Fecal Bile Acid Loss Research Articles

Targeting Gut Microbiota with Probiotics and Phenolic Compounds in the Treatment of Atherosclerosis: A Comprehensive Review.

Atherosclerosis (AS) is a chronic inflammatory vascular disease. Dysregulated lipid metabolism, oxidative stress, and inflammation are the major mechanisms implicated in the development of AS. In addition, evidence suggests that gut dysbiosis plays an important role in atherogenesis, and modulation of the gut microbiota with probiotics and phenolic compounds has emerged as a promising strategy for preventing and treating AS. It has been shown that probiotics and phenolic compounds can improve atherosclerosis-related parameters by improving lipid profile, oxidative stress, and inflammation. In addition, these compounds may modulate the diversity and composition of the gut microbiota and improve atherosclerosis. The studies evaluated in the present review showed that probiotics and phenolic compounds, when consumed individually, improved atherosclerosis by modulating the gut microbiota in various ways, such as decreasing gut permeability, decreasing TMAO and LPS levels, altering alpha and beta diversity, and increasing fecal bile acid loss. However, no study was found that evaluated the combined use of probiotics and phenolic compounds to improve atherosclerosis. The available literature highlights the synergistic potential between phenolic compounds and probiotics to improve their health-promoting properties and functionalities. This review aims to summarize the available evidence on the individual effects of probiotics and phenolic compounds on AS, while providing insights into the potential benefits of nutraceutical approaches using probiotic strains, quercetin, and resveratrol as potential adjuvant therapies for AS treatment through modulation of the gut microbiota.

Time-Restricted Feeding Reduces Atherosclerosis in LDLR KO Mice but Not in ApoE Knockout Mice.

Dyslipidemia increases cardiovascular disease risk, the leading cause of death worldwide. Under time-restricted feeding (TRF), wherein food intake is restricted to a consistent window of <12 hours, weight gain, glucose intolerance, inflammation, dyslipidemia, and hypercholesterolemia are all reduced in mice fed an obesogenic diet. LDLR (low-density lipoprotein receptor) mutations are a major cause of familial hypercholesterolemia and early-onset cardiovascular disease. We subjected benchmark preclinical models, mice lacking LDLR-knockout or ApoE knockout to ad libitum feeding of an isocaloric atherogenic diet either ad libitum or 9 hours TRF for up to 13 weeks and assessed disease development, mechanism, and global changes in hepatic gene expression and plasma lipids. In a regression model, a subset of LDLR-knockout mice were ad libitum fed and then subject to TRF. TRF could significantly attenuate weight gain, hypercholesterolemia, and atherosclerosis in mice lacking the LDLR-knockout mice under experimental conditions of both prevention and regression. In LDLR-knockout mice, increased hepatic expression of genes mediating β-oxidation during fasting is associated with reduced VLDL (very-low-density lipoprotein) secretion and lipid accumulation. Additionally, increased sterol catabolism coupled with fecal loss of cholesterol and bile acids contributes to the atheroprotective effect of TRF. Finally, TRF alone or combined with a cholesterol-free diet can reduce atherosclerosis in LDLR-knockout mice. However, mice lacking ApoE, which is an important protein for hepatic lipoprotein reuptake do not respond to TRF. In a preclinical animal model, TRF is effective in both the prevention and regression of atherosclerosis in LDLR knockout mice. The results suggest TRF alone or in combination with a low-cholesterol diet can be a lifestyle intervention for reducing cardiovascular disease risk in humans.

Effect of carbohydrate source, feeding level (restricted vs. satiation) and their combination on nutrient digestibility, bile acid balance, faecal waste production and characteristics of yellowtail kingfish (Seriola lalandi)

The effect of carbohydrate source on nutrient digestibility, bile acid balance, faecal waste production and characteristics were investigated in yellowtail kingfish (Seriola lalandi). A starch diet and two non-starch polysaccharides (NSP) diets with different NSP sources were used in this study. A diet containing 12 % gelatinized wheat flour as the starch diet, and two diets with distinct non-starch polysaccharides (NSP) sources: soybean hulls (SH) and sugar beet pulp (SBP) at an inclusion level of 10 %, were studied. Each diet was tested in triplicate fish tanks. To determine if feeding level affects diet, restricted and satiation feeding levels were used. After four weeks of restrictive feeding, fish were fed satiation for two weeks. The dietary effect on nutrient digestibility and faecal waste production was dependent on feeding level, whereas the dietary effect on faecal waste characterises was independent of feeding level. SBP diet protein and fat digestibility was highest during restricted and satiation feeding. Satiation feeding reduced nutrient digestibility in all diets, most pronounced in SH and least in SBP. Faecal bile acid loss did not explain fat digestibility differences between the three diets. Both NSP diets increased faecal waste production but decreased bile acid content, resulting in similar bile acid loss to the starch diet. SBP had the highest faecal removal efficiency and the lowest non-removed faeces despite high waste production SH resulted in similar amount of non-removed faeces compared to the starch diet. To conclude, NSP type affected nutrient digestibility, bile acid balance, faecal waste production, and faecal characteristics differently than starch in yellowtail kingfish. Starch resulted in higher FCR and thus lower growth performance in yellowtail kingfish compared to NSP despite higher organic matter digestibility. Adding NSP to their RAS diet may improve faecal integrity without affecting macronutrient digestibility. However, different NSP forms affect nutrient digestion and faeces integrity differently.

Divergence in aerobic capacity influences hepatic and systemic metabolic adaptations to bile acid sequestrant and short-term high-fat/sucrose feeding in rats.

High versus low aerobic capacity significantly impacts the risk for metabolic diseases. Rats selectively bred for high or low intrinsic aerobic capacity differently modify hepatic bile acid metabolism in response to high-fat diets (HFDs). Here we tested if a bile acid sequestrant would alter hepatic and whole body metabolism differently in rats with high and low aerobic capacity fed a 1-wk HFD. Male rats (8 mo of age) that were artificially selected to be high (HCR) and low-capacity runners (LCR) with divergent intrinsic aerobic capacities were transitioned from a low-fat diet (LFD, 10% fat) to an HFD (45% fat) with or without a bile acid sequestrant (BA-Seq, 2% cholestyramine resin) for 7 days while maintained in an indirect calorimetry system. HFD + BA-Seq increased fecal excretion of lipids and bile acids and prevented weight and fat mass gain in both strains. Interestingly, HCR rats had increased adaptability to enhance fecal bile acid and lipid loss, resulting in more significant energy loss than their LCR counterpart. In addition, BA-Seq induced a greater expression of hepatic CYP7A1 gene expression, the rate-limiting enzyme of bile acid synthesis in HCR rats both on HFD and HFD + BA-Seq diets. HCR displayed a more significant reduction of RQ in response to HFD than LCR, but HFD + BA-Seq lowered RQ in both groups compared with HFD alone, demonstrating a pronounced impact on metabolic flexibility. In conclusion, BA-Seq provides uniform metabolic benefits for metabolic flexibility and adiposity, but rats with higher aerobic capacity display adaptability for hepatic bile acid metabolism.NEW & NOTEWORTHY The administration of bile acid sequestrant (BA-Seq) has uniform metabolic benefits in terms of metabolic flexibility and adiposity in rats with high and low aerobic capacity. However, rats with higher aerobic capacity demonstrate greater adaptability in hepatic bile acid metabolism, resulting in increased fecal bile acid and lipid loss, as well as enhanced fecal energy loss.

Treatment of intestinal and liver features in cystic fibrosis mice by the osmotic laxative polyethylene glycol

BackgroundCystic Fibrosis (CF) is a genetic disease affecting multiple organs, primarily the lungs and digestive system. Improved pulmonary management significantly improved life expectancy of CF patients. As a result, extrapulmonary manifestations, including gastrointestinal and liver-related symptoms, have become more relevant. We previously reported that the osmotic laxative polyethylene glycol (PEG), which hydrates the CF gut, decreased fecal bile acid loss in a CF knockout mouse model. In the current study we investigated the effect of PEG on intestinal fat and cholesterol absorption and on CF-related liver features in a CF mouse model with the most common CF-causing mutation. MethodsCftrΔF508/ΔF508 (n=13) and wild-type (WT) (n=12) mice were treated with PEG for 2 weeks. The intestinal and hepatic effects of PEG were assessed by analysis of intestinal bile acid, cholesterol, and fat fluxes, transcriptome analysis as well as histology. ResultsPEG improved intestinal malabsorption of bile acids, fat, and cholesterol in CftrΔF508/ΔF508 mice. Transcriptome analysis showed that PEG partially restored the intestinal signaling of nuclear receptors RXR, FXR, and CAR/PXR, which are involved in bile acid and xenobiotic metabolism. PEG also reduced liver inflammation in CF mice as assessed by transcriptome and histological analyses. ConclusionsPEG, a non-absorbable osmotic laxative, improved intestinal nutrient absorption, intestinal bile acid and xenobiotic signaling, as well as CF-related liver features. These findings highlight the potential for osmotic laxation to improve gastrointestinal complications of CF in humans.

Effect of dietary NSP level and bile acid supplementation on nutrient digestibility and the bile acid metabolism in rainbow trout (Oncorhynchus mykiss)

The effects of dietary bile acid supplementation (BAS) on apparent digestibility coefficients (ADC) and the bile acid metabolism in rainbow trout (Oncorhynchus mykiss) were investigated for diets differing in non-starch polysaccharide (NSP) level. Four experimental diets were formulated according to an 2 by 2 factorial design. A low-NSP and High-NSP diet (0 vs. 160 g kg−1 inclusion of an NSP-rich ingredient mixture) were first formulated. The aim of this was to create differences in the amount of faecal waste produced, and consequently as previously shown in rainbow, the amount of faecal bile acid loss (FBAL). Both NSP-level diets were tested with 0% and 0.3% BAS (0 vs. 3 g kg−1 inclusion of a bile acid mixture). The bile acid mixture contained taurocholic acid (T-CA) and glycocholic acid (G-CA) in a 2:1 ratio. Glycocholic acid does not naturally occur in trout and was used as marker to see if supplemented bile acids are efficiently absorbed and enter enterohepatic circulation (EHC). Fish were fed to apparent satiation for 42 days. Dietary NSP level did not enhance FBAL. BAS was beneficial for fat ADC, but not for the ADC of protein and carbohydrates. BAS improved fat ADC regardless of NSP level, which suggests that bile acids are a limiting factor for fat digestion in rainbow trout. Total bile acid synthesis was a 4-fold lower in fish fed the 0.3% BAS diets compared to the 0% BAS diets. Lower bile acid synthesis with BAS occurred alongside enlarged body and liver + gallbladder bile acid pools and a higher content of bile acids in the chyme. These higher bile acid levels most likely caused a negative feedback inhibition of bile acid synthesis. Negative synthesis rates of G-CA were found when feeding the 0.3% BAS diets, which suggests that this bile acid is catabolised or converted into other bile acid types in rainbow trout. The enlarged pool of T-CA, but especially of the body foreign G-CA, with BAS in both the body and liver + gallbladder shows that dietary bile acids are effectively taking part in EHC. The relative absorption of T-CA and G-CA over the different intestinal compartments was comparable, which shows that EHC does not differentiate between T-CA and G-CA. While relative absorption of bile acids was highest between the distal intestine and the faeces, the absolute decrease in chyme bile acid content was highest between the pyloric region and the mid intestine. The latter shows that significant bile acid absorption occurs more proximal in the intestine of rainbow trout than previously thought.

Rats with high aerobic capacity display enhanced transcriptional adaptability and upregulation of bile acid metabolism in response to an acute high-fat diet.

Rats selectively bred for the high intrinsic aerobic capacity runner (HCR) or low aerobic capacity runner (LCR) show pronounced differences in susceptibility for high‐fat/high sucrose (HFHS) diet‐induced hepatic steatosis and insulin resistance, replicating the protective effect of high aerobic capacity in humans. We have previously shown multiple systemic differences in energy and substrate metabolism that impacts steatosis between HCR and LCR rats. This study aimed to investigate hepatic‐specific mechanisms of action via changes in gene transcription. Livers of HCR rats had a greater number of genes that significantly changed in response to 3‐day HFHS compared with LCR rats (171 vs. 75 genes: >1.5‐fold, p < 0.05). HCR and LCR rats displayed numerous baseline differences in gene expression while on a low‐fat control diet (CON). A 3‐day HFHS diet resulted in greater expression of genes involved in the conversion of excess acetyl‐CoA to cholesterol and bile acid (BA) synthesis compared with the CON diet in HCR, but not LCR rats. These results were associated with higher fecal BA loss and lower serum BA concentrations in HCR rats. Exercise studies in rats and mice also revealed higher hepatic expression of cholesterol and BA synthesis genes. Overall, these results suggest that high aerobic capacity and exercise are associated with upregulated BA synthesis paired with greater fecal excretion of cholesterol and BA, an effect that may play a role in protection against hepatic steatosis in rodents.

Effect of type of dietary non‐protein energy source (starch vs. fat) on the body bile acid pool size and composition, faecal bile acid loss and bile acid synthesis in rainbow trout (Oncorhynchusmykiss)

Effect of type of dietary non‐protein energy source (starch vs. fat) on the body bile acid pool size and composition, faecal bile acid loss and bile acid synthesis in rainbow trout (<i>Oncorhynchus</i><i>mykiss</i>)

Time‐related changes in nutrient digestibility and faecal bile acid loss of rainbow trout ( Oncorhynchus mykiss ) as affected by dietary fat level and non‐starch polysaccharide level

Time-related changes in apparent digestibility coefficients (ADC) and faecal bile acid loss as affected by dietary fat level and non-starch polysaccharide (NSP) level were studied in rainbow trout (Oncorhynchus mykiss). Low-Fat versus High-Fat and Low-NSP versus High-NSP diets were formulated. Fish were fed for 6 weeks to apparent satiation and faeces were sampled in week 2, 4 and 6. Most nutrient ADC increased with time and increases were consistently larger for the High-Fat and High-NSP diets. Nevertheless, time of adaptation was equal between diets/nutrients and steady-state digestion was reached at week 3. Although faecal bile acid loss was affected by diet, the observed time-related decrease in faecal bile acid loss was mainly driven by a decrease in feed intake and faeces production. Fat ADC improved over time regardless of NSP level, which does not support the hypothesis that enhanced faecal bile acid loss (related to satiation feeding of high-NSP diets) causes a depletion of the total body bile acid pool size that is critical for proper fat digestion. The high-fat diets consistently resulted in the lowest Fat ADC, which might have been related to a lower availability of bile acids relative to the level of dietary fat.

The effect of dietary non-starch polysaccharide level and bile acid supplementation on fat digestibility and the bile acid balance in rainbow trout (Oncorhynchus mykiss)

This study investigated in rainbow trout (Oncorhynchus mykiss) if dietary bile acid supplementation is effective in restoring hampered fat digestibility related to conditions that enhance fecal bile acid loss (i.e., high dietary non-starch polysaccharide (NSP) level and high feeding level). Four diets were formulated according to a two-by-two factorial design. A Low- and High-NSP level (0 vs. 160 g kg-1 inclusion of a NSP-rich ingredient mixture) and two bile acid supplementation levels (0 vs. 2 g kg-1 inclusion of sodium taurocholate) were tested. A contrast in feeding level (i.e., feed intake) was created by subsequently feeding fish restrictively (1.1% BW d-1) for four weeks and to satiation for three weeks. The apparent digestibility coefficient (ADC) of all nutrients was affected by feeding period (i.e., restricted vs. satiation feeding), but the effect was dependent on diet composition with the ADC decline between feeding periods being larger for the High-NSP diets. The ADC of all macronutrients decreased alongside dietary NSP level, but this decrease was much more pronounced for fat compared to starch and protein, especially during satiation feeding (6.7%). This large drop in fat ADC during satiation feeding of NSP-rich diets occurred alongside enhanced fecal bile acid loss and correlated with a negative bile acid balance. The correlation between the bile acid balance and fat ADC found during satiation feeding of diets without bile acid supplementation was not present in fish fed diets with bile acid supplementation. In contrast to fat ADC, the ADC of protein and starch were independent from bile acid supplementation. In conclusion, dietary bile acid supplementation is an effective way to remediate decreased fat ADC related to enhanced fecal bile acid loss in rainbow trout, but is not effective in improving protein and starch ADC.

The effect of dietary protein source (fishmeal vs. plant protein) and non‐starch polysaccharide level on fat digestibility and faecal bile acid loss in rainbow trout (Oncorhynchus mykiss)

This study investigated in rainbow trout (Oncorhynchus mykiss) if diet composition and feeding level affect faecal bile acid loss, and whether this reflects on the apparent digestibility coefficient (ADC) of fat. Six diets were formulated with either fishmeal or plant protein as main protein source. This created a contrast in the supply of bile acids, the bile acid precursor cholesterol, taurine and the taurine precursors (methionine + cysteine) involved in bile acid conjugation. For both protein sources, three diets were formulated with increasing inclusion of a non-starch polysaccharide (NSP)-rich ingredient mixture (0.0, 82.0 and 164.2 g/kg diet). This aimed at enhancing faecal bile acid loss. Fish were fed both restrictively (1.2% BW/day) and to satiation. A similar fat ADC was found when substituting fishmeal with a plant protein mixture, suggesting that the lower content of bile acids, cholesterol, taurine, methionine and cysteine in the plant-based diets did not limit fat digestion. Faecal bile acid loss increased alongside dietary NSP level, however, only during satiation feeding and most strongly for fish fed the fishmeal-based diets. Enhanced faecal bile acid loss was not caused by NSP-bile acid binding/entrapment, but by an increase in faeces production. During satiation feeding, fat ADC negatively correlated with faecal bile acid loss. From this it is concluded that bile acid availability/synthesis can become limiting for fat digestion in rainbow trout under conditions that enhance faecal bile acid loss (i.e. dietary NSP level and feeding level).

Chronic diarrhea, bile acids, and Clostridia.

Excessive fecal bile acid (BA) loss causes symptoms in a large proportion of people diagnosed with irritable bowel syndrome with diarrhea, a common functional bowel disorder. This BA diarrhea (BAD) results from increased hepatic synthesis of BAs, with impaired negative feedback regulation by the ileal hormone fibroblast growth factor 19 (FGF19). In this issue of the JCI, Zhao et al. investigated BA metabolism, including fecal BAs, serum BAs, and FGF19, in patients and controls. They identified associations between fecal bacterial BA metabolism and specific microbiota, especially Clostridium scindens. These findings have been tested in a mouse model using microbiota transplants and antibiotic treatment. This group of organisms has potential as a biomarker for BAD and to be a target for therapy.

Cholecystectomy and Biliary Sphincterotomy Increase Fecal Bile Loss and Improve Lipid Profile in Dyslipidemia.

Bile is the only significant pathway for cholesterol elimination. Cholecystectomy (CS) increases fecal bile acid loss, and endoscopic biliary sphincterotomy (ES) is thought to have a similar effect. We speculated that a combined effect of ES + CS would further enhance fecal bile acid loss, potentially causing lipid profile changes in these patients. Fecal bile acids and sterols were determined using gas chromatography in cohorts of post-CS + ES, post-CS and in healthy controls. The effect of ES + CS on blood lipid profile was assessed retrospectively in a single-center cohort of post-CS + ES patients, using a computerized database. Parameters of interest included demographics, medical history, and lipid profiles. Fecal primary bile acid concentrations were increased after CS + ES compared to CS and controls (cholic acid [CA] 1.4ng/mg vs. 0.26ng/mg, p = 0.02 vs. 0.23ng/mg, p = 0.004, chenodeoxycholic acid [CDCA] 1.92ng/mg vs. 0.39ng/mg, p = 0.02 vs. 0.23ng/mg, p = 0.01, respectively). Fecal cholesterol excretion was similar in all three groups. Baseline serum lipid profile and subsequent changes following CS + ES were correlated. In patients with baseline hypercholesterolemia (total cholesterol (TC) > 200mg/dl), TC levels decreased by 28.5mg/dl, and LDL levels decreased by 21.5mg/dl. The effect was more pronounced in those with TC > 200mg/dl, despite of statin intake. In patients with hypertriglyceridemia [triglycerides (TG) > 200mg/dl], TG decreased by 67.8mg/dl following ES + CS. Among patients without dyslipidemia or dyslipidemia with adequate response to statins, the effect of ES + CS on lipid profile was minor. Fecal bile acid loss increases following CS + ES. The effect on blood lipid profile depends on baseline TC and TG levels. Lipid profile is improved in dyslipidemic patients, while the impact of CS + ES is minimal on the normolipemic population.

Defective FXR-FGF15 signaling and bile acid homeostasis in cystic fibrosis mice can be restored by the laxative polyethylene glycol.

The gastrointestinal phenotype of cystic fibrosis (CF) features intestinal bile acid (BA) malabsorption, impaired intestinal farnesoid X receptor (FXR) activation, and consequently reduced fibroblast growth factor 19 (FGF19, FGF15 in mice) production. The osmotic laxative polyethylene glycol (PEG) has been shown to decrease intestinal mucus accumulation in CF mice and could, by doing so, improve BA reabsorption. Here we determined the effect of PEG on BA excretion and FXR-FGF15 signaling in CF mice. Male Cftr-/-tm1Unc (CF) and wild-type (WT) littermates were administered PEG 4000 in drinking water and fed either chow or a semisynthetic diet. PEG was withdrawn for 3 days before termination. Fecal BA excretion was measured at PEG dosages of 37 g/l (100%) and 0 g/l (0%). Ileal FXR activation was assessed by gene expression of its downstream targets Fgf15 and small heterodimer partner ( Shp). In CF mice, PEG withdrawal increased fecal BA excretion on either diet compared with full PEG dosage (chow, 2-fold, P = 0.06; semisynthetic, 4.4-fold, P = 0.007). PEG withdrawal did not affect fecal BA excretion in WT mice on either diet. After PEG withdrawal, gene expression levels of intestinal FXR target genes Fgf15 and Shp were decreased in CF mice but unaffected in WT littermates. PEG did not affect the gene expression of the main intestinal BA transporter apical sodium-dependent bile acid transporter (ASBT). PEG treatment ameliorates intestinal BA malabsorption in CF mice and restores intestinal FXR-FGF15 signaling, independent from Asbt gene expression. These findings highlight the potential of PEG in the prevention and treatment of the gastrointestinal phenotype of CF. NEW & NOTEWORTHY A gastrointestinal feature of cystic fibrosis is bile acid malabsorption and consequent impairment of farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signaling. FXR-FGF15 signaling regulates various metabolic processes and could be implicated in metabolic and gastrointestinal complications of cystic fibrosis, such as diabetes and liver disease. In cystic fibrosis mice, treatment with the osmotic laxative polyethylene glycol is associated with decreased fecal bile acid loss and restoration of FXR-FGF15 signaling.

Infant Formula Feeding Increases Hepatic Cholesterol 7α Hydroxylase (CYP7A1) Expression and Fecal Bile Acid Loss in Neonatal Piglets

During the postnatal feeding period, formula-fed infants have higher cholesterol synthesis rates and lower circulating cholesterol concentrations than their breastfed counterparts. Although this disparity has been attributed to the uniformly low dietary cholesterol content of typical infant formulas, little is known of the underlying mechanisms associated with this altered cholesterol metabolism phenotype. We aimed to determine the molecular etiology of diet-associated changes in early-life cholesterol metabolism with the use of a postnatal piglet feeding model. Two-day-old male and female White-Dutch Landrace piglets were fed either sow milk (Sow group) or dairy-based (Milk group; Similac Advance powder) or soy-based (Soy group; Emfamil Prosobee Lipil powder) infant formulas until day 21. In addition to measuring serum cholesterol concentrations, hepatic and intestinal genes involved in enterohepatic circulation of cholesterol and bile acids were analyzed by real-time reverse-transcriptase polymerase chain reaction and Western blot. Bile acid concentrations were measured by liquid chromatography-mass spectrometry in serum, liver, and feces. Compared with the Sow group, hepatic cholesterol 7α hydroxylase (CYP7A1) protein expression was 3-fold higher in the Milk group (P < 0.05) and expression was 10-fold higher in the Soy group compared with the Milk group (P < 0.05). Likewise, fecal bile acid concentrations were 3-fold higher in the Soy group compared with the Milk group (P<0.05). Intestinal mRNA expression of fibroblast factor 19 (Fgf19) was reduced in the Milk and Soy groups, corresponding to 54% and 67% decreases compared with the Sow group. In the Soy group, small heterodimer protein (SHP) protein expression was 30% lower compared with the Sow group (P<0.05). These results indicate that formula feeding leads to increased CYP7A1 protein expression and fecal bile acid loss in neonatal piglets, and this outcome is linked to reduced efficacy in inhibiting CYP7A1 expression through FGF19 and SHP transcriptional repression mechanisms.

Glucocorticoid treatment alters systemic bile acid homeostasis by regulating the biosynthesis and transport of bile salts

BackgroundDysregulation of systemic bile acid homeostasis can lead to cholestatic liver diseases and metabolic syndromes. As important anti-inflammatory and immunosuppressive drugs, synthetic glucocorticoids (GCs) are used to treat several cholestatic disorders, including biliary atresia (BA), because of their effects on the regulation of bile acid metabolism. However, the molecular mechanisms that underlie GCs regulation of bile acid homeostasis remain unclear. AimsTo provide a mechanistic basis for the effects of GCs on bile acid homeostasis. MethodsMale rats were treated with methylprednisolone for 7 days with slow-release osmotic pumps under physiological and cholestatic status that was induced by bile duct ligation (BDL). Expression of glucocorticoid receptor (GR) and genes related to bile acid metabolism was investigated using western blotting, qRT-PCR and immunohistochemistry. ResultsWe show here that sustained treatment with GCs in rats disrupts the normal changes in systemic bile acid distribution by elevating plasma bile acid levels and reducing faecal bile acid loss. Treatment with GCs stimulated bile acid absorption in the ileum by increasing expression of the apical sodium-dependent bile acid transporter (Asbt). Concomitantly, administration of GCs enhanced liver bile acid uptake by increasing the expression of the major hepatocyte basolateral bile transporter (Ntcp). The reduced expression of a bile acid synthesis rate-controlling enzyme, Cyp7a1, suggests that treatment with GCs suppressed hepatic bile acid synthesis. ConclusionOur study provides evidence that GCs can increase enterohepatic bile acid circulation through regulation of the biosynthesis and transport of bile salts, which suggests that plasma bile acid levels should be monitored during treatment with GCs in patients with BA.

PTU-326 A positive faecal calprotectin does not predict bile acid diarrhoea

<h3>Introduction</h3> Bile acid diarrhoea (BAD) is a common disorder which in the primary, idiopathic form may affect up to 1% of the population. ⁷⁵Selenium Homocholic Acid Taurate (SeHCAT) 7 day retention is used in diagnosis, predicting faecal bile acid loss but is not available to primary care practitioners. The condition is chronic, causes significant morbidity and is easily treatable with bile acid sequestrants. Calprotectin is released into the intestinal lumen during neutrophil activation and apoptosis. A Faecal Calprotectin (FC) of &gt;50 µg/g in the primary care setting has been reported to have a sensitivity and specificity of 82% and 77% respectively for organic GI disease.¹In 2013 NICE recommended its use in primary care as a decision aid.²Since primary BAD does not have an inflammatory pathogenesis, we hypothesised that the faecal calprotectin test was not sensitive for bile acid diarrhoea. <h3>Method</h3> Faecal calprotectin was measured in patients attending for SeHCAT testing at Imperial Healthcare NHS trust between March 2014 and July 2014. Patients with known bile acid diarrhoea, or inflammatory bowel disease were also recruited from the gastroenterology clinic during the same period. All patients had undergone lower GI endoscopy previously. Faecal samples were analysed in the Imperial Healthcare Biochemistry Laboratory using a commercially available ELISA kit (EliA, Phadia AB, Uppsala, Sweden). <h3>Results</h3> 55 patients were recruited. Of these 32 (58%) were female, the mean age was 53 (range 23–88) and 41 (75%) had a SeHCAT scan, of which 25 (61%) were positive (&lt;15% 7d retention). Overall 23 (42%) had a positive FC (&gt;50 µg/g); 21 (38%) were known, or subsequently found to have traditional organic GI disease (14 Crohn’s, 3 ulcerative colitis, 1 radiation colitis, 3 hepatobiliary). 9 (22%) patients with a positive SeHCAT had a positive FC, all patients (n = 5, 12%) with IBD and a positive SeHCAT had a positive FC. If primary bile acid diarrhoea was excluded in the definition of organic disease, FC had a negative predictive value of 88% (95% CI: 71–96%) and a sensitivity and specificity of 83% (95% CI: 61–95%) and 88% (95% CI: 71–96%) respectively. However, if primary bile acid diarrhoea was included in the definition of organic disease, then FC has a negative predictive value of 43% (95% CI: 26–62%) and a sensitivity and specificity of 54% (35% CI: 37–70%) and 88% (95% CI: 62–98%) respectively. <h3>Conclusion</h3> By including primary bile acid diarrhoea in the definition of organic disease the sensitivity of FC falls to 54%, which is unacceptable for a screening test. Patients with undiagnosed BAD are likely to be denied referral to secondary care for diagnosis and subsequent treatment due to the current guidance. <h3>Disclosure of interest</h3> None Declared. <h3>References</h3> Polychronis P, <i>et al</i>. Scand J Gastroenterol. 2013;48:1048–1054 NICE diagnostics guidance 11, Issued Oct 2013

PTH-251 Bile acid diarrhoea is associated with gallstones

Introduction Bile acid diarrhoea (BAD) is a common disorder which in the primary, idiopathic form may result from low serum fibroblast growth factor 19 (FGF19) producing impaired regulation of bile acid synthesis. 75 Selenium Homocholic Acid Taurate (SeHCAT) 7day retention is used in diagnosis, predicting faecal bile acid loss and correlating with fasting serum FGF19. Several groups have shown that overweight and obesity are associated with BAD and low FGF19. Reduced FXR target gene expression, of which FGF19 is one, is associated with gallstones. We hypothesised that the two conditions might share pathophysiologic mechanisms and commonly coexist. Method SeHCAT 7 day retention values were collected between 2003–2014 in patients being investigated for chronic diarrhoea. Other conditions known to be associated with BAD such as cholecystectomy or Crohn’s disease were recorded. A subset of these patients had fasting FGF19 measured. Retrospectively, gallbladder imaging was added to database following cross-referencing with the NHS trust’s PACS system. Where multiple investigations had been performed, the test nearest to the date of the SeHCAT test was recorded. Imaging reporting gallbladder polyps without gallstones were excluded from the final analysis. Results Of 578 SeHCAT values on the database, 303 (52%) were positive with a value Conclusion Bile acid diarrhoea is associated with gallstones, even when adjusted for cholecystectomy which is a known risk factor for BAD. Bile acid diarrhoea and gallstones may share a pathophysiological mechanism. Disclosure of interest None Declared.

Micelle Sequestrant Polymers as Novel Therapeutics to Treat Obesity

Thirty‐five percent of the United States population is classified as overweight or obese. Several options exist to treat obese patients; however, currently available therapies are associated with side effects or poor long term compliance necessitating development of more efficacious and accepted therapeutics for treating obesity. We synthesized and evaluated a library of Micelle Sequestrant Polymers (MSP) as novel orally dosed non‐absorbable molecules that bind intestinal micelles (i.e., dietary triglycerides, bile acids, and cholesterol) and prevent their digestive absorption. Individual MSPs were incorporated into a high fat diet (HFD, 45% kcal from fat) at 0.5% (wt/wt) and fed to mice. Feeding mice a MSP containing HFD increased fecal elimination of triglycerides. Interestingly, fecal elimination of bile acids was increased by some, but not all MSP containing HFDs. Of importance, fecal bile acid, fecal triglyceride, and weight loss was increased in mice treated with 300 or 1,500 mg/kg/day of a top performing MSP via daily oral gavage for 5‐days compared to mice fed HFD given control gavage (H2O), although weight loss in the 300 mg/kg group did not achieve the level of statistical significance. The data suggest that MSPs can bind whole intestinal micelles and enhance fecal elimination of bile acids and triglycerides. Taken together, MSPs may serve as a novel weight loss platform for inhibiting excess caloric intake by preventing absorption of dietary triglycerides. Furthermore, increasing fecal elimination of bile acids may also simultaneously serve as a cholesterol lowering agent by increasing de novo bile acid synthesis, a metabolite of cholesterol.

PTH-107 A Preliminary Study Of The Effects Of Obeticholic Acid, A Farnesoid X Receptor Agonist, In Patients With Chronic Diarrhoea Secondary To Crohn’s Ileal Disease

IntroductionChronic diarrhoea occurs frequently as a result of excess faecal bile acid (BA) loss. Secondary bile acid diarrhoea (SBAD) is common in Crohn’s disease with ileal inflammation and/or resection. The...