8-fold compared with F1 in subjects with cirrhosis due to NASH. Both cohorts showed robust changes in farnesoid X receptor activation markers with OCA treatment and marked decreases in alanine transaminase, aspartate transaminase and gamma-glutamyltransferase. CONCLUSIONS: Despite higher drug exposures in subjects with NASH cirrhosis, short-term daily treatment with OCA 10 or 25 mg was generally safe and well tolerated in subjects with NASH fibrosis or NASH CP-A cirrhosis. Both cohorts experienced improvements in nonhistologic pharmacodynamic markers consistent with previously conducted OCA phase 2 and phase 3 studies in NASH fibrosis.

Hepatic-Accumulated Obeticholic Acid and Atorvastatin Self-Assembled Nanocrystals Potentiate Ameliorative Effects in Treatment of Metabolic-Associated Fatty Liver Disease.

Exploration of medicines for efficient and safe management of metabolic-associated fatty liver disease (MAFLD) remains a challenge. Obeticholic acid (OCA), a selective farnesoid X receptor agonist, has been reported to ameliorate injury and inflammation in various liver diseases. However, its clinical application is mainly limited by poor solubility, low bioavailability, and potential side effects. Herein a hepatic-targeted nanodrugs composed of OCA and cholesterol-lowering atorvastatin (AHT) with an ideal active pharmaceutical ingredient (API) content for orally combined treatment of MAFLD is created. Such carrier-free nanocrystals (OCAHTs) are self-assembled, not only improving the stability in gastroenteric environments but also achieving hepatic accumulation through the bile acid transporter-mediated enterohepatic recycling process. Orally administrated OCAHT outperforms the simple combination of OCA and AHT in ameliorating of liver damage and inflammation in both acetaminophen-challenged mice and high-fat diet-induced MAFLD mice with less systematic toxicity. Importantly, OCAHT exerts profoundly reverse effects on MAFLD-associated molecular pathways, including impairing lipid metabolism, reducing inflammation, and enhancing the antioxidation response. This work not only provides a facile bile acid transporter-based strategy for hepatic-targeting drug delivery but also presents an efficient and safe full-API nanocrystal with which to facilitate the practical translation of nanomedicines against MAFLD.

Chenodeoxycholic Acid-Loaded Nanoparticles Are Sufficient to Decrease Adipocyte Size by Inducing Mitochondrial Function.

Excess fat accumulation is not only associated with metabolic diseases but also negatively impacts physical appearance and emotional well-being. Bile acid, the body's natural emulsifier, is one of the few FDA-approved noninvasive therapeutic options for double chin (submental fat) reduction. Synthetic sodium deoxycholic acid (NaDCA) causes adipose cell lysis; however, its side effects include inflammation, bruising, and necrosis. Therefore, we investigated if an endogenous bile acid, chenodeoxycholic acid (CDCA), a well-known signaling molecule, can be beneficial without many of the untoward effects. We first generated CDCA-loaded nanoparticles to achieve sustained and localized delivery. Then, we injected them into the subcutaneous fat depot and monitored adipocyte size and mitochondrial function. Unlike NaDCA, CDCA did not cause cytolysis. Instead, we demonstrate that a single injection of CDCA-loaded nanoparticles into the subcutaneous fat reduced the adipocyte size by promoting fat burning and mitochondrial respiration, highlighting their potential for submental fat reduction.

Measuring the experience of social connection within specific social interactions: The Connection During Conversations Scale (CDCS).

Decades of research have demonstrated that social connection is fundamental to health and well-being. The benefits of connection are observed with both close and distant others, within both new and established relationships, and even with exchanges that unfold over a relatively short timeframe. Because social connection is fundamental to well-being, many existing measures in the literature aim to assess either a global sense of connection or partner-specific (relationship-specific) connection. What is missing are measures of connection felt in specific social interactions or conversations. In three studies (Study 1: N = 351; Study 2: Time 1 N = 397, Time 2 N = 336, Time 3 N = 299; Study 3: N = 235), we developed the Connection During Conversations Scale (CDCS), a 14-item measure of conversation-specific social connection that assesses connection experienced during a social interaction (or conversation). Confirmatory factor analyses demonstrated that a four-factor model fit our samples well, which resulted in four subscales: Shared Reality, Partner Responsiveness, Participant Interest, and Affective Experience. The overall CDCS measure, along with its four subscales, was significantly correlated with established measures of loneliness, partner responsiveness, relatedness, positivity resonance, and shared reality. Because of the importance of frequent interactions-whether with family, friends, coworkers, or strangers-our new scale will allow researchers to better understand how, when, and where such conversations may contribute to social connection and well-being. (225 words).

The gut microbiome predicts response to UDCA/CDCA treatment in gallstone patients: comparison of responders and non-responders.

The treatment of gallbladder (GB) stones depends on condition severity. Ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) are commonly used to treat GB stones, but the factors affecting response rates have not been fully identified. Therefore, we investigated the relationship between response to UDCA/CDCA treatment and changes in the gut microbiomes of patients with GB stones with the intention of identifying gut microbiomes that predict susceptibility to UDCA/CDCA treatment and treatment response. In this preliminary, prospective study, 13 patients with GB stones were treated with UDCA/CDCA for 6 months. Patients were classified into responder and non-responder groups based on treatment outcomes. Gut microbiomes were analyzed by 16S rDNA sequencing. Taxonomic compositions and abundances of bacterial communities were analyzed before and after UDCA/CDCA treatment. Alpha and beta diversities were used to assess similarities between organismal compositions. In addition, PICRUSt2 analysis was conducted to identify gut microbial functional pathways. Thirteen patients completed the treatment; 8 (62%) were assigned to the responder group and the remainder to the non-responder group. Low abundances of the Erysipelotrichi lineage were significantly associated with favorable response to UDCA/CDCA treatment, whereas high abundances of Firmicutes phylum indicated no or poor response. Our results suggest that a low abundance of the Erysipelotrichi lineage is significantly associated with a favorable response to UDCA/CDCA and that a high abundance of Firmicutes phylum is indicative of no or poor response. These findings suggest that some gut microbiomes are susceptible to UDCA/CDCA treatment and could be used to predict treatment response in patients with GB stones.