Mass Balance, Metabolic Pathways, Absolute Bioavailability, And Pharmacokinetics of Giredestrant In Healthy Subjects.

Giredestrant is a potent and selective small molecule estrogen receptor degrader. The objectives of this study were to assess the absolute bioavailability (aBA) of giredestrant and to determine the mass balance, routes of elimination and metabolite profile of [14C]giredestrant. In Part 1 (mass balance), a single 30.8 mg oral dose of [14C]giredestrant (105 µCi) was administered to women of non-childbearing potential (WNCBP, n = 6). The mean recovery of total radioactivity (TR) in excreta was 77.0%, with 68.0% of the dose excreted in feces and 9.04% excreted in urine over a 42-day sample collection period. The majority of the circulating radioactivity (56.8%) in plasma was associated with giredestrant. Giredestrant was extensively metabolized with giredestrant representing only 20.0% and 1.90% of the dose in feces and urine, respectively. All metabolites in feces resulted from oxidative metabolism and represented 44.7% of the dose. In Part 2 (absolute bioavailability, aBA), WNCBP (n = 10) received an oral (30 mg capsule) or intravenous (30 mg solution) dose of giredestrant. The aBA of giredestrant after oral administration was 58.7%. Following the intravenous dose, giredestrant had a plasma clearance and volume of distribution of 5.31 L/h and 266 L, respectively. In summary, giredestrant was well tolerated, rapidly absorbed, and showed moderate oral bioavailability with low recovery of the dose as parent drug in excreta. Oxidative metabolism followed by excretion in feces was identified as the major route of elimination of giredestrant. Significance Statement This study provides definitive insight into the absorption, distribution, metabolism, and excretion of giredestrant in humans. The results show that giredestrant exhibits low clearance, high volume of distribution, and moderate oral bioavailability in humans. In addition, the data show that oxidative metabolism followed by excretion in feces is the primary elimination route of giredestrant in humans. These results will be used to further inform the clinical development of giredestrant.

Regulating the absorption and excretion of perfluorooctane sulfonate and its alternatives through influencing enterohepatic circulation.

Enterohepatic circulation has been reported to play a significant role in the bioaccumulation of PFASs. In this study, the tissue distribution and excretion of PFOS and its alternatives, namely 6:2 and 8:2 fluorotelomer sulfonic acid (FTSA) was investigated using a mouse assay with a focus on role of enterohepatic circulation. Liver was the primarily accumulating organ for PFOS and 8:2 FTSA (33.4 % and 25.8 % of total doses absorbed after 14 days), whereas 65 % of 6:2 FTSA was excreted via urine within 24 h. Peak levels of 8:2 FTSA and PFOS were found in the gallbladder, implying the important role of enterohepatic circulation in PFASs reabsorption. The role of enterohepatic circulation was further evaluated through co-exposure of 8:2 FTSA and PFOS with medicines (namely metformin (MET) and ursodeoxycholic acid (UDCA)). MET reduced accumulation of 8:2 FTSA and PFOS in the liver by 68.6 % and 65.8 %, through down-regulation of bile acid transporter (Asbt) and enhancement of fecal excretion. Conversely, UDCA raised their concentrations by 21.9 % and 34.6 % compared to that exposed solely to PFASs. A strong positive correlation was identified between PFASs serum levels and Asbt expression. This study illuminated PFAS bioaccumulation mechanisms and suggested potential strategies to mitigate the exposure risks.

Emerging drugs for the treatment of progressive familial intrahepatic cholestasis: a focus on phase II and III trials.

INTRODUCTION: Progressive familial intrahepatic cholestasis (PFIC) is a group of disorders characterized by inappropriate bile formation, causing hepatic accumulation of bile acids and, subsequently, liver injury. Until recently, no approved treatments were available for these patients. AREAS COVERED: Recent clinical trials for PFIC treatment have focused on intestine-restricted ileal bile acid transporter (IBAT) inhibitors. These compounds aim to reduce the pool size of bile acids by interrupting their enterohepatic circulation. Other emerging treatments in the pipeline include systemic IBAT inhibitors, synthetic bile acid derivatives, compounds targeting bile acid synthesis via the FXR/FGF axis, and chaperones/potentiators that aim to enhance the residual activity of the mutated transporters. EXPERT OPINION: Substantial progress has been made in drug development for PFIC patients during the last couple of years. Although data concerning long-term efficacy are as yet only scarcely available, new therapies have demonstrated robust efficacy in a considerable fraction of patients at least on the shorter term. However, a substantial fraction of PFIC patients do not respond to these novel therapies and thus still requires surgical treatment, including liver transplantation before adulthood. Hence, there is still an unmet medical need for long-term effective medical, preferably non-surgical, treatment for all PFIC patients.

Normally, the liver produces bile which is a route of secretion of waste products from the body and also helps in the intestinal absorption of fats from the diet. The bile goes from the liver, through the bile duct to the intestines and components are taken up again at the end of the intestine and transported back to the liver. However, progressive familial intrahepatic cholestasis (PFIC in short) is a group of diseases where bile stays in the liver and damages it. PFIC often causes symptoms already in very young children, like itch and jaundice (getting a slight yellow color). Patients get more and worse symptoms over time and may eventually need a liver transplantation. This review discusses what drugs have been developed for PFIC recently and what drugs are in development now. Two new drugs for PFIC have been developed and approved in the last few years: odevixibat and maralixibat. These drugs help bile in the intestines leave the body via the stool and prevent bile from going back to the liver instead. Drugs in development aim to either 1) do the same, 2) make the bile less toxic, 3) reduce the production of bile, or 4) help bile go from the liver into the bile ducts. There has been a lot of progress in drug development for PFIC in the last few years. The new drugs have helped a considerable number of patients, but many patients still do not respond to these new drugs, keep having symptoms and may need surgery. Therefore, despite considerable progress, research needs to continue for an effective treatment for all PFIC patients.

Determination of Bile Acids in Canine Biological Samples: Diagnostic Significance.

The comprehensive examination of bile acids is of paramount importance across various fields of health sciences, influencing physiology, microbiology, internal medicine, and pharmacology. While enzymatic reaction-based photometric methods remain fundamental for total BA measurements, there is a burgeoning demand for more sophisticated techniques such as liquid chromatography-tandem mass spectrometry (LC-MS/MS) for comprehensive BA profiling. This evolution reflects a need for nuanced diagnostic assessments in clinical practice. In canines, a BA assessment involves considering factors, such as food composition, transit times, and breed-specific variations. Multiple matrices, including blood, feces, urine, liver tissue, and gallbladder bile, offer insights into BA profiles, yet interpretations remain complex, particularly in fecal analysis due to sampling challenges and breed-specific differences. Despite ongoing efforts, a consensus regarding optimal matrices and diagnostic thresholds remains elusive, highlighting the need for further research. Emphasizing the scarcity of systematic animal studies and underscoring the importance of ap-propriate sampling methodologies, our review advocates for targeted investigations into BA alterations in canine pathology, promising insights into pathomechanisms, early disease detection, and therapeutic avenues.

The role of bile acids in human aging.

Bile acids are recognized as important signaling molecules that enable fine-tuned inter-communication from the liver, through the intestine, to virtually any organ, thus encouraging their pleiotropic physiological effects. Aging is a complex natural process defined as a progressive decline in cellular and organismal functions. A causal link between bile acids and the aging process is emerging. However, there are gaps in our understanding of the molecular mechanisms and precise targets responsible for the alteration of bile acid profiles and their role in the aging process. Intestinal barrier dysfunction leads to endotoxemia, systemic inflammation, insulin resistance, diabetes, lipid accumulation, obesity and fatty liver diseases, and health decline and death. In fact, intestinal barrier dysfunction is suggested to be an evolutionarily conserved hallmark of aging. Bile acids may modulate the aging process by regulating intestinal barrier integrity.

Importance of Considering Fed-State Gastrointestinal Physiology in Predicting the Reabsorption of Enterohepatic Circulation of Drugs.

PURPOSE: The purpose of this study was to develop a simulation model for the pharmacokinetics (PK) of drugs undergoing enterohepatic circulation (EHC) with consideration to the environment in the gastrointestinal tract in the fed state in humans. The investigation particularly focused on the necessity of compensating for the permeability rate constant in the reabsorption process in consideration of drug entrapment in bile micelles. METHODS: Meloxicam and ezetimibe were used as model drugs. The extent of the entrapment of drugs inside bile micelles was evaluated using the solubility ratio of Fed State Simulated Intestinal Fluid version 2 (FeSSIF-V2) to Fasted State Simulated Intestinal Fluid version 2 (FaSSIF-V2). Prediction accuracy was evaluated using the Mean Absolute Percentage Error (MAPE) value, calculated from the observed and predicted oral PK profiles. RESULTS: The solubilization of ezetimibe by bile micelles was clearly observed while that of meloxicam was not. Assuming that only drugs in the free fraction of micelles permeate through the intestinal membrane, PK simulation for ezetimibe was performed in both scenarios with and without compensation by the permeation rate constant. The MAPE value of Zetia® tablet, containing ezetimibe, was lower with compensation than without compensation. By contrast, Mobic® tablet, containing meloxicam, showed a relatively low MAPE value even without compensation. CONCLUSION: For drugs which undergo EHC and can be solubilized by bile micelles, compensating for the permeation rate constant in the reabsorption process based on the free fraction ratio appears an important factor in increasing the accuracy of PK profile prediction.

The Significance of Bile in the Biliopancreatic Limb on Metabolic Improvement After Duodenal-Jejunal Bypass.

INTRODUCTION: Duodenal-jejunal bypass (DJB) is an experimental procedure in metabolic surgery that does not have a restrictive component. Changes in bile acid (BA) dynamics and intestinal microbiota are possibly related to metabolic improvement after DJB. Our previous studies involving obese diabetic rats showed the crucial role of the biliopancreatic limb (BPL) in metabolic improvement after DJB caused by BA reabsorption. We established a new DJB procedure to prevent bile from flowing into the BPL and aimed to elucidate the importance of bile in the BPL after DJB. METHODS: Otsuka Long-Evans Tokushima Fatty rats with diabetes were divided into three groups: two DJB groups and a sham group (n = 11). Duodenal-jejunal anastomosis was performed proximal to the papilla of Vater in the DJB group (n = 11). However, the DJB-D group (n = 11) underwent a new procedure with duodenal-jejunal anastomosis distal to the papilla of Vater for preventing bile flow into the BPL. RESULTS: Glucose metabolism improved and weight gain was suppressed in the DJB group, but not in the DJB-D and sham groups. Serum BA level and conjugated BA concentration were elevated in the DJB group. The gut microbiota was altered only in the DJB group; the abundance of Firmicutes and Bacteroidetes decreased and that of Actinobacteria increased. However, the DJB-D group exhibited no apparent change in the gut microbiota, similar to the sham group. CONCLUSION: BAs are essential in the BPL for metabolic improvement after DJB; they can improve the gut microbiota in these processes.

Vagal activation alters prandial bile acid composition and glycemia in patients with hypoglycemia after Roux-en-Y gastric bypass surgery.

BACKGROUND: Altered prandial glycemic response after Roux-en-Y gastric bypass (RYGB) is exaggerated in patients with post-RYGB hypoglycemia. Increased contribution of glucagon-like peptide 1 (GLP-1) to prandial insulin secretion plays a key role in developing hypoglycemia after RYGB, but the role of nonhormonal gut factors remains unknown. Here, the effect of vagal activation on prandial bile acid (BA) composition in relation to glucose, insulin and gut hormone responses was examined in a small size group of nondiabetic subjects after RYGB with intact gallbladder compared to nonoperated controls. METHODS: Concentrations of blood glucose, hormones, and BAs were measured in two RYGB subjects with documented hypoglycemia (HGB), three asymptomatic RYGB-treated subjects (AGB), and four nonoperated controls with intact gallbladders during a meal-tolerance test with (MTT-Sham) and without (MTT) preceding modified sham feeding (chew and spit). KEY RESULTS: Meal ingestion raised serum total BAs in RYGB-treated subjects without any effect in nonoperated controls. Modified sham feeding similarly increased meal-induced responses of conjugated BAs (CBAs) in all subjects (p < 0.05 compared to MTT alone), whereas unconjugated BAs (UBAs), mainly deoxycholic and chenodeoxycholic acid, were raised only in the HGB group (p < 0.001 for interaction). Prandial UBAs had an inverse correlation with glucose nadir (r = -0.75, p < 0.05) and were directly associated with ISR and GLP-1 during MTT-Sham. CONCLUSIONS & INFERENCES: In this small cohort, vagal activation by modified sham feeding increases prandial CBAs in both operated and nonoperated subjects but enhances UBAs only in patients with documented post-RYGB hypoglycemia. Our findings highlight a potential role for nonhormonal gut factors, such as BA and gut microbiome, in glucose abnormalities after RYGB.

Assessment of Fetal Exposure and Elimination of Perfluoroalkyl and Polyfluoroalkyl Substances: New Evidence from Paired Serum, Placenta, and Meconium Samples.

Multiple pieces of evidence have shown that prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) is closely related to adverse birth outcomes for infants. However, difficult access to human samples limits our understanding of PFASs transport and metabolism across the human placental barrier, as well as the accurate assessment of fetal PFASs exposure. Herein, we assess fetal exposure to 28 PFASs based on paired serum, placenta, and meconium samples. Overall, 21 PFASs were identified first to be exposed to the fetus prenatally and to be metabolized and excreted by the fetus. In meconium samples, 25 PFASs were detected, with perfluorooctane sulfonate and perfluorohexane sulfonic acid being the dominant congeners, suggesting the metabolism and excretion of PFASs through meconium. Perfluoroalkyl sulfonic acids might be more easily eliminated through the meconium than perfluorinated carboxylic acids. Importantly, based on molecular docking, MRP1, OATP2B1, ASCT1, and P-gp were identified as crucial transporters in the dynamic placental transfer of PFASs between the mother and the fetus. ATSC5p and PubchemFP679 were recognized as critical structural features that affect the metabolism and secretion of PFASs through meconium. With increasing carbon chain length, both the transplacental transfer efficiency and meconium excretion efficiency of PFASs showed a structure-dependent manner. This study reports, for the first time, that meconium, which is a noninvasive and stable biological matrix, can be strong evidence of prenatal PFASs exposure.

Interactions of Body Weight Loss with Lipophilic Toxin Storage: Commentary.

A high incidence of obesity and surplus body fat has been observed in wealthy countries for many decades. It is generally recognized that these excesses contribute to serious disease states, including type 2 diabetes and cardiovascular diseases. On the other hand, the adipose tissue stores relatively safely many environmental lipophilic toxins. However, rapid weight loss mobilizes these toxins to the blood to be exposed to vital organs, such as the brain, lungs, and others. With the introduction of potent diabetic drugs causing rapid weight reduction, the question of mobilization of lipophilic toxins to the blood should be considered. In this commentary, we raised this mobilization of adipose tissue toxins to the readers. Also, we discussed how these toxins may be eliminated from the body through the use of nondigestible fat, such as olestra or lipase inhibitors, such as Xenical.

Polymethoxyflavones in citrus extract has a beneficial effect on hypercholesterolemia rats by promoting liver cholesterol metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyperlipidemia is characterized by the disorder of lipid metabolism accompanied by oxidative stress damage, and low-grade inflammation, with the pathway of cholesterol and bile acid metabolic are an important triggering mechanism. Polymethoxyflavones (PMFs) are the active constituents of Aurantii Fructus Immaturus, which have many biological effects, including anti-inflammatory, antioxidant activities, anti-obesity, suppressing adipogenesis in adipocytes, and ameliorate type 2 diabetes, with potential roles for regulation of lipid metabolism. However, its associated mechanisms on hyperlipidemia remain unclear. AIM OF THE STUDY: This study aims to identify the anti-hypercholesterolemia effects and mechanisms of PMFs in a hypercholesterolemia model triggered by high-fat compounds in an excessive alcohol diet (HFD). MATERIALS AND METHODS: A hypercholesterolemia rat model was induced by HFD, and PMFs was intragastric administered at 125 and 250 mg/kg daily for 16 weeks. The effects of PMFs on hypercholesterolemia were assessed using serum lipids, inflammatory cytokines, and oxidative stress levels. Hematoxylin & eosin (H&E) and Oil Red O staining were performed to evaluate histopathological changes in the rat liver. The levels of total cholesterol (TC) and total bile acid (TBA) in the liver and feces were determined to evaluate lipid metabolism. RAW264.7 and BRL cells loaded with NBD-cholesterol were used to simulate the reverse cholesterol transport (RCT) process in vitro. The signaling pathway of cholesterol and bile acid metabolic was evaluated by Western Blotting (WB) and qRT-PCR. RESULTS: Lipid metabolism disorders, oxidative stress injury, and low-grade inflammation in model rats were ameliorated by PMFs administration. Numerous vacuoles and lipid droplets in hepatocytes were markedly reduced. In vitro experiments results revealed decreased NBD-cholesterol levels in RAW264.7 cells and increased NBD-cholesterol levels in BRL cells following PMFs intervention. PMFs upregulated the expression of proteins associated with the RCT pathway, such as LXRα, ABCA1, LDLR, and SR-BI, thereby promoting TC entry into the liver. Meanwhile, the expression of proteins associated with cholesterol metabolism and efflux pathways such as CYP7A1, CYP27A1, CYP7B1, ABCG5/8, ABCB1, and BSEP were regulated, thereby promoting cholesterol metabolism. Moreover, PMFs treatment regulated the expression of proteins related to the pathway of enterohepatic circulation of bile acids, such as ASBT, OSTα, NTCP, FXR, FGF15, and FGFR4, thereby maintaining lipid metabolism. CONCLUSIONS: PMFs might ameliorate hypercholesterolemia by promoting the entry of cholesterol into the liver through the RCT pathway, followed by excretion via metabolism pathways of cholesterol and bile acid. These findings provide a promising therapeutic potential for PMFs to treat hypercholesterolemia.

Roles for Bile Acid Signaling and Nonsense-Mediated Ribonucleic Acid Decay in Small Bowel Resection-Associated Liver Injury.

INTRODUCTION: Massive intestinal loss resulting in short bowel syndrome has been linked to intestinal failure associated liver disease. Efforts to elucidate the driving force behind the observed hepatic injury have identified inflammatory mediators, alterations in the microbiome, extent of structural and functional intestinal adaptation, and toxic shifts in the bile acid pool. In the present study, we posit that ileocecal resection interrupts the delivery of these hepatotoxic substances to the liver by physically disrupting the enterohepatic circulation, thereby shielding the liver from exposure to the aforementioned noxious stimuli. METHODS: Mice underwent sham, 50% proximal, or 50% distal small bowel resection (SBR), with or without tauroursodeoxycolic acid supplementation. Enterohepatic signaling and nonsense-mediated ribonucleic acid (RNA) decay were evaluated and correlated with hepatic injury. RESULTS: When compared to 50% proximal SBR, mice that underwent ileocecal resection exhibited reduced hepatic oxidative stress and exhibited a more physiological bile acid profile with increased de novo bile acid synthesis, enhanced colonic bile acid signaling, and reduced hepatic proliferation. Distal intestinal resection promoted an adaptive response including via the nonsense-mediated RNA decay pathway to satisfactorily process injurious messenger RNA and successfully maintain homeostasis. By contrast, this adaptive response was not observed in the proximal SBR group and hepatic injury persisted. CONCLUSIONS: In summary, interruption of enterohepatic circulation via ileocecal resection abrogates the liver's exposure to toxic and inflammatory mediators while promoting physiological adaptations in bile acid metabolism and maintaining existing homeostatic pathways.

Bile Acid Sequestration via Colesevelam Reduces Bile Acid Hydrophobicity and Improves Liver Pathology in Cyp2c70-/- Mice with a Human-like Bile Acid Composition.

Bile acids (BAs) and their signaling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated Cyp2c70-/- (KO) mice that were not able to convert chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and, hence, possessed a more hydrophobic, human-like BA pool. Recently, we have shown that KO mice display cholangiopathic features with the development of liver fibrosis. The aim of this study was to determine whether BA sequestration modulates liver pathology in Western type-diet (WTD)-fed KO mice. The BA sequestrant colesevelam was mixed into the WTD (2% w/w) of male Cyp2c70+/+ (WT) and KO mice and the effects were evaluated after 3 weeks of treatment. Colesevelam increased fecal BA excretion in WT and KO mice and reduced the hydrophobicity of biliary BAs in KO mice. Colesevelam ameliorated diet-induced hepatic steatosis in WT mice, whereas KO mice were resistant to diet-induced steatosis and BA sequestration had no additional effects on liver fat content. Total cholesterol concentrations in livers of colesevelam-treated WT and KO mice were significantly lower than those of untreated controls. Of particular note, colesevelam treatment normalized plasma levels of liver damage markers in KO mice and markedly decreased hepatic mRNA levels of fibrogenesis-related genes in KO mice. Lastly, colesevelam did not affect glucose excursions and insulin sensitivity in WT or KO mice. Our data show that BA sequestration ameliorates liver pathology in Cyp2c70-/- mice with a human-like bile acid composition without affecting insulin sensitivity.

The Potential of Bile Acids as Biomarkers for Metabolic Disorders.

Bile acids (BAs) are well known to facilitate the absorption of dietary fat and fat-soluble molecules. These unique steroids also function by binding to the ubiquitous cell membranes and nuclear receptors. As chemical signals in gut-liver axis, the presence of metabolic disorders such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), and even tumors have been reported to be closely related to abnormal levels of BAs in the blood and fecal metabolites of patients. Thus, the gut microbiota interacting with BAs and altering BA metabolism are critical in the pathogenesis of numerous chronic diseases. This review intends to summarize the mechanistic links between metabolic disorders and BAs in gut-liver axis, and such stage-specific BA perturbation patterns may provide clues for developing new auxiliary diagnostic means.

Urine-based Detection of Congenital Portosystemic Shunt in C57BL/6 Mice.

Sporadic occurrence of congenital portosystemic shunt (PSS) at a rate of ∼1 out of 10 among C57BL/6 J mice, which are widely used in biomedical research, results in aberrancies in serologic, metabolic, and physiologic parameters. Therefore, mice with PSS should be identified as outliers in research. Accordingly, we sought methods to, reliably and efficiently, identify PSS mice. Serum total bile acids ≥ 40 µm is a bona fide biomarker of PSS in mice but utility of this biomarker is limited by its cost and invasiveness, particularly if large numbers of mice are to be screened. This led us to investigate if assay of urine might serve as a simple, inexpensive, noninvasive means of PSS diagnosis. Metabolome profiling uncovered that Krebs cycle intermediates, that is, citrate, α-ketoglutarate, and fumarate, were strikingly and distinctly elevated in the urine of PSS mice. We leveraged the iron-chelating and pH-lowering properties of such metabolites as the basis for 3 urine-based PSS screening tests: urinary iron-chelation assay, pH strip test, and phenol red assay. Our findings demonstrate the feasibility of using these colorimetric assays, whereby their readout can be assessed by direct observation, to diagnose PSS in an inexpensive, rapid, and noninvasive manner. Application of our urinary PSS screening protocols can aid biomedical research by enabling stratification of PSS mice, which, at present, likely confound numerous ongoing studies.

The Effect of MSTN Mutation on Bile Acid Metabolism and Lipid Metabolism in Cattle.

Myostatin (MSTN) is a negative regulator of skeletal muscle genesis during development. MSTN mutation leads to increased lean meat production and reduced fat deposition in livestock. However, the mechanism by which MSTN promotes myogenesis by regulating metabolism is not clear. In this study, we compared the metabolomics of the livers of wild-type (WT) and MSTN mutation cattle (MT), and found changes in the content and proportion of fatty acids and bile acids in MT cattle. The differential metabolites were enriched in sterol synthesis and primary bile acid synthesis. We further analyzed the expression of genes involved in the regulation of lipid and bile acid metabolism, and found that the loss of MSTN may alter lipid synthesis and bile acid metabolism. This study provides new basic data for MSTN mutations in beef cattle breeding.

Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis.

Background & Aims: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis. Methods: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 µg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22-24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0-4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs). Results: In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22-24 of PEDFIC 2 in sBAs was -201 µmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22-24 in sBAs were -144 and -104 µmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred. Conclusions: Odevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT03659916). Impact and Implications: Disrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients.

The interaction of bile acids and gut inflammation influences the pathogenesis of inflammatory bowel disease.

Bile acids (BA) are amphipathic molecules originating from cholesterol in the liver and from microbiota-driven biotransformation in the colon. In the gut, BA play a key role in fat digestion and absorption and act as potent signaling molecules on the nuclear farnesoid X receptor (FXR) and membrane-associated G protein-coupled BA receptor-1 (GPBAR-1). BA are, therefore, involved in the maintenance of gut barrier integrity, gene expression, metabolic homeostasis, and microbiota profile and function. Disturbed BA homeostasis can activate pro-inflammatory pathways in the gut, while inflammatory bowel diseases (IBD) can induce gut dysbiosis and qualitative and/or quantitative changes of the BA pool. These factors contribute to impaired repair capacity of the mucosal barrier, due to chronic inflammation. A better understanding of BA-dependent mechanisms paves the way to innovative therapeutic tools by administering hydrophilic BA and FXR agonists and manipulating gut microbiota with probiotics and prebiotics. We discuss the translational value of pathophysiological and therapeutic evidence linking BA homeostasis to gut inflammation in IBD.

Chronic Heat Stress Affects Bile Acid Profile and Gut Microbiota in Broilers.

Heat stress (HS) can inhibit the growth performance of broilers and cause substantial economic losses. Alterations in bile acid (BA) pools have been reported to be correlated with chronic HS, yet the specific mechanism and whether it is related to gut microbiota remains unclear. In this study, 40 Rugao Yellow chickens were randomly selected and distributed into two groups (20 broilers in each group) when reaching 56-day age: a chronic heat stress group (HS, 36 ± 1 °C for 8 h per day in the first 7 days and 36 ± 1 °C for 24 h in the last 7 days) and a control group (CN, 24 ± 1 °C for 24 h within 14 days). Compared with the CN group, total BAs' serum content decreased, while cholic acid (CA), chenodeoxycholic acid (CDCA), and taurolithocholic acid (TLCA) increased significantly in HS broilers. Moreover, 12α-hydroxylase (CYP8B1) and bile salt export protein (BSEP) were upregulated in the liver, and the expression of fibroblast growth factor 19 (FGF19) decreased in the ileum of HS broilers. There were also significant changes in gut microbial composition, and the enrichment of Peptoniphilus was positively correlated with the increased serum level of TLCA. These results indicate that chronic HS disrupts the homeostasis of BA metabolism in broilers, which is associated with alterations in gut microbiota.

Metabolism of Acetaminophen by Enteric Epithelial Cells Mitigates Hepatocellular Toxicity In Vitro.

The gut-liver axis is defined by dietary and environmental communication between the gut, microbiome and the liver with its redox and immune systems, the overactivation of which can lead to hepatic injury. We used media preconditioning to mimic some aspects of the enterohepatic circulation by treating the human Caco-2 intestinal epithelial cell line with 5, 10 and 20 mM paracetamol (N-acetyl-para-aminophenol; APAP) for 24 h, after which cell culture supernatants were transferred to differentiated human hepatic HepaRG cells for a further 24 h. Cell viability was assessed by mitochondrial function and ATP production, while membrane integrity was monitored by cellular-based impedance. Metabolism by Caco-2 cells was determined by liquid chromatography with tandem mass spectrometry. Caco-2 cell viability was not affected by APAP, while cell membrane integrity and tight junctions were maintained and became tighter with increasing APAP concentrations, suggesting a reduction in the permeability of the intestinal epithelium. During 24 h incubation, Caco-2 cells metabolised 64-68% of APAP, leaving 32-36% of intact starting compound to be transferred to HepaRG cells. When cultured with Caco-2-preconditioned medium, HepaRG cells also showed no loss of cell viability or membrane integrity, completely in contrast to direct treatment with APAP, which resulted in a rapid loss of cell viability and membrane integrity and, ultimately, cell death. Thus, the pre-metabolism of APAP could mitigate previously observed hepatotoxicity to hepatic tight junctions caused by direct exposure to APAP. These observations could have important implications for the direct exposure of hepatic parenchyma to APAP, administered via the intravenous route.