Bile Acid Profiles Research Articles

Diagnostic Potential of Alternations of Bile Acid Profiles in the Plasma of Patients with Huntington's Disease.

Huntington's disease (HD) is characterized by progressive involuntary chorea movements and cognitive decline. Recent research indicates that metabolic disturbance may play a role in its pathogenesis. Bile acids, produced during cholesterol metabolism in the liver, have been linked to neurodegenerative conditions. This study investigated variations in plasma bile acid profiles among individuals with HD. Plasma levels of 16 primary and secondary bile acids and their conjugates were analyzed in 20 healthy controls and 33 HD patients, including 24 with symptoms (symHD) and 9 carriers in the presymptomatic stage (preHD). HD patients exhibited significantly higher levels of glycochenodeoxycholic acid (GCDCA) and glycoursodeoxycholic acid (GUDCA) compared to healthy controls. Conversely, isolithocholic acid levels were notably lower in the HD group. Neurotoxic bile acids (glycocholic acid (GCA) + glycodeoxycholic acid (GDCA) + GCDCA) were elevated in symHD patients, while levels of neuroprotective bile acids (ursodeoxycholic acid (UDCA) + GUDCA + tauroursodeoxycholic acid (TUDCA)) were higher in preHD carriers, indicating a compensatory response to early neuronal damage. These results underscore the importance of changes in plasma bile acid profiles in HD and their potential involvement in disease mechanisms. The identified bile acids (GCDCA, GUDCA, and isolithocholic acid) could potentially serve as markers to distinguish between HD stages and healthy individuals. Nonetheless, further research is warranted to fully understand the clinical implications of these findings and their potential as diagnostic or therapeutic tools for HD.

Metabolomics and network pharmacology exploration of the effects of bile acids on carotid atherosclerosis and potential underlying mechanisms.

Bile acids (BAs), products of gut microbiota metabolism, have long been implicated in atherosclerotic disease pathogenesis. Characterizing the serum bile acid profile and exploring its potential role in carotid atherosclerosis (CAS) development are crucial tasks. In this study, we recruited 73 patients with CAS as the disease group and 77 healthy individuals as the control group. We systematically measured the serum concentrations of 15 bile acids using ultrahigh-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Multivariate logistic regression and least absolute shrinkage and selection operator (LASSO) regression were applied to analyze the impact of bile acids on the disease and select the key BAs. The possible molecular mechanism was elucidated by network pharmacology. (1) The BA profile of patients with CAS significantly differed. (2) Multifactorial logistic regression analysis identified elevated levels of GCDCA (OR: 1.01, P < 0.001), DCA (OR: 1.01, P = 0.005), and TDCA (OR: 1.05, P = 0.002) as independent risk factors for CAS development. Conversely, GCA (OR: 0.99, P = 0.020), LCA (OR: 0.83, P = 0.002), and GUDCA (OR: 0.99, P = 0.003) were associated with protective effects against the disease. GCA, DCA, LCA, and TDCA were identified as the four key BAs. (3) TNF, FXR, GPBAR1, ESR1 and ACE were predicted to be targets of BAs against AS. These four BAs potentially impact AS progression by triggering signaling pathways, including cAMP, PPAR, and PI3K-AKT pathways, via their targets. This study offers valuable insights into potential therapeutic strategies for atherosclerosis that target bile acids.

SLC10A5 deficiency causes hypercholanemia.

Solute Carrier Family 10 Member 5 (SLC10A5) is a member of SLC10, comprising transporters of bile acids, steroidal hormones, and other substrates, but its function remains unclear. The aim of the current investigation was to clarify its function in the metabolism of bile acid and hypercholanemia. Whole-exome sequencing and Sanger sequencing were used to identify and confirm the variant in the subjects of hypercholanemia. CRISPR/Cas9-mediated genome engineering was used to establish the knockout and point mutation mice. Primary mouse hepatocytes were isolated, and cell lines were cultured. SLC10A5 was silenced by siRNA and overexpressed by wild-type and mutant plasmids. The fluorescent bile acid derivative was used for the bile acid uptake assay. Bile acids were assessed with ultra-performance liquid chromatography tandem mass spectrometry. A heterozygous variant SLC10A5 : c.994_995del (p.D332X) was identified in subjects with elevated total bile acid or altered bile acid profiles. Bile acids were increased in the serum and liver of knockout and point mutation mice. The expressions of FXR and SHP, regulators involved in the negative feedback of bile acid synthesis, were downregulated, while the bile acid synthesis genes CYP7A1 and CYP8B1 were upregulated in both gene-edited mice. Both the wild and mutant SLC10A5 proteins were localized on the plasma membrane. Knockdown, knockout, or targeted mutation of SLC10A5 led to the inhibition of bile acid uptake by cell lines and primary mouse hepatocytes. SLC10A5 is involved in the uptake of bile acid, and its deficiency causes hypercholanemia.

Inflammatory bowel disease associated with primary sclerosing cholangitis is associated with an altered gut microbiome and bile acid profile.

Primary sclerosing cholangitis associated with inflammatory bowel disease (IBD-PSC) carries significant morbidity compared to IBD without PSC. Alterations in microbial composition and bile acid (BA) profiles have been shown to modulate chronic inflammation in IBD, but data in IBD-PSC is scarce. We aimed to assess the differences in gut microbiome composition as well as in the BA profile and BA-related microbial functions between IBD-PSC and IBD-only. 54 IBD-PSC and 62 IBD-only subjects were enrolled from 2012 to 2021. Baseline samples were collected for fecal DNA shotgun metagenomic sequencing, fecal and serum BA quantitation using mass spectrometry and fecal calprotectin. Liver fibrosis measured by transient elastography (TE) was assessed in the IBD-PSC group. Data was analyzed using general linear regression models and Spearman rank correlation tests. Patients with IBD-PSC had reduced microbial gene richness (p=0.004) and significant compositional shifts (PERMANOVA: R2=0.01, p=0.03) compared to IBD-only. IBD-PSC was associated with altered microbial composition and function, including decreased abundance of Blautia obeum, increased abundance of Veillonella atypica, Veillonella dispar and Clostridium scindens (q<0.05 for all), and increased abundance of microbial genes involved in secondary BA metabolism. Decreased serum sulfated and increased serum conjugated secondary BA were associated with IBD-PSC and increased liver fibrosis. We identified differences in microbial species, functional capacity and serum BA profiles in IBD-PSC compared with IBD-only. Our findings provide insight into the pathophysiology of IBD associated with PSC and suggest possible targets for modulating the risk and course of IBD in subjects with PSC.

Differences in bile acid profiles between cholestatic diseases – Development of a high throughput assay for dried bloodspots

BackgroundCholestasis causes accumulation of bile acids (BAs) and changes the circulating bile acid profile. Quantification of circulating BAs in dried bloodspots (DBS) may demonstrate obstruction of bile flow and altered bile acid metabolism in the liver. High sample throughput enables rapid screening of cholestatic diseases. Materials and methodsUltra high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) was used for optimizing separation and detection of the primary unconjugated BAs cholic acid (CA) and chenodeoxycholic acid (CDCA); the secondary unconjugated BAs ursodeoxycholic acid (UDCA), hyodeoxycholic acid (HDCA) and deoxycholic acid (DCA), as well as the glycine- and taurine-conjugated variants of CA, CDCA, DCA and UDCA. Donor blood was obtained to prepare DBS calibrators and quality controls for method development and validation. ResultsWe developed a quantitative bile acid assay with a run-time of two minutes, and one-step sample preparation of 3.2 mm DBS discs. Validation results demonstrated overall good performance and was considered fit for purpose. Children with Alagille syndrome, Aagenaes syndrome and alpha-1 antitrypsin deficiency had increased BAs in DBS from newborn screening samples compared with age matched controls, and had different bile acids profiles. ConclusionWe propose that our high throughput assay allows bile acid profiling in DBS that can be a valuable assessment tool for early screening of cholestasis in children. Assaying BAs in dried bloodspots is key for early detection of cholestasis, and provides transferability to a newborn screening setting.

Recent solid-phase microextraction-based analytical approaches for the profiling of biliary bile acids in pre-transplant assessments of liver grafts subjected to normothermic ex vivo liver perfusion

BackgroundLiver transplantation is the definitive treatment for end-stage liver failure, but the scarcity of donor organs remains a significant challenge. Leveraging organs from extended criteria donors (ECD) offers a potential avenue to address worldwide shortages, though these organs are more susceptible to post-reperfusion injury. This study explores the use of normothermic ex vivo liver perfusion (NEVLP) as a method for organ preservation – an approach that sustains liver metabolism and facilitates pre-transplant assessments of organ viability via bile analysis. The focal point of this study revolves on the development of analytical methods for determining the bile acid profile throughout the peritransplantation period as a potential indicator of liver function and viability. ResultsThe study optimized and validated a high-throughput analytical method to quantify selected bile acids in bile samples using a thin-film microextraction-liquid chromatography-mass spectrometry (TFME-LC-MS) platform. Furthermore, it introduced a solid-phase microextraction-microfluidic open interface-mass spectrometry (SPME-MOI-MS) method for rapid direct analysis of bile acid isobar groups. In the animal study, discernible variations in the concentrations of specific bile acids were observed between donors after circulatory death (DCD) and heart-beating donors (HBD), particularly following normothermic perfusion and reperfusion. Noteworthy fluctuations in individual bile acid concentrations were observed throughout the entire organ transplantation process, with taurocholic acid (TCA), glycocholic acid (GCA), and glycochenodeoxycholic acid (GCDCA) emerging as promising indicators of organ quality. The efficacy of the SPME-MOI-MS platform in corroborating these trends highlights its potential for real-time bile acid analysis during liver transplantation procedures. SignificanceOur findings underscore the efficacy of NEVLP in tandem with advanced bile acid analysis methods as a reliable strategy for pre-transplant assessments of organ viability, potentially increasing the use of ECD organs and reducing organ shortages. The ability to monitor bile acid profiles in real-time provides crucial insights into liver function and ischemic injury, making significant strides in improving transplant outcomes and patient survival rates.

Integrated serum metabolomics, 16S rRNA sequencing and bile acid profiling to reveal the potential mechanism of gentiopicroside against nonalcoholic steatohepatitis in lean mice

Ethnopharmacological relevanceLean nonalcoholic steatohepatitis (NASH) poses a serious threat to public health worldwide. Herbs of the genus Gentiana have been used for centuries to treat hepatic disease or have been consumed for hepatic protection efficiency. Gentiopicroside (GPS), the main bioactive component of Gentiana herbs, has been shown to be beneficial for protecting the liver, improving intestinal disorders, modulating bile acid profiles, ameliorating alcoholic hepatosteatosis, and so on. It is plausible to speculate that GPS may hold potential as a therapeutic strategy for lean NASH. However, no related studies have been conducted thus far. Aim of the studyThe present work aimed to investigate the benefit of GPS on NASH in a lean mouse model. Materials and methodsNASH in a lean mouse model was successfully established via a published method. GPS of 50 and 100 mg/kg were orally administered to verify the effect. Untargeted metabolomics, 16S rDNA sequencing and bile acid (BA) profiling, as well as qPCR and Western blotting analysis were employed to investigate the mechanism underlying the alleviating effect. ResultsGPS significantly reduced the increase in serum biochemicals and liver index, and attenuated the accumulation of fat in the livers of lean mice with NASH. Forty-two potential biomarkers were identified by metabolomics analysis, leading to abnormal metabolic pathways of primary bile acid biosynthesis and fatty acid biosynthesis, which were subsequently rebalanced by GPS. A decreased Firmicutes/Bacteroidetes (F/B) ratio and disturbed BA related GM profiles were revealed in lean mice with NASH but were partially recovered by GPS. Furthermore, serum profiling of 23 BAs confirmed that serum BA levels were elevated in the lean model but downregulated by GPS treatment. Pearson correlation analysis validated associations between BA profiles, serum biochemical indices and related GM. qPCR and Western blotting analysis further elucidated the regulation of genes associated with liver lipid synthesis and bile acid metabolism. ConclusionsGPS may ameliorate steatosis in lean mice with NASH, regulating the metabolomic profile, BA metabolism, fatty acid biosynthesis, and BA-related GM. All these factors may contribute to its beneficial effect.

Disturbance of bile acids profile aggravates the diarrhea induced by capecitabine through inhibiting the Wnt/β-catenin pathway

IntroductionDiarrhea is the primary dose-limiting side effect of capecitabine(Cap) hindering its clinical application, but the mechanism is unclear. Clarifying this mechanism may enhance the patient compliance and improve the treatment outcome. ObjectivesTo assess if the endogenous metabolic profile could prodict the diarrhea induced by Cap and explore and validate underlying mechanisms. MethodsUntargeted and targeted bile acids(BAs) metabolomics were performed to analyzed the metabolic profile of baseline samples from colorectal cancer(CRC) patients and the association with the diarrhea induced by Cap was assessed. The toxicity of BAs and Cap and its metabolites alone or their combinations to the human normal intestinal epithelial cell(HIEC) was assessed, and the key genes that mediated the BAs-enhanced toxicity of Cap were discovered by RNA-seq and then validated. A mouse model with high exposure levels of BAs was constructed and then treated with Cap to verify the Cap-induced diarrhea enhanced by BAs. ResultsThe baseline endogenous metabolic profile showed obviously difference between diarrhea and non-diarrhea CRC patients, and the differential metabolites mainly enriched in BAs metabolism; the deoxycholic acid(DCA) and lithocholic acid(LCA) were selected to be the key BAs that enhanced the toxicity of Cap metabolite 5-FU to the HIEC cell; the DCA and LCA could inhibit the Wnt/β-catenin signaling pathway, which then suppressed the P-glycoprotein and increased the exposure level of 5-FU in the HIEC cell. The results of animal experiment verified that the excessive DCA and LCA could aggravate the Cap-induced diarrhea through inhibiting Wnt/β-catenin-P-glycoprotein pathway. ConclusionsThe disordered BAs metabolic profile showed close relationship with diarrhea induced by Cap, and excessive DCA and LCA were proved to be the key BAs, which could aggravate the Cap-induced diarrhea through inhibiting Wnt/β-catenin-P-glycoprotein pathway.

Sex-specific effects of gut microbiome on shaping bile acid metabolism.

Gut microbiome is a group of microorganisms that plays important roles in contributing to health and diseases. These bacterial compositions have been demonstrated to impact bile acids (BAs) profiles, either by directly metabolizing primary BAs to secondary BAs or indirect ways through host metabolism by influencing BAs synthesis, transportation and conjugation in liver. It has been observed sexually dimorphic gut microbiome and bile acids composition, with variations in expression levels of bile acid metabolizing genes in the liver. However, associations between sex-specific differences in gut microbiome and BAs profiles are not well understood. This study aimed to investigate whether gut microbiome could influence BAs profiles in host in a sexspecific manner. We transplanted cecum feces of male and female C57BL/6 mice to male mice and measured BAs concentrations in feces, serum and liver samples 7 days after fecal transplantation. We found different BAs profiles between mice with male and female gut microbiome, including altering levels and proportions of secondary BAs. We also observed varied expression levels of genes related to bile acid metabolism in the liver and distal ileum. Our results highlight sex-specific effects of gut microbiome on shaping bile acid metabolism through gut bacteria and regulation of host genes.

Impact of Western Diet on Enterohemorrhagic Escherichia coli Colonization in the Human In Vitro Mucosal Artificial Colon as Mediated by Gut Microbiota.

Enterohemorrhagic Escherichia coli (EHEC) is a major food-borne pathogen that causes human disease ranging from diarrhea to life-threatening complications. Accumulating evidence demonstrates that the Western diet enhances the susceptibility to enteric infection in mice, but the effect of diet on EHEC colonization and the role of human gut microbiota remains unknown. Our research aimed to investigate the effects of a Standard versus a Western diet on EHEC colonization in the human in vitro Mucosal ARtificial COLon (M-ARCOL) and the associated changes in the gut microbiota composition and activities. After donor selection using simplified fecal batch experiments, two M-ARCOL bioreactors were inoculated with a human fecal sample (n = 4) and were run in parallel, one receiving a Standard diet, the other a Western diet and infected with EHEC O157:H7 strain EDL933. EHEC colonization was dependent on the donor and diet in the luminal samples, but was maintained in the mucosal compartment without elimination, suggesting a favorable niche for the pathogen, and may act as a reservoir. The Western diet also impacted the bacterial short-chain fatty acid and bile acid profiles, with a possible link between high butyrate concentrations and prolonged EHEC colonization. The work demonstrates the application of a complex in vitro model to provide insights into diet, microbiota, and pathogen interactions in the human gut.

Sex differences in lipidomic and bile acid plasma profiles in patients with and without coronary artery disease

BackgroundLipids, including phospholipids and bile acids, exert various signaling effects and are thought to contribute to the development of coronary artery disease (CAD). Here, we aimed to compare lipidomic and bile acid profiles in the blood of patients with and without CAD stratified by sex.MethodsFrom 2015 to 2022, 3,012 patients who underwent coronary angiography were recruited in the INTERCATH cohort. From the overall cohort, subgroups were defined using patient characteristics such as CAD vs. no CAD, 1st vs. 3rd tertile of LDL-c, and female vs. male sex. Hereafter, a matching algorithm based on age, BMI, hypertension status, diabetes mellitus status, smoking status, the Mediterranean diet score, and the intake of statins, triglycerides, HDL-c and hs-CRP in a 1:1 ratio was implemented. Lipidomic analyses of stored blood samples using the Lipidyzer platform (SCIEX) and bile acid analysis using liquid chromatography with tandem mass spectrometry (LC‒MS/MS) were carried out.ResultsA total of 177 matched individuals were analyzed; the median ages were 73.5 years (25th and 75th percentile: 64.1, 78.2) and 71.9 years (65.7, 77.2) for females and males with CAD, respectively, and 67.6 years (58.3, 75.3) and 69.2 years (59.8, 76.8) for females and males without CAD, respectively. Further baseline characteristics, including cardiovascular risk factors, were balanced between the groups. Women with CAD had decreased levels of phosphatidylcholine and diacylglycerol, while no differences in bile acid profiles were detected in comparison to those of female patients without CAD. In contrast, in male patients with CAD, decreased concentrations of the secondary bile acid species glycolithocholic and lithocholic acid, as well as altered levels of specific lipids, were detected compared to those in males without CAD. Notably, male patients with low LDL-c and CAD had significantly greater concentrations of various phospholipid species, particularly plasmalogens, compared to those in high LDL-c subgroup.ConclusionsWe present hypothesis-generating data on sex-specific lipidomic patterns and bile acid profiles in CAD patients. The data suggest that altered lipid and bile acid composition might contribute to CAD development and/or progression, helping to understand the different disease trajectories of CAD in women and men.Registrationhttps://clinicaltrials.gov/ct2/show/NCT04936438, Unique identifier: NCT04936438.

Effect of bile salts on intestinal epithelial function in gilthead seabream (Sparus aurata)

In the context of modern aquaculture, the effort to reduce the reliance on fishmeal/marine ingredients in fish diets has led to the exploration of plant-based protein sources as potential substitutes, a dietary shift that disrupts the bile acid profile in fish. Therefore, bile salts are being sought as additives. However, artificially increased intestinal levels of bile acids may significantly impact mucosal function. Therefore, here, we explored the regulatory role in the intestine of gilthead sea bream (Sparus aurata) of (i) chenodeoxycholic acid (CDC), (ii) a mixture formed by two bile acids, 3% cholic acid and 97% deoxycholic acid (MIX), and (iii) a conjugated bile salt sodium taurocholate (TC) in Ussing chambers with the epithelial voltage clamp technique. We tested the bile salts in a 50–500 μg/ml concentration range, and all of them promoted ion absorption. Yet, clear concentration-dependent and more pronounced effects on the ion transport were observed in the posterior intestine. On the other hand, bile salts had no or minor effects on tissue resistance. However, there are indications that the MIX could have adverse effects at high concentrations (500 μg/ml), promoting a threefold increase in tissue permeability measured using FITC-dextran (4 kD) regardless of the intestinal region, thus suggesting an alteration in intestinal permeability at high bile salt concentrations. The findings from our study emphasize the importance of considering intestinal function when contemplating the possible use of a particular bile salt as a dietary supplement. It appears that bile salts, whether acting individually or in combination, play a pivotal role in orchestrating nutrient absorption by influencing the function of epithelial ion transport. However further research is needed to fully grasp the region-dependent nuances of bile salt effects on ion transport and the ultimate consequences for nutrient absorption in the context of fish aquaculture.

Idiosyncratic Drug-Induced Liver Injury and Amoxicillin-Clavulanate: Spotlight on Gut Microbiota, Fecal Metabolome and Bile Acid Profile in Patients.

Several hepatic disorders are influenced by gut microbiota, but its role in idiosyncratic drug-induced liver injury (iDILI), whose main causative agent is amoxicillin-clavulanate, remains unknown. This pioneering study aims to unravel particular patterns of gut microbiota composition and associated metabolites in iDILI and iDILI patients by amoxicillin-clavulanate (iDILI-AC). Thus, serum and fecal samples from 46 patients were divided into three study groups: healthy controls (n = 10), non-iDILI acute hepatitis (n = 12) and iDILI patients (n = 24). To evaluate the amoxicillin-clavulanate effect, iDILI patients were separated into two subgroups: iDILI non-caused by amoxicillin-clavulanate (iDILI-nonAC) (n = 18) and iDILI-AC patients (n = 6). Gut microbiota composition and fecal metabolome plus serum and fecal bile acid (BA) analyses were performed, along with correlation analyses. iDILI patients presented a particular microbiome profile associated with reduced fecal secondary BAs and fecal metabolites linked to lower inflammation, such as dodecanedioic acid and pyridoxamine. Moreover, certain taxa like Barnesiella, Clostridia UCG-014 and Eubacterium spp. correlated with significant metabolites and BAs. Additionally, comparisons between iDILI-nonAC and iDILI-AC groups unraveled unique features associated with iDILI when caused by amoxicillin-clavulanate. In conclusion, specific gut microbiota profiles in iDILI and iDILI-AC patients were associated with particular metabolic and BA status, which could affect disease onset and progression.

Astragalus mongholicus Bunge and Curcuma aromatica Salisb. modulate gut microbiome and bile acid metabolism to inhibit colon cancer progression.

Alterations in the gut microbiome and bile acid metabolism are known to play a role in the development and progression of colon cancer. Medicinal plants like Astragalus mongholicus Bunge and Curcuma aromatica Salisb. (AC) have shown preferable therapeutic effect on cancer therapy, especially digestive tract tumors like colon cancer. However, the precise mechanisms of AC inhibiting colon cancer, particularly in relation to the gut microbiome and bile acid dynamics, are not fully understood. Our research aimed to investigate the anti-tumor properties of AC in mice with CT26 colon cancer and further investigate its underlying mechanism via intestinal microbiota. The size and pathological changes of solid tumors in colon cancer are used to evaluate the inhibitory effect of AC on colon cancer. Metagenomics and 16s rRNA gene sequencing were employed to clarify the dysbiosis in the gut microbiome of colon cancer and its impact on colon cancer. The levels of bile acids (BAs) in the feces of mice from each group were measured using UPLC-Qtrap-MS/MS. AC effectively suppressed the growth of colon cancer and reduced histological damage. Notably, AC treatment led to changes in the gut microbiome composition, with a decrease in pathogenic species like Citrobacter and Candidatus_Arthromitus, and an increase in beneficial microbial populations including Adlercreutzia, Lachnospiraceae_UCG-001, and Parvibacter. Additionally, AC altered bile acid profiles, resulting in a significant decrease in pro-carcinogenic bile acids such as deoxycholic acid (DCA) and lithocholic acid (LCA), while increasing the concentration of the cancer-inhibitory bile acid, ursodeoxycholic acid (UDCA). Tracking and analyzing the data, AC may mainly upregulate FabG and baiA genes by increasing the relative abundance of Adlercreutzia and Parvibacter bacteria, which promoting the metabolism of pro-carcinogenic LCA. These findings provide strong evidence supporting the role of AC in regulating gut microbiome-mediated bile acid metabolism, which is crucial in impeding the progression of colon cancer.

Serum bile acid profiles are associated with heart failure with preserved ejection fraction in patients with metabolic dysfunction-associated fatty liver disease: An exploratory study.

To analyse the association between serum bile acid (BA) profile and heart failure (HF) with preserved ejection fraction (HFpEF) in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). We enrolled 163 individuals with biopsy-proven MAFLD undergoing transthoracic echocardiography for any indication. HFpEF was defined as left ventricular ejection fraction >50% with at least one echocardiographic feature of HF (left ventricular diastolic dysfunction, abnormal left atrial size) and at least one HF sign or symptom. Serum levels of 38 BAs were analysed using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Among the 163 patients enrolled (mean age 47.0 ± 12.8 years, 39.3% female), 52 (31.9%) and 43 (26.4%) met the HFpEF and pre-HFpEF criteria, and 38 serum BAs were detected. Serum ursodeoxycholic acid (UDCA) and hyocholic acid (HCA) species were lower in patients with HFpEF and achieved statistical significance after correction for multiple comparisons. Furthermore, decreases in glycoursodeoxycholic acid and tauroursodeoxycholic acid were associated with HF status. In this exploratory study, specific UDCA and HCA species were associated with HFpEF status in adults with biopsy-confirmed MAFLD.

Bile acid profiles and messenger RNA expression of bile acid-related genes in the liver of dairy cows with high versus normal body condition

Bile acids (BA) play a crucial role not only in lipid digestion but also in the regulation of overall energy homeostasis, including glucose and lipid metabolism. The aim of this study was to investigate BA profiles and mRNA expression of BA-related genes in the liver of high versus normal body condition in dairy cows. We hypothesized that body condition and the transition from gestation to lactation affect hepatic BA concentrations as well as the mRNA abundance of BA-related receptors, regulatory enzymes, and transporters. Therefore, we analyzed BA in the liver as well as the mRNA abundance of BA-related synthesizing enzymes, transporters, and receptors in the liver during the transition period in cows with different body conditions around calving. In a previously established animal model, 38 German Holstein cows were divided into groups with high body condition score (BCS) (HBCS; n = 19) or normal BCS (NBCS; n = 19) based on BCS and backfat thickness (BFT). Cows were fed diets aimed at achieving the targeted differences in BCS and BFT (NBCS: BCS <3.5, BFT <1.2 cm; HBCS: BCS >3.75, BFT >1.4 cm) until they were dried off at wk 7 before parturition. Both groups were fed identical diets during the dry period and subsequent lactation. Liver biopsies were taken at wk -7, 1, 3, and 12 relative to parturition. For BA measurement, a targeted metabolomics approach with LC-ESI-MS/MS was used to analyze BA in the liver. The mRNA abundance of targeted genes related to BA-synthesizing enzymes, transporters, and receptors in the liver was analyzed using microfluidic quantitative PCR. In total, we could detect 14 BA in the liver: 6 primary and 8 secondary BA, with glycocholic acid (GCA) being the most abundant one. The increase of glycine-conjugated BA after parturition, in parallel to increasing serum glycine concentrations may originate from an enhanced mobilization of muscle protein to meet the high nutritional requirements in early lactating cows. Higher DMI in NBCS cows compared with HBCS cows was associated with higher liver BA concentrations such as GCA, deoxycholic acid (DCA), and cholic acid (CA). The mRNA abundance of BA-related enzymes measured herein suggests the dominance of the alternative signaling pathway in the liver of HBCS cows. Overall, BA profiles and BA metabolism in the liver depend on both, the body condition and lactation-induced effects in periparturient dairy cows.

Tomato juice regulates bile acid-TGR5 signaling and reverses cognitive deficit and neuroinflammation in high-fat high-cholesterol diet-induced mice

Cognitive deficits and neuroinflammation are significant complications associated with metabolic diseases induced by a high-fat, high-cholesterol (HFHC) diet. Although tomato juice (TJ) has shown potential benefits for brain health, its specific interventional role remains unclear. This research examined the capability of TJ to mitigate HFHC-induced cognitive deficits and delineated TJ's specific mechanisms against neuroinflammation. The results demonstrated that TJ effectively ameliorated cognitive impairments triggered by HFHC diets, improving spatial working memory, novel object recognition, and reducing anxiety-like behaviors in open space and elevated maze tests. Moreover, TJ mitigated neuronal damage, decreased the activity of immune cells, and diminished the level of COX-2 and iNOS in the hippocampus. Additionally, TJ decreased serum TNF-α and lipopolysaccharide levels, reduced liver inflammation, and improved intestinal barrier markers Claudin-1 and Mucin-2 expression. Fecal metabolomics demonstrated that TJ significantly upregulated bile acid metabolism-related pathways. TJ also altered the profile of serum bile acids, elevating the levels of Takeda G protein-coupled receptor 5 (TGR5)-activating bile acids, including deoxycholic acid, ursodeoxycholic acid, and tauroursodeoxycholic acid. TJ upregulated TGR5 protein expression and inhibited the phosphorylation of protein kinase B and nuclear factor kappa B proteins in the hippocampus. Notably, the positive effects of TJ on cognition and TGR5 activation were nullified in an antibiotic-treated mouse model, underscoring the essential role of the gut-brain axis in mediating TJ's neuroprotective effects. These findings propose that bile acid-TGR5 signaling may be associated with the anti-neuroinflammatory effects of TJ, which may represent a novel approach for neurogenic disease prevention.

Bile acid profiles and classification model accuracy for inflammatory bowel disease diagnosis

Bile acid profiles and classification model accuracy for inflammatory bowel disease diagnosis

Gut microbiota-bile acid crosstalk contributes to intestinal damage after nitrate exposure in Bufo gargarizans tadpoles

Bile acids (BAs) are amphipathic steroid acids whose production and diversity depend on both host and microbial metabolism. Nitrate (NO3−) is a widespread pollutant in aquatic ecosystems, which can cause rapid changes in microbial community structure and function. However, the effect of gut microbiota reshaped by nitrate‑nitrogen (NO3-N) on BAs profiles remains unclarified. To test this, intestinal targeted BAs metabolomics and fecal metagenomic sequencing were performed on Bufo gargarizans tadpoles treated with different concentrations of NO3-N. NO3-N exposure induced a reduction in the abundance of microbiota with bile acid-inducible enzymes (BAIs) and/or hydroxysteroid dehydrogenases (HSDHs), thus inhibiting the conversion of primary BAs to secondary BAs. Inhibition of BAs biotransformation decreased protective hydrophilic BAs (UDCA) and increased toxic hydrophobic BAs (CA and CDCA), which may contribute to intestinal histopathological damage. Moreover, we found that NO3-N treatment increased microbial virulence factors and decreased Glycoside hydrolases, further highlighting the deleterious risk of NO3-N. Overall, this study shed light on the complex interactions of NO3-N, gut microbiota, and BAs, and emphasized the hazardous effects of NO3-N pollution on the health of amphibians.

Metabolomics of IgE-Mediated Food Allergy and Oral Immunotherapy Outcomes based on Metabolomic Profiling.

The immunometabolic mechanisms underlying variable responses to oral immunotherapy (OIT) in patients with IgE-mediated food allergy are unknown. To identify novel pathways associated with tolerance in food allergy, we used metabolomic profiling to find pathways important for food allergy in multi-ethnic cohorts and responses to OIT. Untargeted plasma metabolomics data were generated from the VDAART healthy infant cohort (N=384), a Costa Rican cohort of children with asthma (N=1040), and a peanut OIT trial (N=20) evaluating sustained unresponsiveness (SU, protection that lasts after therapy) versus transient desensitization (TD, protection that ends immediately afterwards). Generalized linear regression modeling and pathway enrichment analysis identified metabolites associated with food allergy and OIT outcomes. Compared with unaffected children, those with food allergy were more likely to have metabolomic profiles with altered histidines and increased bile acids. Eicosanoids (e.g., arachidonic acid derivatives) (q=2.4×10 -20 ) and linoleic acid derivatives (q=3.8×10 -5 ) pathways decreased over time on OIT. Comparing SU versus TD revealed differing concentrations of bile acids (q=4.1×10 -8 ), eicosanoids (q=7.9×10 -7 ), and histidine pathways (q=0.015). In particular, the bile acid lithocholate (4.97[1.93,16.14], p=0.0027), the eicosanoid leukotriene B4 (3.21[1.38,8.38], p=0.01), and the histidine metabolite urocanic acid (22.13[3.98,194.67], p=0.0015) were higher in SU. We observed distinct profiles of bile acids, histidines, and eicosanoids that vary among patients with food allergy, over time on OIT and between SU and TD. Participants with SU had higher levels of metabolites such as lithocholate and urocanic acid, which have immunomodulatory roles in key T-cell subsets, suggesting potential mechanisms of tolerance in immunotherapy. - Compared with unaffected controls, children with food allergy demonstrated higher levels of bile acids and distinct histidine/urocanic acid profiles, suggesting a potential role of these metabolites in food allergy. - In participants receiving oral immunotherapy for food allergy, those who were able to maintain tolerance-even after stopping therapyhad lower overall levels of bile acid and histidine metabolites, with the exception of lithocholic acid and urocanic acid, two metabolites that have roles in T cell differentiation that may increase the likelihood of remission in immunotherapy. This is the first study of plasma metabolomic profiles of responses to OIT in individuals with IgE-mediated food allergy. Identification of immunomodulatory metabolites in allergic tolerance may help identify mechanisms of tolerance and guide future therapeutic development.