Fecal Bile Acid Excretion Research Articles

Alisol B 23-acetate adjusts bile acid metabolisim via hepatic FXR-BSEP signaling activation to alleviate atherosclerosis

BackgroundPostmenopausal women have a high incidence of atherosclerosis. Phytosterols have been shown to have cholesterol-lowering properties. Alisa B 23-acetate (AB23A) is a biologically active plant sterol isolated from Chinese herbal medicine Alisma. However, the atherosclerosis effect of AB23A after menopause and its possible mechanism have not been reported yet. PurposeTo explore whether AB23A can prevent atherosclerosis by regulating farnesoid X receptor and subsequently increasing fecal bile acid and cholesterol excretion to reduce plasma cholesterol levels. MethodsAortic samples from premenopausal and postmenopausal women with ascending aortic arteriosclerosis were analyzed, and bilateral ovariectomized (OVX) female LDLR−/− mice and free fatty acid (FFA)-treated L02 cells were used to analyze the effect of AB23A supplementation therapy. ResultsAB23A increased fecal cholesterol and bile acids (BAs) excretion dependent on activation of hepatic farnesoid X receptor (FXR) in ovariectomized mice. AB23A inhibited hepatic cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) via inducing small heterodimer partner (SHP) expression. On the other hand, AB23A increased the level of hepatic chenodeoxycholic acid (CDCA), and activated the hepatic BSEP signaling. The activation of hepatic FXR-BSEP signaling by AB23A in ovariectomized mice was accompanied by the reduction of liver cholesterol, hepatic lipolysis, and bile acids efflux, and reduced the damage of atherosclerosis. In vitro, AB23A fixed abnormal lipid metabolism in L02 cells and increased the expression of FXR, BSEP and SHP. Moreover, the inhibition and silencing of FXR canceled the regulation of BSEP by AB23A in L02 cells. ConclusionOur results shed light into the mechanisms behind the cholesterol-lowering of AB23A, and increasing FXR-BSEP signaling by AB23A may be a potential postmenopausal atherosclerosis therapy.

The Hypolipidemic and Antioxidant Activity of Wheat Germ and Wheat Germ Protein in High-Fat Diet-Induced Rats.

Background: So far, no articles have discussed the hypolipidemic effect of wheat germ protein in in vivo experiments. Objective: In this study, we investigated the effects of wheat germ protein (WGP, 300 mg/kg/day) and wheat germ (WG, 300 mg/kg/day) on cholesterol metabolism, antioxidant activities, and serum and hepatic lipids in rats fed a high-fat diet through gavage. Methodology: We used 4-week-old male Wistar 20 rats in our animal experiment. Biochemical indicators of fecal, serum and liver were tested by kits or chemical methods. We also conducted the cholesterol micellar solubility experiment in vitro. Results: After 28 days of treatment, our results showed that WGP significantly reduced the serum levels of total cholesterol (p < 0.05) and nonhigh-density lipoprotein cholesterol (p < 0.05), improved the enzymatic activities of cholesterol 7-α hydroxylase (p < 0.01) and low-density lipoprotein receptor (p < 0.01) and increased bile acid excretion in feces (p < 0.05). Conclusion: WG did not significantly increase bile acid excretion in feces or decrease serum levels of total cholesterol. Moreover, WGP and WG both presented significant antioxidant activity in vivo (p < 0.05) and caused a significant reduction in cholesterol micellar solubility in vitro (p < 0.001). Therefore, WGP may effectively prevent hyperlipidemia and its complications as WGP treatment enhanced antioxidant activity, decreased the concentration of serum lipids and improved the activity of enzymes involved in cholesterol metabolism.

Impact of elobixibat on serum and fecal bile acid levels and constipation symptoms in patients with chronic constipation.

Background and AimElobixibat is a locally acting inhibitor of the ileal bile acid transporter. We compared bile acid metabolism between healthy subjects and patients with chronic constipation and assessed changes in the bile acid profile after elobixibat administration in the latter group.MethodsHealthy subjects (n = 10) and patients with chronic constipation (n = 19) were assessed as inpatients for 7 days, during which they received meals containing ~60 g/day of fat. Patients with chronic constipation remained as inpatients for a further 7 days for once‐daily elobixibat administration. Assessments included concentrations of fecal and serum bile acids, serum 7α‐hydroxy‐4‐cholesten‐3‐one (C4) and fibroblast growth factor 19, and bowel movements and constipation symptoms.ResultsFecal total and primary bile acids were significantly lower in patients with chronic constipation versus healthy subjects. Serum C4 and fibroblast growth factor 19 levels were comparable between groups. Elobixibat treatment increased fecal total and primary bile acids and decreased levels of fecal lithocholic acid and serum total as well as secondary bile acids in patients with chronic constipation. Bowel movements and other constipation‐related symptoms were also improved by elobixibat to levels almost comparable with those of healthy subjects.ConclusionsDespite comparable C4 levels, patients with chronic constipation demonstrated decreased levels of fecal bile acids versus healthy subjects. Elobixibat treatment increased fecal bile acid excretion and reduced serum bile acid concentrations. The improvement of constipation after elobixibat treatment was associated with increased total bile acids, particularly primary bile acids.

Dietary supplementation with okara and Bacillus coagulans lilac-01 improves hepatic lipid accumulation induced by cholic acids in rats

Cholic acid supplementation induced lipid accumulation in the liver and a reduction in iron concentration in rats. Dietary supplementation with okara, a by-product of tofu manufacturing from soybean, and Bacillus coagulans lilac-01, protects against leaky gut and lipid accumulation with reducing the expression of fatty acid synthase ( Fasn ) in the liver and enhancement of fecal triglyceride and non-12αhydroxylated bile acid excretion accompanied by an increase in cecal propionic acid concentration. • Okara and Bacillus coagulans lilac-01 is a dietary synbiotic (Syn) • Cholic acid (CA) induces lipid accumulation in rats in a 2-week study. • Syn ameliorates CA-induced hepatic lipid accumulation and leaky gut. • Syn enhances fecal excretion of triglyceride and non-12αhydroxylated bile acids. A dietary symbiotic supplement of okara, a by-product of tofu manufacturing with Bacillus coagulans lilac-01 found to reduce secondary bile acid (BA) in a rat study and cholic acid (CA), a primary 12α-hydroxylated (12αOH) BA, induces lipid accumulation in rats. In this study, we investigated whether dietary supplementation of a synbiotic with okara and Bacillus coagulans lilac-01 improves CA-induced hepatic lipid accumulation. Male Wistar/ST rats (4 weeks old) were fed with or without CA-supplementation combined with the synbiotic for 2 weeks. The CA diet increased hepatic triglycerides and the synbiotic diet in combination with CA normalized liver triglyceride concentration accompanied by suppression of hepatic fatty acid synthase expression, enhancement of fecal triglyceride excretion, and increase in fecal non-12αOH BA excretion. Dietary supplementation with the okara synbiotic ameliorated hepatic lipid accumulation probably by reducing de novo lipogenesis and enhancing fecal triglyceride excretion.

Sexual dimorphism: increased sterol excretion leads to hypocholesterolaemia in female hyperbilirubinaemic Gunn rats.

Circulating bilirubin is associated with reduced serum cholesterol concentrations in humans and in hyperbilirubinaemic Gunn rats. However, mechanisms contributing to hypocholesterolaemia remain unknown. Therefore, this study aimed to investigate cholesterol synthesis, transport and excretion in mutant Gunn rats. Adult Gunn and control rats were assessed for daily faecal sterol excretion using metabolic cages, and water was supplemented with [1‐13C]‐acetate to determine cholesterol synthesis. Bile was collected to measure biliary lipid secretion. Serum and liver were collected for biochemical analysis and for gene/protein expression using RT‐qPCR and western blot, respectively. Additionally, serum was collected and analysed from juvenile rats. A significant interaction of sex, age and phenotype on circulating lipids was found with adult female Gunn rats reporting significantly lower cholesterol and phospholipids. Female Gunn rats also demonstrated elevated cholesterol synthesis, greater biliary lipid secretion and increased total faecal cholesterol and bile acid excretion. Furthermore, they possessed increased hepatic low‐density lipoprotein (LDL) receptor and SREBP2 expression. In contrast, there were no changes to sterol metabolism in adult male Gunn rats. This is the first study to demonstrate elevated faecal sterol excretion in female hyperbilirubinaemic Gunn rats. Increased sterol excretion creates a negative intestinal sterol balance that is compensated for by increased cholesterol synthesis and LDL receptor expression. Therefore, reduced circulating cholesterol is potentially caused by increased hepatic uptake via the LDL receptor. Future studies are required to further evaluate the sexual dimorphism of this response and whether similar findings occur in females with benign unconjugated hyperbilirubinaemia (Gilbert's syndrome).Key points Female adult hyperbilirubinaemic (Gunn) rats demonstrated lower circulating cholesterol, corroborating human studies that report a negative association between bilirubin and cholesterol concentrations.Furthermore, female Gunn rats had elevated sterol excretion creating a negative intestinal sterol balance that was compensated for by elevated cholesterol synthesis and increased hepatic low‐density lipoprotein (LDL) receptor expression.Therefore, elevated LDL receptor expression potentially leads to reduced circulating cholesterol levels in female Gunn rats providing an explanation for the hypocholesterolaemia observed in humans with elevated bilirubin levels.This study also reports a novel interaction of sex with the hyperbilirubinaemic phenotype on sterol metabolism because changes were only reported in females and not in male Gunn rats.Future studies are required to further evaluate the sexual dimorphism of this response and whether similar findings occur in females with benign unconjugated hyperbilirubinaemia (Gilbert's syndrome).

Malay apple (Syzygium malaccense) promotes changes in lipid metabolism and a hepatoprotective effect in rats fed a high-fat diet

This study aimed to investigate the effects of Malay apple (MA) on the glycaemic response, lipid metabolism and liver health of rats fed a normal- or high-fat diet. Male Wistar rats were initially randomized into two groups: normal-fat diet (NF, n = 16) and high-fat diet (HF, n = 16) for three weeks. Then, they were subdivided into: normal-fat diet (NF, n = 8); normal-fat diet supplemented with MA (NFMA, n = 8); high-fat diet (HF, n = 8); high-fat diet supplemented with MA (HFMA, n = 8), continuing for another three weeks with their respective diets. Simultaneously, the supplemented groups received MA (400 mg/kg body weight) via gavage. MA contains anthocyanins (26.59 mg/100 g), catechin (2.55 ± 0.33 mg/100 g) and gallic acid (1.07 ± 0.20 mg/100 g) as the main phenolics. MA had a low-key effect on insulin and glucose tolerance, however decreased serum lipids and protected the liver from steatosis induced by the high-fat diet. HFMA rats showed changes in the fatty acid composition of the liver and faeces and decreased liver cholesterol levels (20.5%); as well as increased faecal excretion of fat (98%), cholesterol (10.5%) and bile acids (42.2%) when comparing to HF. MA supplementation reduced food and fat intake in HFMA in the last two weeks of the experiment, which may also have influenced these results. Our results suggest that MA was not able to improve glycaemic parameters, however, had hepatoprotective effect and minimizes changes in lipid metabolism caused by high-fat diet intake, which can relate mainly to the phenolic compounds present in this fruit.

Disordered Gut Microbiota Correlates With Altered Fecal Bile Acid Metabolism and Post-cholecystectomy Diarrhea.

Post-cholecystectomy diarrhea (PCD) is a common complication of gallbladder removal, and gut microbiota changes have been determined in PCD patients. Bile acid diarrhea (BAD) is supposed to be the main pathogenic factor for PCD due to the disrupted fecal bile acid metabolism in diarrheal patients. However, the profiling of bile acid metabolite alteration in PCD is unclear and whether changed gut microbiota and fecal bile acid metabolism are correlated is also underdetermined. The fecal bile acid metabolites from fecal samples were profiled by targeted UPLC/MS (ultra-high-performance liquid chromatography coupled with a triple-quadrupole mass spectrometer) and the composition of fecal bile acid metabolites in PCD patients was demonstrated to be distinct from those in Non-PCD and HC groups. In addition, the quantification of bile acid excretion in feces of diarrheal patients was significantly elevated. Furthermore, 16S rRNA sequencing results revealed that PCD patients had the lowest operational taxonomic units (OTU) and significant reduction in microbial richness and evenness. Bacterial composition was remarkably shifted in PCD patients, which mainly lay in dominated phyla Firmicutes and Bacteroidota. Besides, the co-abundance network among genus bacteria declined in PCD. Among the genera, Prevotella, Enterococcus, and Erysipelotrichaceae_UCG-003 were enriched, but Alistipes, Bacteroides, Ruminococcus, and Phascolarctobacterium were reduced. Moreover, these disease-linked genera were closely associated with several diarrheal phenotypes. Notably, changed bile acid metabolites exhibited strong correlations with gut microbiota as well. Conclusively, this study reveals associations between PCD-linked microbes and bile acid metabolites, which may synergistically correlate to postoperative diarrhea.

Dietary acetic acid suppress high-fat diet-induced obesity in mice by altering taurine conjugated bile acids metabolism

Vinegar is widely used in Chinese diet as a traditional condiment, and its functional component acetic acid has been proposed to prevent obesity, while its mechanism is still unclear. Bile acids (BAs) have been reported to have a protective effect on obesity. This study demonstrated that high-fat diet induced obesity (DIO) seriously disturbed BAs balance by significantly decreasing hepatic BAs synthesis and increasing fecal BAs excretion. However, acetate supplemented in the high-fat diet can restore BAs balance by mainly promoting hepatic taurine conjugated BAs (tauro-BAs) synthesis and decreasing fecal tauro-BAs excretion. The tauro-BAs, as the antagonists, inhibited the intestinal-liver farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15)-FGF receptor 4 (FGFR4) signaling pathway, and negatively regulated the production of hepatic BAs. Present study provided important clues for further investigation of the mechanism of acetic acid inhibiting DIO.

Fragrant rapeseed oil consumption prevents blood cholesterol accumulation via promoting fecal bile excretion and reducing oxidative stress in high cholesterol diet fed rats

• Long-term effect of three rapeseed oils fed in hypercholesterolemic rats was tested. • Fragrant rapeseed oils lowered plasma cholesterol and boosted fecal bile acid efflux. • Fragrant rapeseed oils altered liver redox status and increased EPA and DHA output. • Such beneficial impact probably owed to high α-linolenic acid and polyphenols levels. We investigated the compositional changes and effects of long-term supplementation on blood lipids in three rapeseed oils [refined (RO), roasted at 120 °C (FO-120) and roasted at 150 °C (FO-150)]. Sixty Sprague-Dawley rats were fed either a basal diet or one of five high-cholesterol diets comprising lard, lard with cholestyramine, or three rapeseed oils for 12 weeks. Results showed that FO-120 and FO-150 alleviated plasma total cholesterol and increased fecal bile acid excretion, but RO had no significant effect. In the liver, cholesterol synthesis and conversion mRNA expression were altered by FO-120 or FO-150 feeding, like the inhibition of Hmgcr and activation of Cyp7a1 . Furthermore, FO-120 or FO-150 increased hepatic eicosapentaenoic and docosahexaenoic acid production and favorably improved hepatic redox status. Overall, the hypocholesterolemic effects may be attributed to their high levels of α-linolenic acid and polyphenols, linked closely to regulating cholesterol metabolism, promoting highly-unsaturated fatty acids synthesis, and reducing oxidative stress.

The Effects of Fermentation of Low or High Tannin Fava Bean-Based Diets on Glucose Response, Cardiovascular Function, and Fecal Bile Acid Excretion during a 28-Day Feeding Period in Dogs: Comparison with Commercial Diets with Normal vs. High Protein.

We have shown that feeding dogs fava bean (FB)-based diets for 7 days is safe and FB flour fermentation with Candida utilis has the potential to decrease FB anti-nutritional factors. In the present study, the effects of 28-day feeding of 4 different FB-based test dog foods containing moderate protein (~27% dry matter (DM)) were compared with two commercial diets with normal protein (NP, grain-containing, ~31% DM protein) or high protein (HP, grain-free, ~41% DM protein). Health parameters were investigated in beagles fed the NP or HP diets or using a randomized, crossover, 2 × 2 Latin square design of the FB diets: unfermented high-tannin (UF-HT), fermented high-tannin (FM-HT), unfermented low-tannin (UF-LT), and fermented low-tannin (FM-LT). The results showed that fermentation increased glucose tolerance, increased red blood cell numbers and increased systolic blood pressure, but decreased flow-mediated vasodilation. Taken together, the overall effect of fermentation appears to be beneficial and improved FB nutritional value. Most interesting, even though the HP diet was grain-free, the diet did contain added taurine, and no adverse effects on cardiac function were observed, while glucose tolerance was impaired compared to NP-fed dogs. In summary, this study did not find evidence of adverse cardiac effects of pulses in ‘grain-free’ diets, at least not in the relatively resistant beagle breed over a 28-day period. More importantly, fermentation with C. utilis shows promise to enhance health benefits of pulses such as FB in dog food.

Ilexsaponin A1 Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease by Regulating Bile Acid Metabolism in Mice.

Bile acid (BA) metabolism is an attractive therapeutic target in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the effect of ilexsaponin A1 (IsA), a major bioactive ingredient of Ilex, on high-fat diet (HFD)-induced NAFLD in mice with a focus on BA homeostasis. Male C57BL/6J mice were fed an HFD to induce NAFLD and were treated with IsA (120 mg/kg) for 8 weeks. The results showed that administration of IsA significantly decreased serum total cholesterol (TC), attenuated liver steatosis, and decreased total hepatic BA levels in HFD-induced NAFLD mice. IsA-treated mice showed increased BA synthesis in the alternative pathway by upregulating the gene expression levels of sterol 27-hydroxylase (CYP27A1) and cholesterol 7b-hydroxylase (CYP7B1). IsA treatment accelerated efflux and decreased uptake of BA in liver by increasing hepatic farnesoid X receptor (FXR) and bile salt export pump (BSEP) expression, and reducing Na+-taurocholic acid cotransporting polypeptide (NTCP) expression. Alterations in the gut microbiota and increased bile salt hydrolase (BSH) activity might be related to enhanced fecal BA excretion in IsA-treated mice. This study demonstrates that consumption of IsA may prevent HFD-induced NAFLD and exert cholesterol-lowering effects, possibly by regulating the gut microbiota and BA metabolism.

NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice.

Niemann–Pick C1-like 1 (NPC1L1) mediates intestinal uptake of dietary and biliary cholesterol and is the target of ezetimibe, a cholesterol absorption inhibitor used to treat hypercholesterolemia. Genetic deletion of NPC1L1 or ezetimibe treatment protects mice from high-fat diet (HFD)-induced obesity; however, the molecular mechanisms responsible for this therapeutic benefit remain unknown. A major metabolic fate of cholesterol is its conversion to bile acids. We found that NPC1L1 knockout (L1-KO) mice fed an HFD had increased energy expenditure, bile acid pool size, and fecal bile acid excretion rates. The elevated bile acid pool in the HFD-fed L1-KO mice was enriched with tauro-β-muricholic acid. These changes in the L1-KO mice were associated with reduced ileal mRNA expression of fibroblast growth factor 15 (FGF15) and increased hepatic mRNA expression of cholesterol 7α-hydroxylase (Cyp7A1) and mitochondrial sterol 27-hydroxylase (Cyp27A1). In addition, mRNA expression of the membrane bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and type 2 iodothyronine deiodinase (Dio2) were elevated in brown adipose tissue of L1-KO mice, which is known to promote energy expenditure. Thus, altered bile acid homeostasis and signaling may play a role in protecting L1-KO mice against HFD-induced obesity.

The Impact of Lab4 Probiotic Supplementation in a 90-Day Study in Wistar Rats.

The anti-inflammatory and cholesterol lowering capabilities of probiotic bacteria highlight them as potential prophylactics against chronic inflammatory diseases, particularly cardiovascular disease. Previous studies in silico, in vitro, and in vivo suggest that the Lab4 probiotic consortium may harbour such capabilities and in the current study, we assessed plasma levels of cytokines/chemokines, short chain fatty acids and lipids and faecal levels of bile acids in a subpopulation of healthy Wistar rats included in 90-day repeat dose oral toxicity study. In the rats receiving Lab4, circulating levels of pro-inflammatory interleukin-6, tumour necrosis factor-α and keratinocyte chemoattractant/growth regulated oncogene were significantly lower compared to the control group demonstrating a systemic anti-inflammatory effect. These changes occurred alongside significant reductions in plasma low density lipoprotein cholesterol and increases in faecal bile acid excretion implying the ability to lower circulating cholesterol via the deconjugation of intestinal bile acids. Correlative analysis identified significant associations between plasma tumour necrosis factor-α and the plasma total cholesterol:high density lipoprotein cholesterol ratio and faecal levels of bifidobacteria in the Lab4 rats. Together, these data highlight Lab4 supplementation as a holistic approach to CVD prevention and encourages further studies in humans.

Longitudinal assessment of taurine and amino acid concentrations in dogs fed a green lentil diet.

A recent association between the inclusion of pulses in canine diets and taurine deficiency has become a prevalent issue in the pet food industry. Although dogs do not currently have a nutritional requirement for taurine, taurine deficiencies that do occur can result in serious health issues, such as dilated cardiomyopathy. The objective of this study was to determine the circulating concentrations of plasma and whole blood taurine, indispensable and dispensable amino acid concentrations in the plasma, and taurine and creatinine concentrations in the urine of adult dogs fed a green lentil diet. Twelve adult, intact, female beagles were randomly assigned to a diet containing 45% green lentils (GLD) or a poultry byproduct meal diet (CON) for 90 d. Fresh urine samples were collected every 30 d and analyzed for taurine and creatinine concentrations. A blood sample was also collected every 30 d and analyzed for amino acids including taurine. Animal procedures were approved by the University of Illinois Institutional Animal Care and Use Committee. All diets were formulated to meet or exceed the nutrient requirements for adult dogs at maintenance. The concentrations of taurine in the plasma and whole blood showed no differences (P > 0.05) between dietary treatments or across time points. Similarly, no differences (P > 0.05) in plasma methionine concentrations were observed between treatments or across time points. A treatment effect (P < 0.05) showed dogs fed GLD had higher total primary fecal bile acid excretion compared with dogs fed CON. The differential abundance of fecal microbial communities showed Firmicutes as the predominant phyla in dogs fed both GLD and CON, with Bacteroidaceae, Erysipelotrichaceae, and Lactobacillaceae as predominant families in dogs fed GLD. The α-diversity of dogs fed GLD (P < 0.05) was lower than in dogs fed CON. These data suggest that the inclusion of 45% green lentil in extruded diets does not lower whole blood and plasma taurine concentrations during a 90-d period and is appropriate for use in a complete and balanced formulation for dogs.

Effects of Tartary Buckwheat Protein on Gut Microbiome and Plasma Metabolite in Rats with High-Fat Diet.

The prevalence of lipid metabolism diseases, mainly obesity, fatty liver, and hyperlipidemia, is increasing in the world. Tartary buckwheat is a kind of medicinal and edible crop, and clinical experiments have also confirmed that dietary Tartary buckwheat can effectively regulate lipid metabolism disorders. Tartary buckwheat protein (TBP), as the main active ingredient of Tartary buckwheat, has an effect of blood lipid reduction that has been widely reported. In this paper, we investigated the constituents of TBP and then evaluated the hypolipidemic effect of TBP in hyperlipidemia rats. Male Sprague–Dawley rats were fed a high-fat diet for six weeks to induce hyperlipidemia and then given TBP orally for five weeks. The effects of TBP on body weight, serum lipids, liver lipids, liver oxidative stress, pathological organization, gut microbiota, and plasma metabolites were analyzed. At the serum level, TBP supplement significantly decrease the level of LDL-C and increase the level of HDL-C. At the liver level, it can reduce the levels of TC, TG, and LDL-C. The potential mechanism of action is, on the one hand, to increase the abundance of the Lachnospiraceae and the Ruminococcaceae by modulating the gut microbiota, facilitating the productivity of short-chain fatty acids, and increasing fecal bile acid excretion and, on the other hand, may be related to the improvement of bile acid metabolism.

Western Diet Changes Gut Microbiota and Ameliorates Liver Injury in a Mouse Model with Human-Like Bile Acid Composition.

Western‐style high‐fat/high‐sucrose diet (HFHSD) changes gut microbiota and bile acid (BA) profiles. Because gut microbiota and BAs could influence each other, the mechanism of changes in both by HFHSD is complicated and remains unclear. We first aimed to clarify the roles of BAs in the HFHSD‐induced change of gut microbiota. Then, we studied the effects of the changed gut microbiota on BA composition and liver function. Male wild‐type (WT) and human‐like Cyp2a12/Cyp2c70 double knockout (DKO) mice derived from C57BL/6J were fed with normal chow or HFHSD for 4 weeks. Gut microbiomes were analyzed by fecal 16S ribosomal RNA gene sequencing, and BA composition was determined by liquid chromatography–tandem mass spectrometry. The DKO mice exhibited significantly reduced fecal BA concentration, lacked muricholic acids, and increased proportions of chenodeoxycholic and lithocholic acids. Despite the marked difference in the fecal BA composition, the profiles of gut microbiota in the two mouse models were quite similar. An HFHSD resulted in a significant increase in the BA pool and fecal BA excretion in WT mice but not in DKO mice. However, microbial composition in the two mouse models was drastically but similarly changed by the HFHSD. In addition, the HFHSD‐induced change of gut microbiota inhibited BA deconjugation and 7α‐dehydroxylation in both types of mice, which improved chronic liver injury observed in DKO mice. Conclusion: The HFHSD itself causes the change of gut microbiota due to HFHSD, and the altered composition or concentration of BAs by HFHSD is not the primary factor. On the contrary, the gut microbiota formed by HFHSD affects BA composition and ameliorates liver injury in the mouse model with human‐like hydrophobic BA composition.

Anti-Obesity and Hypocholesterolemic Actions of Protamine-Derived Peptide RPR (Arg-Pro-Arg) and Protamine in High-Fat Diet-Induced C57BL/6J Mice.

Dietary protamine can ameliorate hyperlipidemia; however, the protamine-derived active peptide and its hypolipidemic mechanism of action are unclear. Here, we report the discovery of a novel anti-obesity and hypocholesterolemic peptide, RPR (Arg-Pro-Arg), derived from protamine in mice fed a high-fat diet for 50 days. Serum cholesterol levels were significantly lower in the protamine and RPR groups than in the control group. White adipose tissue weight was significantly decreased in the protamine and RPR groups. The fecal excretion of cholesterol and bile acid was significantly higher in the protamine and RPR groups than in the control group. We also observed a significant decrease in the expression of hepatic SCD1, SREBP1, and adipocyte FAS mRNA, and significantly increased expression of hepatic PPARα and adipocyte PPARγ1 mRNA in the protamine group. These findings demonstrate that the anti-obesity effects of protamine are linked to the upregulation of adipocyte PPARγ1 and hepatic PPARα and the downregulation of hepatic SCD1 via SREBP1 and adipocyte FAS. RPR derived from protamine has a crucial role in the anti-obesity action of protamine by evaluating the effective dose of adipose tissue weight loss.

Mucosal Biofilms Are an Endoscopic Feature of Irritable Bowel Syndrome and Ulcerative Colitis

Background & AimsIrritable bowel syndrome (IBS) and inflammatory bowel diseases result in a substantial reduction in quality of life and a considerable socioeconomic impact. In IBS, diagnosis and treatment options are limited, but evidence for involvement of the gut microbiome in disease pathophysiology is emerging. Here we analyzed the prevalence of endoscopically visible mucosal biofilms in gastrointestinal disease and associated changes in microbiome composition and metabolism.MethodsThe presence of mucosal biofilms was assessed in 1426 patients at 2 European university-based endoscopy centers. One-hundred and seventeen patients were selected for in-depth molecular and microscopic analysis using 16S ribosomal RNA gene amplicon-sequencing of colonic biopsies and fecal samples, confocal microscopy with deep learning–based image analysis, scanning electron microscopy, metabolomics, and in vitro biofilm formation assays.ResultsBiofilms were present in 57% of patients with IBS and 34% of patients with ulcerative colitis compared with 6% of controls (P < .001). These yellow-green adherent layers of the ileum and right-sided colon were microscopically confirmed to be dense bacterial biofilms. 16S-sequencing links the presence of biofilms to a dysbiotic gut microbiome, including overgrowth of Escherichia coli and Ruminococcus gnavus. R. gnavus isolates cultivated from patient biofilms also formed biofilms in vitro. Metabolomic analysis found an accumulation of bile acids within biofilms that correlated with fecal bile acid excretion, linking this phenotype with a mechanism of diarrhea.ConclusionsThe presence of mucosal biofilms is an endoscopic feature in a subgroup of IBS and ulcerative colitis with disrupted bile acid metabolism and bacterial dysbiosis. They provide novel insight into the pathophysiology of IBS and ulcerative colitis, illustrating that biofilm can be seen as a tipping point in the development of dysbiosis and disease.

Atorvastatin Modulates Bile Acid Homeostasis in Mice with Diet-Induced Nonalcoholic Steatohepatitis.

Bile acids (BA) play a significant role in the pathophysiology of nonalcoholic steatohepatitis (NASH). The present study evaluates the modulation of bile acid metabolomics by atorvastatin, a cholesterol-lowering agent commonly used to treat cardiovascular complications accompanying NASH. NASH was induced in mice by 24 weeks of consuming a high–saturated fat, high-fructose, and high-cholesterol diet (F), with atorvastatin administered orally (20 mg/kg/day) during the last three weeks. Biochemical and histological analyses confirmed the effectiveness of the F diet in inducing NASH. Untreated NASH animals had significantly reduced biliary secretion of BA and increased fecal excretion of BA via decreased apical sodium-dependent bile salt transporter (Asbt)-mediated reabsorption. Atorvastatin decreased liver steatosis and inflammation in NASH animals consistently with a reduction in crucial lipogenic enzyme stearoyl–coenzyme A (CoA) desaturase-1 and nuclear factor kappa light chain enhancer of activated B-cell pro-inflammatory signaling, respectively. In this group, atorvastatin also uniformly enhanced plasma concentration, biliary secretion and fecal excretion of the secondary BA, deoxycholic acid (DCA). However, in the chow diet–fed animals, atorvastatin decreased plasma concentrations of BA, and reduced BA biliary secretions. These changes stemmed primarily from the increased fecal excretion of BA resulting from the reduced Asbt-mediated BA reabsorption in the ileum and suppression of synthesis in the liver. In conclusion, our results reveal that atorvastatin significantly modulates BA metabolomics by altering their intestinal processing and liver synthesis in control and NASH mice.

Soyasaponin A2 Alleviates Steatohepatitis Possibly through Regulating Bile Acids and Gut Microbiota in the Methionine and Choline-Deficient (MCD) Diet-induced Nonalcoholic Steatohepatitis (NASH) Mice.

Nonalcoholic steatohepatitis (NASH) is a chronic progressive disease with complex pathogenesis of which the bile acids (BAs) and gut microbiota are involved. Soyasaponins (SS) exhibits many health-promoting effects including hepatoprotection, but its prevention against NASH is unclear. This study aims to investigate the preventive bioactivities of SS monomer (SS-A2 ) against NASH and further clarify its mechanism by targeting the BAs and gut microbiota. The methionine and choline deficient (MCD) diet-fed male C57BL/6 mice were intervened with obeticholic acid or SS-A2 for 16 weeks. Hepatic pathology is assessed by hematoxylin-eosin and Masson's trichrome staining. BAs in serum, liver, and colon are measured by ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-TQMS). Gut microbiota in caecum are determined by 16S rDNA amplicon sequencing. In the MCD diet-induced NASH mice, SS-A2 significantly reduces hepatic steatosis, lobular inflammation, ballooning, nonalcoholic fatty liver disease activity score (NAS) scores, and fibrosis, decreases Erysipelotrichaceae (Faecalibaculum) and Lactobacillaceae (Lactobacillus) and increases Desulfovibrionaceae (Desulfovibrio). Moreover, SS-A2 reduces serum BAs accumulation and promotes fecal BAs excretion. SS-A2 changes the BAs profiles in both liver and serum and specifically increases the taurohyodeoxycholic acid (THDCA) level. Faecalibaculum is negatively correlated with serum THDCA. SS-A2 alleviates steatohepatitis possibly through regulating BAs and gut microbiota in the MCD diet-induced NASH mice.