Search

• Fiber decreased lipopolysaccharide-binding protein (LBP) in those with high LBP • LBP was negatively correlated with microbial genes for antibiotic synthesis • LBP was positively correlated with sulfated molecules like perfluorooctanesulfonate Although the beneficial effects of fiber supplementation on overall health and the gut microbiome are well-known, it is not clear whether fiber supplementation can also alter the concentrations of lipopolysaccharide-binding protein (LBP), a marker of intestinal permeability. A secondary analysis of a previously conducted study was performed. In the randomized-order, placebo-controlled, double-blinded, cross-over study 20 healthy, young participants consuming a low-fiber diet at baseline were administered a daily dose of 12 g of prebiotic fiber compared with a placebo over a period of 4 weeks with a 4-week washout between arms. In this secondary analysis, we hypothesized that the fiber supplement would reduce LBP concentration. We further hypothesized that lecithin cholesterol acyltransferase activity, a measure of high-density lipoprotein functional capacity, would be altered. Fiber supplementation did not significantly alter LBP concentration or lecithin cholesterol acyltransferase activity in the overall cohort. However, in a subgroup of individuals with elevated baseline LBP concentrations, fiber supplementation significantly reduced LBP from 9.27 ± 3.52 to 7.02 ± 2.32 µg/mL (P =.003). Exploratory analyses found positive correlations between microbial genes involved in lipopolysaccharide synthesis and conversely negative correlations with genes involved in antibiotic synthesis and LBP. Positive correlations between LBP and multiple sulfated molecules including sulfated bile acids and perfluorooctanesulfonate, and ibuprofen metabolites were also found. These findings highlight multiple environmental and lifestyle factors such as exposure to industrial chemicals and medication intake, in addition to diet, which may influence the association between the gut microbiome and gut barrier function. The study involved 20 healthy, young adults participating in a double-blinded, randomized-order, placebo-controlled intervention study. Participants were randomized to either first receive a prebiotic fiber or a placebo over a 4-week treatment period, followed by a 4-week washout phase, and then crossed over to the alternate treatment. The impact of the intervention on LBP concentrations was assessed using a 96-well ELISA kit. Participants were also stratified by those with above- and below-median LBP concentrations at baseline. A significant reduction in LBP (P =.020) was found after the prebiotic fiber intervention arm in those individuals who had above-median LBP concentrations at baseline. Abbreviations: ELISA, enzyme-linked immunosorbent assay; LBP, lipopolysaccharide-binding protein. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Transcriptomic, metabolome, and 16S rRNA sequencing reveal chronic arsenic toxicity. • Arsenic treatment induced chicken liver dysfunction and ileum microbiota dysbiosis. • Chronic inorganic arsenic exposure evidently promoted liver fibrosis in chickens. • Long-term arsenic exposure disrupted enterohepatic circulation of bile acid. • Arsenic exposure provoked liver-microbiota-gut axis disruption in chickens. Arsenic has been ranked as the most hazardous substance by the U.S. Agency for Toxic Substances and Disease Registry. Environmental arsenic exposure-evoked health risks have become a vital public health concern worldwide owing to the widespread existence of arsenic. Multi-omics is a revolutionary technique to data analysis providing an integrated view of bioinformation for comprehensively and systematically understanding the elaborate mechanism of diseases. This study aimed at uncovering the potential contribution of liver-microbiota-gut axis in chronic inorganic arsenic exposure-triggered biotoxicity in chickens based on multi-omics technologies. Forty Hy-Line W-80 laying hens were chronically exposed to sodium arsenite with a dose-dependent manner (administered with drinking water containing 10, 20, or 30 mg/L arsenic, respectively) for 42 d, followed by transcriptomics, serum non-targeted metabolome, and 16S ribosomal RNA gene sequencing accordingly. Arsenic intervention induced a serious of chicken liver dysfunction, especially severe liver fibrosis, simultaneously altered ileal microbiota populations, impaired chicken intestinal barrier, further drove enterogenous lipopolysaccharides translocation via portal vein circulation aggravating liver damage. Furtherly, the injured liver disturbed bile acids (BAs) homoeostasis through strongly up-regulating the BAs synthesis key rate-limiting enzyme CYP7A1, inducing excessive serum total BAs accumulation, accompanied by the massive synthesis of primary BA—chenodeoxycholic acid. Moreover, the concentrations of secondary BAs—ursodeoxycholic acid and lithocholic acid were markedly repressed, which might involve in the repressed dehydroxylation of Ruminococcaceae and Lachnospiraceae families. Abnormal BAs metabolism in turn promoted intestinal injury, ultimately perpetuating pernicious circle in chickens. Notably, obvious depletion in the abundance of four profitable microbiota, Christensenellaceae , Ruminococcaceae , Muribaculaceae , and Faecalibacterium , were correlated tightly with this hepato-intestinal circulation process in chickens exposed to arsenic. Our study demonstrates that chronic inorganic arsenic exposure evokes liver-microbiota-gut axis disruption in chickens and establishes a scientific basis for evaluating health risk induced by environmental pollutant arsenic. [ABSTRACT FROM AUTHOR]

Bile acids (BAs) serve as signalling molecules, efficiently regulating their own metabolism and transport, as well as key aspects of lipid and glucose homeostasis. BAs shape the gut microbial flora and conversely are metabolised by microbiota. Disruption of BA transport, metabolism and physiological signalling functions contribute to the pathogenesis and progression of a wide range of liver diseases including cholestatic disorders and MASLD (metabolic dysfunction-associated steatotic liver disease), as well as hepatocellular and cholangiocellular carcinoma. Additionally, impaired BA signalling may also affect the intestine and kidney, thereby contributing to failure of gut integrity and driving the progression and complications of portal hypertension, cholemic nephropathy and the development of extrahepatic malignancies such as colorectal cancer. In this review, we will summarise recent advances in the understanding of BA signalling, metabolism and transport, focusing on transcriptional regulation and novel BA-focused therapeutic strategies for cholestatic and metabolic liver diseases. [ABSTRACT FROM AUTHOR]

Combining probiotics and prebiotics in synbiotics may present a synergistic approach to improve type 2 diabetes mellitus (T2DM); however, further evidence is required to establish the comparative efficacy of synbiotics versus probiotics. This study aimed to evaluate the effects of Bifidobacterium animalis subsp. lactis MN-Gup (MN-Gup) and a synbiotic mixture of MN-Gup and galactooligosaccharide (MN-Gup-GOS) on glycemic control in T2DM patients and explore possible mechanisms. This randomized, double-blind, placebo-controlled clinical trial assigned 120 T2DM patients, to receive MN-Gup, MN-Gup-GOS, or placebo intervention for 12 weeks. The primary outcome was fasting blood glucose (FBG), with secondary outcomes including hemoglobin A1C (HbA1C), insulin, homeostatic model assessment of insulin resistance (HOMA-IR), inflammatory indicators, oxidative stress indicators, gastrointestinal hormones, gut microbiota, and bile acids (BAs). The median age of the 120 participants was 59 years (interquartile range: 55–62 years), with 40 being men. Compared to baseline, all three groups exhibited significant reductions in FBG. Additionally, the MN-Gup-GOS group demonstrated significant decreases in HbA1c, serum insulin, and HOMA-IR after intervention, whereas no such reductions were observed in the placebo and MN-Gup groups. Regarding the between-group comparisons, the MN-Gup-GOS intervention showed a significantly greater reduction in FBG compared to the placebo (least squares mean difference [95 % CI], −0.69 [-1.29, −0.10] mmol/L, P = 0.022) and MN-Gup (−0.59 [-1.17, −0.01], P = 0.047) group, but not for other indicators of glucose metabolism. Additionally, MN-Gup and MN-Gup-GOS intervention, especially the latter, significantly modified inflammation, oxidative stress, gut microbiota, serum BAs, and GLP-1 levels. Correlation analysis showed significant associations between changes in certain gut microbiota (Bifidobacterium) and BAs (deoxycholic acid and lithocholic acid) with glycemic indicators. The auxiliary effect of synbiotics MN-Gup-GOS on reducing FBG levels surpassed that of MN-Gup probiotics alone in T2DM patients, potentially attributed to the enhanced modulation of gut microbiota, BAs, and GLP-1 secretion. This study was registered on the website of www.chictr.org.cn , number ChiCTR2100052187. [ABSTRACT FROM AUTHOR]

Cholesterol is a key sterol whose homeostasis is primarily maintained through bile acid metabolism. Proper bile acid formation is vital for nutrient and fat-soluble vitamin absorption and emulsification of lipids. Synthesis of bile acids occurs through two main pathways, both of which rely on 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) to begin epimerization of the 3β hydroxyl of cholesterol into its active 3α conformation. In this sequence, HSD3B7 catalyzes the dehydrogenation of the 3β-hydroxy group followed by isomerization of the Δ5-cholestene-3-one. These reactions are some of the many steps that transform cholesterol for either storage or secretion. HSD3B7 has distinct activity from other 3β-HSD family members leaving significant gaps in our understanding of its mode of catalysis and substrate specificity. In addition, the role of HSD3B7 in health and disease positions it as a metabolic vulnerability that could be harnessed as a therapeutic target. To this end, we evaluated the mechanism of HSD3B7 catalysis and reveal that HSD3B7 displays activity toward diverse 7α-hydroxylated oxysterols. HSD3B7 retains its catalytic efficiency toward these substrates, suggesting that its substrate binding pocket can withstand changes in polarity upon alterations to this hydrocarbon tail. Experiments aimed at determining substrate order are consistent with HSD3B7 catalyzing a sequential ordered bi–bi reaction mechanism with the binding of NAD+ followed by 7α-hydroxycholesterol to form a central complex. HSD3B7 bifunctional activity is dependent on membrane localization through a putative membrane–associated helix giving insight into potential regulation of enzyme activity. We found strong binding of the NADH product thought to activate the isomerization reaction. Homology models of HSD3B7 reveal a potential substrate pocket that allows for oxysterol binding, and mutagenesis was utilized to support this model. Together, these studies offer an understanding of substrate specificity and kinetic mechanism of HSD3B7, which can be exploited for future drug development. [ABSTRACT FROM AUTHOR]

Regression of cirrhosis has been observed in patients with viral and non-viral etiologies of liver disease in whom the underlying cause of liver injury was effectively suppressed. However, the understanding of the factors contributing to reversibility of fibrosis and cirrhosis is limited. Our aims were to assess clinical factors, perform genotyping of known variants, and comprehensive metabolic phenotyping to characterize the regression of fibrosis in patients with compensated advanced chronic liver disease (cACLD). In a case-control pilot study of 81 patients with cACLD, we compared individuals exhibiting histological or clinical evidence of cACLD regression ("regressors"; n = 44) with those showing no improvement ("non-regressors"; n = 37) after a minimum of 24 months of successful treatment of the cause of liver disease. Data were validated using an external validation cohort (n = 30). Regardless of the cause of cACLD, the presence of obesity (odds ratio [OR] 0.267 95% CI 0.072-0.882; p = 0.049), high liver stiffness (OR 0.960, 95% CI 0.925-0.995; p = 0.032), and carriage of GCKR variant rs1260326 (OR 0.148, 95% CI 0.030-0.773; p = 0.019) are associated with a reduced likelihood of fibrosis regression in a subgroup of 60 patients with ACLD genotyped for known genetic variants. Using liver tissue transcriptomics, we identified metabolic pathways differentiating regressors from non-regressors, with top pathways associated with lipid metabolism – especially fatty acids, bile acids, phospholipids, triacylglycerides (biosynthesis), and the carnitine shuttle. In the entire discovery cohort, we further measured metabolites within the defined pathways, which led to the identification of 33 circulating markers differentiating regressors from non-regressors after etiological therapy. The validation cohort confirmed 14 of the differentially expressed markers. We identified and validated a group of lipid biomarkers associated with regression of fibrosis that could be used as non-invasive biomarkers for detecting regression of fibrosis in cACLD. Regression of cirrhosis/advanced chronic liver disease (ACLD) after removal of the underlying cause of liver injury has been observed in human cirrhosis. However, detailed characterization of ACLD regression remains an unmet need. In this study, we provide a comprehensive phenotyping of individuals likely to experience ACLD regression. While obesity, carriage of GCKR variant rs1260326 and high liver stiffness were associated with lower likelihood of regression of ACLD, a signature of circulating lipid metabolites enabled differentiation of regressors from non-regressors after effective etiologic therapy. The lipid signature we discovered and externally validated could be used as non-invasive biomarker to detect regression of fibrosis in patients with compensated ACLD. [Display omitted] • We demonstrate that fibrosis regression of cACLD is shaped by a multifaceted interplay of clinical, genetic, and metabolic factors. • Obesity, high LSM and carrying the rs1260326 variant of GCKR were associated with a lower probability of fibrosis regression. • Metabolomics revealed lipid perturbations associated with fibrosis regression, with taurocholic and taurochenodeoxycholic acid emerging as key predictors. • We identified a lipid signature associated with regression of ACLD that could be used as a non-invasive biomarker. [ABSTRACT FROM AUTHOR]

The transition from pregnancy to lactation is critical in dairy cows. Among others, dairy cows experience a metabolic stress due to a large change in glucose and lipid metabolism. Recent studies revealed that bile acids (BA), other than being involved in both the emulsification and solubilization of fats during intestinal absorption, can also affect the metabolism of glucose and lipids, both directly or indirectly by affecting the gut microbiota. Thus, we used untargeted and targeted metabolomics and 16S rRNA gene sequencing approaches to investigate the concentration of plasma metabolites and BA, the composition of the rectum microbial community, and assess their interaction in transition dairy cows. In Experiment 1, we investigated BA and other blood parameters and gut microbiota in dairy cows without clinical diseases during the transition period, which can be seen as well adapted to the challenge of changed glucose and lipid metabolism. As expected, we detected an increased plasma concentrations of BHB and nonesterified fatty acids (NEFA) but decreased concentrations of glucose, cholesterol, and triglycerides (TG). Untargeted metabolomic analysis of the plasma revealed primary BA biosynthesis was one of the affected pathways, and was consistent with the increased concentration of BA in the plasma. A correlation approach revealed a complex association between BA and microbiota with the host plasma concentration of glucose and lipid metabolites. Among BA, chenodeoxycholic acid derivates such as glycolithocholic acid, taurolithocholic acid, lithocholic acid, taurochenodeoxycholic acid, and taurodeoxycholic acid were the main hub nodes connecting microbe and blood metabolites (such as glucose, TG, and NEFA). In Experiment 2, we investigated early postpartum dairy cows with or without hyperketonemia (HPK). As expected, HPK cows had increased concentration of NEFA and decreased concentrations of glucose and triglycerides. The untargeted metabolomic analysis of the plasma revealed that primary BA biosynthesis was also one of the affected pathways. Even though the BA concentration was similar among the 2 groups, the profiles of taurine-conjugated BA changed significantly. A correlation analysis also revealed an association between BA and microbiota with the concentration in plasma of glucose and lipid metabolites (such as BHB). Among BA, cholic acid and its derivates such as taurocholic acid, tauro α-muricholic acid, and taurodeoxycholic acid were the main hub nodes connecting microbe and blood metabolites. Our results indicated an association between BA, intestinal microbe, and glucose and lipid metabolism in transition dairy cows. These findings provide new insight into the adaptation mechanisms of dairy cows during the transition period. The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. [ABSTRACT FROM AUTHOR]

The bile salt hydrolases (BSHs) are significant constituents of animal microbiomes. An evolving appreciation of their roles in health and disease has established them as targets of pharmacological inhibition. These bacterial enzymes belong to the N-terminal nucleophile superfamily and are best known to catalyze the deconjugation of glycine or taurine from bile salts to release bile acid substrates for transformation and or metabolism in the gastrointestinal tract. Here, we identify and describe the BSH from a common member of the Plains bison microbiome, Arthrobacter citreus (BSHAc). Steady-state kinetic analyses demonstrated that BSHAc is a broad-spectrum hydrolase with a preference for glycine-conjugates and deoxycholic acid (DCA). Second-order rate constants (kcat/KM) for BSHAc-catalyzed reactions of relevant bile salts--glyco- and tauro-conjugates of cholic acid and DCA--varied by -30-fold and measured between 1.4 × 105 and 4.3 × 106 M-1s-1. Interestingly, a pan-BSH inhibitor named AAA-10 acted as a slow irreversible inhibitor of BSHAc with a rate of inactivation (kinact) of -2 h-1 and a second order rate constant (kinact/KI) of -24 M-1s-1 for the process. Structural characterization of BSHAc reacted with AAA-10 showed covalent modification of the N-terminal cysteine nucleophile, providing molecular details for an enzyme-stabilized product formed from this mechanism-based inhibitor's a-fluoromethyl ketone warhead. Structural comparison of the BSHs and BSH:inhibitor complexes highlighted the plasticity of the steroid-binding site, including a flexible loop that is variable across well-studied BSHs. [ABSTRACT FROM AUTHOR]

The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. 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 (HBCS; n = 19) or normal body condition score (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 liquid chromatography electrospray ionization 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, and cholic acid. 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. [ABSTRACT FROM AUTHOR]

The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. Bile acids are cholesterol-derived molecules that are primarily produced in the liver. In nonruminants with fatty liver, overproduction of bile acids is associated with liver injury. During the transition period, fatty liver is a metabolic disorder that can affect up to 50% of high-producing dairy cows. The purpose of this study was to provide a comprehensive evaluation of hepatic bile acid metabolism in dairy cows with fatty liver by assessing the expression changes of genes involved in bile acid synthesis, export, and uptake. The serum activities of aspartate aminotransferase, alanine aminotransferase, and glutamate dehydrogenase and the concentration of total bile acids were all greater, whereas the serum concentration of total cholesterol was lower in cows with fatty liver than in healthy cows. The content of total bile acids was higher, but total cholesterol was slightly lower in liver tissues from fatty liver cows than from healthy cows. The hepatic mRNA abundance of cholesterol 7a-hydroxylase (CYP7A1); hydroxy-delta-5-steroid dehydrogenase, 3 β- and steroid delta-isomerase 7 (HSD3B7); and sterol 12α-hydroxylase (CYP8B1), enzymes involved in the classic pathway of bile acid synthesis, was higher in fatty liver cows than in healthy cows. Compared with healthy cows, the hepatic mRNA abundance of alternative bile acid synthesis pathway-related genes sterol 27-hydroxylase (CYP27A1) and oxysterol 7α-hydroxylase (CYP7B1) did not differ in cows with fatty liver. The protein and mRNA abundances of bile acid transporter bile salt efflux pump (BSEP) were lower in the liver of dairy cow with fatty liver. Compared with healthy cows, the hepatic mRNA abundance of bile acid transporters solute carrier family 51 subunit α (SLC51A) and ATP binding cassette subfamily C member 1 (ABCC1) and 3 (ABCC3) was greater in cows with fatty liver, whereas the solute carrier family 51 subunit β (SLC51B) did not differ. The expression of genes involved in bile acid uptake, including solute carrier family 10 member 1 (NTCP), solute carrier organic anion transporter family member 1A2 (SLCO1A2) and 2B1 (SLCO2B1) was upregulated in dairy cows with fatty liver. Furthermore, the hepatic protein and mRNA abundance of bile acid metabolism regulators farnesoid X receptor (FXR) and small heterodimer partner (SHP) were lower in cows with fatty liver than in healthy cows. Overall, these data suggest that inhibition of the FXR signaling pathway may lead to increased bile acid synthesis and uptake and decreased secretion of bile acids from hepatocytes to the bile, which elevates hepatic bile acid content in dairy cows with fatty liver. Because the hepatotoxicity of bile acids has been demonstrated on nonruminant hepatocytes, it is likely that liver injury is induced by increased hepatic bile acid content in dairy cows with fatty liver. [ABSTRACT FROM AUTHOR]

• Bile acid malabsorption (BAM) can generate functional chronic diarrhea. • Derangement of the gut-liver axis is involved in BAM. • BAM is frequently underdiagnosed but specific tests are available. • Therapies target enterohepatic BAs circulation by sequestrants and novel approaches. Bile acid malabsorption (BAM) is an important disorder of digestive pathophysiology as it generates chronic diarrhoea. This condition originates from intricate pathways involving bile acid synthesis and metabolism in the liver and gut, the composition of gut microbiota, enterohepatic circulation and key receptors as farnesoid X receptor (FXR), fibroblast growth factor receptor 4 (FGFR4), and the G-protein bile acid receptor-1 (GPBAR-1). Although symptoms can resemble those related to disorders of gut brain interaction, accurate diagnosis of BAM may greatly benefit the patient. The empiric diagnosis of BAM is primarily based on the clinical response to bile acid sequestrants. Specific tests including the 48-hour fecal bile acid test, serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19), and the 75Selenium HomotauroCholic Acid Test (SeHCAT) are not widely available. Nevertheless, lack of diagnostic standardization of BAM may account for poor recognition and delayed management. Beyond bile acid sequestrants, therapeutic approaches include the use of FXR agonists, FGF19 analogues, glucagon-like peptide-1 (GLP-1) receptor agonists, and microbiota modulation. These novel agents can best make their foray into the therapeutic armamentarium if BAM does not remain a diagnosis of exclusion. Ignoring BAM as a specific condition may continue to contribute to increased healthcare costs and reduced quality of life. Here, we aim to provide a comprehensive review of the pathophysiology, diagnosis, and management of BAM. [ABSTRACT FROM AUTHOR]

Unveiling a metabolic mystery, this article explores how 3-O-acylated bile acids, specifically 3-O-succinylated cholic acid (3-sucCA) and 3-acetylated cholic acid (3-acetyCA), modified by gut microbes Bacteroides uniformis and Christensenella minuta , respectively, may either disrupt or harmonize our metabolic processes, offering novel therapeutic avenues for conditions such as metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes mellitus (T2D). [ABSTRACT FROM AUTHOR]

Tryptophan metabolites exhibit chemical diversity and engage multiple receptors, resulting in pleiotropic effects that modulate tumor development, therapeutic response, host defense against pathogens, regulation of metabolic syndrome, and potential correlations with neurological disorders. Bile acids, synthesized in the liver and modified by gut microbiota, exhibit structural and functional diversity, and play vital roles in immunomodulation, gut–liver signaling, energy metabolism, disease progression, and treatment. Despite advances in microbiome studies, comprehending the complex network of host–microbe molecular interactions remains challenging. Emerging techniques – such as stable isotope tracing, high-throughput microbial culturomics, metabolomics, chemical genetic screens, and chemoproteomics – are essential for deeper insights. With a better understanding of host–microbe interaction mechanisms, exploiting the chemophysiology of microbiota metabolites offers significant therapeutic potential, including the development of small-molecule inhibitors and engineered probiotics. Human physiology is profoundly influenced by the gut microbiota, which generates a wide array of metabolites. These microbiota-derived compounds serve as signaling molecules, interacting with various cellular targets in the gastrointestinal tract and distant organs, thereby impacting our immune, metabolic, and neurobehavioral systems. Recent advancements have unveiled unique physiological functions of diverse metabolites derived from tryptophan (Trp) and bile acids (BAs). This review highlights the emerging chemophysiological diversity of these metabolites and discusses the role of chemical and biological tools in analyzing and therapeutically manipulating microbial metabolism and host targets, with the aim of bridging the chemical diversity with physiological complexity in host–microbe molecular interactions. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) poses a substantial global health challenge, ranking as the fourth leading cause of cancer-related deaths due to its high mortality rate. Late-stage diagnoses are common due to the absence of specific symptoms. Pancreatic ductal adenocarcinoma (PDAC) accounts for the majority of PC cases. Recent research has suggested a potential link between elevated serum levels of bile acids (BAs) and tumorigenesis of PDAC. This study aims to understand how taurochenodeoxycholic acid (TCDCA), a secondary BA, influences PDAC using RNA sequencing techniques on the Capan-1 cell line. We identified 2,950 differentially expressed genes (DEGs) following TCDCA treatment, with 1,597 upregulated and 1,353 downregulated genes. These DEGs were associated with critical PDAC pathways, including coagulation, angiogenesis, cell migration, and signaling regulation. Furthermore, we reviewed relevant literature highlighting genes like DKK-1, KRT80, UPLA, and SerpinB2, known for their roles in PDAC tumorigenesis and metastasis. Our study sheds light on the complex relationship between BAs and PDAC, offering insights into potential diagnostic markers and therapeutic targets. Further research is needed to unravel these findings' precise mechanisms and clinical implications, potentially improving PDAC diagnosis and treatment. • High Mortality and Late Diagnosis: Pancreatic cancer (PC) is a major global health concern, ranking as the fourth leading cause of cancer-related deaths, primarily due to its high mortality rate and the tendency for late-stage diagnoses. • Bile Acids and Tumorigenesis: Recent studies, including ours, have shown a promising link between elevated serum bile acids (BAs) and the initiation of Pancreatic Ductal Adenocarcinoma (PDAC), the most common form of PC. • Impact of TCDCA: Our research focused on taurochenodeoxycholic acid (TCDCA), a secondary bile acid, and its effects on PDAC using RNA sequencing of the Capan-1 cell line. The sequencing revealed 2,950 differentially expressed genes (DEGs) due to TCDCA exposure. • Key Pathways and Genes: The DEGs identified are connected to critical PDAC pathways such as coagulation, angiogenesis, cell migration, and signaling regulation. Key genes like DKK-1, KRT80, UPLA, and SerpinB2, known for their roles in tumorigenesis and metastasis, were highlighted. • Future Research Directions: While our study provides significant insights into the molecular changes induced by TCDCA, it underscores the necessity for further research to fully understand the mechanisms and clinical implications. This could potentially lead to new diagnostic and therapeutic strategies for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Statins are widely used to treat hyperlipidemia; however, their mechanism—inhibiting cholesterol production without promoting its utilization—causes problems, such as inducing diabetes. In our research, we develop, for the first time, a chemically engineered statin conjugate that not only inhibits cholesterol production but also enhances its consumption through its multifunctional properties. The novel rosuvastatin (RO) and ursodeoxycholic acid (UDCA) conjugate (ROUA) is designed to bind to and inhibit the core of the apical sodium-dependent bile acid transporter (ASBT), effectively blocking ASBT's function in the small intestine, maintaining the effect of rosuvastatin. Consequently, ROUA not only preserves the cholesterol-lowering function of statins but also prevents the reabsorption of bile acids, thereby increasing cholesterol consumption. Additionally, ROUA's ability to self-assemble into nanoparticles in saline—attributable to its multiple hydroxyl groups and hydrophobic nature—suggests its potential for a prolonged presence in the body. The oral administration of ROUA nanoparticles in animal models using a high-fat or high-fat/high-fructose diet shows remarkable therapeutic efficacy in fatty liver, with low systemic toxicity. This innovative self-assembling multifunctional molecule design approach, which boosts a variety of therapeutic effects while minimizing toxicity, offers a significant contribution to the advancement of drug development. [Display omitted] • ROUA, the new bioconjugates, reduces cholesterol production while increasing its consumption. • ROUA binds to the ASBT, preventing bile acid reabsorption and improving cholesterol consumption. • ROUA treatment in obese animal models effectively treats fatty livers. • This innovative nanoparticle design improves drug delivery and therapeutics while minimizing toxicity. [ABSTRACT FROM AUTHOR]

The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. Besides their lipid-digestive role, bile acids (BA) influence overall energy homeostasis, such as glucose and lipid metabolism. We hypothesized that BA along with their receptors, regulatory enzymes, and transporters are present in subcutaneous adipose tissue (scAT). In addition, we hypothesized that their mRNA abundance varies with the body condition of dairy cows around calving. Therefore, we analyzed BA in serum and scAT as well as the mRNA abundance of BA-related enzymes, transporters, and receptors in scAT 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 either a high (HBCS; n = 19) or normal BCS (NBCS; n = 19) group based on their BCS and back-fat thickness (BFT). Cows were fed different diets to achieve the targeted differences in BCS and BFT (NBCS: BCS <3.5, BFT <1.2 cm; HBCS: BCS >3.75, BFT >1.4 cm) until dry-off at 7 wk antepartum. During the dry period and subsequent lactation, both groups were fed the same diets according to their energy demands. Using a targeted metabolomics approach via liquid chromatography-electrospray ionization-MS /MS, BA were analyzed in serum and scAT at wk −7, 1, 3, and 12 relative to parturition. In serum, 15 BA were observed: cholic acid (CA), chenodeoxycholic acid (CDCA), glycocholic acid (GCA), taurocholic acid (TCA), glycochenodeoxycholic acid (GCDCA), taurochenodeoxycholic acid, deoxycholic acid (DCA), lithocholic acid, glycodeoxycholic acid (GDCA), glycolithocholic acid, taurodeoxycholic acid, taurolithocholic acid, β-muricholic acid, tauromuricholic acid (sum of α and β), and glycoursodeoxycholic acid, whereas in scAT 7 BA were detected: CA, GCA, TCA, GCDCA, taurochenodeoxycholic acid, GDCA, and taurodeoxycholic acid. In serum and scAT samples, the primary BA CA and its conjugate GCA were predominantly detected. Increasing serum concentrations of CA, CDCA, TCA, GCA, GCDCA, DCA, and β-muricholic acid with the onset of lactation might be related to the increasing DMI after parturition. Furthermore, serum concentrations of CA, CDCA, GCA, DCA, GCDCA, TCA, lithocholic acid, and GDCA were lower in HBCS cows compared with NBCS cows, concomitant with increased lipolysis in HBCS cows. The correlation between CA in serum and scAT may point to the transport of CA across cell membranes. Overall, the findings of the present study suggest a potential role of BA in lipid metabolism depending on the body condition of periparturient dairy cows. [ABSTRACT FROM AUTHOR]

Obesity is a chronic and debilitating disorder that originates from alterations in energy-sensing brain circuits controlling body weight gain and food intake. The dysregulated syntheses and actions of lipid mediators in the hypothalamus induce weight gain and overfeeding, but the molecular and cellular underpinnings of these alterations remain elusive. In response to changes in the nutritional status, different lipid sensing pathways in the hypothalamus direct body energy needs in a Yin-Yang model. Endocannabinoids orchestrate the crosstalk between hypothalamic circuits and the sympathetic nervous system to promote food intake and energy accumulation during fasting, whereas bile acids act on the same top-down axis to reduce energy intake and possibly storage after the meal. In obesity, the bioavailability and downstream cellular actions of endocannabinoids and bile acids are altered in hypothalamic neurons involved in body weight and metabolic control. Thus, the onset and progression of this disease might result from an imbalance in hypothalamic sensing of multiple lipid signals, which are possibly integrated by common molecular nodes. In this viewpoint, we discuss a possible model that explains how bile acids and endocannabinoids may exert their effects on energy balance regulation via interconnected mechanisms at the level of the hypothalamic neuronal circuits. Therefore, we propose a new conceptual framework for understanding and treating central mechanisms of maladaptive lipid action in obesity. • Endocannabinoids and bile acids act as Yin-Yang regulators of the body energy needs. • Master lipid sensors in the brain could integrate the actions of multiple lipid signals. • Obesity might originate from dysregulation of master lipid sensors in the brain. [ABSTRACT FROM AUTHOR]

Bile acids (BAs) are natural metabolites in mammals and have the potential to function as drugs against viral infection. However, the limited understanding of chenodeoxycholic acid (CDCA) receptors and downstream signaling, along with its lower suppression efficiency in inhibiting virus infection limits its clinical application. In this study, we demonstrate that farnesoid X receptor (FXR), the receptor of CDCA, negatively regulates interferon signaling, thereby contributing to the reduced effectiveness of CDCA against virus replication. FXR deficiency or pharmacological inhibition enhances interferon signaling activation to suppress virus infection. Mechanistically, FXR impairs the DNA binding and transcriptional abilities of activated interferon regulatory factor 3 (IRF3) through interaction. Reduced IRF3 transcriptional activity by FXR–IRF3 interaction significantly undermines the expression of Interferon Beta 1 (IFNB1) and the antiviral response of cells, especially upon the CDCA treatment. In FXR -deficient cells, or when combined with Z -guggulsterone (GUGG) treatment, CDCA exhibits a more potent ability to restrict virus infection. Thus, these findings suggest that FXR serves as a limiting factor for CDCA in inhibiting virus replication, which can be attributed to the "signaling-brake" roles of FXR in interferon signaling. Targeting FXR inhibition represents a promising pharmaceutical strategy for the clinical application of BAs metabolites as antiviral drugs. FXR inhibition enhances antiviral potency of chenodeoxycholic acid by relieving FXR interference with interferon signaling, indicating FXR as a promising target for augmenting bile acids' antiviral effects. [Display omitted] [ABSTRACT FROM AUTHOR]