RESUMO
BACKGROUND: Dysregulation of bile acids (BAs) has been reported in alcohol-associated liver disease. However, the causal relationship between BA dyshomeostasis and alcohol-associated liver disease remains unclear. The study aimed to determine whether correcting BA perturbation protects against alcohol-associated liver disease and elucidate the underlying mechanism. METHODS: BA sequestrant cholestyramine (CTM) was administered to C57BL/6J mice fed alcohol for 8 weeks to assess its protective effect and explore potential BA targets. The causal relationship between identified BA metabolite and cellular damage was examined in hepatocytes, with further manipulation of the detoxifying enzyme cytochrome p450 3A11. The toxicity of the BA metabolite was further validated in mice in an acute study. RESULTS: We found that CTM effectively reversed hepatic BA accumulation, leading to a reversal of alcohol-induced hepatic inflammation, cell death, endoplasmic reticulum stress, and autophagy dysfunction. Specifically, nordeoxycholic acid (NorDCA), a hydrophobic BA metabolite, was identified as predominantly upregulated by alcohol and reduced by CTM. Hepatic cytochrome p450 3A11 expression was in parallel with NorDCA levels, being upregulated by alcohol and reduced by CTM. Moreover, CTM reversed alcohol-induced gut barrier disruption and endotoxin translocation. Mechanistically, NorDCA was implicated in causing endoplasmic reticulum stress, suppressing autophagy flux, and inducing cell injury, and such deleterious effects could be mitigated by cytochrome p450 3A11 overexpression. Acute NorDCA administration in mice significantly induced hepatic inflammation and injury along with disrupting gut barrier integrity, leading to subsequent endotoxemia. CONCLUSIONS: Our study demonstrated that CTM treatment effectively reversed alcohol-induced liver injury in mice. The beneficial effects of BA sequestrant involve lowering toxic NorDCA levels. NorDCA not only worsens hepatic endoplasmic reticulum stress and inhibits autophagy but also mediates gut barrier disruption and systemic translocation of pathogen-associated molecular patterns in mice.
Assuntos
Ácidos e Sais Biliares , Resina de Colestiramina , Hepatopatias Alcoólicas , Camundongos Endogâmicos C57BL , Animais , Camundongos , Resina de Colestiramina/farmacologia , Resina de Colestiramina/uso terapêutico , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/prevenção & controle , Masculino , Ácidos e Sais Biliares/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Autofagia/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
The aim of this study was to investigate the effects of aflatoxin B1 (AFB1) on cholestasis in duck liver and its nutritional regulation. Three hundred sixty 1-day-old ducks were randomly divided into six groups and fed for 4 weeks. The control group was fed a basic diet, while the experimental group diet contained 90 µg/kg of AFB1. Cholestyramine, atorvastatin calcium, taurine, and emodin were added to the diets of four experimental groups. The results show that in the AFB1 group, the growth properties, total bile acid (TBA) serum levels and total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and glutathione (GSH) liver levels decreased, while the malondialdehyde (MDA) and TBA liver levels increased (p < 0.05). Moreover, AFB1 caused cholestasis. Cholestyramine, atorvastatin calcium, taurine, and emodin could reduce the TBA serum and liver levels (p < 0.05), alleviating the symptoms of cholestasis. The qPCR results show that AFB1 upregulated cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and cytochrome P450 family 8 subfamily B member 1 (CYP8B1) gene expression and downregulated ATP binding cassette subfamily B member 11 (BSEP) gene expression in the liver, and taurine and emodin downregulated CYP7A1 and CYP8B1 gene expression (p < 0.05). In summary, AFB1 negatively affects health and alters the expression of genes related to liver bile acid metabolism, leading to cholestasis. Cholestyramine, atorvastatin calcium, taurine, and emodin can alleviate AFB1-induced cholestasis.
Assuntos
Aflatoxina B1 , Colestase , Patos , Fígado , Animais , Aflatoxina B1/toxicidade , Colestase/induzido quimicamente , Colestase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/sangue , Doenças das Aves Domésticas/induzido quimicamente , Resina de Colestiramina/farmacologia , Ração AnimalRESUMO
Cognitive impairment in the elderly is associated with alterations in bile acid (BA) metabolism. In this study, we observe elevated levels of serum conjugated primary bile acids (CPBAs) and ammonia in elderly individuals, mild cognitive impairment, Alzheimer's disease, and aging rodents, with a more pronounced change in females. These changes are correlated with increased expression of the ileal apical sodium-bile acid transporter (ASBT), hippocampal synapse loss, and elevated brain CPBA and ammonia levels in rodents. In vitro experiments confirm that a CPBA, taurocholic acid, and ammonia induced synaptic loss. Manipulating intestinal BA transport using ASBT activators or inhibitors demonstrates the impact on brain CPBA and ammonia levels as well as cognitive decline in rodents. Additionally, administration of an intestinal BA sequestrant, cholestyramine, alleviates cognitive impairment, normalizing CPBAs and ammonia in aging mice. These findings highlight the potential of targeting intestinal BA absorption as a therapeutic strategy for age-related cognitive impairment.
Assuntos
Envelhecimento , Amônia , Ácidos e Sais Biliares , Disfunção Cognitiva , Absorção Intestinal , Animais , Ácidos e Sais Biliares/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Absorção Intestinal/efeitos dos fármacos , Masculino , Feminino , Humanos , Camundongos , Envelhecimento/metabolismo , Amônia/metabolismo , Idoso , Camundongos Endogâmicos C57BL , Resina de Colestiramina/farmacologia , Simportadores/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Ratos , Idoso de 80 Anos ou maisRESUMO
Irritable bowel syndrome (IBS) is a widespread gastrointestinal disorder known for its multifaceted pathogenesis and varied extraintestinal manifestations, yet its implications for bone and muscle health are underexplored. Recent studies suggest a link between IBS and musculoskeletal disorders, but a comprehensive understanding remains elusive, especially concerning the role of bile acids (BAs) in this context. This study aimed to elucidate the potential contribution of IBS to bone and muscle deterioration via alterations in gut microbiota and BA profiles, hypothesizing that cholestyramine could counteract these adverse effects. We employed a mouse model to characterize IBS and analysed its impact on bone and muscle health. Our results revealed that IBS promotes bone and muscle loss, accompanied by microbial dysbiosis and elevated BAs. Administering cholestyramine significantly mitigated these effects, highlighting its therapeutic potential. This research not only confirms the critical role of BAs and gut microbiota in IBS-associated bone and muscle loss but also demonstrates the efficacy of cholestyramine in ameliorating these conditions, thereby contributing significantly to the field's understanding and offering a promising avenue for treatment.
Assuntos
Ácidos e Sais Biliares , Resina de Colestiramina , Microbioma Gastrointestinal , Síndrome do Intestino Irritável , Camundongos Endogâmicos C57BL , Animais , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/metabolismo , Resina de Colestiramina/farmacologia , Ácidos e Sais Biliares/metabolismo , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Modelos Animais de Doenças , Masculino , Disbiose/tratamento farmacológico , Disbiose/metabolismoRESUMO
BACKGROUND: Cholesterol levels and bile acid metabolism are important drivers of metabolic dysfunction-associated steatohepatitis (MASH) progression. Using a mouse model, we investigated the mechanism by which cholesterol exacerbates MASH and the effect of colestyramine (a bile acid adsorption resin) and elobixibat (an apical sodium-dependent bile acid transporter inhibitor) concomitant administration on bile acid adsorption and MASH status. METHODS: Mice were fed a high-fat high-fructose diet with varying concentrations of cholesterol to determine changes in fatty liver according to liver status, water intake, defecation status, insulin resistance, bile acid levels, intestinal permeability, atherosclerosis (in apolipoprotein E knockout mice), and carcinogenesis (in diethylnitrosamine mice). Using small interfering ribonucleic acid (siRNA), we evaluated the effect of sterol regulatory element binding protein 1c (SREBP1c) knockdown on triglyceride synthesis and fatty liver status following the administration of elobixibat (group E), colestyramine (group C), or both (group EC). RESULTS: We found greater reductions in serum alanine aminotransferase levels, serum lipid parameters, serum primary bile acid concentrations, hepatic lipid levels, and fibrosis area in EC group than in the monotherapy groups. Increased intestinal permeability and watery diarrhea caused by elobixibat were completely ameliorated in group EC. Group EC showed reduced plaque formation rates in the entire aorta and aortic valve of the atherosclerosis model, and reduced tumor counts and tumor burden in the carcinogenesis model. CONCLUSIONS: Excessive free cholesterol in the liver can promote fatty liver disease. Herein, combination therapy with EC effectively reduced free cholesterol levels in MASH model mice. Our study provides strong evidence for combination therapy as an effective treatment for MASH.
Assuntos
Aterosclerose , Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Resina de Colestiramina/farmacologia , Resina de Colestiramina/uso terapêutico , Ácidos e Sais Biliares , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Modelos Animais de Doenças , CarcinogêneseRESUMO
Bile acid metabolism, involved with the digestion and absorption of nutrients in the gut, is linked to the gut microbiota community, greatly impacting the host's metabolism. We examined the hypothesis that the modulation of bile acid metabolism by dietary fat contents, gallbladder removal (GBX; cholecystectomy), and bile acid sequestrant (BAS; cholestyramine) treatment could alter energy, glucose, and lipid metabolism through the changes in the gut microbiota. Mice were randomly assigned to the following six groups: (1) Sham GBX surgery (Sham) + low fat/high carbohydrate diet (LFD), (2) Sham + high fat diet (HFD), (3) Sham + HFD + BAS, (4) GBX + LFD, (5) GBX + HFD, and (6) GBX + HFD + BAS. BAS groups received 2% cholestyramine. After an 8-week intervention, energy, glucose, and lipid metabolism, and the gut microbiota community were measured. HFD groups exhibited higher body weight gain than LFD, and GBX increased the weight gain comped to Sham groups regardless of BAS in HFD (p < 0.05). Homeostatic model assessment for insulin resistance (HOMA-IR) was higher in HFD than LFD, and GBX increased it regardless of BAS. Serum lipid profiles were worsened in GBX + HFD compared to Sham + LFD, whereas BAS alleviated them, except for serum HDL cholesterol. Hepatic tumor-necrosis-factor-α (TNF-α) mRNA expression and lipid peroxide contents increased with GBX and BAS treatment compared to Sham and no BAS treatment (p < 0.05). Hepatic mRNA expression of sterol regulatory element-binding transcription factor 1c (SREBP1c) and peroxisome proliferator-activated receptor gamma (PPAR-γ) exhibited the same trend as that of tumor necrosis factor-α (TNF-α). The α-diversity of gut bacteria decreased in GBX + HFD and increased in GBX + HFD + BAS. Akkermentia, Dehalobacterium, SMB53, and Megamonas were high in the Sham + LFD, and Veillonella and Streptococcus were rich in the Sham + HFD, while Oscillospira and Olsenella were high in Sham + HFD + BAS (p < 0.05). GBX + LFD increased Lactobacillus and Sutterella while GBX + HFD + BAS elevated Clostridium, Alistipes, Blautia, Eubacterium, and Coprobacillus (p < 0.05). In conclusion, the modulation of bile acid metabolism influences energy, glucose, and lipid metabolisms, and it might be linked to changes in the gut microbiota by bile acid metabolism modulation.
Assuntos
Gorduras na Dieta , Microbioma Gastrointestinal , Animais , Ácidos e Sais Biliares/metabolismo , Colecistectomia , Resina de Colestiramina/metabolismo , Resina de Colestiramina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/farmacologia , Glucose/metabolismo , Hipolipemiantes/farmacologia , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Aumento de PesoRESUMO
Medical treatment is the primary therapeutic option for thyrotoxicosis/hyperthyroidism. Two groups of causes of thyrotoxicosis (i.e. thyrotoxicosis with hyperthyroidism and thyrotoxicosis without hyperthyroidism) need to be considered for therapeutic reasons. Herein we provide an updated review on the role of conventional medical therapies (i.e. ß-blockers, antithyroid drugs [ATDs], corticosteroids, inorganic iodide, perchlorate, cholecystographic agents, lithium, cholestyramine) in the main causes of thyrotoxicosis, starting from the rationale subtending their clinical application.
Assuntos
Antitireóideos/química , Tireotoxicose/tratamento farmacológico , Corticosteroides/farmacologia , Antitireóideos/farmacologia , Resina de Colestiramina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Iodetos/farmacologia , Lítio/farmacologia , Percloratos/farmacologia , Transdução de Sinais , Tireotoxicose/fisiopatologiaRESUMO
Egg yolk, a major semen extender constituent, lacks a defined composition, therefore, there are biosecurity concerns with use of egg yolk. Cryopreservation of bull semen without inclusion of animal protein in the semen extender, therefore, is an important consideration. Cholesterol may be delivered and incorporated into the sperm plasma membrane by cyclodextrins to protect sperm during cryopreservation. The aim of this study was to determine suitability of a cholesterol-cyclodextrin semen extender, without inclusion of egg yolk, for cryopreservation of bull semen. Bull semen was collected and cryopreserved in either egg yolk or with inclusions of three different concentrations of cholesterol-cyclodextrin complex (0.5, 1 or 2â¯mg/mL semen) in Tris-glycerol (TG) extender. Sperm motion characteristics examined using the computer-assisted sperm analysis, and plasma membrane and acrosome integrity examined using flow cytometry, were similar for all extenders. The inclusion of the greatest concentration of cholesterol-cyclodextrin complex (2â¯mg/mL semen) followed by dilution in TG extender resulted in lesser pregnancy rates (Pâ¯<⯠0.05). There was a pregnancy rate of as great as 56 % when sperm cryopreserved in 0.5 mg/mL cholesterol-cyclodextrin Tris-glycerol extender were used for artificial insemination following imposing of a hormonal treatment regimen for synchrony of timing of ovarian functions among cows for conducting fixed-time artificial insemination (FTAI). Results indicate cholesterol-cyclodextrin Tris-glycerol extender, with a chemically defined composition and without inclusion of egg yolk, may be used to cryopreserve bull sperm with there being acceptable pregnancy rates when this semen is used for FTAI.
Assuntos
Bovinos , Resina de Colestiramina/farmacologia , Ciclodextrinas/farmacologia , Preservação do Sêmen/veterinária , Animais , Resina de Colestiramina/química , Criopreservação , Ciclodextrinas/química , Gema de Ovo , Sincronização do Estro/efeitos dos fármacos , Feminino , Congelamento , Inseminação Artificial , Letrozol/farmacologia , Masculino , Gravidez , Progesterona/farmacologia , Espermatozoides/efeitos dos fármacosRESUMO
A key challenge in antibiotic stewardship is figuring out how to use antibiotics therapeutically without promoting the evolution of antibiotic resistance. Here, we demonstrate proof of concept for an adjunctive therapy that allows intravenous antibiotic treatment without driving the evolution and onward transmission of resistance. We repurposed the FDA-approved bile acid sequestrant cholestyramine, which we show binds the antibiotic daptomycin, as an 'anti-antibiotic' to disable systemically-administered daptomycin reaching the gut. We hypothesized that adjunctive cholestyramine could enable therapeutic daptomycin treatment in the bloodstream, while preventing transmissible resistance emergence in opportunistic pathogens colonizing the gastrointestinal tract. We tested this idea in a mouse model of Enterococcus faecium gastrointestinal tract colonization. In mice treated with daptomycin, adjunctive cholestyramine therapy reduced the fecal shedding of daptomycin-resistant E. faecium by up to 80-fold. These results provide proof of concept for an approach that could reduce the spread of antibiotic resistance for important hospital pathogens.
Antibiotics are essential for treating infections. But their use can inadvertently lead to the emergence of antibiotic-resistant bacteria that do not respond to antibiotic drugs, making infections with these bacteria difficult or impossible to treat. Finding ways to prevent antibiotic resistance is critical to preserving the effectiveness of antibiotics. Many bacteria that cause infections in hospitals live in the intestines, where they are harmless. But these bacteria can cause life-threatening infections when they get into the bloodstream. When patients with bloodstream infections receive antibiotics, the bacteria in their intestines are also exposed to the drugs. This can kill off all antibiotic-susceptible bacteria, leaving behind only bacteria that have mutations that allow them to survive the drugs. These drug-resistant bacteria can then spread to other patients causing hard-to-treat infections. To stop this cycle of antibiotic treatment and antibiotic resistance, Morley et al. tested whether giving a drug called cholestyramine with intravenous antibiotics could protect the gut bacteria. In the experiments, mice were treated systemically with an antibiotic called daptomycin, which caused the growth of daptomycin-resistant strains of bacteria in the mice's intestines. In the laboratory, Morley et al. discovered that cholestyramine can inactivate daptomycin. Giving the mice cholestyramine and daptomycin together prevented the growth of antibiotic-resistant bacteria in the mice's intestines. Moreover, cholestyramine is taken orally and is not absorbed into the blood. It therefore only inactivates the antibiotic in the gut, but not in the blood. The experiments provide preliminary evidence that giving cholestyramine with antibiotics might help prevent the spread of drug resistance. Cholestyramine is already used to lower cholesterol levels in people. More studies are needed to determine if cholestyramine can protect gut bacteria and prevent antibiotic resistance in people.
Assuntos
Antibacterianos/uso terapêutico , Resina de Colestiramina/uso terapêutico , Daptomicina/antagonistas & inibidores , Daptomicina/uso terapêutico , Farmacorresistência Bacteriana , Enterococcus faecium/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Quimioterapia Adjuvante , Resina de Colestiramina/farmacologia , Daptomicina/farmacologia , Interações Medicamentosas , Feminino , Gastroenteropatias/microbiologia , Gastroenteropatias/prevenção & controle , Infecções por Bactérias Gram-Positivas/microbiologia , Infecções por Bactérias Gram-Positivas/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Background: Radiation is a mode of treatment for many pelvic malignancies, most of which originate in the gynecologic, gastrointestinal, and genitourinary systems. However, the healthy gut is unavoidably included in the irradiation volume, resulting in undesirable results that manifest as radiation-induced diarrhea (RID), which is the most common side effect of radiation therapy and significantly affects the patients' quality of life. This study aimed to investigate the potential mechanism of diarrhea after pelvic radiotherapy in rats based on the effect of radiation on bile acid homeostasis and sodium-dependent bile acid transporter (Asbt).Methods: In this experimental study, male Sprague-Dawley rats were divided into the following groups - pelvic irradiation, cholestyramine-concurrent radiation, and control groups. The rats in the pelvic irradiation group were irradiated in the pelvic region with 2 Gy per day for five consecutive days. The total bile acid (TBA) levels in the ileum, colon, and feces were measured using automatic biochemical analyzer, and the levels of individual bile acids were evaluated by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). The mRNA and protein expression of Asbt in ileum were assessed by qRT-PCR and Western blot assay. The rats in the cholestyramine-concurrent radiation group were administered with cholestyramine, a bile acid-chelating resin, and concurrent radiation for 5 days. The body weight of rats was monitored daily, and the degree of diarrhea was scored.Results: Diarrhea was observed at 2 and 3 days post-pelvic radiation. The TBA levels were significantly decreased at 4 and 5 days post-radiation in the ileum (p < .01, p < .01) and increased at 4 and 5 days post-radiation in the colon (p < .05, p < .05). The fecal excretions of TBA were significantly increased at 3, 4, and 5 days post-radiation (p < .05). The levels of individual bile acids were significantly decreased in the ileum and increased in the colon and feces, post-radiation. The mRNA and protein expression of Asbt in the ileum gradually decreased with increasing days of pelvic radiation and significantly decreased at 3 and 5 days post-radiation, respectively. Furthermore, a significant decrease in body weight was observed post-pelvic radiation, and cholestyramine administration did not reverse the weight loss. However, the incidence of RID was decreased after administration of cholestyramine.Conclusions: Bile acid malabsorption is partially responsible for RID post-pelvic radiation in rats, and the potential mechanism is related to the downregulation of the ileal Asbt.
Assuntos
Ácidos e Sais Biliares/metabolismo , Diarreia/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/fisiologia , Pelve/efeitos da radiação , Lesões por Radiação/metabolismo , Esteatorreia/etiologia , Simportadores/fisiologia , Animais , Resina de Colestiramina/farmacologia , Diarreia/etiologia , Masculino , Lesões por Radiação/etiologia , Ratos , Ratos Sprague-DawleyRESUMO
Bile acid sequestrants are used as medicinal drugs to treat dyslipidemia and type 2 diabetes. We found that cholestyramine, a bile acid sequestrant, increases cecal short-chain fatty acid (SCFA) production and intestinal immunoglobulin A (IgA) in C57BL/6J mice. In a 12-week high-fat diet study, feeding cholestyramine (2% (w/w)) significantly promoted C2-C4 SCFAs in the cecum by approximately 1.6-fold and fecal IgA by 1.8-fold. In an 8-week normal-fat diet study, feeding cholestyramine (1 and 2%) increased the cecal propionic acid content by approx. 2.0-fold. Fecal IgA was also significantly increased at 4 weeks (1%: 1.7-fold; 2%: 2.1-fold) and 8 weeks (1%: 1.8-fold; 2%: 2.0-fold) in the normal-fat diet study. These results indicate that bile acid sequestrants may exert their physiological functions, such as intestinal IgA production, through SCFA-dependent signaling pathways.
Assuntos
Ceco/metabolismo , Resina de Colestiramina/farmacologia , Ácidos Graxos Voláteis/metabolismo , Imunoglobulina A/metabolismo , Animais , Ácidos e Sais Biliares/análise , Ácidos e Sais Biliares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The FGFR4/FGF19 signaling axis is overactivated in 20% of liver tumors and currently represents a promising targetable signaling mechanism in this cancer type. However, blocking FGFR4 or FGF19 has proven challenging due to its physiological role in suppressing bile acid synthesis which leads to increased toxic bile acid plasma levels upon FGFR4 inhibition. An FGFR4-targeting antibody, U3-1784, was generated in order to investigate its suitability as a cancer treatment without major side effects.U3-1784 is a high-affinity fully human antibody that was obtained by phage display technology and specifically binds to FGFR4. The antibody inhibits cell signaling by competing with various FGFs for their FGFR4 binding site thereby inhibiting receptor activation and downstream signaling via FRS2 and Erk. The inhibitory effect on tumor growth was investigated in 10 different liver cancer models in vivo The antibody specifically slowed tumor growth of models overexpressing FGF19 by up to 90% whereas tumor growth of models not expressing FGF19 was unaffected. In cynomolgus monkeys, intravenous injection of U3-1784 caused elevated serum bile acid and liver enzyme levels indicating potential liver damage. These effects could be completely prevented by the concomitant oral treatment with the bile acid sequestrant colestyramine, which binds and eliminates bile acids in the gut. These results offer a new biomarker-driven treatment modality in liver cancer without toxicity and they suggest a general strategy for avoiding adverse events with FGFR4 inhibitors.
Assuntos
Anticorpos Monoclonais/toxicidade , Anticorpos Monoclonais/uso terapêutico , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/imunologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resina de Colestiramina/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Íleo/efeitos dos fármacos , Íleo/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Transdução de Sinais/efeitos dos fármacos , Sorafenibe/farmacologiaRESUMO
BACKGROUND & AIMS: Bile diversion to the ileum (GB-IL) has strikingly similar metabolic and satiating effects to Roux-en-Y gastric bypass (RYGB) in rodent obesity models. The metabolic benefits of these procedures are thought to be mediated by increased bile acids, although parallel changes in body weight and other confounding variables limit this interpretation. METHODS: Global G protein-coupled bile acid receptor-1 null (Tgr5-/-) and intestinal-specific farnesoid X receptor null (FxrΔ/E) mice on high-fat diet as well as wild-type C57BL/6 and glucagon-like polypeptide 1 receptor deficient (Glp-1r-/-) mice on chow diet were characterized following GB-IL. RESULTS: GB-IL induced weight loss and improved oral glucose tolerance in Tgr5-/-, but not FxrΔ/E mice fed a high-fat diet, suggesting a role for intestinal Fxr. GB-IL in wild-type, chow-fed mice prompted weight-independent improvements in glycemia and glucose tolerance secondary to augmented insulin responsiveness. Improvements were concomitant with increased levels of lymphatic GLP-1 in the fasted state and increased levels of intestinal Akkermansia muciniphila. Improvements in fasting glycemia after GB-IL were mitigated with exendin-9, a GLP-1 receptor antagonist, or cholestyramine, a bile acid sequestrant. The glucoregulatory effects of GB-IL were lost in whole-body Glp-1r-/- mice. CONCLUSIONS: Bile diversion to the ileum improves glucose homeostasis via an intestinal Fxr-Glp-1 axis. Altered intestinal bile acid availability, independent of weight loss, and intestinal Akkermansia muciniphila appear to mediate the metabolic changes observed after bariatric surgery and might be manipulated for treatment of obesity and diabetes.
Assuntos
Ácidos e Sais Biliares/metabolismo , Glicemia/metabolismo , Vesícula Biliar/cirurgia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Íleo/cirurgia , Receptores Citoplasmáticos e Nucleares/metabolismo , Anastomose Cirúrgica , Animais , Anticolesterolemiantes/farmacologia , Cirurgia Bariátrica , Resina de Colestiramina/farmacologia , Dieta Hiperlipídica , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Teste de Tolerância a Glucose , Resistência à Insulina , Intestinos/microbiologia , Linfa/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Citoplasmáticos e Nucleares/genética , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais , Verrucomicrobia , Redução de PesoRESUMO
Absorption of dietary lipids in the small intestine is dependent on the emulsification by bile acids (BA) and the formation of chylomicrons. Cholestyramine is a common drug used in humans-and potentially dogs-to treat BA malabsorption associated with chronic diarrhea. It is known to bind BA to form insoluble complexes, preventing their reabsorption and possibly proper emulsification and absorption of dietary fats. The objective of this study was to evaluate the effects of cholestyramine on 1) macronutrient apparent total tract digestibility (ATTD), and 2) fecal characteristics and metabolites of healthy adult dogs. We hypothesized that cholestyramine would decrease ATTD of fat and organic matter (OM), increase fecal dry matter (DM) content, and increase fecal output. Twelve healthy beagles (3.2 ± 0.8 yr; 10.4 ± 0.9 kg) were used in a randomized crossover design. All procedures were approved by the University of Illinois Institutional Animal Care and Use Committee before the study. The study included a baseline period and two 14-d experimental periods separated by a 14-d washout. All dogs were fed the same experimental diet, formulated to meet all nutrient needs recommended by AAFCO, throughout the study. Dogs were randomized into 2 groups [diet only (control) or diet + 11.4 g/d cholestyramine (8 g/d active ingredient)] in Period 1 and received the other treatment in Period 2. During the washout, all dogs were fed the diet only. Dogs were fed once daily (0800 h) to maintain BW. Total fecal output was collected during the last 4 d of each period for ATTD analysis. On day 14 of each of period, fresh fecal and blood samples were collected for metabolite analysis. Dogs fed cholestyramine had lower (P < 0.001) ATTD of DM, OM, energy, crude protein, and fat and lower (P < 0.01) fecal scores (firmer stools) than controls. Dogs fed cholestyramine had greater (P < 0.01) as-is and dry fecal output than controls. Dogs fed cholestyramine had lower (P < 0.05) fecal ammonia and phenol concentrations, but greater (P < 0.05) fecal indole, acetate, butyrate, and total short-chain fatty acid concentrations than controls. Fecal DM% and pH were greater (P < 0.01) in dogs fed cholestyramine. Our results indicate that cholestyramine, when given with a meal, is safe and well tolerated but significantly decreases nutrient digestibility and alters fecal characteristics. Future studies are required to explore the effects of cholestyramine on dogs with gastrointestinal disease.
Assuntos
Resinas de Troca Aniônica/farmacologia , Resina de Colestiramina/farmacologia , Digestão/efeitos dos fármacos , Cães/fisiologia , Trato Gastrointestinal/fisiologia , Absorção Intestinal/efeitos dos fármacos , Amônia , Ração Animal , Fenômenos Fisiológicos da Nutrição Animal , Animais , Resinas de Troca Aniônica/uso terapêutico , Butiratos , Resina de Colestiramina/uso terapêutico , Estudos Cross-Over , Dieta , Gorduras na Dieta , Ácidos Graxos Voláteis , Fezes/química , Trato Gastrointestinal/efeitos dos fármacos , Nutrientes , Distribuição AleatóriaRESUMO
BACKGROUND AND OBJECTIVES: Bile acids (BAs) traversing the enterohepatic circulation (EHC) influence important metabolic pathways. By determining individual serum BAs in relation to markers of metabolic activity, we explored how diurnal variations in their EHC relate to hepatic metabolism in normal humans. METHODS: Serum BAs, fibroblast growth factor 19 (FGF19), lipoproteins, glucose/insulin and markers of cholesterol and BA syntheses were monitored for 32 h in 8 healthy males. Studies were conducted at basal state and during initiation of cholestyramine treatment, with and without atorvastatin pretreatment. Time series cross-correlation analysis, Bayesian structural model and Granger causality test were applied. RESULTS: Bile acids synthesis dominated daytime, and cholesterol production at night. Conjugated BAs peaked after food intake, with subsequent FGF19 elevations. BA synthesis was reduced following conjugated BA and FGF19 peaks. Cholestyramine reduced conjugated BAs and FGF19, and increased BA and cholesterol production; the latter effects attenuated by atorvastatin. The relative importance of FGF19 vs. conjugated BAs in this feedback inhibition could not be discriminated. Unconjugated BAs displayed one major peak late at night/early morning that was unrelated to FGF19 and BA synthesis, and abolished by cholestyramine. The normal suppression of serum triglycerides, glucose and insulin observed at night was attenuated by cholestyramine. CONCLUSIONS: Conjugated and unconjugated BAs have asynchronous rhythms of EHC in humans. Postprandial transintestinal flux of conjugated BAs increases circulating FGF19 levels and suppresses BA synthesis. Unconjugated BAs peak late at night, indicating a non-postprandial diurnal change in human gut microflora, the physiological implications of which warrants further study.
Assuntos
Ácidos e Sais Biliares/metabolismo , Ritmo Circadiano , Redes e Vias Metabólicas , Adulto , Anticolesterolemiantes/farmacologia , Atorvastatina/farmacologia , Ácidos e Sais Biliares/sangue , Ácidos e Sais Biliares/fisiologia , Biomarcadores/sangue , Glicemia/análise , Resina de Colestiramina/farmacologia , Ritmo Circadiano/fisiologia , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Insulina/sangue , Lipoproteínas/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/fisiologia , Pessoa de Meia-Idade , Adulto JovemRESUMO
Patients exposed to long acting anticoagulant rodenticides (LAARs) are typically administered large amounts of oral vitamin K1 (VK1) to counteract life-threatening anticoagulant effects. Although VK1 treatment effectively prevents mortality, additional methods are needed to reduce the long duration of VK1 treatment which can last for months at high expense. We developed a model of brodifacoum (BDF) poisoning, one of the most potent LAARs, in adult male New Zealand White (NZW) rabbits. The LD50 for oral BDF was determined to be 192 µg/kg, similar to that calculated for adult rats. However, in contrast to rats, NZW rabbits exhibited severe internal hemorrhage including in the brain, symptoms which mimic what occurs in cases of human poisoning. Similar to warfarin, BDF and other LAARs undergo enterohepatic recirculation which contributes to their long half-lives. We therefore tested effects of cholestyramine (CSA), an FDA-approved bile sequestrant, on BDF-induced mortality. When given daily (0.67 g/kg, oral) starting the day of BDF administration, CSA reduced mortality from 67% to 11%. At the same CSA prevented the increase in clotting time, and reduced the decrease in core body temperature due to BDF. Given its excellent safety record and that it is approved for children older than 6 years, these findings suggest CSA could be considered as an adjunct to VK1 for treatment of LAAR poisoning.
Assuntos
4-Hidroxicumarinas/intoxicação , Anticoagulantes/intoxicação , Resina de Colestiramina/farmacologia , Hemorragia/tratamento farmacológico , Rodenticidas/intoxicação , Animais , Ácidos e Sais Biliares/metabolismo , Resina de Colestiramina/administração & dosagem , Resina de Colestiramina/uso terapêutico , Hemorragia/induzido quimicamente , Dose Letal Mediana , Masculino , Coelhos , Análise de Sobrevida , Vitamina K 1/administração & dosagem , Vitamina K 1/uso terapêuticoRESUMO
The FGF19- fibroblast growth factor receptor (FGFR4)-ßKlotho (KLB) pathway plays an important role in the regulation of bile acid (BA) homeostasis. Aberrant activation of this pathway has been described in the development and progression of a subset of liver cancers including hepatocellular carcinoma, establishing FGFR4 as an attractive therapeutic target for such solid tumors. FGF401 is a highly selective FGFR4 kinase inhibitor being developed for hepatocellular carcinoma, currently in phase I/II clinical studies. In preclinical studies in mice and dogs, oral administration of FGF401 led to induction of Cyp7a1, elevation of its peripheral marker 7alpha-hydroxy-4-cholesten-3-one, increased BA pool size, decreased serum cholesterol and diarrhea in dogs. FGF401 was also associated with increases of serum aminotransferases, primarily alanine aminotransferase (ALT), in the absence of any observable adverse histopathological findings in the liver, or in any other organs. We hypothesized that the increase in ALT could be secondary to increased BAs and conducted an investigative study in dogs with FGF401 and coadministration of the BA sequestrant cholestyramine (CHO). CHO prevented and reversed FGF401-related increases in ALT in dogs in parallel to its ability to reduce BAs in the circulation. Correlation analysis showed that FGF401-mediated increases in ALT strongly correlated with increases in taurolithocholic acid and taurodeoxycholic acid, the major secondary BAs in dog plasma, indicating a mechanistic link between ALT elevation and changes in BA pool hydrophobicity. Thus, CHO may offer the potential to mitigate elevations in serum aminotransferases in human subjects that are caused by targeted FGFR4 inhibition and elevated intracellular BA levels.
Assuntos
Alanina Transaminase/sangue , Ácidos e Sais Biliares/sangue , Resina de Colestiramina/farmacologia , Fígado/efeitos dos fármacos , Inibidores de Proteínas Quinases/toxicidade , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Alanina Transaminase/biossíntese , Animais , Ácidos e Sais Biliares/biossíntese , Cães , Relação Dose-Resposta a Droga , Feminino , Fígado/enzimologia , Masculino , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/sangue , Piridinas/farmacologia , Testes de Toxicidade , ToxicocinéticaRESUMO
BACKGROUND: Teriflunomide is an oral disease modifying therapy approved for the treatment of relapsing forms of multiple sclerosis. Teriflunomide' s pharmacokinetics (PK) contribute to its slow elimination, on average taking 6-8 months, though it can take up to 2 years in some instances. This slow elimination can become problematic in certain clinical situations - such as during pregnancy, when teriflunomide has potential teratogenic effects. In such scenarios, an accelerated elimination procedure (AEP) is recommended. Currently, AEPs with oral cholestyramine or activated charcoal are available but are restricted by adverse effects, limited administration routes, and dosing frequencies. METHODS: A single-center, PK interaction study was performed in a total of 14 healthy volunteers, to investigate colestipol hydrochloride (HCl) as an alternative to cholestyramine for the elimination of teriflunomide. Participants received teriflunomide for 14 days, followed by an AEP with colestipol HCl for 15 days. RESULTS AND CONCLUSIONS: The administration of colestipol HCl for 15 days was sufficient to reduce plasma teriflunomide concentrations by greater than 96%. Although colestipol HCl did not completely eliminate teriflunomide with the same effectiveness as cholestyramine, it may offer an alternative method for accelerated elimination of teriflunomide with potentially improved tolerability and more favorable dosing and administration options.
Assuntos
Resinas de Troca Aniônica/farmacologia , Colestipol/farmacologia , Crotonatos/farmacocinética , Sequestrantes/farmacologia , Toluidinas/farmacocinética , Adolescente , Adulto , Resinas de Troca Aniônica/administração & dosagem , Resinas de Troca Aniônica/efeitos adversos , Resina de Colestiramina/administração & dosagem , Resina de Colestiramina/efeitos adversos , Resina de Colestiramina/farmacologia , Colestipol/administração & dosagem , Colestipol/efeitos adversos , Crotonatos/administração & dosagem , Feminino , Humanos , Hidroxibutiratos , Masculino , Nitrilas , Sequestrantes/administração & dosagem , Sequestrantes/efeitos adversos , Toluidinas/administração & dosagem , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Bile acid binding resin (BAR) absorbs intestinal bile acids, and improves obesity and metabolic disorders, but the precise mechanism remains to be clarified. Recent findings reveal that obesity is associated with skewed intestinal microbiota. Thus, we investigated the effect of BAR on intestinal microbiota and the role of microbiota in the prevention of obesity in high-fat diet-induced obesity in mice. PROCEDURES: Male Balb/c mice were fed a low-fat diet (LFD), high-fat diet (HFD), or HFD with BAR (HFD+BAR), and then metabolic parameters, caecal microbiota, and metabolites were investigated. The same interventions were conducted in germ-free and antibiotic-treated mice. MAIN FINDINGS: The frequency of Clostridium leptum subgroup was higher in both HFD-fed and HFD+BAR-fed mice than in LFD-fed mice. The frequency of Bacteroides-Prevotella group was lower in HFD-fed mice than in LFD-fed mice, but the frequency was higher in HFD+BAR-fed mice than in HFD-fed mice. Caecal propionate was lower in HFD-fed mice than in LFD-fed mice, and higher in HFD+BAR-fed mice than in HFD-fed mice. HFD+BAR-fed mice showed lower adiposity than HFD-fed mice, and the reduction was not observed in germ-free or antibiotic-treated mice. Colonized germ-free mice showed a reduction in adiposity by BAR administration. Energy expenditure was lower in HFD-fed mice and higher in HFD+BAR-fed mice, but the increments induced by administration of BAR were not observed in antibiotic-treated mice. CONCLUSIONS: Modulation of intestinal microbiota by BAR could be a novel therapeutic approach for obesity.
Assuntos
Ácidos e Sais Biliares/metabolismo , Resina de Colestiramina/farmacologia , Gorduras na Dieta/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/prevenção & controle , Animais , Carga Bacteriana , Bacteroides/efeitos dos fármacos , Ceco/microbiologia , Clostridium/efeitos dos fármacos , Dieta Hiperlipídica , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Prevotella/efeitos dos fármacos , Aumento de Peso/efeitos dos fármacosRESUMO
Emerging evidence points to a strong association between sex and gut microbiota, bile acids (BAs), and gastrointestinal cancers. Here, we investigated the mechanistic link between microbiota and hepatocellular carcinogenesis using a streptozotocin-high fat diet (STZ-HFD) induced nonalcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) murine model and compared results for both sexes. STZ-HFD feeding induced a much higher incidence of HCC in male mice with substantially increased intrahepatic retention of hydrophobic BAs and decreased hepatic expression of tumor-suppressive microRNAs. Metagenomic analysis showed differences in gut microbiota involved in BA metabolism between normal male and female mice, and such differences were amplified when mice of both sexes were exposed to STZ-HFD. Treating STZ-HFD male mice with 2% cholestyramine led to significant improvement of hepatic BA retention, tumor-suppressive microRNA expressions, microbial gut communities, and prevention of HCC. Additionally the sex-dependent differences in BA profiles in the murine model can be correlated to the differential BA profiles between men and women during the development of HCC. These results uncover distinct male and female profiles for gut microbiota, BAs, and microRNAs that may contribute to sex-based disparity in liver carcinogenesis, and suggest new possibilities for preventing and controlling human obesity-related gastrointestinal cancers that often exhibit sex differences.