Hyodeoxycholic Acid Research Articles

Predicting cholangiocarcinoma in primary sclerosing cholangitis: using artificial intelligence, clinical and laboratory data

BackgroundPrimary sclerosing cholangitis (PSC) patients have a risk of developing cholangiocarcinoma (CCA). Establishing predictive models for CCA in PSC is important.MethodsIn a large cohort of 1,459 PSC patients seen at Mayo Clinic (1993–2020), we quantified the impact of clinical/laboratory variables on CCA development using univariate and multivariate Cox models and predicted CCA using statistical and artificial intelligence (AI) approaches. We explored plasma bile acid (BA) levels’ predictive power of CCA (subset of 300 patients, BA cohort).ResultsEight significant risk factors (false discovery rate: 20%) were identified with univariate analysis; prolonged inflammatory bowel disease (IBD) was the most important one. IBD duration, PSC duration, and total bilirubin remained significant (p < 0.05) with multivariate analysis. Clinical/laboratory variables predicted CCA with cross-validated C-indexes of 0.68–0.71 at different time points of disease, significantly better compared to commonly used PSC risk scores. Lower chenodeoxycholic acid, higher conjugated fraction of lithocholic acid and hyodeoxycholic acid, and higher ratio of cholic acid to chenodeoxycholic acid were predictive of CCA. BAs predicted CCA with a cross-validated C-index of 0.66 (std: 0.11, BA cohort), similar to clinical/laboratory variables (C-index = 0.64, std: 0.11, BA cohort). Combining BAs with clinical/laboratory variables leads to the best average C-index of 0.67 (std: 0.13, BA cohort).ConclusionsIn a large PSC cohort, we identified clinical and laboratory risk factors for CCA development and demonstrated the first AI based predictive models that performed significantly better than commonly used PSC risk scores. More predictive data modalities are needed for clinical adoption of these models.

Metagenomic and targeted metabolomic analyses reveal distinct phenotypes of the gut microbiota in patients with colorectal cancer and type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is an independent risk factor for colorectal cancer (CRC), and the patients with CRC and T2DM have worse survival. The human gut microbiota (GM) is linked to the development of CRC and T2DM, respectively. However, the GM characteristics in patients with CRC and T2DM remain unclear. We performed fecal metagenomic and targeted metabolomics studies on 36 samples from CRC patients with T2DM (DCRC group, n = 12), CRC patients without diabetes (CRC group, n = 12), and healthy controls (Health group, n = 12). We analyzed the fecal microbiomes, characterized the composition and function based on the metagenomics of DCRC patients, and detected the short-chain fatty acids (SCFAs) and bile acids (BAs) levels in all fecal samples. Finally, we performed a correlation analysis of the differential bacteria and metabolites between different groups. Compared with the CRC group, LefSe analysis showed that there is a specific GM community in DCRC group, including an increased abundance of Eggerthella , Hungatella , Peptostreptococcus , and Parvimonas , and decreased Butyricicoccus , Lactobacillus , and Paraprevotella . The metabolomics analysis results revealed that the butyric acid level was lower but the deoxycholic acid and 12-keto-lithocholic acid levels were higher in the DCRC group than other groups ( P < 0.05). The correlation analysis showed that the dominant bacterial abundance in the DCRC group ( Parvimonas , Desulfurispora , Sebaldella , and Veillonellales , among others) was negatively correlated with butyric acid, hyodeoxycholic acid, ursodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, cholic acid and glycocholate. However, the abundance of mostly inferior bacteria was positively correlated with these metabolic acid levels, including Faecalibacterium , Thermococci , and Cellulophaga . Unique fecal microbiome signatures exist in CRC patients with T2DM compared to those with non-diabetic CRC. Alterations in GM composition and SCFAs and secondary BAs levels may promote CRC development.

A Novel Drug Delivery System: Hyodeoxycholic Acid-Modified Metformin Liposomes for Type 2 Diabetes Treatment.

Metformin is a first-line drug for the clinical treatment of type 2 diabetes; however, it always leads to gastrointestinal tolerance, low bioavailability, short half-life, etc. Liposome acts as an excellent delivery system that could reduce drug side effects and promote bioavailability. Hyodeoxycholic acid, a cholesterol-like structure, can regulate glucose homeostasis and reduce the blood glucose levels. As an anti-diabetic active ingredient, hyodeoxycholic acid modifies liposomes to make it overcome the disadvantages of metformin as well as enhance the hypoglycemic effect. By adapting the thin-film dispersion method, three types of liposomes with different proportions of hyodeoxycholic acid and metformin were prepared (HDCA:ME-(0.5:1)-Lips, HDCA:ME-(1:1)-Lips, and HDCA:ME-(2:1)-Lips). Further, the liposomes were characterized, and the anti-type 2 diabetes activity of liposomes was evaluated. The results from this study indicated that three types of liposomes exhibited different characteristics-Excessive hyodeoxycholic acid decreased encapsulation efficiency and drug loading. In the in vivo experiments, liposomes could reduce the fasting blood glucose levels, improve glucose tolerance, regulate oxidative stress markers and protect liver tissue in type 2 diabetic mice. These results indicated that HDCA:ME-(1:1)-Lips was the most effective among the three types of liposomes prepared and showed better effects than metformin. Hyodeoxycholic acid can enhance the hypoglycemic effect of metformin and play a suitable role as an excipient in the liposome.

Characterization of Calculus bovis by principal component analysis assisted qHNMR profiling to distinguish nefarious frauds

A new approach is developed for the reliable classification of Calculus bovis along with the identification of willfully contaminated C. bovis species and the quantification of unclaimed adulterants. Guided by a principal component analysis, NMR data mining achieved a near-holistic chemical characterization of three types of authenticated C. bovis, including natural C. bovis (NCB), in vitro cultured C. bovis (Ivt-CCB), and artificial C. bovis (ACB). In addition, species-specific markers used for quality evaluation and species classification were confirmed. That is, the content of taurine in NCB is near negligible, while choline and hyodeoxycholic acid are characteristic for identifying Ivt-CCB and ACB, respectively. Besides, the peak shapes and chemical shifts of H2-25 of glycocholic acid could assist in the recognition of the origins of C. bovis. Based on these discoveries, a set of commercial NCB samples, macroscopically identified as problematic species, was examined with deliberately added sugars and outliers discovered. Absolute quantification of the identified sugars was realized by qHNMR using a single, nonidentical internal calibrant (IC). This study represents the first systematic study of C. bovis metabolomics via an NMR-driven methodology, which advances the toolbox for quality control of TCM and provides a more definitive reference point for future chemical and biological studies of C. bovis as a valuable materia medica.

Investigation of α,ω-Disubstituted Polyamine-Cholic Acid Conjugates Identifies Hyodeoxycholic and Chenodeoxycholic Scaffolds as Non-Toxic, Potent Antimicrobials

With the increased incidence of antibiotic resistance, the discovery and development of new antibacterials is of increasing importance and urgency. The report of the natural product antibiotic squalamine in 1993 has stimulated a lot of interest in the study of structurally simplified cholic acid-polyamine derivatives. We report the synthesis of a focused set of deoxycholic acid-polyamine conjugates and the identification of hyodeoxycholic acid derivatives as being potently active towards S. aureus MRSA and some fungal strains, but with no attendant cytotoxicity or hemolytic properties. Analogue 7e exhibited bactericidal activity towards a range of Gram-positive bacteria, while preliminary investigation of its mechanism of action ruled out the bacterial membrane as being a primary cellular target as determined using an ATP-release bioluminescence assay.

Medium chain fatty acid supplementation improves animal metabolic and immune status during the transition period: A study on dairy cattle.

The transition period is the stage of the high incidence of metabolic and infectious diseases in dairy cows. Improving transition dairy cows' health is crucial for the industry. This study aimed to determine the effects of dietary supplementation medium-chain fatty acids (MCFAs) on immune function, metabolic status, performance of transition dairy cows. Twenty multiparous Holstein cows randomly assigned to two treatments at 35 d before calving. 1) CON (fed the basal 2) MCFA treatment (basal diet was supplemented at an additional 20 g MCFAs mixture every day) until 70 d after calving. The results showed that the serum amyloid A myeloperoxidase concentrations in the blood of cows in MCFA treatment significantly decreased during the early lactation (from 1 d to 28 d after calving) 0.03, 0.04, respectively) compared with the CON, while the tumor necrosis factor concentration was significantly decreased at 56 d after calving (P = 0.02). In addition, the concentration of insulin in the pre-calving (from 21 d before calving to calving) blood of cows in MCFA treatment was significantly decreased (P = 0.04), and concentration of triglyceride also showed a downward trend at 28 d after calving 0.07). Meanwhile, MCFAs supplementation significantly decreased the concentrations of lithocholic acid, hyodeoxycholic acid, and hyocholic acid in the blood at 1 d calving (P = 0.02, < 0.01, < 0.01, respectively), and the level of hyocholic acid taurocholic acid concentrations (P < 0.01, = 0.01, respectively) decreased dramatically at 14 d after calving. However, compared with the CON, the pre-calving dry matter intake and the early lactation milk yield in MCFA treatment were significantly decreased (P = 0.05, 0.02, respectively). In conclusion, MCFAs supplementation transition diet could improve the immune function and metabolic status of dairy cows, and the health of transition cows might be beneficial from the endocrine status.

Gut microbial metabolite hyodeoxycholic acid targets the TLR4/MD2 complex to attenuate inflammation and protect against sepsis

Sepsis, a critical condition resulting from the systemic inflammatory response to a severe microbial infection, represents a global public health challenge. However, effective treatment or intervention to prevent and combat sepsis is still lacking. Here, we report that hyodeoxycholic acid (HDCA) has excellent anti-inflammatory properties in sepsis. We discovered that the plasma concentration of HDCA was remarkably lower in patients with sepsis and negatively correlated with the severity of the disease. Similar changes in HDCA levels in plasma and cecal content samples were observed in a mouse model of sepsis, and these changes were associated with a reduced abundance of HDCA-producing strains. Interestingly, HDCA administration significantly decreased systemic inflammatory responses, prevented organ injury, and prolonged the survival of septic mice. We demonstrated that HDCA suppressed excessive activation of inflammatory macrophages by competitively blocking lipopolysaccharide binding to the Toll-like receptor 4 (TLR4) and myeloid differentiation factor 2 receptor complex, a unique mechanism that characterizes HDCA as an endogenous inhibitor of inflammatory signaling. Additionally, we verified these findings in TLR4 knockout mice. Our study highlights the potential value of HDCA as a therapeutic molecule for sepsis.

Fecal Microbiota Was Reshaped in UCP1 Knock-In Pigs via the Adipose-Liver-Gut Axis and Contributed to Less Fat Deposition.

The relationship between the host gut microbiota and obesity has been well documented in humans and mice; however, few studies reported the association between the gut microbiota and fat deposition in pigs. In a previous study, we generated uncoupling protein 1 (UCP1) knock-in pigs (UCP1 pigs), which exhibited a lower fat deposition phenotype. Whether the gut microbiota was reshaped in these pigs and whether the reshaped gut microbiota contributes to the lower fat content remain unknown. Here, we revealed that the fecal microbiota composition and metabolites were significantly altered under both chow diet (CD) and high-fat/high-cholesterol (HFHC) diet conditions in UCP1 pigs compared to those in wild-type (WT) pigs. The abundance of Oscillospira and Coprococcus and the level of metabolite hyodeoxycholic acid (HDCA) from feces were observed to be significantly increased in UCP1 pigs. An association analysis revealed that Oscillospira and Coprococcus were significantly negatively related to backfat thickness. In addition, after fecal microbiota transplantation (FMT), the mice that were orally gavaged with feces from UCP1 pigs exhibited less fat deposition under both CD and high-fat diet (HFD) conditions, suggesting that the fecal microbes of UCP1 pigs participate in regulating host lipid metabolism. Consistently, HDCA-treated mice also exhibited reduced fat content. Mechanistically, we found that UCP1 expression in white adipose tissue alters the gut microbiota via the adipose-liver-gut axis in pigs. Our study provides new data concerning the cross talk between host genetic variations and the gut microbiota and paves the way for the potential application of microbes or their metabolites in the regulation of fat deposition in pigs. IMPORTANCE This article investigated the effect of the ectopic expression of UCP1 on the regulation of fecal microbiota composition and metabolites and which alters the fat deposition phenotype. Bacteria, including Oscillospira and Coprococcus, and the metabolite HDCA were found to be significantly increased in feces of UCP1 pigs and had a negative relationship with backfat thickness. Mice with fecal microbiota transplantation phenocopied the UCP1 pigs under both CD and HFD conditions, suggesting that the fecal microbes of UCP1 pigs participate in regulating host lipid metabolism. Our study provides new data regarding the cross talk between host genetic variations and the gut microbiota and paves the way for the potential application of microbes or their metabolic production in the regulation of fat deposition in pigs.

"Component-target-efficacy" network analysis and experimental verification of Qingkailing Oral Preparation

This study aims to explore the mechanism of Qingkailing(QKL) Oral Preparation's heat-clearing, detoxifying, mind-tranquilizing effects based on &quot;component-target-efficacy&quot; network. To be specific, the potential targets of the 23 major components in QKL Oral Preparation were predicted by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and SwissTargetPrediction. The target genes were obtained based on UniProt. OmicsBean and STRING 10 were used for Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment of the targets. Cytoscape 3.8.2 was employed for visualization and construction of &quot;component-target-pathway-pharmacological effect-efficacy&quot; network, followed by molecular docking between the 23 main active components and 15 key targets. Finally, the lipopolysaccharide(LPS)-induced RAW264.7 cells were adopted to verify the anti-inflammatory effect of six monomer components in QKL Oral Preparation. It was found that the 23 compounds affected 33 key signaling pathways through 236 related targets, such as arachidonic acid metabolism, tumor necrosis factor α(TNF-α) signaling pathway, inflammatory mediator regulation of TRP channels, cAMP signaling pathway, cGMP-PKG signaling pathway, Th17 cell differentiation, interleukin-17(IL-17) signaling pathway, neuroactive ligand-receptor intera-ction, calcium signaling pathway, and GABAergic synapse. They were involved in the anti-inflammation, immune regulation, antipyretic effect, and anti-convulsion of the prescription. The &quot;component-target-pathway-pharmacological effect-efficacy&quot; network of QKL Oral Preparation was constructed. Molecular docking showed that the main active components had high binding affinity to the key targets. In vitro cell experiment indicated that the six components in the prescription(hyodeoxycholic acid, baicalin, chlorogenic acid, isochlorogenic acid C, epigoitrin, geniposide) can reduce the expression of nitric oxide(NO), TNF-α, and interleukin-6(IL-6) in cell supernatant(P&lt;0.05). Thus, the above six components may be the key pharmacodynamic substances of QKL Oral Preparation. The major components in QKL Oral Prescription, including hyodeoxycholic acid, baicalin, chlorogenic acid, isochlorogenic acid C, epigoitrin, geniposide, cholic acid, isochlorogenic acid A, and γ-aminobutyric acid, may interfere with multiple biological processes related to inflammation, immune regulation, fever, and convulsion by acting on the key protein targets such as IL-6, TNF, prostaglandin-endoperoxide synthase 2(PTGS2), arachidonate 5-lipoxygenase(ALOX5), vascular cell adhesion molecule 1(VCAM1), nitric oxide synthase 2(NOS2), prostaglandin E2 receptor EP2 subtype(PTGER2), gamma-aminobutyric acid receptor subunit alpha(GABRA), gamma-aminobutyric acid type B receptor subunit 1(GABBR1), and 4-aminobutyrate aminotransferase(ABAT). This study reveals the effective components and mechanism of QKL Oral Prescription.

Gut microbiota involved in desulfation of sulfated progesterone metabolites: A potential regulation pathway of maternal bile acid homeostasis during pregnancy.

Abnormally raised circulating bile acids (BA) during pregnancy threat fetal and offspring health. Our previous study has identified sulfated progesterone metabolites (PMSs) in part account for dysregulation of maternal BA homeostasis during pregnancy, however, limited intervention strategies to remedy increased serum BA through PMSs during pregnancy are available. The purpose of this study is to test the feasibility of manipulating BA homeostasis and progesterone metabolism through steering gut microbiota. A total of 19 pregnant sows were randomly treated with standard diet or vancomycin-supplemented diet, to investigate the intercorrelation of PMSs, intestinal microbiota, and maternal BA metabolism from day 60 of gestation (G60) until farrowing (L0). Pregnant mice orally gavaged with epiallopregnanolone sulfate (PM5S) or vehicle and nonpregnant mice were sampled and further analyzed to verify the effect of PM5S on maternal BA metabolism. The present study revealed that oral vancomycin reduced maternal fasting serum total BA (TBA) levels and postprandial serum TBA levels at day 90 of gestation (G90). BA profile analysis showed the decreased TBA after vancomycin treatment was attributed to the decrease of primary BA and secondary BA, especially hyodeoxycholic acid (HDCA). By using newly developed UPLC-MS/MS methods, we found vancomycin increased fecal excretion of allopregnanolone sulfate (PM4S) and PM5S during late gestation and thus maintaining the relative stability of serum PM4S and PM5S, which play an important role in BA metabolism. Further study in mice showed that pregnant mice have higher serum and liver TBA levels compared with nonpregnant mice, and PM5S administration induced higher gallbladder TBA levels and TBA pool in pregnant mice. In addition, after oral vancomycin, the continuously decreased Parabacteroides genus, potentially enriched with genes encoding steroids sulfatase, may explain the increased fecal PMSs excretion in pregnant sows. Taken together, our study provides the evidence that pregnancy-induced elevation of BA levels in sow is likely regulated by manipulation of gut microbiota, which offer new insights into the prevention and treatment of disrupted BA homeostasis during pregnancy by targeting specific microbiota.

Alginate Alleviates Dextran Sulfate Sodium-Induced Colitis by Promoting Bifidobacterium animalis and Intestinal Hyodeoxycholic Acid Synthesis in Mice.

Alginate (ALG) is known to alleviate intestinal inflammation in inflammatory bowel disease, but its mechanism of action remains elusive. In the present study, we studied the involvement of the intestinal microbiota and bile acid (BA) metabolism in ALG-mediated anti-inflammatory effects in mice. A combination of 16S rRNA gene amplicon sequencing, shotgun metagenomic sequencing, and targeted BA metabolomic profiling was employed to investigate structural and functional differences in the colonic microbiota and BA metabolism in dextran sulfate sodium (DSS)-treated mice with or without dietary supplementation of ALG. We further explored the role of the intestinal microbiota as well as a selected ALG-enriched bacterium and BA in DSS-induced colitis. Dietary ALG alleviated DSS-mediated intestinal inflammation and enriched a small set of bacteria including Bifidobacterium animalis in the colon (P < 0.05). Additionally, ALG restored several bacteria carrying secondary BA-synthesizing enzymes such as 7α-hydroxysteroid dehydrogenase and BA hydrolase to healthy levels in DSS-treated mice. Although a majority of BAs were suppressed by DSS, a few secondary BAs such as hyodeoxycholic acid (HDCA) were markedly enriched by ALG. Furthermore, ALG significantly upregulated the expression of a major BA receptor, the farnesoid X receptor, while suppressing NF-κB and c-Jun N-terminal kinase (JNK) activation. Depletion of the intestinal microbiota completely abrogated the protective effect of ALG in DSS-treated mice. Similar to ALG, B. animalis and HDCA exerted a strong anti-inflammatory effect in DSS-induced colitis by downregulating inflammatory cytokines (interleukin-1β [IL-1β], IL-6, and tumor necrosis factor alpha [TNF-α]). Taken together, these results indicated that ALG achieves its alleviating effect on intestinal inflammation through regulation of the microbiota by enriching B. animalis to promote the biosynthesis of specific secondary BAs such as HDCA. These findings have revealed intricate interactions among the intestinal microbiota, BA metabolism, and intestinal health and further provided a novel strategy to improve intestinal health through targeted manipulation of the intestinal microbiota and BA metabolism. IMPORTANCE ALG has been shown to ameliorate inflammatory bowel disease (IBD), but little is known about the mechanism of its anti-inflammatory action. This study was the first to demonstrate that ALG provided a preventive effect against colitis in an intestinal microbiota-dependent manner. Furthermore, we confirmed that by selectively enriching intestinal B. animalis and secondary BA (HDCA), ALG contributed to the attenuation of DSS-induced colitis. These findings contribute to a better understanding of the mechanism of action of ALG on the attenuation of colitis and provide new approaches to IBD therapy by regulating gut microbial BA metabolism.

Duyun compound green tea extracts regulate bile acid metabolism on mice induced by high-fat diet.

Duyun compound green tea (DCGT) is a healthy beverage with lipid-lowering effect commonly consumed by local people, but its mechanism is not very clear. We evaluated the effect of DCGT treatment on bile acids (BA) metabolism of mice with high-fat diet (HFD) - induced hyperlipidaemia by biochemical indexes and metabolomics and preliminarily determined the potential biomarkers and metabolic pathways of hyperlipidaemia mice treated with DCGT as well as investigated its lipid-lowering mechanism. The results showed that DCGT treatment could reduce HFD - induced gain in weight and improve dyslipidaemia. In addition, a total of ten types of BA were detected, of which seven changed BA metabolites were observed in HFD group mice. After DCGT treatment, glycocholic acid, tauroursodeoxycholic acid and taurochenodeoxycholic acid were significantly down-regulated, while hyodeoxycholic acid, deoxycholic acid and chenodeoxycholic acid were markedly up-regulated. These results demonstrated that DCGT treatment was able to make the BA metabolites in the liver of hyperlipidaemia mice normal and alleviate hyperlipidaemia by regulating the metabolites such as glycocholic acid, tauroursodeoxycholic acid and taurochenodeoxycholic, as well as the BA metabolic pathway and cholesterol metabolic pathway involved.

Analysis of the effect of phototherapy on intestinal probiotics and metabolism in newborns with jaundice.

BackgroundIn clinical practice, oral probiotics are often given to children with hyperbilirubinaemia who receive phototherapy, but the exact mechanism of the action of the probiotics on hyperbilirubinaemia remains unclear. It is unclear how the effects of phototherapy on the probiotic flora in the neonatal gut, in particular.Materials and methodsFifty newborns who needed phototherapy from June 2018 to June 2020 were selected as the study subjects, and five healthy newborns in the same period were used as controls to analyse the changes in probiotic bacteria in their faeces.Results1. In the intestinal tracts of newborns, Bifidobacterium is the main probiotic strain, with a small amount of Lactobacillus. There were probiotic species changes in the neonatal intestinal microbiota after phototherapy for 24 and 48 h. The amount of Bifidobacterium and Lactobacillus decreased significantly (P < 0.05). 2. A correlation analysis of probiotic species and bile acid metabolism indexes showed that Bifidobacterium was positively correlated with many metabolites (P < 0.05), such as chenodeoxycholic acid, hyodeoxycholic acid, cholic acid, allocholic acid, and β-cholic acid. It was also negatively correlated with many metabolites (P < 0.05), such as glycocholic acid, sodium, sodium tudca, and chenodeoxycholic acid. Lactobacillus was negatively correlated with metabolites (P < 0.05) such as α-sodium cholate and β-cholic acid. 3. A correlation analysis between the changes in probiotics and intestinal short-chain fatty acid metabolites after phototherapy showed that acetic acid, butyric acid, caproic acid, and propionic acid decreased and were significantly correlated with Bifidobacterium (P < 0.05). 4. After phototherapy, 17 metabolites changed significantly (P < 0.05). This correlated with many probiotics (P < 0.05). The significantly changed probiotics in this study showed a significant correlation with some intestinal metabolites (P < 0.05).ConclusionIt was found that phototherapy can significantly affect the intestinal probiotic flora and the metabolic indicators of newborns, which may be an important reason for the side effects of phototherapy, and also provides the theoretical basis for the provision of probiotics to newborns with jaundice.

Hyodeoxycholic Acid (HDCA) Prevents Development of Dextran Sulfate Sodium (DSS)-Induced Colitis in Mice: Possible Role of Synergism between DSS and HDCA in Increasing Fecal Bile Acid Levels

Secondary bile acids (SBAs) with high hydrophobicity are abundant in the colonic lumen. However, both aggravating and protective roles of SBAs have been proposed in the pathogenesis of inflammatory bowel diseases (IBDs). We observed that oral administration of hyodeoxycholic acid (HDCA), a hydrophilic bile acid, prevented the development of dextran sulfate sodium (DSS)-induced colitis in mice. We then examined the individual effects of DSS and HDCA as well as their combined effects on fecal bile acid profile in mice. HDCA treatment increased the levels of most of fecal bile acids, whereas DSS treatment had limited effects on the levels of fecal bile acids. The combined treatment with DSS and HDCA synergistically increased the levels of fecal chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) in feces, which are potent activators of the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5). The overall hydrophobicity of fecal bile acids was not modified by any treatments. Our data suggest that the preventive effect of HDCA on DSS-induced colitis in mice is due to the synergism between DSS and HDCA in increasing the levels of the fecal bile acids with potencies to activate FXR and TGR5.

Transcriptome and targeted metabolome analysis provide insights into bile acids' new roles and mechanisms on fat deposition and meat quality in lamb

Higher quality lamb carcasses with more muscle and less fat are crucial for consumer preference and healthy eating. This study evaluated bile acids' functional roles and mechanisms on fat deposition in lambs. Forty-five lambs were arranged into three groups with control (CON) and two types of bile acid treatments (BA1, mainly hyocholic acid; BA2, mainly hyodeoxycholic acid, ruminally protected). The BA1 treatment did not affect the dry matter intake, body weight, and the average daily gain but significantly decreased the body fat (assessed as GR value) compared to the CON (7.92 vs 5.55 mm). The BA2 decreased tail fat weight compared to CON (1.99 vs 1.51 kg). Both BA1 and BA2 significantly decreased the tail fat ratio (110 vs 89.8 vs 78.6 g/kg of carcass weight). No significant differences were found between the three groups' blood antioxidant capacity and immune characteristics. The RNA-sequencing analysis identified 46 differentially expressed genes between CON and BA2. Several pathways, including ferroptosis and fatty acid biosynthesis and core genes such as HSPA8, HIFIA, HEXB, ACSL6, and MAP1LC3B were changed mainly or significantly correlated with the tail fat weight or proportion phenotypes, can be selected as targeted gene markers related to regulating the tail fat. This study provided new insight into bile acids' roles and revealed their comprehensive mechanism in regulating fat distribution in ruminants and will facilitate improvements of lamb meat production with decreased subcutaneous and tail fat deposition.

Beneficial effects of UDCA and norUDCA in a rodent model of steatosis are linked to modulation of GPBAR1/FXR signaling

Non-alcoholic steatosis (NAFLD) and steatohepatitis (NASH) are two highly prevalent human disorders for which therapy remains suboptimal. Bile acids play an essential role in regulating liver metabolism, and several bile acids-based therapy are currently investigated for their potential therapeutic efficacy in NAFLD/NASH. Bile acids exert their functions, at least in part, by modulating two main receptors the Farnesoid-x-receptor (FXR) and the G protein-coupled receptor, GPBAR1. In the present study we have compared the pharmacological effects of two bile acids, the ursodeoxycholic acid (UDCA) and its derivative norUDCA, in a model of NAFLD/NASH induced by feeding mice with a Western diet for 12 weeks. The results of these studies demonstrated that both UDCA and norUDCA protected against development of steatosis and fibrosis, but did not reduce the hepatocytes ballooning nor the development of a pro-atherogenic lipid profile. Both agents reduced liver lipogenesis and ameliorated insulin sensitivity and adipocytes signaling as shown by increased expression of adiponectin. Mechanistically, UDCA acts as weak GPBAR1 agonist, while norUDCA exerted no effect on both GPBAR1 and FXR. In vivo administration of UDCA resets bile acid synthesis and promotes a shift toward bile acids species that are GPBAR1 agonists, UDCA, TUDCA and hyodeoxycholic acid, and increases GLP1 expression in the ileum. In contrast norUDCA is poorly metabolized exerting a minimal impact on GPBAR1 signaling. Together, these data, highlight the potential role of UDCA and norUDCA in treating of NAFLD, though these beneficial effects are supported by different mechanisms.

Integrative network analysis revealed the molecular function of folic acid on immunological enhancement in a sheep model.

We previously observed the beneficial role of folic acid supplemented from maternal or offspring diet on lamb growth performance and immunity. Twenty-four Hu lambs from four groups (mother received folic acid or not, offspring received folic acid or not) were used in the current study, which was conducted consecutively to elucidate the molecular regulatory mechanisms of folic acid in lambs by analyzing blood metabolome, liver transcriptome, and muscle transcriptome. Serum metabolomics analysis showed that L-homocitrulline, hyodeoxycholic acid, 9-Hpode, palmitaldehyde, N-oleoyl glycine, hexadecanedioic acid, xylose, 1,7-dimethylxanthine, nicotinamide, acetyl-N-formyl-5-methoxykynurenamine, N6-succinyl adenosine, 11-cis-retinol, 18-hydroxycorticosterone, and 2-acetylfuran were down-regulated and methylisobutyrate was up-regulated by the feeding of folic acid from maternal and/or offspring diets. Meanwhile, folic acid increased the abundances of S100A12 and IRF6 but decreased TMEM25 in the liver. In the muscle, RBBP9, CALCR, PPP1R3D, UCP3, FBXL4, CMBL, and MTFR2 were up-regulated, CYP26B1 and MYH9 were down-regulated by the feeding of folic acid. The pathways of bile secretion, biosynthesis of unsaturated fatty acids, linoleic acid metabolism, and herpes simplex virus 1 infection were changed by folic acid in blood, liver, or muscle. Further integrated analysis revealed potential interactions among the liver, blood, and muscle, and the circulating metabolites, hub gene, and pathways, which might be the predominant acting targets of folic acid in animals. These findings provide fundamental information on the beneficial function of folic acid no matter from maternal or offspring, in regulating animal lipid metabolism and immune enhancement, providing a theoretical basis for the use of folic acid from the view of animal health care.

6α-hydroxylated bile acids mediate TGR5 signalling to improve glucose metabolism upon dietary fiber supplementation in mice

ObjectiveDietary fibres are essential for maintaining microbial diversity and the gut microbiota can modulate host physiology by metabolising the fibres. Here, we investigated whether the soluble dietary fibre oligofructose improves...

Hyodeoxycholic acid inhibits lipopolysaccharide-induced microglia inflammatory responses through regulating TGR5/AKT/NF-κB signaling pathway.

Hyodeoxycholic acid (HDCA) is a natural secondary bile acid with enormous pharmacological effects, such as modulating inflammation in neuron. However, whether HDCA could suppress microglial inflammation has not been elucidated yet. To determine the anti-microglial inflammatory effect of HDCA in lipopolysaccharide (LPS) models and its mechanisms. The effect of HDCA was evaluated in LPS-stimulated BV2 microglial cells in vitro and the cortex of LPS-treated mice in vivo. Immunohistochemistry and immunofluorescence were used to visualize the localization of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and ionized calcium-binding adaptor protein-1 (Iba-1), respectively. The mRNA expression of inflammatory cytokines was measured by RT-qPCR. The protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), takeda G-coupled protein receptor 5 (TGR5), and the phosphorylation of protein kinase B (AKT), NF-κB, and inhibitor of NF-κB protein α (IκBα) was examined by Western blot. HDCA inhibited the inflammatory responses in LPS-treated BV2 cells and in the cortex of LPS-treated mice, evidenced by decreased production of inflammatory mediators such as iNOS, COX-2, tumor necrosis factor (TNF-α), interleukin (IL)-6, and IL-1β. Further study demonstrated that HDCA repressed the phosphorylation, nuclear translocation, and transcriptional activity of NF-κB and inhibited the activation of AKT in BV-2 cells induced by LPS. Meanwhile, addition of TGR5 inhibitor, triamterene, abolished the effects of HDCA on TGR5, AKT, and NF-κB. The present study demonstrated that HDCA prevents LPS-induced microglial inflammation in vitro and in vivo, the action of which is via regulating TGR5/AKT/NF-κB signaling pathway.

Ferrous Bisglycinate Supplementation Modulates Intestinal Antioxidant Capacity via the AMPK/FOXO Pathway and Reconstitutes Gut Microbiota and Bile Acid Profiles in Pigs.

Multi-omics were applied to compare the risks and benefits of ferrous sulfate (FeSO4) and ferrous bisglycinate (FebisGly) in pigs in the current study. The FebisGly group showed reduced triglyceride (TG) and triglyceride/total cholesterol (TG/CHOL) values in the serum and reduced malondialdehyde (MDA) and increased glutathione (GSH) levels in the duodenum. Transcriptome analysis revealed that differentially expressed genes in the duodenum were enriched in oxidative phosphorylation, AMPK, and FOXO signaling pathways between FeSO4 and FebisGly groups. AMPK phosphorylation and FOXO3 protein expressions were significantly increased in the FebisGly group. Bacterial 16S rRNA gene sequence analysis revealed significantly reduced alpha diversity in the FeSO4 group and increased Firmicutes, reduced Bacteroidetes, and Proteobacteria abundances in the FebisGly group. Targeted metabolome revealed notably increased lithocholic acid (LCA), glycolithocholic acid (GLCA), hyodeoxycholic acid (HDCA), ursodeoxycholic acid (UDCA), and glycoursodeoxycholic acid (GUDCA) in the FebisGly group. RDA analysis indicated that Fusobacteria was positively correlated with TG and TG/high-density lipoprotein in the FeSO4 group while Christensenellaceae_R-7_group, Ruminococcaceae_UCG-002, and Ruminococcaceae_UCG-005 were positively correlated with UDCA and GLCA in the FebisGly group. According to the current study, FebisGly improves serum lipid metabolism, modulates intestinal antioxidant capacity via the AMPK/FOXO pathway, and reconstitutes gut microbiota and bile acid profiles in pigs.