Bile acids(BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor(FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid...Bile acids(BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor(FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins(VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-Ⅱ, very low-density lipoproteins receptor(VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-Ⅲ, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea(BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment.展开更多
Bile acid diarrhea results from excessive amounts of bile acids entering the colon due to hepatic overexcretion of bile acids or bile acid malabsorption in the terminal ileum. The main therapies include bile acid sequ...Bile acid diarrhea results from excessive amounts of bile acids entering the colon due to hepatic overexcretion of bile acids or bile acid malabsorption in the terminal ileum. The main therapies include bile acid sequestrants, such as colestyramine and colesevelam, which may be given in combination with the opioid receptor agonist loperamide. Some patients are refractory to conventional treatments. We report the use of the farnesoid X receptor agonist obeticholic acid in a patient with refractory bile acid diarrhea and subsequent intestinal failure. A 32-year-old woman with quiescent colonic Crohn's disease and a normal terminal ileum had been diagnosed with severe bile acid malabsorption and complained of watery diarrhea and fatigue. The diarrhea resulted in hypokalemia and sodium depletion that made her dependent on twice weekly intravenous fluid and electrolyte infusions. Conventional therapies with colestyramine, colesevelam, and loperamide had no effect. Second-line antisecretory therapies with pantoprazole, liraglutide, and octreotide also failed. Third-line treatment with obeticholic acid reduced the number of stools from an average of 13 to an average of 7 per 24h and improved the patient's quality of life. The fluid and electrolyte balances normalized. The effect was sustained during follow-up for 6 mo with treatment at a daily dosage of 25 mg. The diarrhea worsened shortly after cessation of obeticholic acid. This case report supports the initial report that obeticholic acid may reduce bile acid production and improve symptoms in patients with bile acid diarrhea.展开更多
The etiology of most cases of idiopathic bile acid malabsorption (IBAM) is unknown. In this study, a Swedish family with bile acid malabsorption in three consecutive generations was screened for mutations in the ileal...The etiology of most cases of idiopathic bile acid malabsorption (IBAM) is unknown. In this study, a Swedish family with bile acid malabsorption in three consecutive generations was screened for mutations in the ileal apical sodium-bile acid cotransporter gene (ASBT; gene symbol, SLC10A2) and in the genes for several of the nuclear receptors known to be important for ASBT expression: the farnesoid X receptor (FXR) and peroxisome proliferator activated receptor alpha (PPARa). The patients presented with a clinical history of idiopathic chronic watery diarrhea, which was responsive to cholestyramine treatment and consistent with IBAM. Bile acid absorption was determined using 75Se-homocholic acid taurine (SeHCAT); bile acid synthesis was estimated by measuring the plasma levels of 7a-hydroxy-4-cholesten-3-one (C4). The ASBT, FXR, and PPARa genes in the affected and unaffected family members were analyzed using single stranded conformation polymorphism (SSCP), denaturing HPLC, and direct sequencing. No ASBT mutations were identified and the ASBT gene did not segregate withthe bile acid malabsorption phenotype. Similarly, no mutations or polymorphisms were identified in the FXR or PPARa genes associated with the bile acid malabsorption phenotype. These studies indicate that the intestinal bile acid malabsorption in these patients cannot be attributed to defects in ASBT. In the absence of apparent ileal disease, alternative explanations such as accelerated transit through the small intestine may be responsible for the IBAM.展开更多
目的:对新一代胆汁酸螯合剂考来维仑治疗胆汁酸性腹泻(BAD)的有效性和安全性进行Meta分析,并对比考来维仑和考来烯胺在剂型、剂量、不良反应、价格等方面的优劣。方法:在PubMed、Web of Science、Medline、EMBASE、Cochrane library、C...目的:对新一代胆汁酸螯合剂考来维仑治疗胆汁酸性腹泻(BAD)的有效性和安全性进行Meta分析,并对比考来维仑和考来烯胺在剂型、剂量、不良反应、价格等方面的优劣。方法:在PubMed、Web of Science、Medline、EMBASE、Cochrane library、CNKI和万方等数据库检索文献,纳入使用考来维仑治疗BAD的相关资料。应用Stata 14.0计算考来维仑治疗有效率和不良反应发生率。根据非随机对照研究偏倚风险评估工具ROBINS-I的标准,对纳入研究进行偏倚风险评估。结果:纳入研究中考来维仑初始或二线治疗患者总计94例,有效63例,考来维仑治疗BAD的初始治疗总有效率为61.2%,二线治疗总有效率为53.3%,森林图合并有效率为60%(95%CI为0.34~0.86;I 2=86.57%,P<0.05,存在异质性)。汇总考来维仑不良反应发生率为6%(95%CI为0.00~0.18;I 2=51.74%,P=0.13,存在异质性)。结论:考来维仑对BAD,包括考来烯胺治疗失败后的BAD治疗安全有效。目前由于成本因素等,临床上多将考来维仑用于二线治疗,其有效性和安全性需要更多临床试验研究观察。展开更多
There is overwhelming evidence that functional gastrointestinal disorders(FGIDs) are associated with specific mechanisms that constitute important targets for personalized treatment. There are specific mechanisms in p...There is overwhelming evidence that functional gastrointestinal disorders(FGIDs) are associated with specific mechanisms that constitute important targets for personalized treatment. There are specific mechanisms in patients presenting with functional upper gastrointestinal symptoms(UGI Sx). Among patients with UGI Sx, approximately equal proportions(25%) of patients have delayed gastric emptying(GE), reduced gastric accommodation(GA), both impaired GE and GA,or neither, presumably due to increased gastric or duodenal sensitivity.Treatments targeted to the underlying pathophysiology utilize prokinetics,gastric relaxants, or central neuromodulators. Similarly, specific mechanisms in patients presenting with functional lower gastrointestinal symptoms, especially with diarrhea or constipation, are recognized, including at least 30% of patients with functional constipation pelvic floor dyssynergia and 5% has colonic inertia(with neural or interstitial cells of Cajal loss in myenteric plexus); 25% of patients with diarrhea-predominant irritable bowel syndrome(IBSD) has evidence of bile acid diarrhea; and, depending on ethnicity, a varying proportion of patients has disaccharidase deficiency, and less often sucrose-isomaltase deficiency. Among patients with predominant pain or bloating, the role of fermentable oligosaccharides, disaccharides, monosaccharides and polyols should be considered. Personalization is applied through pharmacogenomics related to drug pharmacokinetics, specifically the role of CYP2 D6, 2 C19 and 3 A4 in the use of drugs for treatment of patients with FGIDs. Single mutations or multiple genetic variants are relatively rare, with limited impact to date on the understanding or treatment of FGIDs. The role of mucosal gene expression in FGIDs, particularly in IBS-D, is the subject of ongoing research. In summary, the time for personalization of FGIDs, based on deep phenotyping, is here;pharmacogenomics is relevant in the use of central neuromodulators. There is still unclear impact of the role of genetics in the management of FGIDs.展开更多
基金the BRET (Bardhan Research Education Trust) charity, which has supported funding for materials and equipment costs
文摘Bile acids(BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor(FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins(VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-Ⅱ, very low-density lipoproteins receptor(VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-Ⅲ, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea(BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment.
文摘Bile acid diarrhea results from excessive amounts of bile acids entering the colon due to hepatic overexcretion of bile acids or bile acid malabsorption in the terminal ileum. The main therapies include bile acid sequestrants, such as colestyramine and colesevelam, which may be given in combination with the opioid receptor agonist loperamide. Some patients are refractory to conventional treatments. We report the use of the farnesoid X receptor agonist obeticholic acid in a patient with refractory bile acid diarrhea and subsequent intestinal failure. A 32-year-old woman with quiescent colonic Crohn's disease and a normal terminal ileum had been diagnosed with severe bile acid malabsorption and complained of watery diarrhea and fatigue. The diarrhea resulted in hypokalemia and sodium depletion that made her dependent on twice weekly intravenous fluid and electrolyte infusions. Conventional therapies with colestyramine, colesevelam, and loperamide had no effect. Second-line antisecretory therapies with pantoprazole, liraglutide, and octreotide also failed. Third-line treatment with obeticholic acid reduced the number of stools from an average of 13 to an average of 7 per 24h and improved the patient's quality of life. The fluid and electrolyte balances normalized. The effect was sustained during follow-up for 6 mo with treatment at a daily dosage of 25 mg. The diarrhea worsened shortly after cessation of obeticholic acid. This case report supports the initial report that obeticholic acid may reduce bile acid production and improve symptoms in patients with bile acid diarrhea.
基金Supported by grants from the Swedish Research Council, the Karolinska Institutet and the Swedish Society of Medicine (to CE) and National Institutes of Health grants DK-47987 (to PAD)
文摘The etiology of most cases of idiopathic bile acid malabsorption (IBAM) is unknown. In this study, a Swedish family with bile acid malabsorption in three consecutive generations was screened for mutations in the ileal apical sodium-bile acid cotransporter gene (ASBT; gene symbol, SLC10A2) and in the genes for several of the nuclear receptors known to be important for ASBT expression: the farnesoid X receptor (FXR) and peroxisome proliferator activated receptor alpha (PPARa). The patients presented with a clinical history of idiopathic chronic watery diarrhea, which was responsive to cholestyramine treatment and consistent with IBAM. Bile acid absorption was determined using 75Se-homocholic acid taurine (SeHCAT); bile acid synthesis was estimated by measuring the plasma levels of 7a-hydroxy-4-cholesten-3-one (C4). The ASBT, FXR, and PPARa genes in the affected and unaffected family members were analyzed using single stranded conformation polymorphism (SSCP), denaturing HPLC, and direct sequencing. No ASBT mutations were identified and the ASBT gene did not segregate withthe bile acid malabsorption phenotype. Similarly, no mutations or polymorphisms were identified in the FXR or PPARa genes associated with the bile acid malabsorption phenotype. These studies indicate that the intestinal bile acid malabsorption in these patients cannot be attributed to defects in ASBT. In the absence of apparent ileal disease, alternative explanations such as accelerated transit through the small intestine may be responsible for the IBAM.
文摘There is overwhelming evidence that functional gastrointestinal disorders(FGIDs) are associated with specific mechanisms that constitute important targets for personalized treatment. There are specific mechanisms in patients presenting with functional upper gastrointestinal symptoms(UGI Sx). Among patients with UGI Sx, approximately equal proportions(25%) of patients have delayed gastric emptying(GE), reduced gastric accommodation(GA), both impaired GE and GA,or neither, presumably due to increased gastric or duodenal sensitivity.Treatments targeted to the underlying pathophysiology utilize prokinetics,gastric relaxants, or central neuromodulators. Similarly, specific mechanisms in patients presenting with functional lower gastrointestinal symptoms, especially with diarrhea or constipation, are recognized, including at least 30% of patients with functional constipation pelvic floor dyssynergia and 5% has colonic inertia(with neural or interstitial cells of Cajal loss in myenteric plexus); 25% of patients with diarrhea-predominant irritable bowel syndrome(IBSD) has evidence of bile acid diarrhea; and, depending on ethnicity, a varying proportion of patients has disaccharidase deficiency, and less often sucrose-isomaltase deficiency. Among patients with predominant pain or bloating, the role of fermentable oligosaccharides, disaccharides, monosaccharides and polyols should be considered. Personalization is applied through pharmacogenomics related to drug pharmacokinetics, specifically the role of CYP2 D6, 2 C19 and 3 A4 in the use of drugs for treatment of patients with FGIDs. Single mutations or multiple genetic variants are relatively rare, with limited impact to date on the understanding or treatment of FGIDs. The role of mucosal gene expression in FGIDs, particularly in IBS-D, is the subject of ongoing research. In summary, the time for personalization of FGIDs, based on deep phenotyping, is here;pharmacogenomics is relevant in the use of central neuromodulators. There is still unclear impact of the role of genetics in the management of FGIDs.
文摘肠易激综合征(irritable bowel syndrome,IBS)是一种以慢性腹痛为主要症状,伴排便习惯改变的一种异质性疾病,其中腹泻型IBS(IBS-diarrhea,IBS-D)最为常见且影响最大。由于IBS的病理生理机制复杂,虽然该领域目前已有大量的相关研究,但其具体的发病机理仍不清楚。近年来,越来越多的研究发现,胆汁酸代谢异常和肠黏膜炎症在IBS-D的发生发展中具有重要作用。约25%的IBS-D患者存在胆汁酸代谢异常,表现为粪便中总胆汁酸增加,初级胆汁酸的比例升高,并且胆汁酸核受体法尼醇X受体(Farnesoid X receptor,FXR)表达及活性下降。一方面,FXR-FGF19信号通路下调引起胆汁酸合成增加,进而导致肠道中水和电解质分泌增加,结肠收缩增加,加重IBS-D。另一方面,由于FXR与NF-κB存在相互抑制作用,其表达及活性的下调减弱了对NF-κB的抑制,导致肠道炎症的反复与慢性化。本文就FXR与肠黏膜炎症在IBS-D发病机制中的作用作一概述。
