Absorption Markers Research Articles

The Effect of a Resistance Training Course with Vitamin D Supplementation on Bone Absorption Markers in Girls

The Effect of a Resistance Training Course with Vitamin D Supplementation on Bone Absorption Markers in Girls

Serum Phytosterols Are Not Associated with Inflammatory Markers in Two Cross-Sectional, Swiss Population-Based Studies (The CoLaus|PsyCoLaus Study).

Background: The association between inflammation and dietary sterols remains poorly assessed at the population level. Aims: To assess the possible association between serum levels of various phytosterols (PS) and inflammatory markers. Methods: Serum levels of six PS (campesterol, campestanol, stigmasterol, sitosterol, sitostanol, brassicasterol), four cholesterol synthesis markers (lathosterol, lanosterol, desmosterol, dihydroxylanosterol) and one cholesterol absorption marker (cholestanol) were measured together with levels of CRP, IL-6 and TNF-α in two cross-sectional surveys of a population-based, prospective study. Results: CRP levels were negatively associated with levels of cholestanol and of sterols of plant origin, although some associations were not statistically significant. CRP levels were positively associated with cholesterol synthesis markers in the first but not in the second follow-up. IL-6 levels were negatively associated with cholestanol in both follow-ups. No associations between IL-6 levels and PS were found in the first follow-up, while significant negative associations with campesterol, sitosterol, brassicasterol, sitostanol and campesterol:TC ratio were found in the second follow-up. TNF-α levels were negatively associated with cholestanol in both follow-ups. These associations did not withstand adjusting for sex, age, BMI and statin administration. Conclusions: In a population-based study, PS serum levels were not significantly associated with inflammatory markers.

Murine in utero exposure to simulated complex urban air pollution disturbs offspring gut maturation and microbiota during intestinal suckling-to-weaning transition in a sex-dependent manner

BackgroundEmerging data indicate that prenatal exposure to air pollution may lead to higher susceptibility to several non-communicable diseases. Limited research has been conducted due to difficulties in modelling realistic air pollution exposure. In this study, pregnant mice were exposed from gestational day 10–17 to an atmosphere representative of a 2017 pollution event in Beijing, China. Intestinal homeostasis and microbiota were assessed in both male and female offspring during the suckling-to-weaning transition.ResultsSex-specific differences were observed in progeny of gestationally-exposed mice. In utero exposed males exhibited decreased villus and crypt length, vacuolation abnormalities, and lower levels of tight junction protein ZO-1 in ileum. They showed an upregulation of absorptive cell markers and a downregulation of neonatal markers in colon. Cecum of in utero exposed male mice also presented a deeply unbalanced inflammatory pattern. By contrast, in utero exposed female mice displayed less severe intestinal alterations, but included dysregulated expression of Lgr5 in colon, Tjp1 in cecum, and Epcam, Car2 and Sis in ileum. Moreover, exposed female mice showed dysbiosis characterized by a decreased weighted UniFrac β-diversity index, a higher abundance of Bacteroidales and Coriobacteriales orders, and a reduced Firmicutes/Bacteroidetes ratio.ConclusionPrenatal realistic modelling of an urban air pollution event induced sex-specific precocious alterations of structural and immune intestinal development in mice.

Impact of Pancreatic Enzymes on Enteral Fat and Nitrogen Absorption in Short Bowel Syndrome.

Patients with short bowel syndrome (SBS) can have a high morbidity rate. To minimize morbidity, enteral autonomy is the primary goal in clinical management of patients with SBS. This is often difficult to achieve because of significant malabsorption. To date, there are limited therapies that improve absorption in patients with SBS. The impact of pancreatic enzyme replacement treatment on enteral absorption has not been studied in this population and was the primary aim of this study. This was an interventional study in 11 subjects (6 pediatric subjects ages 4.0-17.9 years, 5 adult subjects 18-75 years) that compared enteral absorption in each subject before and after pancreatic enzyme medication (Creon). Coefficient of fat absorption (CFA) and coefficient of nitrogen absorption (CNA) were used as markers of enteral absorption of fat and protein, respectively. There was no statistically significant mean change in CFA and CNA before and after pancreatic enzyme medication therapy. Six subjects demonstrated an increase in CFA and 8 subjects demonstrated an increase in CNA after the use of pancreatic enzyme medication therapy. There was no statistically significant improvement in enteral fat and protein absorption in the cohort as a whole, though several subjects demonstrated an improvement. These results suggest that some patients with SBS may benefit from treatment with pancreatic enzymes. Further studies are needed to better evaluate the effect of pancreatic enzyme therapy on enteral absorption in subjects with SBS and to characterize factors that may predict a positive response.

No association between serum phytosterols and inflammatory marker levels in a population-based study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation Background The association between inflammation and dietary sterols remains poorly assessed at the population level. Aims To assess the possible association between serum levels of various phytosterols (PS) and inflammatory markers. Methods Serum levels of six PS (campesterol, campestanol, stigmasterol, sitosterol, sitostanol, brassicasterol), four cholesterol synthesis markers (lathosterol, lanosterol, desmosterol, dihydrolanosterol) and one cholesterol absorption marker (cholestanol) were measured together with levels of CRP, IL-6 and TNF-alpha in two cross-sectional surveys of a population-based, prospective study. Results PS levels and their ratios to cholesterol were significantly positively correlated to other PS and cholesterol absorption marker and negatively correlated to cholesterol synthesis markers, with a good agreement between follow-ups. Bivariate correlations showed a generally negative, sometimes significant, association between PS levels (or PS:total cholesterol ratio) and CRP in both follow-ups. The association between PS (or PS:total cholesterol) and IL6 or TNF alpha was mostly negative and, for some PS, significant in the second follow-up (Figure). These associations did not withstand adjusting for confounding factors such as sex, age, BMI and statin administration. Conclusion In this population-based study, PS serum levels were not significantly associated with inflammatory markers.

Enantioselective high-performance liquid chromatography of aryl-substituted oxazolines as an efficient tool for determination of chiral purity of serine medicinal components.

A new approach for the evaluation of chiral purity of serine esterification products bearing long-chain alkyl substituents was developed. The compounds were simply converted to aryl-substituted oxazolines which: (i) facilitates effective chromatographic enantioseparation and (ii) enables direct detection using ultraviolet absorption. The method employs a polysaccharide-based chiral stationary phase and allows enantioseparation of highly stable oxazoline products in less than 6 min using a simple binary mobile phase. As opposed to the previously used normal phase method the developed method was performed in the reversed-phase mode. Aside from the benefits of switching to less hazardous solvents with regard to the principles of Green Chemistry, this has also led to a reduction in the analysis time. In comparison with known serine chromophores, the best enantioseparation of aryloxazoline rigid structure may be achieved only based on non-polar interactions with the chiral stationary phase. In contrast, the substitution of the chromophore moiety with hydroxyl substituent affected intra and intermolecular interactions that caused enantioseparation differences. Concurrently, we found high chirality retention of (R)- and (S)-configuration oxazoline standards (≥99% enantiomeric excess) during the introduction of the ultraviolet label. The method is suitable for rapid injection of the mixture containing the ultraviolet absorption marker without prior purification.

Cholesterol Metabolic Markers for Differential Evaluation of Patients with Hyperlipidemia and Familial Hypercholesterolemia.

The cholesterol metabolism in humans can be indirectly reflected by measuring cholesterol metabolism marker levels. We aimed to investigate the association of cholesterol homeostasis markers on standard lipid profiling components in familial hypercholesteremia and hyperlipidemia patients. A total of 69 hyperlipidemia patients, 25 familial hypercholesteremia (FHC) patients, and 64 healthy controls were enrolled in this study. We performed routine testing of blood lipid water. Gas chromatography was used to determine the changes in the concentration of cholesterol synthesis (squalene, desmosterol, and lathosterol) and absorption markers (campesterol, sitosterol, and stigmasterol) in the blood. Baseline hyperlipidemia patients displayed significantly higher total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels in comparison to the control group, which was reflected in the increased levels of squalene, desmosterol, campesterol, and sitosterol observed (P < 0.05) in the hyperlipidemia patients. The desmosterol, lathosterol, campesterol, stigmasterol, and sitosterol were statistically different in the FHC group than the hyperlipidemic group (P < 0.05). The proportions of squalene/cholesterol, lathosterol/cholesterol, stigmasterol/cholesterol, and sitosterol/cholesterol in the FHC group were lower than those in the hyperlipidemic group; only desmosterol/cholesterol was higher than that in the hyperlipidemic group. Correlation studies between lipid metabolic factors showed that the proportion of moderate and strong correlations was much higher in the FHC group than in the other two groups (76.92% vs. 32.50% and 31.25%). Logistic regression analysis showed that the concentrations of glucose, LDL-C, lactosterol, and sitosterol were all independent risk factors for developing hyperlipidemia. This result was further confirmed by the ROC curve. These results indicated that the study of cholesterol synthesis and decomposition markers can serve as a reference index for related diseases caused by changes in its concentration.

Effects of Diet-Induced Weight Loss on Plasma Markers for Cholesterol Absorption and Synthesis: Secondary Analysis of a Randomized Trial in Abdominally Obese Men.

Cross-sectional studies have shown that obesity is associated with lower intestinal cholesterol absorption and higher endogenous cholesterol synthesis. These metabolic characteristics have also been observed in patients with type 2 diabetes, metabolic syndrome, steatosis or cholestasis. The number of intervention studies evaluating the effect of weight loss on these metabolic characteristics is, however, limited, while the role of the different fat compartments has not been studied into detail. In a randomized trial, abdominally obese men (N = 54) followed a 6-week very low caloric (VLCD) diet, followed by a 2 week weight-maintenance period. Non-cholesterol sterols were measured at baseline and after 8 weeks, and compared to levels in lean participants (N = 25). After weight loss, total cholesterol (TC)-standardized cholestanol levels increased by 0.18 µmol/mmol (p < 0.001), while those of campesterol and lathosterol decreased by 0.25 µmol/mmol (p < 0.05) and 0.39 µmol/mmol (p < 0.001), respectively. Moreover, after weight loss, TC-standardized lathosterol and cholestanol levels were comparable to those of lean men. Increases in TC-standardized cholestanol after weight loss were significantly associated with changes in waist circumference (p < 0.01), weight (p < 0.001), BMI (p < 0.001) and visceral fat (p < 0.01), but not with subcutaneous and intrahepatic lipids. In addition, cross-sectional analysis showed that visceral fat fully mediated the association between BMI and TC-standardized cholestanol levels. Intrahepatic lipid content was a partial mediator for the association between BMI and TC-standardized lathosterol levels. In conclusion, diet-induced weight loss decreased cholesterol synthesis and increased cholesterol absorption. The increase in TC-standardized cholestanol levels was not only related to weight loss, but also to a decrease in visceral fat volume. Whether these metabolic changes ameliorate other metabolic risk factors needs further study.

Effects of ileal glucose infusion on enteropancreatic hormone secretion in humans: relationship to glucose absorption

BackgroundsThe distal small intestine plays an important role in regulating the secretion of entero-pancreatic hormones that are critical to the control of glucose metabolism and appetite, but the quantitative contribution of a specific segment to these effects is unknown. PurposesTo determine the effects of 30 cm of the ileum exposed to glucose on the secretion of ghrelin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) insulin, C-peptide and glucagon, in relation to glucose absorption in non-diabetic subjects. Basic procedures10 non-diabetic subjects with a loop ileostomy after early-stage rectal cancer resection were studied on 2 days in a double-blind, randomized and crossover fashion, when a catheter was inserted retrogradely 30 cm from the ileostomy for infusion of a glucose solution containing 30 g glucose and 3 g 3-O-methylglucose (as a marker of active glucose absorption), or 0.9% saline, over 60 min. Ghrelin, GIP, GLP-1, insulin, C-peptide, glucagon and ileal glucose absorption (from concentrations of 3-O-methylglucose in serum and glucose in ileostomy effluent) were measured over 180 min. Main findings12.0 ± 1.2 g glucose was absorbed over 180 min. Compared to saline, ileal glucose resulted in minimal increases in blood glucose and plasma insulin and C-peptide, but substantial increases in plasma GLP-1, without affecting ghrelin, GIP or glucagon. The magnitude of the GLP-1 response to glucose was strongly related to the increase in serum 3-O-methylglucose. Principal conclusionsStimulation of the terminal ileum by glucose, even over a short length (30 cm), induces substantial GLP-1 release, coupled primarily to active glucose absorption.Clinical registration:NCT05030376 (ClinicalTrials.gov).

Plasma LncRNA MALAT1 Expressions Are Negatively Associated with Disease Severity of Postmenopausal Osteoporosis.

Long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (LncRNA MALAT1) has been proven to promote osteogenesis in different health conditions. However, the role of plasma MALAT1 in postmenopausal osteoporosis (PMOP) has not been investigated. To investigate whether plasma MALAT1 expressions are associated with severity of PMOP. A total of 126 patients with PMOP and 126 healthy female control individuals were drafted into study participation. Plasma MALAT1 was detected using RT-PCR. Bone formation marker bone-specific alkaline phosphatase plasma concentration was determined using chemiluminescence immunoassay. Levels of bone absorption marker cross-linked N-telopeptidases of type I collagen were measured in duplicate using enzyme immunoassay. Bone mineral density (BMD) was examined in the total hips, femoral neck, and lumbar (L1-L4) spine using dual-energy x-ray absorptiometry. We used Genant semiquantitative (GSQ) criteria to assess the degree of vertebral deformity and fracture. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the potential diagnostic value of MALAT1 with regard to the GSQ grading. We used the Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) to evaluate the symptomatic severity in and functional ability of the study participants. Plasma MALAT1 expressions were significantly lower in patients with PMOP, compared with healthy controls. Plasma MALAT1 expressions in patients with PMOP were positively associated with total hip, femoral neck, and lumbar (L1-L4) spine BMD. In total, 95 patients experienced vertebral deformity or fracture (VF), and 31 had no fractures. Plasma MALAT1 expressions were markedly decreased in patients with VF, compared with patients without fractures. Plasma MALAT1 expressions were negatively related to GSQ grading in patients with VF. ROC curve analysis demonstrated that decreased plasma MALAT1 expression exhibits decent diagnostic value with regard to GSQ grading. Finally, we discovered that plasma MALAT1 expression was also negatively associated with VAS and ODI. Plasma MALAT1 expressions are negatively associated with severity of PMOP.

Plasma advanced glycation end products and soluble receptor for advanced glycation end products as indicators of sterol content in human carotid atherosclerotic plaques.

Advanced glycation end products (AGEs) are independently related to cardiovascular disease (CVD) and favor cholesterol and oxysterol accumulation in macrophage foam cells. Soluble RAGE (sRAGE) impairs cellular AGE signaling alleviating the deleterious effects of AGE in atherogenesis. The association between plasma AGEs and sRAGE with the content of cholesterol, markers of cholesterol synthesis and absorption, and oxysterols in atherosclerotic plaques was evaluated in subjects undergoing carotid endarterectomy.Plasma and carotid plaques were obtained from symptomatic (n = 23) and asymptomatic subjects (n = 40). Lipids from plaques were extracted and sterols (oxysterols, cholesterol, desmosterol, lathosterol, sitosterol, and campesterol) were determined by using gas chromatography/mass spectrometry. Plasma total AGEs and pentosidine were measured by using fluorimetry and sRAGE by using ELISA.In symptomatic subjects´ atherosclerotic plaques, an increased amount of cholesterol (3x) and oxysterols [7 α-hydroxycholesterol (1.4x); 7 β−hydroxycholesterol (1.2x); 25-hydroxycholesterol (1.3x); 24-hydroxycholesterol (2.7x), and 27-hydroxycholesterol, (1.15x)], with exception to 7 ketocholesterol, were found in comparison to asymptomatic individuals. Plasma total AGEs and pentosidine significantly and positively correlated to sterols accumulated in the atherosclerotic lesion, including cholesterol, desmosterol, campesterol, sitosterol, and oxysterols. On the other hand, sRAGE inversely correlated to total AGEs and pentosidine in plasma, and with major species of oxysterols, cholesterol, and markers of cholesterol synthesis and absorption in the atherosclerotic lesion. In multiple regression analyses, it was observed a significant inverse correlation between sRAGE and 24-hydroxycholesterol and desmosterol, and a positive significant correlation between pentosidine and 24-hydroxycholesterol, 27-hydroxycholesterol, and campesterol.In conclusion, the plasma concentration of AGEs and sRAGE is a tool to predict the accumulation of sterols in atherosclerotic lesions in symptomatic and asymptomatic individuals, helping to prevent and improve the management of acute cardiovascular complications.

Engineering pre-vascularized bone-like tissue from human mesenchymal stem cells through simulating endochondral ossification

Currently, most in vitro engineered bone tissues do not contain viable blood vessel systems, so the vascularization depends on post-implantation angiogenesis from the host, which is often insufficient for repairing large bone defects. In this study, we aimed to create pre-vascularized bone-like tissue from human bone marrow-derived mesenchymal stem cells (HBMSCs) within the self-generated extracellular matrix by simulating the developmental endochondral ossification. Afterward, a three-dimensional (3D) culture of human umbilical vein endothelial cells (HUVECs)/HBMSCs was introduced to cover bone-like constructs surface for vascularization. Lastly, the pre-vascularized bone-like tissues were subcutaneously implanted into mice and the quality of newly formed blood vessels and bones were later assessed. We particularly examined whether the pre-existing HUVECs/HBMSCs vascular networks within the implants were able to integrate with the host’s blood vessels and facilitate bone formation. Our results showed that this developmentally informed procedure resulted in a robust osteogenic differentiation of HBMSCs. Moreover, the bone-like constructs markedly promoted HUVEC/HBMSCs network formation in vitro. After 28 days of implantation in mice, the experimental group, in which bone-like constructs were pre-vascularized with HUVEC/HBMSCs networks, exhibited significantly more functional blood vessels than the control group that contained HUVEC and HBMSC single cells. Interestingly, increased levels of bone formation and absorption markers were also observed in the pre-vascularized bone-like constructs. Taken together, these findings demonstrated the potential of pre-vascularized bone-like constructs in repairing bone defects.

A Complex of Cirsium japonicum var. maackii (Maxim.) Matisum. and Thymus vulgaris L. Improves Menopausal Symptoms and Supports Healthy Aging in Women.

We evaluated the efficacy and safety of MS-10® for the treatment of menopausal symptoms. A double-blind randomized placebo-controlled clinical trial was performed in 71 premenopausal women for 4 and 12 weeks. A total of 12 individual menopausal symptom scores were assessed using the Kupperman index. MS-10 treatment effectively improved the symptoms by ∼48%. In addition, the quality of life of the women improved by 36% from four perspectives: vasomotor, psychosocial, physical, and sexual symptoms as evaluated using the menopause-specific quality of life (MenQoL) questionnaire. Our results show that MS-10 improves insulin-like growth factor-1 (IGF-1) and estrogen utilization through receptor activation, which are thought to have causative therapeutic effects on menopause and aging inhibition in women. Improvement of Enthotheline-1 (ET-1) in the blood after MS-10 intake led to an improvement in menopausal vascular symptoms. Improvements in bone formation and absorption markers such as osteocalcin, bone-specific alkaline phosphatase (BSALP), C-telopeptides of type I collagen (CTx), deoxypyridinoline (deoxyPYD), and N-telopeptides of type I collagen (NTx) in blood or urine indicate that MS-10 fundamentally improves bone health in women. By confirming the improvement of the psychological well-being index based on the improvement of stress hormone cortisol, MS-10 can solve causative psychological and physical stress-related symptoms. Moreover, various safety tests, such as those for female hormones, were confirmed. Therefore, it can be confirmed that MS-10 is a natural pharmaconutraceutical that causatively and safely improves health of women and aids in antiaging processes.

Common variant p.D19H of the hepatobiliary sterol transporter ABCG8 increases the risk of gallstones in children

Gallstones are increasingly common in children. Genetic analyses of adult cohorts demonstrated that the sterol transporter ABCG8 p.D19H and Gilbert UGT1A1*28 variants enhance the odds of developing gallstones. The genetic background of common lithiasis in children remains unknown. Overall, 214 children with gallstone disease (1month-17years, 107 boys) were inclueded. The control cohorts comprised 214 children (age 6-17years, 115 boys) and 172 adults (age 40-92years, 70 men) without gallstones. The ABCG8 p.D19H and UGT1A1*28 polymorphisms as well as ABCB4 (c.504C>T rs1202283, c.711A>T rs2109505) and NPC1L1 variants (p.V1296V rs217434, c.-18C>A rs41279633) were genotyped using TaqMan assays. Serum concentrations of plant sterols and cholesterol precursors were measured by gas chromatography/mass spectrometry. The ABCG8 risk allele was associated with an increased risk of stones (OR=1.82, p=.03). Children carrying the p.19H allele presented with lower serum concentrations of surrogate markers of intestinal cholesterol absorption and decreased ratios of phytosterols to the cholesterol precursor desmosterol. Carriers of the common NPC1L1 rs217434 allele had an increased gallstone risk compared with stone-free adults (OR 1.90, p<.01). This variant also affected the ratio of phytosterols to cholesterol precursors (p=.03). Other tested variants were not associated with gallstone risk. The p.D19H ABCG8 and, to a lesser extent, NPC1L1 rs217434 variants increase the risk of early-onset gallstone formation. These results point to the presence of a common lithogenic pathway in children and adults.

Insulin Prevents Hypercholesterolemia by Suppressing 12α-Hydroxylated Bile Acids.

The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type 1 diabetes, could reveal better treatment strategies. To define the mechanisms by which insulin controls plasma cholesterol levels, we knocked down the insulin receptor, FoxO1, and the key bile acid synthesis enzyme, CYP8B1. We measured bile acid composition, cholesterol absorption, and plasma cholesterol. In parallel, we measured markers of cholesterol absorption and synthesis in humans with type 1 diabetes treated with ezetimibe and simvastatin in a double-blind crossover study. Mice with hepatic deletion of the insulin receptor showed marked increases in 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol. This phenotype was entirely reversed by hepatic deletion of FoxO1. FoxO1 is inhibited by insulin and required for the production of 12α-hydroxylated bile acids, which promote intestinal cholesterol absorption and suppress hepatic cholesterol synthesis. Knockdown of Cyp8b1 normalized 12α-hydroxylated bile acid levels and completely prevented hypercholesterolemia in mice with hepatic deletion of the insulin receptor (n=5-30), as well as mouse models of type 1 diabetes (n=5-22). In parallel, the cholesterol absorption inhibitor, ezetimibe, normalized cholesterol absorption and low-density lipoprotein cholesterol in patients with type 1 diabetes as well as, or better than, the cholesterol synthesis inhibitor, simvastatin (n=20). Insulin, by inhibiting FoxO1 in the liver, reduces 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol levels. Thus, type 1 diabetes leads to a unique set of derangements in cholesterol metabolism, with increased absorption rather than synthesis. These derangements are reversed by ezetimibe, but not statins, which are currently the first line of lipid-lowering treatment in type 1 diabetes. Taken together, these data suggest that a personalized approach to lipid lowering in type 1 diabetes may be more effective and highlight the need for further studies specifically in this group of patients.

P202 Performance characteristics of serum FGF19 measurement compared with the Se-HCAT retention test in the diagnosis of bile acid diarrhoea in Crohn’s Disease

Abstract Background Bile acid diarrhoea (BAD) is common in patients with Crohn’s disease (CD), but its recognition is challenging since symptoms are similar to those of active inflammatory disease. The current clinical gold standard for diagnosing BAD is the Se-HCAT test, however, it is inconvenient to the patient and has limited availability. FGF19 is a hormone produced in the enterocytes of the ileum in response to absorbed BAs. Serum FGF19 levels are a direct marker of BA absorption, and they are reduced in BAD. The aim of this study was to evaluate the performance of FGF19 as a diagnostic tool for BAD in Crohn’s disease. Methods Fasting serum FGF19 levels and Se-HCAT retention were measured before bowel preparation in 63 consecutive Crohn’s disease patients referred for an ileocolonoscopy. Clinical, endoscopic and biologic data were prospectively recorded. BAD was defined as an abdominal retention &amp;lt;10% and severe BAD as &amp;lt;5% at day seven. Results BAD was present in 60% of non-resected CD (NR-CD) patients and in 93% of ileal-resected (IR-CD) patients. FGF19 levels were lower in IR-CD patients (median 23 pg/ml; IQR, 3–44) than in the NR-CD patients (61 pg/ml; IQR, 18–121) (p = 0.02). FGF19 levels were inversely related with ileal resection length in IR-CD patients (rs = -0.52, P = 0.01). FGF19 and Se-HCAT values were positively related (rs = 0.57, P &amp;lt; 0.0001), whereas FGF19 was inversely related with the number of bowel movements (rs = -0.31, P=0.01) and Bristol scale (rs = -0.27, P= 0.04). No significant relation was found between FGF19 and clinical (CDAI) nor endoscopic (SES-CD) scores. Area under the ROC curve for FGF19 to detect SeHCAT at &amp;lt;10% and &amp;lt;5% were 0.75 (95% CI 0.62–0.88) and 0.81 (95% CI 0.71–0.92) respectively. Conclusion Serum FGF19 can be used as a simple blood test to the diagnostic of BAD in CD. FGF19 measurement could be an adjunct in guiding treatments for diarrhoea in CD.

Sodium/hydrogen-exchanger-2 modulates colonocyte lineage differentiation.

The sodium/hydrogen exchanger 2 (NHE2) is an intestinal acid extruder with crypt-predominant localization and unresolved physiological significance. Our aim was to decipher its role in colonic epithelial cell proliferation, differentiation and electrolyte transport. Alterations induced by NHE2-deficiency were addressed in murine nhe2-/- and nhe2+/+ colonic crypts and colonoids, and NHE2-knockdown and control Caco2Bbe cells using pH-fluorometry, gene expression analysis and immunofluorescence. pHi -measurements along the colonic cryptal axis revealed significantly decreased intracellular pH (pHi ) in the middle segment of nhe2-/- compared to nhe2+/+ crypts. Increased Nhe2 mRNA expression was detected in murine colonoids in the transiently amplifying/progenitor cell stage (TA/PE). Lack of Nhe2 altered the differentiation programme of colonic epithelial cells with reduced expression of absorptive lineage markers alkaline phosphatase (iAlp), Slc26a3 and transcription factor hairy and enhancer-of-split 1 (Hes1), but increased expression of secretory lineage markers Mucin 2, trefoil factor 3 (Tff3), enteroendocrine marker chromogranin A and murine atonal homolog 1 (Math1). Enterocyte differentiation was found to be pHi dependent with acidic pHi reducing, and alkaline pHi stimulating the expression of enterocyte differentiation markers in Caco2Bbe cells. A thicker mucus layer, longer crypts and an expanded brush border membrane zone of sodium/hydrogen exchanger 3 (NHE3) abundance may explain the lack of inflammation and the normal fluid absorptive rate in nhe2-/- colon. The results suggest that NHE2 expression is activated when colonocytes emerge from the stem cell niche. Its activity increases progenitor cell pHi and thereby supports absorptive enterocyte differentiation.

Relationship Between Urinary Phosphate and All-Cause and Cardiovascular Mortality in a National Population-Based Longitudinal Cohort Study

High dietary phosphate intake may lead to adverse outcomes including cardiovascular disease (CVD). Urinary phosphate excretion, a marker of intestinal phosphate absorption, may be a more reliable marker of phosphate homeostasis in steady state than serum phosphate. Studies report good agreement between urine phosphate-to-creatinine ratio (uPiCr) and 24-hour urinary phosphate; however, whether uPiCr is associated with increased risk of CVD or mortality remains uncertain. This study aimed to assess the relationship between uPiCr and all-cause and CVD mortality. This is an observational longitudinal cohort study using data from the population-based national Australian Diabetes, Obesity and Lifestyle study (n=10,014 participants). Non-linear association between uPiCr and all-cause and CVD mortality was assessed using fractional polynomial transformations. Cox proportional hazards regression models were used to estimate adjusted hazard ratios for all-cause and CVD mortality. Median age [interquartile range] was 50 [41-62] years, and 46% were male. Median uPiCr was 1.38 [1.02-1.79] mmol/mmol. Median follow-up time was 16.9years with 1,735 deaths. uPiCr was associated with all-cause and CVD mortality in univariate models and when adjusted for age and gender. However, associations were not significant in multivariate models. Sensitivity analyses excluding participants with chronic kidney disease (CKD) revealed a significant J-shaped association between uPiCr and all-cause mortality. Urine phosphate alone showed an association with increased all-cause mortality in a similar J-shape relationship. Although no association between uPiCr and all-cause and CVD mortality was observed in multivariate analyses in the whole cohort, a significant relationship between uPiCr and mortality in those without CKD suggests that uPiCr may have predictive validity for future adverse outcomes in people with no CKD.

Src family kinases inhibit differentiation of intestinal epithelial cells through the Hippo effector YAP1

ABSTRACTIntestinal cell lineage differentiation is a tightly regulated mechanism that involves several intracellular signaling pathways affecting the expression of a variety of transcription factors, which ultimately regulate cell specific gene expression. Absorptive and goblet cells are the two main epithelial cell types of the intestine. Previous studies from our group using an shRNA knockdown approach have shown that YAP1, one of the main Hippo pathway effectors, inhibits the differentiation of these two cell types. In the present study, we show that YAP1 activity is regulated by Src family kinases (SFKs) in these cells. Inhibition of SFKs led to a sharp reduction in YAP1 expression at the protein level, an increase in CDX2 and the P1 forms of HNF4α and of absorptive and goblet cell differentiation specific markers. Interestingly, in Caco-2/15 cells which express both YAP1 and its paralog TAZ, TAZ was not reduced by the inhibition of SFKs and its specific knockdown rather impaired absorptive cell differentiation indicating that YAP1 and TAZ are not always interchangeable for regulating cell functions.This article has an associated First Person interview with the first author of the paper.

A Matched Case-Control Study of Noncholesterol Sterols and Fatty Acids in Chronic Hemodialysis Patients.

Dyslipidemia is common among patients on hemodialysis, but its etiology is not fully understood. Although changes in cholesterol homeostasis and fatty acid metabolism play an important role during dialysis, the interaction of these metabolic pathways has yet to be studied in sufficient detail. In this study, we enrolled 26 patients on maintenance hemodialysis treatment (high-volume hemodiafiltration, HV HDF) without statin therapy (17 men/9 women) and an age/gender-matched group of 26 individuals without signs of nephropathy. The HV-HDF group exhibited more frequent signs of cardiovascular disease, disturbed saccharide metabolism, and altered lipoprotein profiles, manifesting in lower HDL-C, and raised concentrations of IDL-C and apoB-48 (all p < 0.01). HV-HDF patients had higher levels of campesterol (p < 0.01) and β-sitosterol (p = 0.06), both surrogate markers of cholesterol absorption and unchanged lathosterol concentrations. Fatty acid (FA) profiles were changed mostly in cholesteryl esters, with a higher content of saturated and n-3 polyunsaturated fatty acids (PUFA) in the HV-HDF group. However, n-6 PUFA in cholesteryl esters were less abundant (p < 0.001) in the HV-HDF group. Hemodialysis during end-stage kidney disease induces changes associated with higher absorption of cholesterol and disturbed lipoprotein metabolism. Changes in fatty acid metabolism reflect the combined effect of renal insufficiency and its comorbidities, mostly insulin resistance.