Taurocholic acid represents an earlier and more sensitive biomarker and promotes cholestatic hepatotoxicity in ANIT-treated rats.

Bile acid homeostasis is crucial for the normal physiological functioning of the liver. Disruptions in bile acid profiles are closely linked to the occurrence of cholestatic liver injury. As part of our diagnostic and therapeutic approach, we aimed to investigate the disturbance in bile acid profiles during cholestasis and its correlation with cholestatic liver injury. Before the occurrence of liver injury, alterations in bile acid profiles were detected in both plasma and liver between 8 and 16 h, persisting up to 96 h. TCA, TCDCA, and TUDCA in the plasma, as well as TCA, TUDCA, TCDCA, TDCA, TLCA, and THDCA in the liver, emerged as early sensitive and potential markers for diagnosing ANIT-induced cholestasis at 8-16 h. The distinguishing features of ANIT-induced liver injury were as follows: T-BAs exceeding G-BAs and serum biochemical indicators surpassing free bile acids. Notably, plasma T-BAs, particularly TCA, exhibited higher sensitivity to cholestatic hepatotoxicity compared with serum enzyme activity and liver histopathology. Further investigation revealed that TCA exacerbated ANIT-induced liver injury by elevating liver function enzyme activity, inflammation, and bile duct proliferation and promoting the migration of bile duct epithelial cell. Nevertheless, no morphological changes or alterations in transaminase activity indicative of liver damage were observed in the rats treated with TCA alone. Additionally, there were no changes in bile acid profiles or inflammatory responses under physiological conditions with maintained bile acid homeostasis. In summary, our findings suggest that taurine-conjugated bile acids in both plasma and liver, particularly TCA, can serve as early and sensitive markers for predicting intrahepatic cholestatic drugs and can act as potent exacerbators of cholestatic liver injury progression. However, exogenous TCA does not induce liver injury under physiological conditions where bile acid homeostasis is maintained.

Per- and Poly-fluoroalkyl Substances and Bile Acid Profiles in Pregnant Women.

Alterations in bile acid (BA) profiles are closely associated with adverse outcomes in pregnant women and their offspring and may be one potential pathway underlying the related metabolic effects of per- and poly-fluoroalkyl substances (PFAS) exposure. However, evidence of associations between PFAS exposure and BA profiles in pregnant women is scarce. This study examined the associations of individual PFAS and PFAS mixture with BA profiles of pregnant women. We obtained quantitative data on the plasma concentrations of 13 PFAS and 15 BAs in 645 pregnant women from the Jiashan birth cohort. In Bayesian kernel machine regression models, the PFAS mixture was associated with increased plasma CA, TCA, TCDCA, and GLCA levels but with decreased GCA and LCA concentrations. Furthermore, the PFAS mixture was associated with increased concentrations of total BAs and the secondary/primary BA ratio but with decreased conjugated/unconjugated and glycine/taurine-conjugated BA ratios. PFHxS, PFUdA, PFOS, PFNA, and PFDA were the dominant contributors. The results of the linear regression analysis of individual PFAS were generally similar. Our findings provide the first epidemiological evidence for the associations of a PFAS mixture with BA profiles in pregnant women and may provide explanatory insights into the biological pathways underlying the related metabolic effects of PFAS exposure.

Nigakinone alleviates DSS-induced experimental colitis via regulating bile acid profile and FXR/NLRP3 signaling pathways.

The correlation of bile acid (BA) metabolism disorder with the pathogenesis of ulcerative colitis (UC) is realized nowadays. Farnesoid X receptor (FXR), a controller for BA homeostasis and inflammation, is a promising target for UC therapy. Nigakinone has potential therapeutic effects on colitis. Herein, we investigated the anti-UC effects and mechanism of nigakinone in colitic animals induced by dextran sulfate sodium (DSS). The related targets involved in the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) signaling pathway were measured. BA-targeted metabolomics was employed to reveal the regulatory effects of nigakinone on BA profile in colitis, while expressions of FXR and its mediated targets referring to BA enterohepatic circulation were determined. The critical role of FXR in the treatment of nigakinone for colitis was studied via molecule-docking, dual-luciferase reporter® (DLR™) assays, FXR silencing cells, and FXR knockout mice. Results showed nigakinone attenuated DSS-induced colitis symptoms, including excessive inflammatory response by NLRP3 activation, and injury of the intestinal mucosal barrier. Nigakinone regulated BA disorders by controlling cholesterol hydroxylase and transporters mediated by FXR, then decreased BA accumulation in colon. Molecular-docking and DLR™ assays indicated FXR might be a target of nigakinone. In vitro, nigakinone restrained BA-induced inflammation and cell damage via FXR activation and inhibition of inflammatory cytokines. However, ameliorating effects of nigakinone on colitis were suppressed by FXR knockout or silencing in vivo or in vitro. Taken together, nigakinone ameliorated experimental colitis via regulating BA profile and FXR/NLRP3 signaling pathway.

Dietary pectin caused great changes in bile acid profiles of Pelteobagrus fulvidraco.

To reveal the impact of dietary fiber (DF) on the bile acid (BA) profiles of fish, yellow catfish (Pelteobagrus fulvidraco) were fed a diet containing 300 g kg-1 dextrin (CON diet, control) or pectin (a type of soluble DF, PEC diet) for 7 days, and then the BA profiles were analyzed by UHPLC-MS/MS. A total of 26 individuals of BAs were detected in the fish body, with 8, 10, 14, and 22 individuals of BAs detected in the liver, serum, bile, and hindgut digesta, respectively. The conjugated BAs (CBAs) of fish were dominated by taurine CBAs (TCBAs). The concentrations of free BAs (FBAs) and the value of FBAs/CBAs in the bile of fish fed the PEC diet were nearly 5 and 7 times higher, respectively than those in fish fed the CON diet. The value of glycine CBAs/TCBAs in the liver, serum and bile of fish fed the PEC diet was significantly lower, and in the hindgut digesta was higher than that of fish fed the CON diet (P < 0.05). These results suggested that dietary pectin greatly changed the BA profiles of Pelteobagrus fulvidraco, attributed to inhibition of reabsorption of BAs. Therefore, attention should be paid to the impact on BA homeostasis when replacing fishmeal with DF-rich plant ingredients in the fish diet.

Mechanisms of Interactions between Bile Acids and Plant Compounds-A Review.

Plant compounds are described to interact with bile acids during small intestinal digestion. This review will summarise mechanisms of interaction between bile acids and plant compounds, challenges in in vivo and in vitro analyses, and possible consequences on health. The main mechanisms of interaction assume that increased viscosity during digestion results in reduced micellar mobility of bile acids, or that bile acids and plant compounds are associated or complexed at the molecular level. Increasing viscosity during digestion due to specific dietary fibres is considered a central reason for bile acid retention. Furthermore, hydrophobic interactions are proposed to contribute to bile acid retention in the small intestine. Although frequently hypothesised, no mechanism of permanent binding of bile acids by dietary fibres or indigestible protein fractions has yet been demonstrated. Otherwise, various polyphenolic structures were recently associated with reduced micellar solubility and modification of steroid and bile acid excretion but underlying molecular mechanisms of interaction are not yet fully understood. Therefore, future research activities need to consider the complex composition and cell-wall structures as influenced by processing when investigating bile acid interactions. Furthermore, influences of bile acid interactions on gut microbiota need to be addressed to clarify their role in bile acid metabolism.

Detection and analysis of serum bile acid profile in patients with colonic polyps.

BACKGROUND: Analyzing the variations in serum bile acid (BA) profile can provide a certain biological basis for early warning and prevention of various diseases. There is currently no comprehensive study on the relationship between the serum BA profile and colonic polyps. AIM: To study the serum BA profile detection results of patients with colonic polyps, and analyze the correlation between BA and colonic polyps. METHODS: From January 1, 2022, to June 1, 2023, 204 patients with colonic polyps who were diagnosed and treated at Zhongda Hospital Southeast University were chosen as the study subjects, and 135 non-polyp people who underwent physical examination were chosen as the control group. Gathering all patients' clinical information, typical biochemical indicators, and BA profile. RESULTS: Compared with the control group, the serum levels of taurocholic acid, glycocholic acid, glycochenodeoxycholic acid, and taurochenodeoxycholic acid in the colonic polyp group were significantly higher than those in the control group, while the content of deoxycholic acid (DCA) was lower than that in the control group (P < 0.05). When colonic polyps were analyzed as subgroups, it was shown that there was a strong correlation between changes in the BA profile and polyp diameter, location, morphology, pathological kind, etc. CONCLUSION: The serum BA profile showed significant changes in patients with colonic polyps, with a significant increase in primary conjugated BA content and a decrease in secondary free bile acid DCA content. There is a certain correlation between primary free BA and pathological parameters of polyps.

Secondary bile acids are associated with body lipid accumulation in obese pigs.

The aim of this study was to investigate the reasons for the differences in lipid accumulation between lean and obese pigs. The bile acids with varying levels within two types of pigs were found and then in vitro experiments were conducted to identify whether these bile acids can directly affect lipid accumulation. Fourteen pigs, including seven lean and seven obese pigs with body weights of approximately 80 kg, were fed the same diet at an amount approximately equivalent to 3% of their respective body weights daily for 42 d. In vitro, 3T3-L1 preadipocytes were cultured in medium with high glucose levels and were differentiated into mature adipocytes using differentiation medium. Then, bile acids were added to mature adipocytes for 4 d. The results showed that there was a difference in body lipids levels and gut microbiota composition between obese and lean pigs (P < 0.05). According to the results of gut microbial function prediction, the bile acid biosynthesis in colonic digesta of obese pigs were different from that in lean pig. Sixty-five bile acids were further screened by metabolomics, of which 4 were upregulated (P < 0.05) and 2 were downregulated (P < 0.05) in obese pigs compared to lean pigs. The results of the correlation analysis demonstrated that chenodeoxycholic acid-3-ß-D-glucuronide (CDCA-3Gln) and ω-muricholic acid (ω-MCA) had a negative correlation with abdominal fat weight and abdominal fat rate, while isoallolithocholic acid (IALCA) was positively associated with crude fat in the liver and abdominal fat rate. There was a positive correlation between loin muscle area and CDCA-3Gln and ω-MCA (P < 0.05), however, IALCA and 3-oxodeoxycholic acid (3-oxo-DCA) were negatively associated with loin eye muscle area (P < 0.05). Isoallolithocholic acid increased the gene expression of peroxisome proliferator-activated receptor gamma (PPARG) and the number of lipid droplets (P < 0.05), promoting the lipid storage when IALCA was added to 3T3-L1 mature adipocytes in vitro. In conclusion, the concentration of bile acids, especially gut microbiota related-secondary bile acids, in obese pigs was different from that in lean pigs, which may contribute to lipid accumulation within obese pigs.

The bile acid profile.

As a large and structurally diverse family of small molecules, bile acids play a crucial role in regulating lipid, glucose, and energy metabolism. In the human body, bile acids share a similar chemical structure with many isomers, exhibit little difference in polarity, and possess various physiological activities. The types and contents of bile acids present in different diseases vary significantly. Therefore, comprehensive and accurate detection of the content of various types of bile acids in different biological samples can not only provide new insights into the pathogenesis of diseases but also facilitate the exploration of novel strategies for disease diagnosis, treatment, and prognosis. The detection of disease-induced changes in bile acid profiles has emerged as a prominent research focus in recent years. Concurrently, targeted metabolomics methods utilizing high-performance liquid chromatography-mass spectrometry (HPLC-MS) have progressively established themselves as the predominant technology for the separation and detection of bile acids. Bile acid profiles will increasingly play an important role in diagnosis and guidance in the future as the relationship between disease and changes in bile acid profiles becomes clearer. This highlights the growing diagnostic value of bile acid profiles and their potential to guide clinical decision-making. This review aims to explore the significance of bile acid profiles in clinical diagnosis from four perspectives: the synthesis and metabolism of bile acids, techniques for detecting bile acid profiles, changes in bile acid profiles associated with diseases, and the challenges and future prospects of applying bile acid profiles in clinical settings.

Analysis of Serum Bile Acid Profile Characteristics and Identification of New Biomarkers in Lean Metabolic Dysfunction-Associated Fatty Liver Disease Based on LC-MS/MS.

Objectives: Plasma bile acid (BA) has been widely studied as pathophysiological factors in chronic liver disease. But the changes of plasma BA level in lean metabolic dysfunction-associated fatty liver disease (MAFLD) remains unclear. Here, we clarified the BA metabolic characteristics of lean MAFLD and explored its significance and mechanism as a marker. Methods: We employed ultra-performance liquid chromatography tandem mass spectrometry based on BA metabonomics to characterize circulating bile acid in lean MAFLD patients. Explore its significance as serum biomarkers by further cluster analysis, functional enrichment analysis, and serum concentration change analysis of differential BAs. Evaluation of diagnostic value of differential BAs by ROC analysis. Results: A total of 65 BAs were detected and 17 BAs were identified which showed different expression in the lean-MAFLD group compared with the normal group. Functional annotation and enrichment analysis of KEGG and HMDB showed that differential BAs were mainly related to bile acid biosynthesis, bile secretion, cholesterol metabolism, and familial hypercholangitis, involving diseases including but not limited to cirrhosis, hepatocellular carcinoma, chronic active hepatitis, colorectal cancer, acute liver failure, and portal vein obstruction. ROC analysis displayed that the 6 BA metabolites (GCDCA-3S, GUDCA-3S, CDCA-3S, NCA, TCDCA, and HDCA) exhibited well differential diagnostic ability in discriminating between lean MAFLD patients and normal individuals with an area under the curve (AUC) ⩾0.85. Conclusions: We delineated the characteristics of BA level in patients with lean MAFLD, and identified 6 potential plasma BA biomarkers of lean MAFLD.

Analysis of serum bile acid profile characteristics and identification of new biomarkers in fatty liver disease accompanied by metabolic abnormalities in people with normal weight based on the technology of high-resolution mass spectrometry Objectives: The physique of lean MAFLD patient is normal or even leaner. They often does not pay enough attention to the onset of fatty liver disease. Plasma bile acids (BAs) have been extensively studied as pathophysiological actors in chronic liver disease. But the changes of plasma BA level in fatty liver disease accompanied by metabolic abnormalities in people with normal weight remains unclear. Here, we clarified the BA metabolic characteristics of lean MAFLD and explored its significance and mechanism as a marker. Methods: we employed an advanced mass spectrometry technology to characterize circulating bile acid in lean lean MAFLD patients. To explore its significance as a marker by bioinformatics methods, such as cluster analysis, functional enrichment analysis, and relative content change analysis of differential BAs. Evaluation diagnostic accuracy and determine threshold points of BAs by Receiver Operating Characteristic analysis. Results: A total of 65 BAs were detected and 17 BAs were identified which showed different expression in the lean MAFLD group compared with the normal group. Bioinformatics analysis showed that differential BAs were mainly related to bile acid biosynthesis, bile secretion, cholesterol metabolism, and familial hypercholangitis, involving diseases including but not limited to cirrhosis, hepatocellular carcinoma, chronic active hepatitis, colorectal cancer, acute liver failure, and portal vein obstruction. ROC analysis displayed that the six BA metabolites (GCDCA-3S, GUDCA-3S, CDCA-3S, NCA, TCDCA and HDCA) exhibited well differential diagnostic ability in discriminating between lean MAFLD patients and normal individuals with an area under the curve (AUC) ≥ 0.85. Conclusions: We delineated the characteristics of BA level in patients with lean MAFLD, and identified six potential plasma BA biomarkers of lean MAFLD. This strategy provided broad clinical application prospects for disease assessment.

Dietary bile acids supplementation decreases hepatic fat deposition with the involvement of altered gut microbiota and liver bile acids profile in broiler chickens.

BACKGROUND: High-fat diets (HFD) are known to enhance feed conversion ratio in broiler chickens, yet they can also result in hepatic fat accumulation. Bile acids (BAs) and gut microbiota also play key roles in the formation of fatty liver. In this study, our objective was to elucidate the mechanisms through which BA supplementation reduces hepatic fat deposition in broiler chickens, with a focus on the involvement of gut microbiota and liver BA composition. RESULTS: Newly hatched broiler chickens were allocated to either a low-fat diet (LFD) or HFD, supplemented with or without BAs, and subsequently assessed their impacts on gut microbiota, hepatic lipid metabolism, and hepatic BA composition. Our findings showed that BA supplementation significantly reduced plasma and liver tissue triglyceride (TG) levels in 42-day-old broiler chickens (P < 0.05), concurrently with a significant decrease in the expression levels of fatty acid synthase (FAS) in liver tissue (P < 0.05). These results suggest that BA supplementation effectively diminishes hepatic fat deposition. Under the LFD, BAs supplementation increased the BA content and ratio of Non 12-OH BAs/12-OH BAs in the liver and increased the Akkermansia abundance in cecum. Under the HFD, BA supplementation decreased the BAs and increased the relative abundances of chenodeoxycholic acid (CDCA) and cholic acid (CA) in hepatic tissue, while the relative abundances of Bacteroides were dramatically reduced and the Bifidobacterium, Escherichia, and Lactobacillus were increased in cecum. Correlation analyses showed a significant positive correlation between the Akkermansia abundance and Non 12-OH BA content under the LFD, and presented a significant negative correlation between the Bacteroides abundance and CA or CDCA content under the HFD. CONCLUSIONS: The results indicate that supplementation of BAs in both LFD and HFD may ameliorate hepatic fat deposition in broiler chickens with the involvement of differentiated microbiota-bile acid profile pathways.

Poly-hydroxylated bile acids and their prognostic roles in Alagille syndrome.

BACKGROUND: The liver manifestations of Alagille syndrome (ALGS) are highly variable, and factors affecting its prognosis are poorly understood. We asked whether the composition of bile acids in ALGS patients with good clinical outcomes differs from that in patients with poor outcomes and whether bile acids could be used as prognostic biomarkers. METHODS: Blood for bile acid profiling was collected from genetically confirmed JAG1-associated ALGS patients before one year of age. A good prognosis was defined as survival with native liver and total bilirubin (TB) < 85.5 µmol/L, while a poor prognosis was defined as either liver transplantation, death from liver failure, or TB ≥ 85.5 µmol/L at the last follow-up. RESULTS: We found that the concentrations of two poly-hydroxylated bile acids, tauro-2ß,3α,7α,12α-tetrahydroxylated bile acid (THBA) and glyco-hyocholic acid (GHCA), were significantly increased in patients with good prognosis compared to those with poor prognosis [area under curve (AUC) = 0.836 and 0.782, respectively] in the discovery cohort. The same trend was also observed in the molar ratios of GHCA to glyco- chenodeoxycholic acid (GCDCA) and tetrahydroxylated bile acid (THCA) to tauro-chenodeoxycholic acid (TCDCA) (both AUC = 0.836). A validation cohort confirmed these findings. Notably, tauro-2ß,3α,7α,12α-THBA achieved the highest prediction accuracy of 88.00% (92.31% sensitivity and 83.33% specificity); GHCA at > 607.69 nmol/L was associated with native liver survival [hazard ratio: 13.03, 95% confidence interval (CI): (2.662-63.753), P = 0.002]. CONCLUSIONS: We identified two poly-hydroxylated bile acids as liver prognostic biomarkers of ALGS patients. Enhanced hydroxylation of bile acids may result in better clinical outcomes.

Bile acid profiles in choledocholithiasis and their ability to predict common bile duct stone recurrence after endoscopic retrograde cholangiopancreatography treatment.

BACKGROUND/PURPOSE: This study aimed to explore the alteration of bile acid (BA) profiles in patients with choledocholithiasis (CDC) and construct a prediction model for evaluating the risk of common bile duct stone (CBDS) recurrence after endoscopic treatment. METHODS: A total of 320 patients (218 with CDC and 102 with nonneoplastic polyps) were enrolled. The serum BA profiles were compared between groups. Both diagnostic score of CDC and prognostic risk score of CBDS recurrence based on BAs were established by least absolute shrinkage and selection operator regression. A nomogram model was developed combining the risk score with clinical factors selected by Cox regression analysis. RESULTS: The BA profiles of patients with CDC were different from those of controls, which was mainly exhibited by an increase in conjugated BAs and the ratio of primary to secondary BA and a decrease in the hydrophobic BA ratio. The diagnostic model effectively distinguished patients with CDC from controls with an area under the curve of 0.763. Patients with CDC with a low BA risk score exhibited a high possibility of stone recurrence-free survival. The hazard ratios of history of cholecystectomy, multiple stones (n ≥ 2), bile duct angulation ≥132.7, and low BA risk score were 2.43, 4.18, 0.42, and 0.31, respectively. CONCLUSIONS: The serum BA profiles were altered in patients with CDC and could be used to distinguish patients with CDC from controls. The nomogram model developed for predicting the risk of CBDS recurrence in patients with CDC after endoscopic retrograde cholangiopancreatography treatment had high accuracy and clinical usability.

Effects of food emulsifiers on high fat-diet-induced obesity, intestinal inflammation, changes in bile acid profile, and liver dysfunction.

Obesity has become one of the most prevalent health concerns of our time. A long-term high-fat diet is closely related to obesity. Food emulsifiers are incorporated into high-fat foods to enhance the texture and stability. Whether food emulsifiers exacerbate obesity and metabolic disorders induced by a high-fat diet remains unclear. This study aimed to investigate the effects of polysorbate-80 (P80) and polyglycerol polyricinoleate (PGPR) on lipid metabolism, bile acid profile, and gut microbiota in normal and high-fat-diet-induced obesity in mice. The results of this study showed that P80 and PGPR had little effect on body weight but significantly increased epididymal-fat weight, total energy intake, and blood lipid levels. P80 and PGPR stimulated colon inflammation and improved the expression of inflammatory factors in the colon and liver significantly. P80 and PGPR changed the bile acid profile. However, P80 and PGPR did not aggravate inflammation, obesity and alter bile acid profile by altering the composition of the gut microbiota. The results of this study provide an experimental reference for the rational use of food additives and the adjustment of dietary structure, which are important and have application value.

Calculus Bovis Sativus alleviates estrogen cholestasis-induced gut and liver injury in rats by regulating inflammation, oxidative stress, apoptosis, and bile acid profiles.

ETHNOPHARMACOLOGICAL RELEVANCE: Natural Calculus Bovis (NCB) is a traditional Chinese medicine used for anti-inflammation, treating fever, pain, sedation, and recovering hepatobiliary function. Calculus Bovis Sativus (CBS), produced from in vitro artificial cultivation by bioengineering techniques, acts as an ideal substitute for NCB when treating various diseases. AIM OF THE STUDY: Gut-liver injury is an important pathological feature of several cholestatic liver diseases, including estrogen-induced cholestasis (EIC). The strong link between cholestatic liver injury and intestinal damage emphasizes the need of considering gut-liver integrity during treatment. The purpose of this study is to look into the pharmacological activities of CBS on EIC-induced gut and liver damage. MATERIALS AND METHODS: EIC-induced cholestatic rats were given oral gavage daily for five days with or without CBS (150 mg/kg). The liver/body weight, serum biochemistry, and tissue histopathology were then evaluated. Quantitative real-time PCR, Western blot analyses, and immunofluorescence were used to determine the gene expression associated with pathological alterations of the liver and intestine in EIC-induced cholestatic rats. Bile acid profiles within enterohepatic circulation were detected by liquid chromatography-mass spectrometry. RESULTS: CBS significantly reduced relative liver weight, restored serum biochemistry levels, and improved the hepatic and intestinal pathological damage in EIC model rats. CBS reduced EIC-induced hepatic inflammation by inactivation of the NF-κB signaling and inhibition of TNFα, IL-1ß, and IL-6 expression. CBS alleviated EIC-induced hepatic and intestinal oxidative stress by regulating Nrf2-GCLM/GCLC and Nrf2-HO-1 pathways, respectively. CBS treatment upregulated Bcl-2 and downregulated Bax and cleaved caspase3 to improve EIC-induced hepatic and intestinal cell apoptosis. Additionally, CBS reversed the disorders of bile acid profiles in the enterohepatic circulation by reducing bile acid accumulation in the liver and plasma and increasing bile excretion and intestinal reabsorption of bile acids. CONCLUSION: CBS alleviates EIC-induced hepatic and intestinal injury through regulating inflammation, oxidative stress, apoptosis, and bile acid profiles. These results suggest that CBS or drugs targeting the gut-liver axis may be effective therapeutic agents for cholestasis.

Pediatric Autoimmune or Primary Sclerosing Cholangitis: Metronidazole Effectiveness on Biochemical Data, Bile Acid Profile, and Gut Microbiota: A Pilot Study.

Objectives: Autoimmune hepatitis and primary sclerosing cholangitis (PSC) can both be present, resulting in autoimmune sclerosing cholangitis (ASC). PSC physiopathology could be based on the cross-talk between gut microbiota and bile acids (BAs); antibiotics are an innovative therapy. This pilot study assesses metronidazole (MTZ)'s effectiveness in ASC or PSC patients according to the stage of the disease, and its effects on biochemical parameters, BA profiles, and gut microbiota. Methods: ASC or PSC patients from Cliniques universitaires Saint-Luc's pediatric hepato-gastroenterology division were enrolled retrospectively and prospectively; both datasets were merged. MTZ was administered over at least 14 days on top of standard treatment (ursodeoxycholic acid, azathioprine, and steroids). Fecal and blood samples were collected before (T0) and at MTZ day 14 (T14). Sustained biochemical remission was defined by the reduction of transaminases (AST and ALT), gamma-glutamyl transferase (GGT), and CRP until 12 months post-MTZ. Results: A total of 18 patients (mean age, 13.2 ± 4.5 years) were enrolled (13 ASC and 5 PSC), and divided in remission or relapse patients. CRP, AST, ALT, and GGT levels decreased post-MTZ in both groups (excepting GGT in relapse patients), with decreases between T0 and T14 being significant for AST and ALT. Relapse patients were older (P = 0.0351) and in late-disease stage, with mainly large-duct PSC (P = 0.0466). In remission patients, the mean plasma relative abundance of hydrophilic BA increased by +6.3% (P = 0.0391) after MTZ. Neither at baseline nor T14, there were significant differences in gut microbiota recorded. Conclusion: These data are likely indicative of long-term benefits following MTZ therapy at early-stage ASC or PSC, with increased hydrophilic BA abundance. Multicenter prospective studies are needed.

Cholestyramine resin administration alleviated cerebral ischemic injury in obese mice by improving gut dysbiosis and modulating the bile acid profile.

Obesity is a risk factor for cerebrovascular diseases. Accumulating evidence has revealed that gut dysbiosis plays an important role in the pathophysiology of cerebrovascular diseases. However, little is known about the role of gut dysbiosis in stroke in obesity. In this study, we established a rodent middle cerebral artery occlusion (MCAO) model to investigate whether obesity-induced gut dysbiosis exacerbates cerebral ischemic injury and the role of the bile salt sequestrant cholestyramine resin (CR) in gut microbiota and stroke outcome in obese mice. Long-term 45% high-fat diet (HFD) diet (8 weeks) induced an obesity phenotype and caused gut dysbiosis, resulting in a larger infarct volume and higher serum levels of inflammatory cytokines after stroke, compared to those in the lean counterparts. LC-MS/MS and GC analysis revealed that obese mice with stroke developed an obviously perturbed bile acid (BA) profile characterized by higher levels of deoxycholic acid and its conjugated forms, and lower levels of butyrate in the cecal content. CR administration improved the obesity-induced dysbiotic microbiome, attenuated ischemic brain injury and modulated the stroke-perturbed BA profile. Furthermore, fecal microbiota transplantation (FMT) experiments revealed that the impact of obesity on stroke and the neuroprotective effects of CR were mediated by gut microbiota. In conclusion, Obesity induces gut dysbiosis, worsens stroke outcomes, and perturbs the BA profile. The dysbiotic microbiome is an important linkage between obesity and stroke. CR confers metabolic benefits and neuroprotective effects in obesity, perhaps by modulating gut microbial composition and BA metabolism.

Pharmacological Effects of Secondary Bile Acid Microparticles in Diabetic Murine Model.

AIM: Examine bile acids effects in Type 2 diabetes. BACKGROUND: In recent studies, the bile acid ursodeoxycholic acid (UDCA) has shown potent antiinflammatory effects in obese patients while in type 2 diabetics (T2D) levels of the pro-inflammatory bile acid lithocholic acid were increased, and levels of the anti-inflammatory bile acid chenodeoxycholic acid were decreased, in plasma. OBJECTIVE: Hence, this study aimed to examine applications of novel UDCA microparticles in diabetes. METHODS: Diabetic balb/c adult mice were divided into three equal groups and gavaged daily with either empty microcapsules, free UDCA, or microencapsulated UDCA over two weeks. Their blood, tissues, urine, and faeces were collected for blood glucose, inflammation, and bile acid analyses. UDCA resulted in modulatory effects on bile acids profile without antidiabetic effects suggesting that bile acid modulation was not directly linked to diabetes treatment. RESULTS: UDCA resulted in modulatory effects on bile acids profile without antidiabetic effects suggesting that bile acid modulation was not directly linked to diabetes treatment. CONCLUSION: Bile acids modulated the bile profile without affecting blood glucose levels.

Maternal bile acid profile and subtype analysis of intrahepatic cholestasis of pregnancy.

BACKGROUND: ICP pregnant women have a unique profile of serum bile acid metabolism, thus the early and accurate identification of ICP patients is beneficial to early appropriate treatment and improvement of pregnancy outcomes. In this study, ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS) was used to analyze the 15 types of serum bile acid profiles among patients with ICP in third trimester, patients with cholelithiasis, and patients with hepatitis B virus. The ICP diagnostic model established by partial least squares-discriminant analysis (PLS-DA) was used to screen the differential bile acids for clinical subtypes of ICP. 144 cases of ICP patients were involved in this study, and divided into four subgroups according to serum level of TBA, DBIL, and ALT. RESULTS: (1) The differential serum bile acid profiles of ICP group and normal pregnant women were DCA, TDCA, TCA, GDCA and GLCA. (2) The differential serum bile acid profiles of the ICP1 group (ICP with jaundice) and normal pregnant women were TCDCA, TCA, GCA, GCDCA, TUDCA and GUDCA. (3) The differential serum bile acid profiles of the ICP3 group (Hyperchoicemia of pregnancy) and normal pregnant group was GUDCA, LCA, GLCA, UDCA, TUDCA, CDCA, and TLCA (P < 0.05). (4) The differential serum bile acid profiles of ICP4 group (idiopathic aminotransferase abnormality during pregnancy) and normal pregnant group was UDCA, GUDCA, TUDCA, GCA and GLCA (P < 0.05). (5) The occurrence of meconium-stained amniotic fluid, premature delivery and cesarean section in ICP1 group was significantly higher than normal group, ICP2 group, ICP3 group, and ICP4 group (P < 0.05); The occurrence of meconium-stained amniotic fluid, premature delivery and cesarean section in ICP2 group, ICP3 group, and ICP4 group was significantly higher than normal group (P < 0.05), but no difference was found among ICP2 group, ICP3 group, and ICP4 group (P > 0.05). CONCLUSION: Maternal serum bile acid profiles are useful to differentiate the four subtypes of ICP. ICP with jaundice could be an important predictor of adverse pregnancy outcomes of ICP.

Comprehensive metabolic profiling of Parkinson's disease by liquid chromatography-mass spectrometry.

BACKGROUND: Parkinson's disease (PD) is a prevalent neurological disease in the elderly with increasing morbidity and mortality. Despite enormous efforts, rapid and accurate diagnosis of PD is still compromised. Metabolomics defines the final readout of genome-environment interactions through the analysis of the entire metabolic profile in biological matrices. Recently, unbiased metabolic profiling of human sample has been initiated to identify novel PD metabolic biomarkers and dysfunctional metabolic pathways, however, it remains a challenge to define reliable biomarker(s) for clinical use. METHODS: We presented a comprehensive metabolic evaluation for identifying crucial metabolic disturbances in PD using liquid chromatography-high resolution mass spectrometry-based metabolomics approach. Plasma samples from 3 independent cohorts (n = 460, 223 PD, 169 healthy controls (HCs) and 68 PD-unrelated neurological disease controls) were collected for the characterization of metabolic changes resulted from PD, antiparkinsonian treatment and potential interferences of other diseases. Unbiased multivariate and univariate analyses were performed to determine the most promising metabolic signatures from all metabolomic datasets. Multiple linear regressions were applied to investigate the associations of metabolites with age, duration time and stage of PD. The combinational biomarker model established by binary logistic regression analysis was validated by 3 cohorts. RESULTS: A list of metabolites including amino acids, acylcarnitines, organic acids, steroids, amides, and lipids from human plasma of 3 cohorts were identified. Compared with HC, we observed significant reductions of fatty acids (FFAs) and caffeine metabolites, elevations of bile acids and microbiota-derived deleterious metabolites, and alterations in steroid hormones in drug-naïve PD. Additionally, we found that L-dopa treatment could affect plasma metabolome involved in phenylalanine and tyrosine metabolism and alleviate the elevations of bile acids in PD. Finally, a metabolite panel of 4 biomarker candidates, including FFA 10:0, FFA 12:0, indolelactic acid and phenylacetyl-glutamine was identified based on comprehensive discovery and validation workflow. This panel showed favorable discriminating power for PD. CONCLUSIONS: This study may help improve our understanding of PD etiopathogenesis and facilitate target screening for therapeutic intervention. The metabolite panel identified in this study may provide novel approach for the clinical diagnosis of PD in the future.

Alterations of gut microbiota and serum bile acids are associated with parenteral nutrition-associated liver disease.

BACKGROUND: Parenteral nutrition-associated liver disease (PNALD) is a major complication of long-term parenteral nutrition (PN). The pathogenesis of PNALD remains unclear. We investigated the changes in taxonomic and functional composition of gut microbiota and serum bile acid levels in a rat model of PNALD. METHODS: Male 4-week-old Sprague Dawley rats received either total parenteral nutrition or standard chow with 0.9% saline for 7 days. The taxonomic composition of cecal microbiota and its functional composition associated with bile acid metabolism were measured. RESULTS: There were differences in taxonomic composition between the two groups. The abundance of the secondary bile acid biosynthesis pathway was higher in the TPN group (p < 0.05) with an increase in the percentage of bacteria expressing 7-alpha-hydroxysteroid dehydrogenase (p < 0.05). The abundance of enzymes associated with bile salt hydrolase was also higher (p < 0.05) in the TPN group. The TPN group showed a distinct bile acid profile characterized by a higher ratio of secondary bile acids to primary bile acids. CONCLUSIONS: The alteration of bile acid-associated microbiota may lead to increased secondary bile acid production in a rat model of PNALD.