Bile Alcohols Research Articles

Differences in clinical manifestations and the fecal microbiome between irritable bowel syndrome and small intestinal bacterial overgrowth

BackgroundIrritable bowel syndrome (IBS) and small intestinal bacterial overgrowth (SIBO) share similar abdominal symptoms; however, their differentiation remains controversial. AimsTo illustrate the differences between the two conditions. MethodsPatients and healthy controls completed questionnaires and provided stool samples for analysis. ResultsIBS presented with the most severe symptoms and was specifically characterized by intense abdominal pain and frequent episodes of diarrhea. Patients with IBS displayed more dysregulated taxonomy within the fecal microbiota than SIBO. Opportunistic pathogens, including Lachnoclostridium, Escherichia-Shigella, and Enterobacter were enriched in the IBS group which contributed to increased bacterial pathogenicity and positively correlated with abdominal pain and bloating, meanwhile, Lachnoclostridium and Escherichia-Shigella were found to be associated with metabolites affiliated to bile acids, alcohols and derivatives. Bacteria enriched in SIBO group correlated with constipation. The bacterial co-occurrence network within the SIBO group was the most intricate. Ruminococcaceae Group were defined as core bacteria in SIBO. Differential metabolites affiliated to androstane steroids and phenylacetic acids were associated with core bacteria. ConclusionsOur study elucidates the differences between IBS and SIBO in terms of symptoms, microbiota and functions, which provides insights into a better understanding of both diseases and evidence for different treatment strategies.

Genetically and clinically confirmed atypical cerebrotendinous xanthomatosis with normal cholestanol and marked elevations of bile acid precursors and bile alcohols

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid disorder. Affected patients often remain undiagnosed until the age of 20-30 years, when they have already developed significant neurologic disease that may not be reversible. An elevated plasma cholestanol concentration has been accepted as a diagnostic criterion for CTX for decades. Full biochemical characterization was performed for three genetically and clinically confirmed atypical CTX cases with normal plasma cholestanol levels. Clinical assessment and genetic/biochemical testing for patients with CTX was performed by their physician providing routine standard of care. We report three new atypical CTX cases with large extensor tendon xanthomas but normal plasma cholestanol levels. All three cases had marked elevations of bile acid precursors and bile alcohols in plasma and urine that decreased on treatment with chenodeoxycholic acid. We also review eight published cases of atypical CTX with normal/near normal circulating cholestanol levels. The atypical biochemical presentation of these cases provides a diagnostic challenge for CTX, a disorder for which cholestanol has been believed to be a sensitive biomarker. These cases demonstrate measurements of plasma cholestanol alone are insufficient to exclude a diagnosis of CTX. The data presented is consistent with the concept that bile acid precursors and bile alcohols are sensitive biomarkers for atypical CTX with normal cholestanol, and that such testing is indicated, along with CYP27A1 gene analyses, in patients presenting with significant tendon and/or tuberous xanthomas and/or neurologic disease in early adulthood despite normal or near normal cholesterol and cholestanol levels.

Identification of olfactory alarm substances in zebrafish

Escaping from danger is one of the most fundamental survival behaviors for animals. Most freshwater fishes display olfactory alarm reactions in which an injured fish releases putative alarm substances from the skin to notify its shoaling company about the presence of danger. Here, we identified two small compounds in zebrafish skin extract, designated as ostariopterin and daniol sulfate. Ostariopterin is a pterin derivative commonly produced in many freshwater fishes belonging to the Ostariophysi superorder. Daniol sulfate is a novel sulfated bile alcohol specifically present in the Danio species, including zebrafish. Ostariopterin and daniol sulfate activate distinct glomeruli in the olfactory bulb. Zebrafish display robust alarm reactions, composed of darting, freezing, and bottom dwelling, only when they are concomitantly stimulated with ostariopterin and daniol sulfate. These results demonstrate that the fish alarm reaction is driven through a coincidence detection mechanism of the two compounds along the olfactory neural circuitry.

Biological rhythms of the liver.

The biological rhythm is a fundamental aspect of an organism, regulating many physiological processes. This study focuses on the analysis of the molecular basis of circadian rhythms and its impact on the functioning of the liver. The regulation of biological rhythms is carried out by the clock system, which consists of the central clock and peripheral clocks. The central clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and is regulated by signals received from the retinal pathway. The SCN regulates the circadian rhythm of the entire body through its indirect influence on the peripheral clocks. In turn, the peripheral clocks can maintain their own rhythm, independent of the SCN, by creating special feedback loops between transcriptional and translational factors. The main protein families involved in these processes are CLOCK, BMAL, PER and CRY. Disorders in the expression of these factors have a significant impact on the functioning of the liver. In such cases lipid metabolism, cholesterol metabolism, bile acid metabolism, alcohol metabolism, and xenobiotic detoxification can be significantly affected. Clock dysfunctions contribute to the pathogenesis of various disorders, including fatty liver disease, liver cirrhosis and different types of cancer. Therefore understanding circadian rhythm can have significant implications for the therapy of many liver diseases, as well as the development of new preventive and treatment strategies.

Integrated rumen microbiome and serum metabolome analysis responses to feed type that contribution to meat quality in lambs

BackgroundLifestyle factors, such as diet, are known to be a driver on the meat quality, rumen microbiome and serum metabolites. Rumen microbiome metabolites may be important for host health, the correlation between rumen microbiome and production of rumen metabolites are reported, while the impact of rumen microbiome on the serum metabolome and fatty acid of meat are still unclear. This study was designed to explore the rumen microbiome, serum metabolome and fatty acid of meat in response to the grass diet and concentrate diet to lambs, and the relationship of which also investigated.MethodsIn the present study, 12 lambs were randomly divided into two groups: a grass diet (G) and a concentrate diet (C). Here, multiple physicochemical analyses combined with 16S rRNA gene sequences and metabolome analysis was performed to reveal the changes that in response to feed types.ResultsThe concentrate diet could improve the growth performance of lambs compared to that fed with the grass diet. The microbiome composition was highly individual, compared to the concentrate group, the abundance of Rikenellaceae_RC9_gut_group, F082_unclassified, Muribaculaceae_unclassified, Ruminococcaceae_NK4A214_group, Bacteroidetes_unclassified, and Bacteroidales_UCG-001_unclassified were significantly (P < 0.05) lower in the grass group, while, the abundance of Succinivibrio, Succinivibrionaceae_UCG-002, Fibrobacter and Christensenellaceae_R-7_group were significantly (P < 0.05) higher in the grass group. Serum metabolomics analysis combined with enrichment analysis revealed that serum metabolites were influenced by feed type as well as the metabolic pathway, and significantly affected serum metabolites involved in amino acids, peptides, and analogues, bile acids, alcohols and derivatives, linoleic acids derivatives, fatty acids and conjugates. Most of the amino acids, peptides, and analogues metabolites were positively associated with the fatty acid contents. Among the bile acids, alcohols and derivatives metabolites, glycocholic was positively associated with all fatty acid contents, except C18:0, while 25-Hydroxycholesterol and lithocholic acid metabolites were negatively associated with most of the fatty acid contents.ConclusionCorrelation analysis of the association of microbiome with metabolite features, metabolite features with fatty acid provides us with comprehensive understanding of the composition and function of microbial communities. Associations between utilization or production were widely identified among affected microbiome, metabolites and fatty acid, and these findings will contribute to the direction of future research in lamb.

Pathophysiology and Treatment of Lipid Abnormalities in Cerebrotendinous Xanthomatosis: An Integrative Review.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder caused by pathogenic variants in CYP27A1, leading to a deficiency in sterol 27-hydroxylase. This defect results in the accumulation of cholestanol and bile alcohols in various tissues, including the brain, tendons and peripheral nerves. We conducted this review to evaluate lipid profile abnormalities in patients with CTX. A search was conducted in PubMed, Embase and the Virtual Health Library in January 2023 to evaluate studies reporting the lipid profiles of CTX patients, including the levels of cholestanol, cholesterol and other lipids. Elevated levels of cholestanol were consistently observed. Most patients presented normal or low serum cholesterol levels. A decrease in chenodeoxycholic acid (CDCA) leads to increased synthesis of cholesterol metabolites, such as bile alcohols 23S-pentol and 25-tetrol 3-glucuronide, which may serve as surrogate follow-up markers in patients with CTX. Lipid abnormalities in CTX have clinical implications. Cholestanol deposition in tissues contributes to clinical manifestations, including neurological symptoms and tendon xanthomas. Dyslipidemia and abnormal cholesterol metabolism may also contribute to the increased risk of atherosclerosis and cardiovascular complications observed in some CTX patients.

Acute Pancreatitis: an Unusual Complication of COVID 19 - about a Case Report

Covid 19 is an emerging infectious disease, responsible for severe acute respiratory syndrome. It has an essentially respiratory tropism, but this does not prevent it from causing a series of complications affecting several organs. Acute pancreatitis is an acute inflammation of the pancreas caused mainly by bile duct obstruction and alcohol abuse. In this work, we report a rare and unusual complication of this virus affecting the pancreas in a 38-year-old woman who developed acute pancreatitis associated with SARS-CoV-2 infection. We would also discuss the causal link between SARS-CoV-2 and acute pancreatitis, as well as their different diagnostic, epidemiological and therapeutic aspects.

Aloysia citrodora Extracts Cultivated in Greece as Antioxidants and Potent Regulators of Food Microbiota

Plant extracts contain valuable sources of biologically active molecules and, lately, have attracted scientific and industrial interest as inhibitors of food-borne pathogens and growth stimulators of beneficial microbes. In this vein, the aim of this study was to explore and exploit the effect of Aloysia citrodora extracts as potent functional regulators of food microbiota by stimulating the growth of probiotic strains and by suppressing the evolution of common food-spoilage and pathogenic bacteria. Aqueous and ethanolic extracts of A. citrodora, rich in polyphenols, were prepared and their phytochemical composition was unveiled by LC-triple quadruple and LC-QToF mass spectrometry. The growth stimulatory activity of a wild-type Lacticaseibacillus rhamnosus strain, along with L. rhamnosus GG, used as a control, was assessed by monitoring cell growth in the presence of sodium chloride, bile salts, thermal stress, and alcohol. We found that the aqueous extract stimulated the growth of probiotic strains at 0.5 mg/mL. At the same concentration, stimulatory activity was observed for the wild-type L. rhamnosus in the presence of bile salts and alcohol and for L. rhamnosus GG in the presence of NaCl and under thermal stress. The ethanolic extract of A. citrodora exhibited prebiotic activity at 0.25 mg/mL, but did not promote the growth of the strains under the stress conditions tested. In addition, minimum inhibitory (MIC) and minimum bactericidal concentrations (MBC) against food-spoilage and pathogenic microbes were determined. The strongest growth inhibitory activity of foodborne pathogens was noted by the A. citrodora ethanolic extract, while the aqueous A. citrodora extract had no effect against Escherichia coli. Importantly, the spoilage and pathogenic microbes tested were more sensitive to the extracts than the probiotic strains, indicating a significant contribution to the functional regulation of food microbiota, provided that they are used at the optimum concentration.

Newborn screening for Cerebrotendinous Xanthomatosis: A retrospective biomarker study using both flow-injection and UPLC-MS/MS analysis in 20,000 newborns

Background and aimsCerebrotendinous Xanthomatosis (CTX) is a treatable disorder of bile acid synthesis caused by deficiency of 27-sterol hydroxylase -encoded by CYP27A1- leading to gastrointestinal and progressive neuropsychiatric symptoms. Biochemically, CTX is characterized by accumulation of the bile alcohol cholestanetetrol glucuronide (GlcA-tetrol) and the deficiency of tauro-chenodeoxycholic acid (t-CDCA) and tauro-trihydroxycholestanoic acid (t-THCA). Materials and MethodsTo ascertain the feasibility of CTX newborn screening (NBS) we performed a study with deidentified Dutch dried blood spots using reagents and equipment that is frequently used in NBS laboratories. 20,076 deidentified newborn blood spots were subjected to flow-injection (FIA)-MS/MS and UPLC-MS/MS analysis to determine the concentration of GlcA-tetrol and calculate the GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios. ResultsUsing UPLC-MS/MS analysis both GlcA-tetrol concentration and/or metabolite ratios GlcA-tetrol/t-CDCA proved to be informative biomarkers; newborn DBS results did not overlap with those of the CTX patients. For FIA-MS/MS, GlcA-tetrol also was an excellent marker but when using the combination of the GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios also did not yield any screen positives. ConclusionNewborn screening for CTX using only metabolite ratios following the measurement of three CTX biomarkers is possible using either FIA-MS/MS or UPLC-MS/MS, which paves the way for introduction of CTX NBS.

Current trends and future perspectives in the treatment of PBC and PSC: A review

• General pathway of bile acid formation and primary associated cholestatic liver diseases (CLD) are described. • Primary biliary cholangitis and primary sclerosis cholangitis along with their pathogenesis, symptoms and diagnosis have been discussed. • Current advances in both allopathic and natural treatments of PBC and PSC included. • Genetic approaches for PBC and PSC discussed. Cholestatic liver diseases (CLD) are one of the hepatic disorders that lead to scarring of hepatic tissues due to abnormalities like obstruction of bile flow, hepatitis and alcohol abuse. The primary biliary cholangitis (PBC) and primary sclerosis cholangitis (PSC) are slow progressive autoimmune diseases, which are the foremost types of CLD. The pathogenesis for the disease is unclear till date. Only limited therapies are available and liver transplant is the final resort for the same but the number of patients waiting for liver transplantation is quite higher than the number of active donors. Moreover, it is also associated with high risk also like rejection of donated liver and in a study, about 25% of mortality rate within five years of transplantation has been reported. There are some recent advancements in allopathic and natural treatment and some drugs under clinical trials are preferred only to prolong the timeline for liver transplantation but do not treat the disease completely. This review mentions about the pathogenicity, treatments including natural compounds and drugs in use as well as under clinical trials. The future RNA and DNA approaches that can be explored to treat CLD and result in an effective approach for the prevention of this disease have also been discussed here. We are confident that the current review study will assist future medicinal researchers in their quest of rational approaches for the treatment of primary biliary cholangitis and primary sclerosis cholangitis.

A Review on Cerebrotendinous Xanthomatosis (CTX): A Rare Autosomal Recessive Inherited Disease

Cerebrotendinous Xanthomatosis (CTX) is a rare autosomal recessive disease which is caused due to the mutation of CYP27A1 gene that encodes sterol 27-hydroxylase enzyme. Due to the pathogenic variation in this enzyme the bile acid synthesis pathway gets disturbed which results in the production of bile acid intermediates especially cholesterol &amp; bile alcohols and these gets accumulated in various parts of the body resulting in formation of xanthomas. There is no permanent cure for CTX but the early detection and treatment with cholic and chenodexycholic acids have proven to reduce the severity of the condition. CTX is a genetic disease which generally prevails from the early childhood and lasts throughout the life. Thus, proper genetic counseling is recommended to help families understand the genetics and natural history of CTX, and also to provide the psychosocial support.

Development of 3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-sulfate sodium salt (INT-767): Process optimization, synthesis and characterization of metabolites

Herein we report our synthetic efforts in supporting the development of the bile alcohol sulfate INT-767, a FXR/TGR5 dual agonist with remarkable therapeutic potential for liver disorders. We describe the process development to a final route for large scale preparation and analogues synthesis. Key sequences include Grignard addition, a one-pot two-step shortening-reduction of the carboxylic side chain, and the final sulfation reaction. The necessity for additional steps such as the protection/deprotection of hydroxyl groups at the steroidal body was also evaluated for step-economy and formation of side-products. Critical bottlenecks such as the side chain degradation have been tackled using flow technology before scaling-up individual steps. The final synthetic route may be successfully employed to produce the amount of INT-767 required to support late-stage clinical development of the compound. Furthermore, potential metabolites have been synthesized, characterized and evaluated for their ability to modulate FXR and TGR5 receptors providing key reference standards for future drug investigations, as well as offering further insights into the structure-activity relationships of this class of compounds.

Neotropical mustelids: fecal metabolome diversity and its potential for taxonomic discrimination.

Chemical profiles of non-invasive biological material, such as feces, have great potential to study elusive animals or those with low population densities. Here, we use a metabolomic approach to evaluate Neotropical mustelids as a biological model to describe the diversity of the metabolites present in fecal samples, as well as to evaluate the potential of chemical profiles for taxonomic discrimination. We collected fecal samples from captive individuals of 5 species of mustelids occurring in Brazil and analyzed them by liquid chromatography coupled to high-resolution mass spectrometry. Over 200 compounds have been annotated; "bile acids, alcohols and derivatives" was the most expressive class in the metabolome of all the species. We successfully discriminated 3 taxonomic groups: 1-tayra (Eira barbara); 2-otters (Lontra longicaudis and Pteronura brasiliensis; 1); and 3-grisons (Galictis vittata and Galictis cuja). Several compounds seemed to be associated with food intake and the digestive process, while others were found for the first time in Neotropical mustelids. We concluded that mustelids show high metabolome diversity and that species-specific identification through metabolomic profiles is possible, thus contributing to the development and implementation of additional non-invasive approaches in the study of mustelids.

CRAC channel inhibitors in pancreatic pathologies.

CRAC channel inhibitors in pancreatic pathologies.

The comparison of total bile acid concentration and alcohol dehydrogenase activity as markers of intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is the liver disorder in the second or early third trimester of pregnancy. It is characterized by pruritus with increased serum bile acids concentration and other liver function tests. ICP is connected with increased risk of fetal mortality but is unfortunately detected quite late. Therefore, it is important to recognize the disease in its early stages. We aimed to investigate the serum alcohol dehydrogenase (ADH) activity and compare it with the concentration of total bile acid (TBA) in women with ICP. Serum samples were taken for routine investigation from 80 pregnancies with ICP in the second or third trimester of pregnancy and from 80 healthy pregnant women at the same time of pregnancy. For measurement of class I activity, we used the spectrofluorometric methods. The total ADH activity was measured by the photometric method. The analysis of results shows a statistically significant increase in the activity of ADH I and ADH total (about 60% and 41.3%, respectively). Activity of ADH I correlated well with aminotransferases (alanine ALT and aspartate AST) and total bile acids (TBA) concentration. The total ADH activity was also positively correlated with ALT, AST and total bile acids. We can state that the activity of class I alcohol dehydrogenase isoenzyme in the sera of patients with ICP is increased and seems to be a good indicator of liver cells destruction during this disease and is comparable with the value of other markers.

Cerebrotendinous xanthomatosis – three patients, three faces

Background and Aims: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by mutations in the CYP27A1 gene. This results in a reduced bile acid synthesis and tissue accumulation of cholestanol, causing classical symptoms like tendon xanthomas, chronic diarrhoea, juvenile bilateral cataract and progressive neurological dysfunction. Diagnosis is based on the classical symptoms, elevated levels of cholestanol and bile alcohols and on molecular genetic analysis. Chenodeoxycholic acid (CDCA) is the current standard of care.

Cerebrotendinous Xanthomatosis: Molecular Pathogenesis, Clinical Spectrum, Diagnosis, and Disease-Modifying Treatments.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder caused by mutations in the CYP27A1 gene, which encodes the mitochondrial enzyme sterol 27-hydroxylase. Decreased sterol 27-hydroxylase activity results in impaired bile acid synthesis, leading to reduced production of bile acids, especially chenodeoxycholic acid (CDCA), as well as elevated serum cholestanol and urine bile alcohols. The accumulation of cholestanol and cholesterol mainly in the brain, lenses, and tendons results in the characteristic clinical manifestations of CTX. Clinical presentation is characterized by systemic symptoms including neonatal jaundice or cholestasis, refractory diarrhea, juvenile cataracts, tendon xanthomas, osteoporosis, coronary heart disease, and a broad range of neuropsychiatric manifestations. The combinations of symptoms vary from patient to patient and the presenting symptoms, especially in the early disease phase, may be nonspecific, which leads to a substantial diagnostic delay or underdiagnosis. Replacement of CDCA has been approved as a first-line treatment for CTX, and can lead to biochemical and clinical improvements. However, the effect of CDCA treatment is limited once significant neuropsychiatric manifestations are established. The age at diagnosis and initiation of CDCA treatment correlate with the prognosis of patients with CTX. Therefore, early diagnosis and subsequent treatment initiation are essential.

Is cannabidiol hepatotoxic or hepatoprotective: A review

Questions have been raised regarding the potential hepatotoxicity of cannabidiol (CBD). Conversely, several animal studies have demonstrated the hepatoprotective effects of CBD against bile duct ligation, cocaine, thioacetamide, alcohol, and several other chemicals. This review summarizes the current literature concerning the hepatic effects of CBD in humans and animals. Based on the available data, it may be concluded that there is a low probability of serious hepatotoxicity at the high therapeutic doses that are used and a much lower risk of adverse hepatic effects and a potential for hepatoprotection effects at the lower doses commonly used in dietary supplements and food products. However, a detailed safety study in rats using highly purified CBD rather than enriched Cannabis extracts is needed, enabling the determination of hepatic as well as other tissue effects and potential margin of safety.

Keeping mitochondria happy - benefits of a pore choice in acute pancreatitis.

Mitochondrial dysfunction is a key feature of multiple diseases and thus protection of this organelle is an important therapeutic objective. The pancreatic acinar cell, which synthesises and stores digestive enzyme precursors, is the most abundant cell type in pancreatic tissue and considered to be the primary site of acute pancreatitis (AP) initiation. Early investigations at the University of Liverpool and by others discovered that precipitants of AP, including bile acids and alcohol non‐oxidative metabolites, disrupt calcium signalling in acinar cells leading to toxicity. Sustained cytosolic calcium elevations raise mitochondrial matrix calcium, triggering the opening of the mitochondrial permeability transition pore (MPTP), which results in a loss of membrane potential and ATP production vital for cellular processes (Criddle et al . 2006; Mukherjee et al . 2016) (Fig. 1). The prime consequence of pancreatic mitochondrial dysfunction in AP is necrotic cell death, the extent of which is a major determinant of clinical outcome. Subsequent studies have shown that calcium‐dependent mitochondrial dysfunction in response to AP precipitants also occurs in ductal cells, widening the cast of players implicated in the development of AP (Hegyi & Petersen, 2013). There is currently no specific therapy for the disease and protection of mitochondria by MPTP inhibition is considered a promising therapeutic approach.

Six new polyhydroxylated steroids conjugated with taurine, microdiscusols A-F, from the Arctic starfish Asterias microdiscus

Six new polyhydroxylated steroids conjugated with taurine, microdiscusols A-F, were isolated from the alcoholic extract of the Arctic starfish Asterias microdiscus. Three of them have been found to have additional sulfate groups in tetracyclic cores. The structures of new compounds were established by 1D and 2D NMR and HRESIMS techniques. The found steroid taurine conjugates resemble, by their structures, salts of bile acids and alcohols of lower vertebrates.