Fecal Bile Acid Excretion Research Articles

Targeting bile acid metabolism in obesity reduction: A systematic review and meta-analysis.

A systematic review and meta-analysis was conducted of studies that address the association of bile acid (BA) with obesity and of studies on the effects of treatment in patients with obesity on BA metabolism, assessed from systemic BA, fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4) level, and faecal BA. We searched PubMed, Embase, and the Cochrane Library from inception to 1 August 2019 using the keywords obesity, obese, body mass index, and overweight with bile acid, FGF19, FXR, and TGR5. Two reviewers independently searched, selected, and assessed the quality of studies. Data were analysed using either fixed or random effect models with inverse variance weighting. Of 3771 articles, 33 papers were relevant for the association of BA with obesity of which 22 were included in the meta-analysis, and 50 papers were relevant for the effect of obesity interventions on BA of which 20 were included in the meta-analysis. Circulating fasting total BA was not associated with obesity. FGF19 was inversely and faecal BA excretion was positively associated with obesity. Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) modulated BA metabolism, ie, increased BA and FGF19. Our results indicate that BA metabolism is altered in obesity. Certain bariatric surgeries including RYGB and SG modulate BA, whether these underlie the beneficial effect of the treatment should be investigated.

Probiotic Lactobacillus rhamnosus GG Prevents Liver Fibrosis Through Inhibiting Hepatic Bile Acid Synthesis and Enhancing Bile Acid Excretion in Mice.

Background and AimsCholestatic liver disease is characterized by gut dysbiosis and excessive toxic hepatic bile acids (BAs). Modification of gut microbiota and repression of BA synthesis are potential strategies for the treatment of cholestatic liver disease. The purpose of this study was to examine the effects and to understand the mechanisms of the probiotic Lactobacillus rhamnosus GG (LGG) on hepatic BA synthesis, liver injury, and fibrosis in bile duct ligation (BDL) and multidrug resistance protein 2 knockout (Mdr2−/−) mice.Approach and ResultsGlobal and intestine‐specific farnesoid X receptor (FXR) inhibitors were used to dissect the role of FXR. LGG treatment significantly attenuated liver inflammation, injury, and fibrosis with a significant reduction of hepatic BAs in BDL mice. Hepatic concentration of taurine‐β‐muricholic acid (T‐βMCA), an FXR antagonist, was markedly increased in BDL mice and reduced in LGG‐treated mice, while chenodeoxycholic acid, an FXR agonist, was decreased in BDL mice and normalized in LGG‐treated mice. LGG treatment significantly increased the expression of serum and ileum fibroblast growth factor 15 (FGF‐15) and subsequently reduced hepatic cholesterol 7α‐hydroxylase and BA synthesis in BDL and Mdr2−/− mice. At the molecular level, these changes were reversed by global and intestine‐specific FXR inhibitors in BDL mice. In addition, LGG treatment altered gut microbiota, which was associated with increased BA deconjugation and increased fecal and urine BA excretion in both BDL and Mdr2−/− mice. In vitro studies showed that LGG suppressed the inhibitory effect of T‐βMCA on FXR and FGF‐19 expression in Caco‐2 cells.ConclusionLGG supplementation decreases hepatic BA by increasing intestinal FXR–FGF‐15 signaling pathway–mediated suppression of BA de novo synthesis and enhances BA excretion, which prevents excessive BA‐induced liver injury and fibrosis in mice.

New insights into potential nutritional effects of dietary saponins in protecting against the development of obesity

Excessive energy intake, poor physical exercise and genetics/epigenetics are instrumental for the development of obesity. Because of rapidly emerging evidences related to off-target effects and toxicity of anti-obesity drugs, there is a need to search for more effective and targeted drugs for treatment of obesity. Substantial studies have found the nutritional effects of dietary saponins (bio-detergents) in terms of decreasing the synthesis of lipids, suppressing adipogenesis, inhibiting intestinal absorption of lipids, and promoting fecal excretion of bile acids and triglycerides. Dietary saponin have been approved as potent pancreatic lipase inhibitors, disaccharidase enzyme inhibitors, antagonistic to in vitro lipogenesis and in vivo appetite suppressants, antioxidants, immune-regulators, prevent fatty liver formation, protects epithelial vasculature and regulate body weight. Many dietary saponins, such as sibutramine, morgoside, sessiloside, soysaponin B, and diosgenin, have treatment potential against the development of obesity. Excellent scientific achievements have been developed for a better understanding the mechanism of saponins in preventing obesity.

Attenuation of the Hepatoprotective Effects of Ileal Apical Sodium Dependent Bile Acid Transporter (ASBT) Inhibition in Choline-Deficient L-Amino Acid-Defined (CDAA) Diet-Fed Mice.

Non-alcoholic fatty liver disease (NAFLD) is a major growing worldwide health problem. We previously reported that interruption of the enterohepatic circulation of bile acids using a non-absorbable apical sodium-dependent bile acid transporter inhibitor (ASBTi; SC-435) reduced the development of NAFLD in high fat diet fed mice. However, the ability of ASBTi treatment to impact the progression of NAFLD to non-alcoholic steatohepatitis (NASH) and fibrosis in a diet-induced mouse model remains untested. In the current study, we assessed whether ASBTi treatment is hepatoprotective in the choline-deficient, L-amino acid-defined (CDAA) diet model of NASH-induced fibrosis.Methods: Male C57Bl/6 mice were fed with: (A) choline-sufficient L-amino acid-defined diet (CSAA) (31 kcal% fat), (B) CSAA diet plus ASBTi (SC-435; 60 ppm), (C) CDAA diet, or (D) CDAA diet plus ASBTi. Body weight and food intake were monitored. After 22 weeks on diet, liver histology, cholesterol and triglyceride levels, and gene expression were measured. Fecal bile acid and fat excretion were measured, and intestinal fat absorption was determined using the sucrose polybehenate method.Results: ASBTi treatment reduced bodyweight gain in mice fed either the CSAA or CDAA diet, and prevented the increase in liver to body weight ratio observed in CDAA-fed mice. ASBTi significantly reduced hepatic total cholesterol levels in both CSAA and CDAA-fed mice. ASBTi-associated significant reductions in hepatic triglyceride levels and histological scoring for NAFLD activity were observed in CSAA but not CDAA-fed mice. These changes correlated with measurements of intestinal fat absorption, which was significantly reduced in ASBTi-treated mice fed the CSAA (85 vs. 94%, P < 0.001) but not CDAA diet (93 vs. 93%). As scored by Ishak staging of Sirius red stained liver sections, no hepatic fibrosis was evident in the CSAA diet mice. The CDAA diet-fed mice developed hepatic fibrosis, which was increased by the ASBTi.Conclusions: ASBT inhibition reduced intestinal fat absorption, bodyweight gain and hepatic steatosis in CSAA diet-fed mice. The effects of the ASBTi on steatosis and fat absorption were attenuated in the context of dietary choline-deficiency. Inhibition of intestinal absorption of fatty acids may be involved in the therapeutic effects of ASBTi treatment.

Effects of Colesevelam on Bowel Symptoms, Biomarkers, and Colonic Mucosal Gene Expression in Patients With Bile Acid Diarrhea in a Randomized Trial

Approximately one-third of patients with IBS-diarrhea (IBS-D) have increased bile acid (BA) synthesis or excretion. An open-label study showed benefits of colesevelam on bowel functions, consistent with luminal BA sequestration by colesevelam. We compared the effects of colesevelam vs placebo on symptoms and gene expression patterns in the sigmoid colon mucosa in patients with BA diarrhea associated with IBS-D. We performed a double-blind, parallel-group study of 30 adults with IBS-D and evidence of increased BA synthesis or fecal excretion, from December 2017 through December 2018 at a single center. Patients were randomly assigned (1:1) to groups given colesevelam (3 tablets, 625 mg each) or matching placebo, orally twice daily for 4 weeks. Stool diaries documented bowel functions for 8 days before and 28 days during colesevelam or placebo. Stool and fasting serum samples were collected for analyses of fecal BAs and serum levels of C4 and FGF19. We measured colonic transit by scintigraphy, mucosal permeability by invivo excretion of saccharide probes, and mRNA levels in rectosigmoid biopsies. All measurements were made at baseline and on the last days of treatment. The primary endpoints were change in total fecal BA concentration and stool consistency. Compared with placebo, colesevelam was associated with significant changes in sequestered fecal total BA excretion (P < .001) and serum levels of C4 and FGF19 (both P < .001), and with a mean increase in fecal level of deoxycholic acid (10%; P = .07) compared to placebo. Colesevelam decreased colon mucosal expression of NR1H4 and P2RY4 and increased expression of GPBAR1, compared with baseline. Stool frequency and consistency, colonic transit, and permeability did not differ significantly between groups. Colesevelam was well tolerated. In a randomized trial, we found that colesevelam increases delivery of total and secondary BAs to stool, hepatic BA synthesis, and colonic mucosal expression of genes that regulate BA, farnesoid X, and GPBAR1 receptors. Larger studies are needed to determine the effects on clinical responses. ClinicalTrials.gov no: NCT03270085.

Wild Melon Seed Oil Reduces Plasma Cholesterol and Modulates Gut Microbiota in Hypercholesterolemic Hamsters.

Wild melon (Cucumis melo var. agrestis) seed oil (CO) contains 71.3% polyunsaturated fatty acids. The present study investigated the effects of CO on blood cholesterol and gut microbiota. Hamsters (n = 32) were randomly divided into four groups and given one of four diets, namely noncholesterol diet (NCD), high-cholesterol diet containing 0.1% cholesterol (HCD), HCD containing 4.75% CO (COL), and HCD containing 9.5% CO (COH) for 6 weeks. CO supplementation at 9.5% in the diet reduced plasma cholesterol by 24% and enhanced the excretion of fecal bile acids by 150%. CO supplementation upregulated the gene expression of hepatic cholesterol 7α-hydroxylase (CYP7A1). In addition, supplementation of CO in the diet remarkably increased the production of fecal short-chain fatty acids and favorably altered the relative abundances of Eubacteriaceae, Clostridiales_vadinBB60_group, Ruminococcaceae, Streptococcaceae, and Desulfovibrionaceae at a family level. It was concluded that CO could reduce plasma cholesterol via promoting the excretion of fecal acidic sterols and modulating gut microbiota.

Structurally different mixed linkage β-glucan supplements differentially increase secondary bile acid excretion in hypercholesterolaemic rat faeces.

Mixed linkage (1→3),(1→4)-β-d-glucan (BG) is a soluble fibre available from oat and barley grains that has been gaining interest due to its health-promoting role in cardiovascular diseases and its ability to modulate the glycaemic index which is beneficial for people with diabetes. This study investigates the effect of three purified barley BGs, with different molecular weight and block structure, on faecal bile acid excretion in hypercholesterolaemic rats. Wistar rats (48 male) were divided in four groups: Control group fed with the cellulose-rich diet (CON); Glucagel group fed with the commercial BG (GLU, 100 kDa), and rats fed with low molecular weight BG (LBG, 150 kDa) and medium molecular weight BG (MBG, 530 kDa). The bile acid profiles of rat faecal samples were measured using gas chromatography-mass spectrometry (GC-MS). A metabolite profiling approach led to the identification of 7 bile acids and 45 other compounds such as sterols, fatty acids and fatty alcohols. Subsequent application of ANOVA-simultaneous component analysis and Principal Component Analysis revealed that all three BG diets increased bile acid faecal excretion compared to the control group. The bile acid excretion was found to be different in all three BG diets and the MBG group showed a significantly higher level of faecal secondary bile acids, including deoxycholic acid, hyodeoxycholic acid, and lithocholic acid. We hypothesise that the hydrophobic surface of the secondary bile acids, which are known to cause colon cancer, has high affinity to the hydrophobic surfaces of cellulosic blocks of the BG. This in vivo study demonstrates that the molecular weight and/or block structures of BG modulate the excretion of secondary bile acids. This finding suggests that developing diets with designed BGs with an optimal molecular structure to trap carcinogenic bile acids can have a significant impact on counteracting cancer and other lifestyle associated diseases.

Disruption of hepatic small heterodimer partner induces dissociation of steatosis and inflammation in experimental nonalcoholic steatohepatitis

Disruption of hepatic small heterodimer partner induces dissociation of steatosis and inflammation in experimental nonalcoholic steatohepatitis

242 Effects of different carbohydrate sources on taurine status in healthy Beagle dogs

Abstract Consumption of grain-free (GF) diets has recently been linked to canine dilated cardiomyopathy in selected dog breeds. Soluble fiber present in GF carbohydrate sources may be contributing to taurine depletion, thus affecting heart health. The objective of this study was to evaluate the effects of different carbohydrate sources on taurine status in healthy Beagle dogs. Two practical diets sufficient in sulfur-amino acids and taurine were formulated with the same proportion of carbohydrate sources: a grain-based (GB) containing sorghum, millet, and spelt, and a GF containing peas, potatoes and tapioca starch. Twelve Beagle dogs were fed experimental diets for 4-wk in a randomized complete block design. The morning prior to feeding experimental diets (baseline) and two and four weeks after, markers of taurine metabolism were analyzed in blood, urine, and fresh fecal samples. Data were analyzed as a change from baseline in a repeated measures model by GLIMMIX (SAS, version 9.4) in which the main effects of time, diet, and their interaction were evaluated. Greater concentrations of taurine in plasma (158 vs. 117 nmol/mL) and whole blood (254 vs. 234 nmol/mL) were observed during experimental period compared to baseline. An increase in plasma methionine was also observed during experimental period compared to baseline (64 vs. 57nmol/mL). Dogs fed GF exhibited higher plasma taurine concentration compared to those fed GB (181 vs. 138 nmol/mL). There were no significant effects of diet, time, or their interaction on plasma cystine concentration, urinary taurine:creatinine ratio, or total fecal bile acid (BA) excretion (P &amp;gt; 0.05). However, dogs fed GF had greater fecal primary BA (26 vs 14%) as a proportion of total BA compared to those fed GB. This study suggests that GF diets do not impair taurine blood concentration, but the increased proportion of fecal primary BA may decrease recycling of taurine through enterohepatic circulation.

Fasting serum total bile acid level is associated with coronary artery disease, myocardial infarction and severity of coronary lesions

Background and aimsBile acids play important roles in lipid metabolism. Several studies have found that patients with coronary artery disease (CAD) have lower bile acid fecal excretion compared to individuals without CAD. However, few studies have focused on the roles of more accessible serum total bile acids (TBA) in the progression of CAD. The aim of this study was to explore the potential relationship between fasting serum TBA and the presence of CAD, myocardial infarction (MI) and severity of coronary lesions. MethodsA total of 7438 consecutive patients with suspected CAD, who had undergone coronary angiography, were enrolled. The severity of coronary lesions was evaluated using the Gensini score (GS). The relationships between fasting serum TBA and the presence and severity of CAD were evaluated. ResultsCAD patients had lower serum TBA than individuals without CAD, and patients with MI had lower TBA than those without CAD. Spline analyses showed an L-shaped relationship of the fasting serum TBA with the presence and severity of CAD, and the breakpoint approximated the normal upper limit (10 μmol/L). A lower TBA concentration (less than the median 3.6 μmol/L) was independently and significantly associated with the presence and severity of CAD, especially for the presence of MI (odds ratios 2.04, 95% confidence interval (1.71–2.44), C-index 0.9269). ConclusionsFasting serum TBA level is highly associated with the presence and severity of CAD in patients undergoing coronary angiography for suspected CAD.

Methods for diagnosing bile acid malabsorption: a systematic review

BackgroundBile acid malabsorption (BAM) and bile acid-related diarrhea represent an under-recognized cause of chronic diarrhea mainly because of limited guidance on appropriate diagnostic and laboratory tests. We aimed to perform a systematic review of the literature in order to identify and compare the diagnostic accuracy of different diagnostic methods for patients with BAM, despite a proven gold standard test is still lacking.MethodsA PubMed literature review and a manual search were carried out. Relevant full papers, evaluating the diagnostic accuracy of different methods for BAM, were assessed. Available data were analyzed to estimate the sensitivity and specificity of each published test.ResultsOverall, more than one test was considered in published papers on BAM. The search strategy retrieved 574 articles; of these, only 16 were full papers (with a total of 2.332 patients) included in the final review. Specifically, n = 8 studies used 75Selenium-homotaurocholic-acid-test (75SeHCAT) with a < 10% retention threshold; n = 8 studies evaluated fasting serum 7-α-hydroxy-4-cholesten-3-one (C4); n = 3 studies involved total fecal bile acid (BA) excretion over 48 h; n = 4 studies assessed fibroblast growth factor 19 (FGF19). 75SeHCAT showed an average sensitivity and specificity of 87.32 and 93.2%, respectively, followed by serum C4 (85.2 and 71.1%) and total fecal BA (66.6 and 79.3%). Fasting serum FGF19 had the lowest sensitivity and specificity (63.8 and 72.3%). All the extracted data were associated with substantial heterogeneity.ConclusionsOur systematic review indicates that 75SeHCAT has the highest diagnostic accuracy for BAM, followed by serum C4 assay. The diagnostic yield of fecal BA and FGF19 assays is still under investigation. Our review reinforces the need for novel biomarkers aimed to an objective detection of BAM and therefore improving the management of this condition.

Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism

Pu-erh tea displays cholesterol-lowering properties, but the underlying mechanism has not been elucidated. Theabrownin is one of the most active and abundant pigments in Pu-erh tea. Here, we show that theabrownin alters the gut microbiota in mice and humans, predominantly suppressing microbes associated with bile-salt hydrolase (BSH) activity. Theabrownin increases the levels of ileal conjugated bile acids (BAs) which, in turn, inhibit the intestinal FXR-FGF15 signaling pathway, resulting in increased hepatic production and fecal excretion of BAs, reduced hepatic cholesterol, and decreased lipogenesis. The inhibition of intestinal FXR-FGF15 signaling is accompanied by increased gene expression of enzymes in the alternative BA synthetic pathway, production of hepatic chenodeoxycholic acid, activation of hepatic FXR, and hepatic lipolysis. Our results shed light into the mechanisms behind the cholesterol- and lipid-lowering effects of Pu-erh tea, and suggest that decreased intestinal BSH microbes and/or decreased FXR-FGF15 signaling may be potential anti-hypercholesterolemia and anti-hyperlipidemia therapies.

Coordinate Regulation of Cholesterol and Bile Acid Metabolism by the Clock Modifier Nobiletin in Metabolically Challenged Old Mice.

Cholesterol and bile acid (BA) homeostasis plays a central role in systemic metabolism. Accumulating evidence suggests a key regulatory function of the circadian clock, our biological timer, in lipid metabolism, particularly cholesterol and bile acid flux. Previously, we showed that Nobiletin (NOB), a natural compound targeting the ROR (Retinoic acid receptor-related orphan receptor) nuclear receptors in the circadian oscillator, strongly protects lipid homeostasis, including normal serum cholesterol levels in high-fat (HF) fed mice at both young and old ages. In this study, we further examined the role of NOB in cholesterol metabolism in HF-fed aged mice, and found that NOB lowered the serum LDL/VLDL cholesterol levels and consequently the LDL/HDL ratio. BA levels in the serum were markedly reduced in the HF.NOB group, and examination of additional hepatic markers further indicate a protective role of NOB in the liver. At the molecular level, whereas HF feeding downregulated hepatic expression of several ROR target genes involved in bile acid synthesis, NOB treatment (HF.NOB) was able to rescue it. In accordance, fecal BA excretion was enhanced by NOB, and microbial 16S sequencing revealed alteration of several taxa known to be involved in secondary BA production in the gut. Together, these results demonstrate concerted effects of the clock-modulating compound NOB in cholesterol and BA metabolism, suggesting pharmacological manipulation of the clock as a novel therapeutic strategy against metabolic disorders and age-related decline.

Multi-Compartment Profiling of Bacterial and Host Metabolites Identifies Intestinal Dysbiosis and Its Functional Consequences in the Critically Ill Child.

Adverse physiology and antibiotic exposure devastate the intestinal microbiome in critical illness. Time and cost implications limit the immediate clinical potential of microbial sequencing to identify or treat intestinal dysbiosis. Here, we examined whether metabolic profiling is a feasible method of monitoring intestinal dysbiosis in critically ill children. Prospective multicenter cohort study. Three U.K.-based PICUs. Mechanically ventilated critically ill (n = 60) and age-matched healthy children (n = 55). Collection of urine and fecal samples in children admitted to the PICU. A single fecal and urine sample was collected in healthy controls. Untargeted and targeted metabolic profiling using 1H-nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry or urine and fecal samples. This was integrated with analysis of fecal bacterial 16S ribosomal RNA profiles and clinical disease severity indicators. We observed separation of global urinary and fecal metabolic profiles in critically ill compared with healthy children. Urinary excretion of mammalian-microbial co-metabolites hippurate, 4-cresol sulphate, and formate were reduced in critical illness compared with healthy children. Reduced fecal excretion of short-chain fatty acids (including butyrate, propionate, and acetate) were observed in the patient cohort, demonstrating that these metabolites also distinguished between critical illness and health. Dysregulation of intestinal bile metabolism was evidenced by increased primary and reduced secondary fecal bile acid excretion. Fecal butyrate correlated with days free of intensive care at 30 days (r = 0.38; p = 0.03), while urinary formate correlated inversely with vasopressor requirement (r = -0.2; p = 0.037). Disruption to the functional activity of the intestinal microbiome may result in worsening organ failure in the critically ill child. Profiling of bacterial metabolites in fecal and urine samples may support identification and treatment of intestinal dysbiosis in critical illness.

Screening for Cholesterol-Lowering Probiotics from Lactic Acid Bacteria Isolated from Corn Silage Based on Three Hypothesized Pathways.

A total of 85 strains of lactic acid bacteria were isolated from corn silage in this study and analyzed in vitro for their cholesterol removal, NPC1L1 protein down-regulation and bile salt deconjugation ability, respectively. Nineteen strains were selected for further analysis for their probiotic potential. Finally, 3 strains showing better probiotic potential were evaluated for their cholesterol-lowering activity in hamsters. The strains showing the greater cholesterol removal and NPC1L1 protein down-regulation activity had no significant effects on serum and hepatic cholesterol levels in hamsters (p > 0.05). However, Lactobacillus plantarum CAAS 18008 (1 × 109 CFU/d) showing the greater bile salt deconjugation ability significantly reduced serum low-density lipoprotein cholesterol, total cholesterol, and hepatic total cholesterol levels by 28.8%, 21.7%, and 30.9%, respectively (p < 0.05). The cholesterol-lowering mechanism was attributed to its bile salt hydrolase activity, which enhanced daily fecal bile acid excretion levels and thereby accelerated new bile acid synthesis from cholesterol in liver. This study demonstrated that the strains showing greater cholesterol removal and NPC1L1 protein down-regulation activity in vitro hardly reveal cholesterol-lowering activity in vivo, whereas the strains showing greater bile salt deconjugation ability in vitro has large potential to decrease serum cholesterol levels in vivo.

EXERCISE AND SEX IMPACT HEPATIC BILE ACID METABOLISM AND FECAL EXCRETION

Exercise can improve metabolic outcomes associated with obesity including hepatic steatosis, however, precise mechanisms are not fully established, nor is the impact of sex. In this study we tested the hypothesis that exercise (via voluntary wheel running (VWR)) would increase expression of hepatic genes controlling cholesterol (Chol) and bile acid (BA) synthesis, and increase fecal BA excretion in male and female C57BL/6 mice providing a mechanism for diverting hepatic acetyl‐CoA away from de novo lipogenesis and towards fecal excretion. A time restricted feeding paradigm was also examined because nutrient availability (fed vs. fasting) impacts the Chol/BA pathway and may impact the capacity for VWR to modulate liver metabolism. Male and female, eight‐week old mice were randomly assigned to one of the following treatment groups (n = 8/group) while consuming a chow diet: sedentary plus ad libitum access to food (SED‐AL), sedentary plus overnight food restricted (SED‐OFR), voluntary wheel running ad libitum access to food (VWR‐AL), and voluntary wheel running plus overnight food restricted (VWR‐OFR) for a period of 4 weeks. Additionally, half of the mice in each group were either fed or fasted immediately prior to tissue collection. Females displayed across the board higher fecal bile acid concentration and higher hepatic gene expression for ACLY, CYP7A1, HMGCR, and FXR compared to males regardless of treatment condition. VWR only increased fecal BA concentration in fed females (VWR‐AL) while the effects of VWR and feeding status on hepatic expression of ACLY, CYP7a1, and HMGCR were mixed and largely insignificant compared to the male vs. female differences. Females had lower serum cholesterol and triglyceride levels. Exercise reduces susceptibility for hepatic steatosis, and female rodents are known to be protected against steatosis and these results suggest that these effects are associated with increased fecal BA excretion and/or an upregulation of Chol/BA synthesis gene expression.Support or Funding InformationVA Merit Review grant (1I01BX002567‐01) (JPT)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Polysaccharide peptides from Ganoderma lucidum ameliorate lipid metabolic disorders and gut microbiota dysbiosis in high-fat diet-fed rats

This study aimed to investigate the effects of polysaccharide peptides from Ganoderma lucidum (GLPP) on hyperlipidaemia and gut microbiota dysbiosis in high-fat diet (HFD)-exacerbated hypercholesterolemic rats. Results showed that oral administrations of GLPP markedly alleviated the dyslipidaemia through decreasing the serum levels of triglyceride (TG), cholesterol (TC), free fatty acids (FFA) and low-density lipoprotein cholesterol (LDL-C), and significantly suppressing hepatic lipid accumulation and steatosis. Metagenomic analysis revealed that GLPP supplementation produced significant structure changes on the intestinal microbiota in HFD-fed rats, in particular modulating the relative abundance of functionally relevant microbial phylotypes compared with the HFD group. The Spearman's correlation analysis revealed that the serum and hepatic lipid profiles were negatively correlated with Jeotgalicoccus, Ignavigranum, Sporosarcina, Bacteroides, Anaerovorax, Parasutterella, Alistipes and Alloprevotella, but positively correlated with Allobaculum, Phascolarctobacterium, Psychrobacter, Enterorhabdus, Blautia and Roseburia. Meanwhile, the GLPP treatment regulated the mRNA expression responsible for hepatic lipid metabolism and promoted fecal excretion of total bile acids (BAs). These findings indicated that GLPP ameliorate lipid metabolic disorders through modulating gut microbiota structure and regulating the genes involved in hepatic lipid and cholesterol metabolism.

Increased Cadmium Excretion Due to Oral Administration of Lactobacillus plantarum Strains by Regulating Enterohepatic Circulation in Mice

The heavy metal cadmium (Cd) is a contaminant widely distributed in the food chain. In the present study, 8-week oral administration of a probiotic strain, Lactobacillus plantarum CCFM8610, markedly decreased blood Cd levels in volunteers. Further animal study showed that three L. plantarum strains administered orally exhibited significantly different effects on the regulation of bile acid (BA) metabolism and Cd excretion in mice. Among the strains, L. plantarum CCFM8610 showed the most significant effects on enhancing hepatic BA synthesis, biliary glutathione output, and fecal BA excretion. Biliary Cd output and fecal Cd excretion were markedly increased after L. plantarum CCFM8610 administration, resulting in a marked reduction in tissue Cd levels. The regulation of BA homeostasis and Cd excretion was due to the suppression of the enterohepatic farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) axis by L. plantarum CCFM8610 and could be abolished by treatment with the FXR agonist GW4064. The regulatory effects were also related to the gut microbiota, as antibiotic pretreatment reversed L. plantarum CCFM8610-induced effects in BA and Cd metabolism.

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.

Dietary calcium affects body composition and lipid metabolism in rats.

Calcium (Ca) intakes may affect cardiovascular disease risk by altering body composition (body weight and fat) and serum lipid profile, but results have been inconsistent and the underlying mechanisms are not well understood. The effects of dietary Ca on body composition and lipid metabolism were examined in rats. Male Sprague-Dawley rats were fed high-fat, high-energy diets containing (g/kg) low (0.75Ca, 0.86 ± 0.05; 2Ca, 2.26 ± 0.02), normal (5Ca, 5.55 ± 0.08) or high (10Ca, 11.03 ± 0.17; 20Ca, 21.79 ± 0.15) Ca for 10 weeks. Rats fed the lowest Ca diet (0.75Ca) had lower (p < 0.05) body weight and fat mass compared to other groups. Rats fed the high Ca diets had lower serum total and LDL cholesterol compared to rats fed normal or low Ca. Liver total cholesterol was lower in rats fed high compared to low Ca. In general, liver mRNA expression of genes involved in cholesterol uptake from the circulation (Ldlr), cholesterol synthesis (Hmgcr and Hmgcs1), fatty acid oxidation (Cpt2) and cholesterol esterification (Acat2) were higher in rats fed higher Ca. Apparent digestibility of total trans, saturated, monounsaturated and polyunsaturated fatty acids was lower in rats fed the high compared to the low Ca diets, with the largest effects seen on trans and saturated fatty acids. Fecal excretion of cholesterol and total bile acids was highest in rats fed the highest Ca diet (20Ca). The results suggest little effect of dietary Ca on body composition unless Ca intakes are very low. Decreased bile acid reabsorption and reduced absorption of neutral sterols and saturated and trans fatty acids may contribute to the better serum lipid profile in rats fed higher Ca.