Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis

Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are rare, inherited cholestatic liver disorders that manifest in infants and children and are associated with impaired bile flow (ie cholestasis), pruritus and potentially fatal liver disease. There are no effective or approved pharmacologic treatments for these diseases (standard medical treatments are supportive only), and new, noninvasive options would be valuable. Typically, bile acids undergo biliary secretion and intestinal reabsorption (ie enterohepatic circulation). However, in these diseases, disrupted secretion of bile acids leads to their accumulation in the liver, which is thought to underlie pruritus and liver-damaging inflammation. One approach to reducing pathologic bile acid accumulation in the body is surgical biliary diversion, which interrupts the enterohepatic circulation (eg by diverting bile acids to an external stoma). These procedures can normalize serum bile acids, reduce pruritus and liver injury and improve quality of life. A novel, nonsurgical approach to interrupting the enterohepatic circulation is inhibition of the ileal bile acid transporter (IBAT), a key molecule in the enterohepatic circulation that reabsorbs bile acids from the intestine. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of paediatric cholestatic liver diseases. This review explores the rationale of inhibition of the IBAT as a therapeutic target, describes IBAT inhibitors in development and summarizes the current data on interrupting the enterohepatic circulation as treatment for cholestatic liver diseases including ALGS and PFIC

Rapid and selective manipulation of milk fatty acid composition in mice through the maternal diet during lactation

Dietary fatty acid (FA) composition in early postnatal life can modulate growth and development and later metabolic health. Investigating programming effects of early dietary FA manipulations in rodents may be stressful and complicated due to the need of artificial feeding techniques. It is largely unknown to what extent breast milk (BM) FA composition can be directly manipulated by the diet. We exposed dams to different dietary FA compositions from postnatal day (PN) 2 until PN28. Dams with litters were randomly assigned to control (CTRL), high-medium-chain FA (MCFA), low-linoleic acid (LowLA), high-n-3 long-chain PUFA (n-3LCP) or high-n-3LCP and MCFA (n-3LCP/MCFA) diets, and diets were continued after weaning until PN28. FA compositions were determined in feeds, milk and in erythrocytes. BM MCFA content was independent from dietary MCFA intake. In contrast, the LowLA diet reduced BM LA content by about 50 % compared with the CTRL diet at PN7. BM of dams fed the n-3LCP or n-3LCP/MCFA diet contained about 6-fold more n-3 LCP than BM of the dams fed the CTRL diet at PN7. These changes in milk FA composition established after 5 d of dietary exposure did not further change over the lactation period. At PN28, the erythrocyte FA composition of the male pups correlated with analysed milk FA profiles. In conclusion, manipulation of the diet of lactating mice can strongly and rapidly affect BM FA composition, in particular of n-6 LA and n-3 LCP. Our present findings will facilitate mechanistic studies on the programming of adult metabolic health by dietary FA in the early postnatal period via direct and selective manipulation of the maternal diet

Albuminuria and markers for cardiovascular risk in 12-year-olds from the general Dutch population:a cross-sectional study

In adults, albuminuria represents a risk factor for cardiovascular disease and is associated with hypertension and obesity. Pediatric data from the general population are inconsistent and largely based on randomly collected urine. A possible association between antenatal programming and albuminuria at school age has still to be investigated. The purpose of this study is to assess albuminuria in first morning void urine samples in a population-based pediatric cohort and to investigate cross-sectionally the association with factors related to cardiovascular risk. Moreover, we investigate the possible association of antenatal factors with albuminuria. A first morning void urine sample was collected in the population-based GECKO (Groningen Expert Center for Kids with Obesity) Drenthe cohort at the age of 12 years. We investigated cross-sectionally associations between albuminuria and body mass index (BMI), waist circumference (WC), blood pressure (BP) and antenatal factors. The prevalence of U ACR (urinary albumin-creatinine ratio) ≥ 3 mg/mmol was 3.3% (95%CI 2.3-4.2). In a multivariate linear regression model, U AC was negatively associated with z-BMI (β-0.08, p = 0.013) and positively with z-systolic BP (β 0.09, p = 0.006), model significance p = 0.002. U ACR was negatively associated with z-BMI (β - 0.13, p &lt; 0.001) and positively with z-diastolic BP (β 0.09, p = 0.003), model significance p = 0.001. Albuminuria was not significantly associated with antenatal factors such as gestational age and standardized birth weight. CONCLUSIONS: Albuminuria in first morning void urine in 12-year-olds has a lower prevalence than previously reported by randomly collected samples. A negative association between albuminuria and BMI is confirmed. A positive association with blood pressure, but no association with antenatal factors was found.WHAT IS KNOWN: • While, in adults, albuminuria is a recognized risk factor for cardiovascular disease and is associated with hypertension and obesity, pediatric data are inconsistent and largely based on randomly collected urine. • A possible association between antenatal programming and albuminuria at school age has still to be investigated.WHAT IS NEW: • In this population study on first morning void urine samples from 12-year-olds of the general population, albuminuria is negatively associated with body mass index, and positively associated with blood pressure, while there is no association with antenatal factors. • The prevalence of albuminuria at 12 years is lower than previously reported in studies based on randomly collected urine samples, probably due to elimination of orthostatic proteinuria.</p

Milk cholesterol concentration in mice is not affected by high cholesterol diet- or genetically-induced hypercholesterolaemia

Breast milk cholesterol content may imply to affect short- and long-term cholesterol homeostasis in the offspring. However, mechanisms of regulating milk cholesterol concentration are only partly understood. We used different mouse models to assess the impact of high cholesterol diet (HC)- or genetically-induced hypercholesterolaemia on milk cholesterol content. At day 14 postpartum we determined milk, plasma and tissue lipids in wild type (WT), LDL receptor knockout (Ldlr-/-), and ATP-binding cassette transporter G8 knockout (Abcg8-/-) mice fed either low- or 0.5% HC diet. In chow-fed mice, plasma cholesterol was higher in Ldlr-/- dams compared to WT. HC-feeding increased plasma cholesterol in all three models compared to chow diet. Despite the up to 5-fold change in plasma cholesterol concentration, the genetic and dietary conditions did not affect milk cholesterol levels. To detect possible compensatory changes, we quantified de novo cholesterol synthesis in mammary gland and liver, which was strongly reduced in the various hypercholesterolaemic conditions. Together, these data suggest that milk cholesterol concentration in mice is not affected by conditions of maternal hypercholesterolaemia and is maintained at stable levels via ABCG8- and LDLR-independent mechanisms. The robustness of milk cholesterol levels might indicate an important physiological function of cholesterol supply to the offspring

Gut Microbiota Composition of Biliary Atresia Patients Before Kasai Portoenterostomy Associates With Long-term Outcome

BACKGROUND AND AIMS: Biliary atresia (BA) is a cholestatic, fibro-obliterative cholangiopathy of unknown etiology. BA is primarily treated by a surgical approach, i.e. the Kasai portoenterostomy (KPE), to obtain clearance of jaundice (COJ). The gut microbiota (GM) composition has been associated with the course of several cholestatic liver diseases. It is largely unknown, however, whether GM composition associates with the outcome of KPE. We compared the GM composition of BA patients and controls and assessed if GM composition before KPE was related to COJ after KPE. METHODS: We compared feces of term born BA patients before KPE and controls (patients undergoing inguinal hernia repair) by 16S rRNA sequencing. Composition and alpha diversity of the GM were compared between BA and controls before KPE and after KPE, between patients with COJ vs. without COJ (total serum bilirubin < or ≥ 20 μmol/L < 6mo post-KPE). RESULTS: Alpha diversity was comparable between BA (n = 12, age 1.6[1.3-1.8]mo) and controls (n = 6, age 2.0[1.4-2.1]mo; P = 0.22). Compared to controls, BA patients had lower abundances of Bifidobacteriaceae (β=-1.98, P < 0.001) and Lachnospiraceae (β=-1.84, P = 0.007), and higher abundances of Streptococcus (β=1.13, P = 0.003). The alpha diversity prior to KPE correlated negatively with COJ (R = -0.63, P = 0.03). Lower alpha diversity pre-KPE was associated with COJ [+] (βlogit = -0.64, P = 0.04). We observed greater abundances of genus Acinetobacter (β=1.27, P = 0.03) and family Clostridiaceae (β=1.45, P = 0.03) and lower abundances of the family Enterobacteriaceae, (genera Klebsiella (β=-1.21, P = 0.01), Salmonella (β=-1.57, P = 0.02)) in COJ [+] vs. COJ [-]. CONCLUSIONS: The gut microbiota of biliary atresia patients prior to Kasai portoenterostomy associates with outcome, clearance of jaundice, suggestive of predictive and mechanistic roles of the gut microbiota composition in bile homeostasis

Enantio- and diastereoselective synthesis of γ-amino alcohols

The γ-amino alcohol structural motif is often encountered in drugs and natural products. We developed two complementary catalytic diastereoselective methods for the synthesis of N-PMP-protected γ-amino alcohols from the corresponding ketones. The anti-products were obtained through Ir-catalyzed asymmetric transfer hydrogenation, the syn-products via Rh-catalyzed asymmetric hydrogenation

Health-Related Quality of Life in Biliary Atresia Patients with Native Liver or Transplantation

Introduction We aimed to assess health-related quality of life (HrQoL) in biliary atresia (BA) patients, based on original data and a literature review, and to determine factors associated with their HrQoL. Materials and Methods We reviewed available studies describing HrQoL in BA patients. We assessed HrQoL in Dutch BA patients (6-16 years) using the validated Child Health Questionnaire. We compared HrQoL scores in BA patients with healthy peers and with children who had undergone major surgery in infancy or children with chronic conditions. We determined the relationship between specific patient-related factors and HrQoL. Results Literature data indicated that HrQoL in children with BA is lower than in healthy peers. In Dutch BA patients (n = 38; age 10 ± 3 years), parent-proxy physical HrQoL (48 ± 11) was significantly lower compared with two reference groups of healthy peers (59 ± 4 and 56 ± 6, respectively, each p < 0.001), and lower than in children with attention deficit hyperactivity disorder (60 ± 5), asthma (54 ± 6), attending a cardiology clinic (52 ± n / r), congenital diaphragmatic hernia (53 ± 7) or D-transposition of the great arteries (54 ± 6; all p < 0.05). Psychosocial HrQoL (50 ± 9) was lower than in healthy peers (54 ± 6, p = 0.02, and 53 ± 6, p = 0.07) and children with asthma (54 ± 6, p = 0.02), and largely comparable to children with other chronic conditions. Parent-proxy physical HrQoL was adversely related to adverse medical event in the past year, special education, and motor impairments; psychosocial HrQoL was adversely related to behavioral problems. Conclusion Children with BA are at risk of impaired HrQoL. Special attention is warranted for children with adverse medical events and special education

Long-Term beta-galacto-oligosaccharides Supplementation Decreases the Development of Obesity and Insulin Resistance in Mice Fed a Western-Type Diet

Scope: The gut microbiota might critically modify metabolic disease development. Dietary fibers such as galacto-oligosaccharides (GOS) presumably stimulate bacteria beneficial for metabolic health. This study assesses the impact of GOS on obesity, glucose, and lipid metabolism. Methods and results: Following Western-type diet feeding (C57BL/6 mice) with or without β-GOS (7% w/w, 15 weeks), body composition, glucose and insulin tolerance, lipid profiles, fat kinetics and microbiota composition are analyzed. GOS reduces body weight gain (p < 0.01), accumulation of epididymal (p < 0.05), perirenal (p < 0.01) fat, and insulin resistance (p < 0.01). GOS-fed mice have lower plasma cholesterol (p < 0.05), mainly within low-density lipoproteins, lower intestinal fat absorption (p < 0.01), more fecal neutral sterol excretion (p < 0.05) and higher intestinal GLP-1 expression (p < 0.01). Fecal bile acid excretion is lower (p < 0.01) in GOS-fed mice with significant compositional differences, namely decreased cholic, α-muricholic, and deoxycholic acid excretion, whereas hyodeoxycholic acid increased. Substantial changes in microbiota composition, conceivably beneficial for metabolic health, occurred upon GOS feeding. Conclusion: GOS supplementation to a Western-type diet improves body weight gain, dyslipidemia, and insulin sensitivity, supporting a therapeutic potential of GOS for individuals at risk of developing metabolic syndrome