Bile Acid Levels Research Articles

Cholestatic insult triggers alcohol-associated hepatitis in mice.

Alcohol-associated hepatitis (AH) is a severe, potentially life-threatening form of alcohol-associated liver disease with limited therapeutic options. Existing evidence shows that biliary dysfunction and cholestasis are common in patients with AH and are associated with poorer prognosis. However, the role of cholestasis in the development of AH is largely unknown. We aimed to examine the hypothesis that cholestasis can be an important etiology factor for AH. To study the interaction of cholestasis and alcohol, chronically ethanol (EtOH)-fed mice were challenged with a subtoxic dose of α-naphthylisothiocyanate (ANIT), a well-studied intrahepatic cholestasis inducer. Liver injury was measured by biochemical and histological methods. RNAseq was performed to determine hepatic transcriptomic changes. The impact of inflammation was assessed using an anti-LY6G antibody to deplete the neutrophils and DNase I to degrade neutrophil extracellular traps. ANIT synergistically enhanced liver injury following a 4-week EtOH feeding with typical features of AH, including increased serum levels of ALT, AST, and total bile acids, cholestasis, necrosis, neutrophil infiltration, and accumulation of neutrophil extracellular traps. RNAseq revealed multiple genes uniquely altered in the livers of EtOH/ANIT-treated mice. Analysis of differentially expressed genes suggested an enrichment of genes related to inflammatory response. Anti-LY6G antibody or DNase I treatment significantly inhibited liver damage in EtOH/ANIT-treated mice. Our results support the hypothesis that cholestasis can be a critical contributor to the pathogenesis of AH. A combined treatment of EtOH and ANIT in mice presents biochemical, histological, and molecular features similar to those found in patients with AH, suggesting that this treatment scheme can be a useful model for studying Alcohol-associated Cholestasis and Hepatitis (AlChoHep).

Maternal Obesity and Differences in Child Urine Metabolome

Background/objective: Approximately one-third of pregnant individuals in the U.S. are affected by obesity, which can adversely impact the in utero environment and offspring. This study aimed to investigate the differences in urine metabolomics between children exposed and unexposed to maternal obesity. Methods: In a study nested within a larger pregnancy cohort of women–offspring pairs, we measured untargeted metabolomics using liquid chromatography–mass spectrometry in urine samples from 68 children at 4–8 years of age. We compared metabolite levels between offspring exposed to maternal obesity (body mass index [BMI] ≥ 30.0 kg/m2) vs. unexposed (maternal BMI 18.5–24.9 kg/m2) and matched them on covariates, using two-sample t-tests, with additional sensitivity analyses based on children’s BMI. This study reports statistically significant results (p ≤ 0.05) and potentially noteworthy findings (fold change > 1 or 0.05 < p < 0.15), considering compounds’ involvement in common pathways or similar biochemical families. Results: The mean (SD) maternal age at study enrollment was 28.0 (6.3) years, the mean child age was 6.6 (0.8) years, 56% of children were male, and 38% of children had a BMI in the overweight/obese range (BMI ≥ 85th percentile). Children exposed to maternal obesity had lower levels of 5-hydroxyindole sulfate and 7-hydroxyindole sulfate and higher levels of secondary bile acids. Phenylacetic acid derivatives were lower in offspring exposed to obesity and in offspring who had a current BMI in the overweight/obese range. Exposure to maternal obesity was associated with lower levels of androgenic steroid dehydroepiandrosterone sulfate (DHEA-S). Conclusions: In this preliminary study, children exposed to maternal obesity in utero had differences in microbiome-related metabolites in urine suggestive of altered microbial catabolism of tryptophan and acetylated peptides. Some of these differences were partially attributable to the offspring’s current BMI status. This study highlights the potential of urine metabolomics to identify biomarkers and pathways impacted by in utero exposure to maternal obesity.

Elucidating Bile Acid Tolerance in Saccharomyces cerevisiae: Effects on Sterol Biosynthesis and Transport Protein Expression

The tolerance of Saccharomyces cerevisiae to high concentrations of bile acids is intricately linked to its potential as a probiotic. While the survival of yeast under high concentrations of bile acids has been demonstrated, the specific mechanisms of tolerance remain inadequately elucidated. This study aims to elucidate the tolerance mechanisms of S. cerevisiae CEN.PK2-1C under conditions of elevated bile acid concentrations. Through growth curve analyses and scanning electron microscopy (SEM), we examined the impact of high bile acid concentrations on yeast growth and cellular morphology. Additionally, transcriptomic sequencing and molecular docking analyses were employed to explore differentially expressed genes under high bile acid conditions, with particular emphasis on ATP-binding cassette (ABC) transporters and steroid hormone biosynthesis. Our findings indicate that high concentrations of bile acids induce significant alterations in the sterol synthesis pathway and transporter protein expression in S. cerevisiae. These alterations primarily function to regulate sterol synthesis pathways to maintain cellular structure and sustain growth, while enhanced expression of transport proteins improves tolerance to elevated bile acid levels. This study elucidates the tolerance mechanisms of S. cerevisiae under high bile acid conditions and provides a theoretical foundation for optimizing fermentation processes and process control.

The development of hepatic steatosis depends on the presence of liver-innervating parasympathetic cholinergic neurons in mice fed a high-fat diet.

Hepatic lipid metabolism is regulated by the autonomic nervous system of the liver, with the sympathetic innervation being extensively studied, while the parasympathetic efferent innervation is less understood despite its potential importance. In this study, we investigate the consequences of disrupted brain-liver communication on hepatic lipid metabolism in mice exposed to obesogenic conditions. We found that a subset of hepatocytes and cholangiocytes are innervated by parasympathetic nerve terminals originating from the dorsal motor nucleus of the vagus. The elimination of the brain-liver axis by deleting parasympathetic cholinergic neurons innervating the liver prevents hepatic steatosis and promotes browning of inguinal white adipose tissue (ingWAT). The loss of liver-innervating cholinergic neurons increases hepatic Cyp7b1 expression and fasting serum bile acid levels. Furthermore, knockdown of the G protein-coupled bile acid receptor 1 gene in ingWAT reverses the beneficial effects of the loss of liver-innervating cholinergic neurons, leading to the reappearance of hepatic steatosis. Deleting liver-innervating cholinergic neurons has a small but significant effect on body weight, which is accompanied by an increase in energy expenditure. Taken together, these data suggest that targeting the parasympathetic cholinergic innervation of the liver is a potential therapeutic approach for enhancing hepatic lipid metabolism in obesity and diabetes.

Loureirin B Ameliorates Glycolipid Metabolism Disorders in Ob/ob Mice by Regulating Bile Acid Levels and Modulating Gut Microbiota Composition.

Loureirin B (LB), an active component of Resina Draconis, exhibits hypoglycemic and hypolipidemic effects; however, its mode of action remains unclear. Here, ob/ob mice were utilized to investigate the effects of LB on the regulation of glucolipid metabolism disorders. Non-targeted metabolomics and 16S rDNA sequencing were performed to elucidate the potential mechanisms involved. Results indicated that LB treatment (45 mg/kg) significantly improved glucose intolerance and insulin resistance, reduced lipid levels, and alleviated hepatic steatosis. Non-targeted metabolomics analysis revealed that LB treatment regulated bile acid levels. Quantification of liver bile acids demonstrated that LB treatment significantly decreased the ratio of 12α-OH to non-12α-OH bile acids in the liver. 16S rDNA sequencing results showed that LB treatment increased the abundance of short-chain fatty acid-producing microbiota while decreasing the abundance of bile salt hydrolase (BSH) enzyme-producing microbiota. In conclusion, LB ameliorates glucolipid metabolism disorders by regulating liver bile acid levels and modulating the composition of the gut microbiota.

Zhi-Kang-Yin formula attenuates high-fat diet-induced metabolic disorders through modulating gut microbiota-bile acids axis in mice

BackgroundMetabolic disorders have become one of the global medical problems. Due to the complexity of its pathogenesis, there is still no effective treatment. Bile acids (BAs) and gut microbiota (GM) have been proved to be closely related to host metabolism, which could be important targets for metabolic disorders. Zhi-Kang-Yin (ZKY) is a traditional Chinese medicine (TCM) formula developed by the research team according to theory of TCM and has been shown to improve metabolism in clinic. However, the underlying mechanisms are unclear.Aim of the studyThis study aimed to investigate the potential mechanisms of the beneficial effect of ZKY on metabolism.MethodsHigh-fat diet (HFD)-fed mice were treated with and without ZKY. The glucose and lipid metabolism-related indexes were measured. BA profile, GM composition and hepatic transcriptome were then investigated to analyze the changes of BAs, GM, and hepatic gene expression. Moreover, the relationship between GM and BAs was identified with functional gene quantification and ex vivo fermentation experiment.ResultsZKY reduced weight gain and lipid levels in both liver and serum, attenuated hepatic steatosis and improved glucose tolerance in HFD-fed mice. BA profile detection showed that ZKY changed the composition of BAs and increased the proportion of unconjugated BAs and non-12-OH BAs. Hepatic transcriptomic analysis revealed fatty acid metabolism and BA biosynthesis related pathways were regulated. In addition, ZKY significantly changed the structure of GM and upregulated the gene copy number of bacterial bile salt hydrolase. Meanwhile, ZKY directly promoted the growth of Bifidobacterium, which is a well-known bile salt hydrolase-producing genus. The ex vivo co-culture experiment with gut microbiota and BAs demonstrated that the changes of BAs profile in ZKY group were mediated by ZKY-shifted GM, which led to increased expression of genes associated with fatty acid degradation in the liver.ConclusionOur study indicated that the effect of ZKY on improving metabolism is associated with the modulation of GM-BAs axis, especially, by upregulating the abundance of bile salt hydrolase-expression bacteria and increasing the levels of unconjugated BAs. This study indicates that GM-BAs axis might be an important pathway for improving metabolic disorders by ZKY.

Non-mitogenic FGF19 mRNA-based therapy for the treatment of experimental metabolic dysfunction-associated steatotic liver disease (MASLD).

Metabolic dysfunction-associated steatohepatitis (MASH) represents a global health threat. MASH pathophysiology involves hepatic lipid accumulation and progression to severe conditions like cirrhosis and, eventually, hepatocellular carcinoma. Fibroblast growth factor (FGF)-19 has emerged as a key regulator of metabolism, offering potential therapeutic avenues for MASH and associated disorders. We evaluated the therapeutic potential of non-mitogenic (NM)-FGF19 mRNA formulated in liver-targeted lipid nanoparticles (NM-FGF19-mRNAs-LNPs) in C57BL/6NTac male mice with diet-induced obesity and MASH (DIO-MASH: 40% kcal fat, 20% kcal fructose, 2% cholesterol). After feeding this diet for 21 weeks, NM-FGF19-mRNAs-LNPs or control (C-mRNA-LNPs) were administered (0.5 mg/kg, i.v.) weekly for another six weeks, in which diet feeding continued. NM-FGF19-mRNAs-LNPs treatment in DIO-MASH mice resulted in reduced body weight, adipose tissue depots, and serum transaminases, along with improved insulin sensitivity. Histological analyses confirmed the reversal of MASH features, including steatosis reduction without worsening fibrosis. NM-FGF19-mRNAs-LNPs reduced total hepatic bile acids (BAs) and changed liver BA composition, markedly influencing cholesterol homeostasis and metabolic pathways as observed in transcriptomic analyses. Extrahepatic effects included the down-regulation of metabolic dysfunction-associated genes in adipose tissue. This study highlights the potential of NM-FGF19-mRNA-LNPs therapy for MASH, addressing both hepatic and systemic metabolic dysregulation. NM-FGF19-mRNA demonstrates efficacy in reducing liver steatosis, improving metabolic parameters, and modulating BA levels and composition. Given the central role played by BA in dietary fat absorption, this effect of NM-FGF19-mRNA may be mechanistically relevant. Our study underscores the high translational potential of mRNA-based therapies in addressing the multifaceted landscape of MASH and associated metabolic perturbations.

Outer membrane barrier impairment by envC deletion reduces gut colonization of Crohn's disease pathobiont Escherichia coli.

Adherent-invasive Escherichia coli (AIEC) has been implicated in the aetiology of Crohn's disease (CD), a chronic inflammatory disorder of the gastrointestinal tract. The presence of Enterobacteriaceae, including AIEC, is heightened in the intestines of CD patients. Therefore, inhibiting AIEC colonization in the gastrointestinal tract could be a promising therapeutic intervention for CD. This study aims to assess the potential of EnvC as a novel therapeutic target, examining how disrupting EnvC activity through the deletion of the envC gene decreases AIEC gut colonization levels. EnvC serves as a catalyst for peptidoglycan (also called murein) amidases, facilitating bacterial cell division. An AIEC mutant lacking the envC gene exhibited impaired cell division. Furthermore, envC deletion led to a diminished outer membrane barrier, as seen in our finding that the envC mutant became susceptible to vancomycin. Finally, we found that the envC mutant is impaired in competitive gut colonization in a dysbiotic mouse model. The colonization defects might be attributable to reduced resistance to colonic bile acids, as evidenced by our finding that increased colonic levels of bile acids inhibited the colonization of the gastrointestinal tract by AIEC strains. The present findings suggest that targeting bacterial cell division through the inhibition of EnvC activity could represent a promising intervention for CD.

RISE IN PLASMA BILE ACIDS FOLLOWING HYPOABSORPTIVE BARIATRIC SURGERIES PREDICT BENEFICIAL METABOLIC AND HOMEOSTATIC OUTCOMES IN MALE RATS.

The effects of three hypoabsorptive bariatric surgeries, Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S), on bile acids (BAs) were assessed including the changes in BA plasma levels associated with the metabolic and homeostatic effects of the surgeries. Male Wistar rats, etheir fed high- (HF) or a low-fat (LF) diets, were divided into seven groups: RYGB HF, BPD-DS HF, SADI-S HF, sleeve-gastrectomy (SG) HF, sham-operation (SHAM) HF, SHAM LF and SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW). The rats were treated 56 days. The results demonstrate the ability of RYGB, BPD-DS and SADI-S to raise plasma levels of BAs, whose elevations, most notably those of the secondary BAs (deoxycholic acid, ursodooxycholic acid and lithocholic acid) associated negatively with body weight gain, fat gain and fasting insulin levels and positively with plasma peptide tyrosine-tyrosine (PYY). Plasma BAs also correlated positively with the fecal levels of Clostridium, Sutterella and Enterobacteriaceae and negatively with Clostridiales_f_g_2, Christensenellaceae, Ruminococcaceae_g_2, Oscillibacter and Oscillospira. Additionally, they associated positively with the short-chain fatty acid (SCFA) levels of propionate, butyrate, isobutyrate, valerate and isovalerate. Altogether, the present study emphasizes the ability of RYGB, BPD-DS and SADI-S to induce circulating BA elevations that predict the beneficial consequences of those hypoabsorptive bariatric surgeries on energy and glucose homeostasis and circulating levels of PYY. The present results also reveal close associations between plasma BAs and SCFAs, whose variations following hypoabsorptive surgeries are also linked to significant fat losses and metabolic health improvements.

Entamoeba muris mitigates metabolic consequences of high-fat diet in mice

ABSTRACT Metabolic syndrome (MetS) is a cluster of several human conditions including abdominal obesity, hypertension, dyslipidemia, and hyperglycemia, all of which are risk factors of type 2 diabetes, cardiovascular disease, and metabolic dysfunction-associated steatotic liver disease (MASLD). Dietary pattern is a well-recognized MetS risk factor, but additional changes related to the modern Western life-style may also contribute to MetS. Here we hypothesize that the disappearance of amoebas in the gut plays a role in the emergence of MetS in association with dietary changes. Four groups of C57B/6J mice fed with a high-fat diet (HFD) or a normal diet (ND) were colonized or not with Entamoeba muris, a commensal amoeba. Seventy days after inoculation, cecal microbiota, and bile acid compositions were analyzed by high-throughput sequencing of 16S rDNA and mass spectrometry, respectively. Cytokine concentrations were measured in the gut, liver, and mesenteric fat looking for low-grade inflammation. The impact of HFD on liver metabolic dysfunction was explored by Oil Red O staining, triglycerides, cholesterol concentrations, and the expression of genes involved in β-oxidation and lipogenesis. Colonization with E. muris had a beneficial impact, with a reduction in dysbiosis, lower levels of fecal secondary bile acids, and an improvement in hepatic steatosis, arguing for a protective role of commensal amoebas in MetS and more specifically HFD-associated MASLD.

Serum levels of total bile acids are associated with an increased risk of HCC in patients with cirrhosis

Serum levels of total bile acids are associated with an increased risk of HCC in patients with cirrhosis

6824 Bile Acid Elevation in Nonalcoholic Steatohepatitis Correlates With Fibrogenesis and Mitochondrial Dysfunction In Vitro

Abstract Disclosure: N. Patel: None. Y. Li: None. M. Raul: None. C. Sottas: None. V. Papadopoulos: None. Nonalcoholic steatohepatitis (NASH) is the most severe form of nonalcoholic fatty liver disease. It is estimated that over 115 million adults are affected by NASH worldwide. The causes of NASH are unclear, and no treatment is yet available. Bile acids (BAs) are steroids synthesized in the liver, promoting lipid absorption. The levels of BAs are tightly regulated in the body. Patients diagnosed with NASH frequently exhibit increased levels of BAs in both liver tissue and plasma, indicating a potential association between elevated BA concentrations and the pathogenesis of NASH. In an in vivo study using a high-fat diet rat model of NASH, we measured plasma BA composition and levels. The results obtained indicated substantial increases in the concentrations of glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), and taurodeoxycholic acid (TDCA) in NASH compared to controls. These findings suggested their potential implication in the development of NASH. To elucidate the mechanistic link between changes in BA synthesis and fibrogenesis, in vitro experiments were conducted using the LX-2 humane hepatic stellate and Huh7 human hepatocellular carcinoma cells. First, the concentrations of the selected bile acids (GCA, GCDCA, GDCA, and TDCA) used in our studies were found to be non-toxic to the cells using the MTT assay. Subsequent qPCR analyses demonstrated the upregulation of key fibrotic genes (TGFβ, COL1A1, ACTA2) in LX-2 cells following exposure to individual bile acids GCA, GCDCA, GDCA, and TDCA. Immunocytochemistry (ICC) studies further demonstrated fibrogenesis by revealing increased expression of COL1A1 following treatment with each of the four bile acids. These data suggest that changes in BA formation are linked to fibrogenesis. We subsequently explored the impact of BAs on mitochondrial function using the Seahorse XF Cell Mito Stress Test in Huh7 cells. The results obtained revealed a reduction in the oxygen consumption rate and ATP production in response to BA treatment. This observation suggests a potential role for modified BAs in disrupting mitochondrial homeostasis, a recognized contributor to the progression of NASH. In summary, the data presented provide valuable insights into the complex effects of modified BAs on NASH pathogenesis, establishing connections between changes in BA composition and fibrogenesis, mitochondrial dysfunction. Presentation: 6/2/2024

Association of Serum Bile Acid Profile with Diet and Physical Activity Habits in Japanese Middle-Aged Men.

Circulating bile acid (BA) profiles change with lifestyle and are closely related to intestinal BA metabolisms such as deconjugation and conversion to secondary BAs. The composition of BA in the blood is involved in systemic nutrient metabolism and intestinal health. Herein, we explored the associations of lifestyle and physical fitness with the circulating BA profile of middle-aged men. Data of 147 male participants (aged 50-64 years; BMI < 26 kg/m2; no medication for diabetes or dyslipidemia) from the Japan Multi-Institutional Collaborative Cohort study were analyzed. Serum concentrations of 15 types of BAs were examined for associations with variables on dietary habits, physical-activity habits, and physical fitness. Green tea intake was positively associated with the deconjugation ratio of total BAs (p = 0.028) and negatively associated with secondary BA levels (free deoxycholic acid [DCA] (p = 0.078), glyco-DCA (p = 0.048), and tauro-DCA (p = 0.037)). In contrast, physical activity was negatively associated with the deconjugation ratio (p = 0.029) and secondary BA levels (free DCA (p = 0.098), and free lithocholic acid (p = 0.009)). Grip strength was also negatively associated with secondary BA levels (tauro-DCA (p = 0.041)) but was not associated with the deconjugation ratio. Energy and fat intake and skeletal muscle mass were not associated with the deconjugation ratio or secondary BA levels. The study findings suggest that lifestyle-associated changes in serum deconjugated and secondary BAs indicate improvements in nutrient metabolism and the intestinal environment.

Elevated plasma bile acids coincide with cardiac stress and inflammation in young Cyp2c70-/- mice.

High plasma bile acids (BAs), for instance due to intrahepatic cholestasis of pregnancy or neonatal cholestasis, are associated with cardiac abnormalities. Here, we exploited the variability in plasma BA levels in Cyp2c70-/- mice with a human-like BA composition to investigate the acute effects of elevated circulating BAs on the heart. RNA sequencing was performed on hearts of 3-week-old Cyp2c70-/- mice lacking mouse-specific BA species that show features of neonatal cholestasis. Cardiac transcriptomes were compared between wild-type pups, Cyp2c70-/- pups with low or high plasma BAs, and Cyp2c70-/- pups from dams that were perinatally treated with ursodeoxycholic acid (UDCA). We identified 1355 genes that were differentially expressed in hearts of Cyp2c70-/- mice with high versus low plasma BAs with enrichment of inflammatory processes. Strikingly, expression of 1053 (78%) of those genes was normalized in hearts of pups of UDCA-treated dams. Moreover, 645 cardiac genes strongly correlated to plasma BAs, of which 172 genes were associated with cardiovascular disease. Elevated plasma BAs alter gene expression profiles of hearts of mice with a human-like BA profile, revealing cardiac stress and inflammation. Our findings support the notion that high plasma BAs induce cardiac complications in early life. Cyp2c70-/- mice with a human-like bile acid composition show features of neonatal cholestasis but the extrahepatic consequences hereof have so far hardly been addressed Elevated plasma bile acids in Cyp2c70-/- pups coincide with cardiac stress and inflammation Perinatal treatment with UDCA prevents dysregulated cardiac gene expression patterns in Cyp2c70-/- pups.

Are Systemic Inflammation Markers Reliable for Diagnosing Intrahepatic Cholestasis of Pregnancy? A Retrospective Cohort Study.

This study aims to evaluate the effectiveness of inflammation indexes (systemic immune-inflammation index [SII], systemic inflammation response index [SIRI], pan-immune inflammation value [PIV], and neutrophil-to-lymphocyte ratio [NLR]) in the diagnosis of intrahepatic cholestasis of pregnancy (ICP). A retrospective study was conducted, reviewing medical records of patients diagnosed with ICP who delivered between October 1, 2022, and May 31, 2023, at the Perinatology clinic of Etlik City Hospital, Ankara. A control group of healthy pregnant women with uncomplicated pregnancies was also included. Demographic data, clinical characteristics, and laboratory results, including systemic inflammation indices and liver enzyme levels, were collected and analyzed. A total of 242 participants were included, with 121 ICP patients and 121 controls. White blood cell count, neutrophil count, and monocyte count showed significant differences between the two groups (p = 0.011, p = 0.004, and p = 0.039, respectively). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were significantly elevated in the ICP group (p < 0.001 for both). SII and NLR were higher in the ICP group compared to controls (p = 0.032 and p = 0.010, respectively). Receiver operating characteristic (ROC) analysis revealed moderate predictive values for SII (area under the curve [AUC] = 0.581, p = 0.030) and NLR (AUC = 0.598, p = 0.009), with no significant difference in their predictive power (p = 0.502). Systemic inflammation indices such as SII and NLR offer a cost-effective and rapid means of diagnosing ICP, potentially complementing or surpassing traditional biomarkers like bile acid levels and liver function tests (LFTs). These indices can be easily integrated into routine clinical practice, providing timely intervention to improve maternal and fetal outcomes. Further research is warranted to confirm these findings and establish standardized protocols for their use in ICP management.

Low polarity fraction of Radix Bupleuri alleviates chronic unpredictable mild stress-induced depression in rats through FXR modulating bile acid homeostasis in liver, gut, and brain

Radix Bupleuri (BR, Bupleurum chinense DC.) is a well-known traditional Chinese medicine (TCM) known for its effects on soothing the liver and alleviating depression, and is widely used in clinical settings to manage depressive symptoms. A dosage of 12.5g crude drug/kg/d of the low-polarity fraction of Radix Bupleuri (LBR) demonstrated effectiveness in treating depression in our previous study. However, the mechanism through which BR ameliorates depression remains unclear. This study aimed to explore the polar fractions of BR and their mechanisms of action in the treatment of depression. Chronic unpredictable mild stress (CUMS) rats were continuously administered BR by oral gavage for 4 weeks. Behavioral and biochemical indicators were evaluated to assess the antidepressant effects of LBR, and transcriptomics was used to explore the relevant pathways. In addition, pseudo-targeted bile acid (BA) metabonomics was used to quantify the BA profiles. Molecular biology techniques have been used to investigate the underlying mechanisms. LBR serves as a more effective active fraction with antidepressant activity. Intervention with LBR, which is characterized by a clearly defined chemical composition, significantly ameliorated depression-like behavior and biochemical indicators in rats subjected to CUMS. Notably, marked improvements were observed in the levels of total bile acids (TBAs) in the blood, liver, and ileum. Mechanistically, liver transcriptome analysis suggested that bile secretion may be a crucial pathway for alleviating depression after LBR treatment. Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) BA metabonomics indicated that TCA, β-MCA, γ-MCA, Tβ-MCA, and UDCA in the liver, Tβ-MCA, TCA, βMCA, GHDCA, and GLCA in the ileum, and β-MCA, CA, and DCA in the hippocampus were the potential therapeutic targets. In addition, molecular biology experiments showed that LBR exerts antidepressant effects by regulating the FXR/SHP/CYP7A1 pathway in the liver, the FXR/FGF15/ASBT pathway in the ileum, and the FXR/CREB/BDNF pathway in the hippocampus. In conclusion, LBR attenuated depression by moderating BA homeostasis through FXR and related genes within the liver-gut-brain axis.

Gut microbiota of miR-30a-5p-deleted mice aggravate high-fat diet-induced hepatic steatosis by regulating arachidonic acid metabolic pathway.

Patients with non-alcoholic fatty liver disease (NAFLD) often exhibit hepatic steatosis and dyslipidemia. Studies have shown that intestinal microorganisms are closely related to the occurrence of NAFLD and atherosclerosis. Our previous study has underscored the protective role of microRNA-30a-5p (miR-30a-5p) against atherosclerosis. In the present study, we aimed to elucidate the effect and underlying mechanism of the intestinal microorganisms of miR-30a-5p knockout (KO) mice on NAFLD. Our findings demonstrated that KO exacerbated high-fat diet (HFD)-induced hepatic steatosis and disrupted liver function, as evidenced by elevated levels of total cholesterol, low-density lipoprotein, alanine aminotransferase, aspartate transaminase, and total bile acids in serum. Fecal microbiota from HFD-fed KO mice induced hepatic steatosis, dyslipidemia, and higher levels of enzymes indicative of liver damage in wild-type mice. Remarkably, KO mice significantly intensified the above effects. 16s rDNA sequencing and metabolomics of the intestinal microbiota in the HFD-treated KO and WT mice showed that the loss of miR-30a-5p resulted in intestinal microbiota imbalance and was highly related to the arachidonic acid metabolic pathway. Targeted metabolomic in the liver tissues unveiled upregulation of COX-related (PGF2a, 8-iso-PGF2a and PGF2) and LOX-related (LTB4, LTD4, 12S-HETE and 15S-HETE) factors in HFD-treated KO mice. Immunohistochemistry and transcriptional analyses showed that miR-30a-5p affected arachidonic acid metabolism through the LOX/COX pathways. Besides, COX/LOX pathways and hepatic steatosis were reversed after reintroducing miR-30a-5p in HFD-treated KO mice. This study reveals the pivotal mechanism by which miR-30a-5p and intestinal microbes regulate hepatic steatosis and abnormal lipid metabolism, offering promising avenues for NAFLD and atherosclerosis therapeutics. MiR-30a-5p deletion aggravated hepatic steatosis and lipid disorder induced by an HFD in mice. Gut microbiota participated in the regulation of hepatic steatosis in the context of miR-30a-5p. Gut microbiota metabolism-related arachidonic acid metabolic pathway contributed to miR-30a-5p-regulated hepatic steatosis and lipid disorder. Reintroducing miR-30a-5p reversed hepatic steatosis and arachidonic acid metabolism disorder caused by HFD and miR-30a-5p deletion.

α-Linolenic acid from Mori Folltfm found as Choloylglycine hydrolase inhibitor by the developed fluorescent probe to alleviate type 2 diabetes

Choloylglycine hydrolase (CH), also known as bile salt hydrolase, is expressed by intestinal microbiota and plays a key role in the hydrolysis of conjugated bile acids, influencing the composition and levels of various bile acids. In this study, a conjugate (CA-ACDI) of cholic acid and a semi-cyanine derivative was developed as an enzyme-activated fluorescent probe for detecting CH activity, showing potential applications in this area. By the high-throughput screening of CH activity using CA-ACDI, Mori Folium was identified as a significant CH inhibitor from a collection of 95 traditional herbal medicines. Further analysis using various chromatographic techniques and spectroscopic data identified α-linolenic acid as the key bioactive component in Mori Folium responsible for inhibiting CH activity. Importantly, α-Linolenic acid, as a natural CH inhibitor, was shown to significantly regulate glucose metabolism in a type 2 diabetes mellitus (T2DM) mouse model via the FXR signaling pathway. This work not only developed a novel fluorescent probe for CH detection but also discovered potential CH inhibitors that may help alleviate type 2 diabetes.

Bile acid metabolites predict multiple sclerosis progression and supplementation is safe in progressive disease.

Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS. Global metabolomics was performed in an observational cohort of people with MS, followed by pathway analysis to examine relationships between baseline metabolite levels and subsequent brain and retinal atrophy. A double-blind, placebo-controlled trial was completed in people with progressive MS (PMS), randomized to receive either TUDCA (2 g/day) or placebo for 16weeks. Participants were followed with serial clinical and laboratory assessments. Primary outcomes were safety and tolerability of TUDCA, and exploratory outcomes included changes in clinical, laboratory, and gut microbiome parameters. In the observational cohort, higher primary bile acid levels at baseline predicted slower whole-brain atrophy, brain substructure atrophy, and specific retinal layer atrophy. In the clinical trial, 47 participants were included in our analyses (21 in placebo arm, 26 in TUDCA arm). Adverse events did not differ significantly between arms (p= 0.77). The TUDCA arm demonstrated increased serum levels of multiple bile acids. No significant differences were noted in clinical or fluid biomarker outcomes. Central memory CD4+ and Th1/17 cells decreased, while CD4+ naive cells increased in the TUDCA arm compared to placebo. Changes in the composition and function of gut microbiota were also noted between the two groups. Bile acid metabolism in MS is linked to brain and retinal atrophy. TUDCA supplementation in PMS is safe, tolerable, and has measurable biological effects that warrant further evaluation in larger trials with a longer treatment duration. National MS Society grant RG-1707-28601 to P.B., R01 NS082347 from the National Institute of Neurological Disorders and Stroke to P.A.C., and National MS Society grant RG-1606-08768 to S.S.

The Role of Bile Acids in Pancreatic Cancer.

Bile acids are well known to promote the digestion and absorption of fat, and at the same time, they play an important role in lipid and glucose metabolism. More studies have found that bile acids such as ursodeoxycholic acid also have anti-inflammatory and immune-regulating effects. Bile acids have been extensively studied in biliary and intestinal tumors but less in pancreatic cancer. Patients with pancreatic cancer, especially pancreatic head cancer, are often accompanied by biliary obstruction and elevated bile acids caused by tumors. Elevated total bile acid levels in pancreatic cancer patients usually have a poor prognosis. There has been controversy over whether elevated bile acids are harmful or beneficial to pancreatic cancer. Still, there is no doubt that bile acids are important for the occurrence and development of pancreatic cancer. This article summarizes the research on bile acid as a biomarker and regulation of the occurrence, development and chemoresistance of pancreatic cancer, hoping to provide some inspiration for future research.