The gut microbiome is altered after bariatric surgery and is associated with weight loss. However, the commensal bacteria involved and the underlying mechanism remain to be determined. We performed shotgun metagenomic sequencing in obese subjects before and longitudinally after sleeve gastrectomy (SG), and found a significant enrichment in microbial species in Clostridia and bile acid metabolizing genes after SG treatment. Bile acid profiling further revealed decreased primary bile acids (PBAs) and increased conjugated secondary bile acids (C-SBAs) after SG. Specifically, glycodeoxycholic acid (GDCA) and taurodeoxycholic acid (TDCA) were increased at different follow-ups after SG, and were associated with the increased abundance of Clostridia and body weight reduction. Fecal microbiome transplantation with post-SG feces increased SBA levels, and alleviated body weight gain in the recipient mice. Furthermore, both Clostridia-enriched spore-forming bacteria and GDCA supplementation increased the expression of genes responsible for lipolysis and fatty acid oxidation in adipose tissue and reduced adiposity via Takeda G-protein-coupled receptor 5 (TGR5) signaling. Our findings reveal post-SG gut microbiome and C-SBAs as contributory to SG-induced weight loss, in part via TGR5 signaling, and suggest SBA-producing gut microbes as a potential therapeutic target for obesity intervention.

Recent studies suggest that secondary bile acids (SBAs) play a role in energy metabolism and feed intake regulation, but their effects in fish remain largely unknown. This study evaluates the impact of intragastric administration of the main SBAs [500 µM lithocholic acid (LCA), 1,500 µM deoxycholic acid (DCA), and their taurine conjugates: 1,000 µM T-LCA and 600 µM T-DCA] on feed intake, regulatory pathways, and bile acid-related elements in rainbow trout. Results show that all tested SBAs influenced bile acid transporters [apical sodium-dependent bile acid transporter (Asbt), Na+ taurocholate co-transporting polypeptide (Ntcp), organic solute transporter α and β (Ostα, and Ostβ)] and receptors [farnesoid X receptor like-α and β (Fxrα, Fxrβ), and Takeda G protein-coupled receptor 5 (Tgr5)], with DCA and T-DCA mainly affecting the gastrointestinal tract and LCA modulating hypothalamic pathways, suggesting a putative orexigenic role. Plasma analysis confirmed SBA absorption from the gastrointestinal tract into the bloodstream. This study provides the first evidence in fish of SBAs modulating gene and protein expression linked to appetite regulation, underscoring their role in gut-brain communication. Although all SBAs influenced fxr expression, gpbar1 remained unaffected, differing from mammals where BAs suppress appetite. Notably, despite taurine-conjugated SBAs being the most abundant in rainbow trout, only nonconjugated LCA showed significant effects. Taken together, these results provide new information on the emerging importance of SBA in feed intake regulation and bile acid mechanisms.NEW & NOTEWORTHY This study determined for the first time in teleost fish (specifically in rainbow trout): 1) the role of secondary bile acids in the regulation of feed intake and associated signaling pathways, highlighting a putative orexigenic role of lithocholic acid (LCA); 2) the response of Asbt and Ostα transporters and Tgr5 receptor in hypothalamus after LCA administration; and 3) the reabsorption of LCA, DCA, and their taurine conjugates from the gastrointestinal tract into the bloodstream.

Bile acids, derived from cholesterol in the liver, consist a steroidal core. Primary bile acids and secondary bile acids metabolized by the gut microbiota make up the bile acid pool, which modulate nuclear hormone receptors to regulate immunity. Disruptions in the crosstalk between bile acids and the gut flora are intimately associated with the development and course of gastrointestinal inflammation.

This review provides an extensive summary of bile acid production, transport and metabolism. It also delves into the impact of bile acid metabolism on the body and explores the involvement of bile acid-microbiota interactions in various disease states. Furthermore, the potential of targeting bile acid signaling as a means to prevent and treat inflammatory bowel disease is proposed.

In this review, we primarily address the functions of bile acid-microbiota crosstalk in diseases. Firstly, we summarize bile acid signalling and the factors influencing bile acid metabolism, with highlighting the immune function of microbially conjugated bile acids and the unique roles of different receptors. Subsequently, we emphasize the vital role of bile acids in maintaining a healthy gut microbiota and regulating the intestinal barrier function, energy metabolism and immunity. Finally, we explore differences of bile acid metabolism in different disease states, offering new perspectives on restoring the host's health and the gastrointestinal ecosystem by targeting the gut microbiota-bile acid-bile acid receptor axis.

Bariatric surgery is currently considered the key treatment method for patients with obesity and related complications. Among the various surgeries, laparoscopic sleeve gastrectomy (LSG) is the most widely used. Obesity is a multifactor chronic disease characterized by the accumulation of visceral adipose tissue (VAT), leading to susceptibility to cardiac metabolic diseases. Many mechanisms, including abnormal lipid metabolism, insulin resistance, inflammation, endothelial dysfunction, adipocytokine imbalance and inflammasome activation, have been identified as the basis for the relationship between obesity and atherosclerosis. Bariatric surgery, such as LSG, reduces the risk of atherosclerosis in people living with obesity by reducing energy intake, disrupting energy balance and reducing the secretion of intestinal hormones to intervene in these risk factors. This review explores the current understanding of how LSG affects VAT and its impact on the risk of atherosclerosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the predominant chronic liver condition globally. Bile acid (BA) metabolism contributes significantly to MASLD progression. In this multicenter clinical study, we aimed to characterize serum BA profiles in patients with MASLD and identify specific alterations compared to healthy controls.

All MASLD cases were sourced from the gastroenterology outpatient departments of Shanghai Baoshan Hospital of Integrated Chinese and Western Medicine, Shanghai Baoshan District Songnan Community Health Service Center, and Lianyungang Oriental Hospital between June 2015 and December 2019. The data were analyzed using SPSS version 26.0, with a p-value of less than 0.05 considered significant.

A total of 215 participants (35.3% women) with MASLD and 49 controls (44.9% women), aged 18-65 years, were included. MASLD patients showed higher levels of serum total BA (TBA), cholic acid (CA), chenodeoxycholic acid (CDCA), and ursodeoxycholic acid (UDCA) (p < 0.05, p < 0.01) when compared to controls. Furthermore, women patients with MASLD demonstrated notably higher levels of lithocholic acid (LCA), glycolithocholic acid (GLCA), and taurolithocholic acid (TLCA) than men patients with MASLD (p < 0.025, p < 0.01). Compared to women, men exhibited a higher proportion of primary to secondary BAs. Additionally, in men patients with MASLD, the serum concentrations of CA, CDCA, glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), and taurochenodeoxycholic acid (TCDCA) exhibited significant negative correlations with ALT levels, while deoxycholic acid (DCA) and TLCA showed negative correlations with BMI.

Patients with MASLD exhibited notable variations in BA profiles, including sex-specific differences. This study provides corresponding evidence on the association between BAs and MASLD.

Chinese Clinical Trial Registry, NO: ChiCTR-OOC-15006157, registration date: March 25, 2015.

Interactions between the gut microbiome and bile acids are complex and are linked to outcomes in pediatric liver disease by mechanisms that are incompletely understood. In adults, primary bile acids are synthesized in the liver and secreted into the intestine, where complex communities of gut microbes deconjugate, oxidize, epimerize, and 7α-dehydroxylate bile acids into a diverse array of unconjugated, secondary, allo-, iso-, and oxo-bile acids. In contrast, the infant gut microbiota contains a simple, Bifidobacterium-dominant community that transitions to a more diverse, adult-like community as additional microbes colonize the gut. This microbial succession gradually confers deconjugation, oxidation, epimerization, and 7α-dehydroxylation activities that mature the bile acid pool from a profile dominated by primary bile acids early in life to a more diverse, adult-like bile acid profile in later childhood. Altered bile acid profiles in pediatric cholestatic disorders have the potential to change the developmental trajectory of the microbiome. Conversely, alterations in the gut microbiome may re-shape the bile acid pool and hepatic bile acid metabolism. Understanding the mechanisms underlying these interactions will increase our understanding of liver pathophysiology and will motivate new therapeutic strategies for pediatric hepatic disorders. This review aims to highlight differences between the pediatric and adult intestinal microbiome and bile acid pool, and to discuss interactions between gut microbes and bile acids that are critical in early life and that may impact outcomes in infants and children with cholestatic liver disease, including biliary atresia.

Immune-mediated skin disorders arise from dysfunctional immune responses, instigating inflammatory dermatoses and a reduced quality of life. The complex pathogenesis likely involves genetic risks, environmental triggers and aberrant immune activation. An emerging body of evidence suggests that bile acid disturbances may critically promote immune pathology in certain skin conditions. Bile acids synthesised from cholesterol regulate nutrient metabolism and immune cell function via nuclear receptors and G protein-coupled receptors (GPCRs). Altered bile acid profiles and receptor expression have been identified in psoriasis, atopic dermatitis (AD) and autoimmune blistering diseases. Disruptions in bile acid signalling affect the inflammatory and metabolic pathways linked to these disorders. Targeting components of the bile acid axis represents a promising therapeutic strategy. This review elucidates the intricate links between bile acid homeostasis and immune dysfunction in inflammatory skin diseases, synthesising evidence that targeting bile acid pathways may unlock innovative therapeutic avenues. This study compiles clinical and experimental data revealing disrupted bile acid signalling and composition in various immune-mediated dermatoses, highlighting the emerging significance of bile acids in cutaneous immune regulation.

Human ileal bile acid-binding protein (hI-BABP), a member of the family of intracellular lipid-binding proteins, has a key role in the enterohepatic circulation of bile salts. The two internal binding sites of hI-BABP exhibit positive cooperativity accompanied by a site preference of glycocholate (GCA) and glycochenodeoxycholate (GCDA), the two most abundant bile salts in the human body. Previous study of Q51A hI-BABP in its apo state, a mutant with lost site-selectivity, suggests that disruption of the hydrogen-bonding network in the vicinity of the C/D-turn has long-range dynamic effects. To improve our understanding of the determinants of site-selectivity in hI-BABP, a comparative NMR chemical shift and spin relaxation analysis of homo- and heterotypic bile salt complexes of wild-type and Q51A hI-BABP was carried out. The wild-type GCDA-complex shows a striking similarity with the thermodynamically most stable hI-BABP:GCDA:GCA complex in terms of both structure and dynamic behaviour, suggesting that the bound GCDA at site 1 has a decisive role in conveying key stabilizing interactions in the physiologically most abundant heterotypic complex. Destabilization of hI-BABP-GCDA by the functionally impairing mutation Q51A is indicated by both the increase of ms-timescale motions in key segments of the protein as well as by increased ps-ns local fluctuations superimposed on slow motions. Our study suggests that binding interactions in hI-BABP might be modulated by altering the dynamic behaviour of specific segments in the protein with implications for targeting the intracellular trafficking of bile salts and bile salt-induced stimulation of nuclear receptors.

The current definition of a postbiotic is a "preparation of inanimate microorganisms and/or their components that confers a health benefit on the host". Postbiotics can be mainly classified as metabolites, derived from intestinal bacterial fermentation, or structural components, as intrinsic constituents of the microbial cell. Secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) are bacterial metabolites generated by the enzymatic modifications of primary bile acids by microbial enzymes. Secondary bile acids function as receptor ligands modulating the activity of a family of bile-acid-regulated receptors (BARRs), including GPBAR1, Vitamin D (VDR) receptor and RORγT expressed by various cell types within the entire human body. Secondary bile acids integrate the definition of postbiotics, exerting potential beneficial effects on human health given their ability to regulate multiple biological processes such as glucose metabolism, energy expenditure and inflammation/immunity. Although there is evidence that bile acids might be harmful to the intestine, most of this evidence does not account for intestinal dysbiosis. This review examines this novel conceptual framework of secondary bile acids as postbiotics and how these mediators participate in maintaining host health.

Background/Objectives: The gut microbiota plays a pivotal role in host physiology through metabolite production, with lipids serving as essential biomolecules for cellular structure, metabolism, and signaling. This review aims to elucidate the interactions between gut microbiota and lipid metabolism and their implications for enhancing swine production. Methods: We systematically analyzed current literature on microbial lipid metabolism, focusing on mechanistic studies on microbiota-lipid interactions, key regulatory pathways in microbial lipid metabolism, and multi-omics evidence (metagenomic/metabolomic) from swine models. Results: This review outlines the structural and functional roles of lipids in bacterial membranes and examines the influence of gut microbiota on the metabolism of key lipid classes, including cholesterol, bile acids, choline, sphingolipids, and fatty acids. Additionally, we explore the potential applications of microbial lipid metabolism in enhancing swine production performance. Conclusions: Our analysis establishes a scientific framework for microbiota-based strategies to optimize lipid metabolism. The findings highlight potential interventions to improve livestock productivity through targeted manipulation of gut microbial communities.

Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated plasma bile acid levels. ICP is linked to adverse metabolic outcomes, including a reported increased risk of gestational diabetes. The standard therapeutic approach for managing ICP is treatment with ursodeoxycholic acid (UDCA) and induction of labor before 40 wk of gestation. To investigate bile acid and metabolic parameters after UDCA treatment, we enrolled 12 ICP patients with singleton pregnancies-half with and half without gestational diabetes-and 7 controls. Our study reveals that after UDCA treatment, notwithstanding a reduction in total bile acid and alanine aminotransferase levels, imbalances persist in the cholic acid (CA) to chenodeoxycholic acid (CDCA) ratio in maternal and cord blood plasma. This indicates a continued dysregulation of bile acid metabolism despite therapeutic intervention. Maternal plasma lipid analysis showed a distinct maternal dyslipidemia pattern among patients with ICP, marked by elevated cholesterol levels on VLDL particles and heightened triglyceride concentrations on LDL particles, persisting even after UDCA treatment. Cord plasma lipid profiles in patients with ICP exhibited elevated triglyceride and free fatty acid levels alongside a tendency toward increased β-hydroxybutyrate. The changes in lipid metabolism in both maternal and cord blood correlated with the high CA/CDCA ratio but not total bile acid levels or gestational diabetes status. Understanding the imbalances in maternal and cord bile acid and lipid profiles that persist after standard UDCA therapy provides insights for improving management strategies and mitigating the long-term consequences of ICP.NEW & NOTEWORTHY This study uncovers that despite ursodeoxycholic acid treatment, intrahepatic cholestasis of pregnancy (ICP) is associated with increases in the ratio of cholic acid to chenodeoxycholic acid in both maternal and cord blood, suggesting ongoing dysregulation of bile acid metabolism. The high cholic to chenodeoxycholic acid ratio is correlated with maternal dyslipidemia and high cord blood lipids. These findings may inform more targeted approaches to managing ICP.

Fourteen undescribed sesquiterpenes, named curcumaones A-N (1-14), as well as forty-four (15-58) known ones, were isolated from the secondary rhizomes of Curcuma wenyujin. The structures and absolute configurations of 1-14 were elucidated based on NMR spectroscopic analyses, high resolution electrospray ionization mass spectroscopy (HRESIMS) data and electronic circular dichroism (ECD) spectral analysis. Among these, five sesquiterpenes with the peroxide linkage (1-5) were obtained and the change of chemical shift between the α-C connecting the peroxide linkage and the oxygen atom has been discussed. In addition, all the isolated compounds were evaluated for their agonistic effect on farnesoid X receptors (FXR) situated with human embryonic kidney (HEK) 293T cells and the results showed that compounds 12 and 14 exhibited a significant agonistic effect dose-dependently at 20, 50 and 100 μM, while 8, 32, 17 and 34 possessed moderate to weak agonistic effects.

The study aims to investigate the mechanism of Farnesoid X receptor (FXR) activation in sepsis-induced abnormal bile acid metabolism and the metabolism status of each bile acid type.

The sepsis mouse model was developed via lipopolysaccharide intraperitoneal injection and confirmed via hematoxylin and eosin (H&E) staining. FXR agonist activated the FXR/fibroblast growth factor (FGF)15/FGFR pathway via quantitative real-time polymerase chain reaction and Western blot. Consequently, metabolomics and bioinformatics analysis were conducted to identify the alterations in each kind of bile acid content following FXR agonist/inhibitor intervention.

The H&E staining indicated that FXR activation alleviates the liver injury of the sepsis mouse model. The increased FGF15 and FXFR expression levels and decreased CYP7A1 demonstrated FXR/FGF15/FGFR pathway activation following FXR agonist treatment. Furthermore, total bile acid, interleukin (IL)-6, and tumor necrosis factor-α concentrations were downregulated after FXR activation, whereas IL-10 concentration was upregulated, indicating the alleviated effect of FXR agonist in sepsis. Consequently, metabolomics and bioinformatics analysis determined that T-a-MCA were downregulated in both FXR agonist and inhibitor groups, whereas six bile acid types were altered in the control group.

FXR activation was crucial in alleviating sepsis-induced hepatic injury and cholestasis through the FGF15/FGFR signaling pathway, and FXR may act as a potential preventive and intervention target of sepsis.

The Gansu zokor (Eospalax cansus), a subterranean rodent endemic to the Loess Plateau of China, exhibits remarkable adaptability to hypoxic environments. While gut microbiota are known to regulate lipid metabolism through bile acid (BA) pathways, this phenomenon has not been investigated in subterranean rodents exposed to hypoxia. This study employed 16SrRNA sequencing, targeted analysis of BA metabolites in colonic contents, and assessments of BA and lipid metabolites alongside molecular analyses in the liver and ileum under conditions of acute and chronic hypoxia in Gansu zokors. The results revealed that hypoxia altered the composition of gut microbiota and BA pools in Gansu zokors. Hypoxia-induced changes increased the abundance of gut microbiota associated with BA metabolism, thereby modulating lipid metabolism via farnesoid X receptor (FXR) signaling in the distal ileum and liver cells. Under acute hypoxia, FXR upregulated lipid synthesis and suppressed fatty acid β-oxidation by downregulating the carnitine palmitoyl-transferase1A (CPT1A) expression. Conversely, during chronic hypoxia, particularly under long-term exposure, FXR reduced lipid synthesis and enhanced fatty acid β-oxidation by upregulating acyl-CoA oxidase (ACOX1) expression. In both hypoxic conditions, FXR facilitated lipoprotein metabolism. In summary, this study elucidates that gut microbiota-mediated BA metabolic pathways contribute to the Gansu zokor's ability to maintain lipid metabolic homeostasis and adaptation to hypoxia.

Metabolic dysfunction-associated steatohepatitis (MASH) is a complex disease driven by diverse metabolic and inflammatory pathways. Farnesoid X receptor (FXR) is a promising target for MASH due to its role in bile acid and lipid metabolism, while HSD17B13 regulates liver lipid droplet homeostasis. However, the existing HSD17B13 inhibitors have several druglike property challenges due to the common phenolic structure, a key pharmacophore for the HSD17B13 inhibitor. In this study, a two-round high-throughput screening was performed to identify the FXR agonist 2 as the nonphenolic HSD17B13 inhibitor. The multiparameter structural optimization led to the discovery of dual FXR/HSD17B13 modulator 6, with high target selectivity, target tissue distribution, suitable pharmacokinetic properties, and safety profiles. Moreover, even at the lower dose, compound 6 exerted a better therapeutic effect than obeticholic acid (OCA) in multiple MASH models. With attractive pharmacological activity and safety profiles, the dual FXR/HSD17B13 modulator 6 is worthy of further evaluation as a novel anti-MASH agent.

Pyrrolizidine alkaloids (PAs), recognized globally for their hepatotoxic properties, significantly contribute to liver damage through an imbalance in bile acid homeostasis. Addressing this imbalance is crucial for therapeutic interventions in PA-related liver injuries. Chlorogenic acid (Cga), a phenolic compound derived from medicinal plants, has demonstrated hepato-protective effects across a spectrum of liver disorders. The specific influence and underlying mechanisms by which Cga mitigates PA-induced liver damage have not been clearly defined.

To explore the protective effects of Cga against acute PA toxicity, a murine model was established. The influence of Cga on bile acid metabolism was confirmed through a variety of molecular biology techniques. These included RNA sequencing, western blotting, and immunoprecipitation, along with quantitative analyses of bile acid concentrations.

Our findings indicate that Cga enhances sirtuin 1 (SIRT1) activation and increases farnesoid X receptor (FXR) signaling, which are crucial for maintaining bile acid balance in PA-induced hepatic injury. When mice subjected to PA-induced hepatic injury were treated with SIRT1 inhibitors alongside Cga, the hepatoprotective effects of Cga were significantly reduced. In Fxr-KO mice, the ability of Cga to mitigate liver damage induced by PAs was substantially reduced, which underscores the role of the SIRT1/FXR signaling axis in mediating the protective effects of Cga.

Our research suggests that Cga can serve as an effective treatment for PA-mediated hepatotoxicity. It appears that influencing the SIRT1/FXR signaling pathway might provide an innovative pharmacological approach to address liver damage caused by PAs.

Clostridioides difficile, a major cause of antibiotic-associated diarrhea, is suppressed by the gut microbiome, but the precise mechanisms are not fully described. Through a meta-analysis of 12 human studies, we designed a synthetic fecal microbiota transplant (sFMT1) by reconstructing microbial networks negatively associated with C. difficile colonization. This lab-built 37-strain consortium formed a functional community suppressing C. difficile in vitro and in animal models. Using sFMT1 as a tractable model system, we find that bile acid 7α-dehydroxylation is not a determinant of sFMT1 efficacy while one strain performing Stickland fermentation-a pathway of competitive nutrient utilization-is both necessary and sufficient for the suppression of C. difficile, replicating the efficacy of a human fecal transplant in a gnotobiotic mouse model. Our data illustrate the significance of nutrient competition in suppression of C. difficile and a generalizable approach to interrogating complex community function through robust methods to leverage publicly available sequencing data.

Similarly to conventional steroids, bile acids function as signaling molecules, acting on a family of membrane and nuclear receptors. The best-characterized bile acid-regulated receptors are the farnesoid X receptor, activated by primary bile acids, and the G-protein-coupled bile acid receptor 1 (also known as Takeda G protein-coupled receptor 5), which is activated by secondary bile acids, such as lithocholic acid (LCA) and deoxycholic acid. Both the farnesoid X receptor and G-protein-coupled bile acid receptor 1 are expressed in cells of innate immunity, monocytes/macrophages, and natural killer cells. Their activation in these cells provides counter-regulatory signals that are inhibitory in nature and attenuate inflammation. In recent years, however, it has been increasingly appreciated that bile acids biotransformations by intestinal microbiota result in the formation of chemically different secondary bile acids that potently regulate adaptive immunity. The 3-oxoLCA and isoalloLCA, two LCA derivatives, bind receptors such as the retinoic acid receptor-related orphan receptor gamma t (RORγt) and the vitamin D receptor (VDR) that are expressed only by lymphoid cells, extending the regulatory role of bile acids to T cells, including T-helper 17 cells and type 3 innate lymphoid cells (ILC3). In this novel conceptual framework, bile acids have emerged as one of the main components of the postbiota, the waste array of chemical mediators generated by the intestinal microbiota. Deciphering the interaction of these mediators with the immune system in the intestine and liver is a novel and fascinating area of bile acid renaissance.

This study integrated the the effects of dietary Lys/Met ratio in a low protein diet on the meat quality in Tibetan sheep. A total of 90 weaned Tibetan sheep, 2 months old with initial weight of 15.37 ± 0.92 kg were randomly divided into 3 treatments, which were supplemented with Lys/Met ratio at 3 (LP-H), 2 (LP-M), and 1 (LP-L) in the basal diet (10 % crude protein), respectively. After slaughter (150 days of age), the growth performances and meat quality of longissimus dorsi muscle were evaluated. The LP-L group showed significantly higher final body weight compared to the LP-M group (P < 0.05). Serum albumin and total protein levels were significantly higher in the LP-L group than in the LP-H group (P < 0.05). Furthermore, meat from the LP-L group had significantly higher protein, calcium, and vitamin E content compared to the LP-M group (P < 0.05). Transcriptomic analysis revealed 3,479 differentially expressed genes enriched in pathways related to muscle growth, energy metabolism, and signaling transduction. Metabolomic analysis identified 771 differential metabolites, significantly enriched in ABC transporters, beta-alanine metabolism, and taste transduction pathways. Integrated analysis highlighted the upregulation of the ABCD4 gene and L-valine metabolite in the LP-L group, contributing to improved phenotypic traits. These findings provide molecular insights into the regulatory mechanisms underlying the effects of dietary Lys/Met ratios on Tibetan sheep meat quality and offer a basis for developing nutritional strategies to enhance premium meat production.

Type 2 diabetes mellitus (T2DM) and Parkinson's disease (PD) are chronic conditions that affect the aging population, with increasing prevalence globally. The rising prevalence of comorbidity between these conditions, driven by demographic shifts, severely impacts the quality of life of patients, posing a significant burden on healthcare resources. Chinese herbal medicine has been used to treat T2DM and PD for millennia. Pharmacological studies have demonstrated that medicinal herbs effectively lower blood glucose levels and exert neuroprotective effects, suggesting their potential as adjunctive therapy for concurrent management of T2DM and PD.

To elucidate the shared mechanisms underlying T2DM and PD, particularly focusing on the potential mechanisms by which medicinal herbs (including herbal formulas, single herbs, and active compounds) may treat these diseases, to provide valuable insights for developing therapeutics targeting comorbid T2DM and PD.

Studies exploring the mechanisms underlying T2DM and PD, as well as the treatment of these conditions with medicinal herbs, were extracted from several electronic databases, including PubMed, Web of Science, Google Scholar, and China National Knowledge Infrastructure (CNKI).

Numerous studies have shown that inflammation, oxidative stress, insulin resistance, impaired autophagy, gut microbiota dysbiosis, and ferroptosis are shared mechanisms underlying T2DM and PD mediated through the NLRP3 inflammasome, NF-κB, MAPK, Keap1/Nrf2/ARE, PI3K/AKT, AMPK/SIRT1, and System XC--GSH-GPX4 signaling pathways. Thirty-four medicinal herbs, including 2 herbal formulas, 4 single herbs, and 28 active compounds, have been reported to potentially exert anti-T2DM and anti-PD effects by targeting these shared mechanisms.

Traditional Chinese medicine effectively combats T2DM and PD through shared pathological mechanisms, highlighting their potential for application in treating these comorbid conditions.

The Farnesoid X receptor (FXR) has recently been identified as being closely associated with the progression of primary hepatocellular carcinoma. Cancer stem cells (CSCs) play a crucial role in tumor initiation, progression, invasion, metastasis, recurrence, and drug resistance. The elucidation of the role and regulatory mechanism of FXR in CSCs is therefore deemed significant. Here, bioinformatics analysis has revealed a downregulation of FXR in hepatocellular carcinoma (HCC), which showed a negative correlation with HCC malignancy. This result was further confirmed through clinical sample analysis. Subsequently, CSCs were isolated from HCC cell lines and exhibited a significant decrease in the expression of FXR. The activation of FXR resulted in a remarkable inhibition of the proliferation, invasion, and tumorigenicity of CSCs. Furthermore, activated FXR prominently upregulated the expression of SOCS3 while suppressing STAT3 phosphorylation in CSCs. To further investigate this discovery, we established a DEN-induced HCC model in mice and observed that FXR-deficient mice exhibited heightened susceptibility to HCC. This was accompanied by decreased expression levels of SOCS3 and elevated expression and phosphorylation levels of STAT3, as well as significantly enhanced HCC CSCs markers and stemness-related genes expression in DEN-induced HCC tissues of FXR-deficient mice. Additionally, we also found a significant upregulation of CSCs markers and stemness-related genes within HCC clinical samples. Based on these findings, we postulated that targeted regulation of SOCS3 by FXR inhibits STAT3 phosphorylation, thereby exerting an inhibitory effect on CSCs.

Farnesoid X receptor (FXR), a nuclear receptor, is expressed in calvaria and bone marrow stromal cells and plays a role in bone homeostasis. However, the mechanism of FXR-activated osteoblast differentiation remains unclear. In this study, we investigated the regulatory mechanism underlying FXR-activated osteoblast differentiation using bone morphogenetic protein-2 (BMP-2)-induced mouse ST-2 mesenchymal stem cells. We also synthesized a novel FXR agonist, FLG390, and compared its biological effects in osteoblast differentiation with a known FXR agonist, chenodeoxycholic acid (CDCA). As an FXR agonist, FLG390 accelerated osteoblast differentiation to a comparable extent with CDCA, enhancing alkaline phosphatase (ALP) activity and the expression of osteoblast differentiated-related genes such as ALP, collagen type 1 α1 chain (COL1A1), and runt-related transcription factor 2 (RUNX2). FXR activation elevated the expression of cyclooxygenase (COX)-2 and the production of prostaglandin (PG) E2 in the early phase of osteoblast differentiation. A selective COX-2 inhibitor and an antagonist of EP4 receptors, one of PGE2 receptors, partially suppressed FXR-activated osteoblast differentiation. Moreover, treatment with either inhibitor during the first 6 h after initiating osteoblast differentiation repressed FXR-activated osteoblast differentiation to the same extent as did the treatment for 6 d. Therefore, a novel FXR agonist, FLG390, exhibited potency comparable to CDCA. FXR activation promoted the early phase of osteoblast differentiation via the COX-2-PGE2-EP4 axis, representing a potential target for control of bone metabolism.

Lithocholic acid (LCA) is accumulated in mammals during calorie restriction and it can activate AMP-activated protein kinase (AMPK) to slow down ageing1. However, the molecular details of how LCA activates AMPK and induces these biological effects are unclear. Here we show that LCA enhances the activity of sirtuins to deacetylate and subsequently inhibit vacuolar H+-ATPase (v-ATPase), which leads to AMPK activation through the lysosomal glucose-sensing pathway. Proteomics analyses of proteins that co-immunoprecipitated with sirtuin 1 (SIRT1) identified TUB-like protein 3 (TULP3), a sirtuin-interacting protein2, as a LCA receptor. In detail, LCA-bound TULP3 allosterically activates sirtuins, which then deacetylate the V1E1 subunit of v-ATPase on residues K52, K99 and K191. Muscle-specific expression of a V1E1 mutant (3KR), which mimics the deacetylated state, strongly activates AMPK and rejuvenates muscles in aged mice. In nematodes and flies, LCA depends on the TULP3 homologues tub-1 and ktub, respectively, to activate AMPK and extend lifespan and healthspan. Our study demonstrates that activation of the TULP3-sirtuin-v-ATPase-AMPK pathway by LCA reproduces the benefits of calorie restriction.

Although previous studies have established associations between specific gut microbiota (GM) and metabolic dysfunction-associated fatty liver disease (MAFLD), research examining the relationship between functional gastrointestinal symptoms and MAFLD, including advanced fibrosis, remains limited. This study aims to investigate the association between stool consistency, bowel movement frequency (BMF), and the occurrence of MAFLD and advanced fibrosis in U.S. adults.

This population-based study included 9,928 adults from the 2005-2010 National Health and Nutrition Examination Survey (NHANES), with a mean age of 47.19 ± 16.65 years, comprising 47.7% males and 52.3% females. Weighted logistic regression was used to assess the association between stool consistency, BMF, and MAFLD or advanced fibrosis. A linear trend was assessed by treating BMF categories as continuous variables with ordinal values. The dose-response relationship between BMF and MAFLD was analyzed using restricted cubic splines (RCS) regression. Sensitivity and subgroup analyses were performed to confirm the robustness of the findings.

In the RCS regression, no significant nonlinear relationship was observed between BMF and the risk of MAFLD (p-overall < 0.0001; p-nonlinear = 0.0663). The multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for MAFLD were 0.82 (95% CI 0.69-0.98), 1.31 (95% CI 1.16-1.46), and 1.50 (95% CI 1.14-1.99) for participants with 3-6 BMs/week, 1-2 BMs/day, and > 2 BMs/day, respectively, compared to those with once/day (p-trend < 0.001). For stool consistency, hard stools were associated with a decreased risk of MAFLD (OR 0.77; 95% CI 0.62-0.95), whereas loose stools increased the risk (OR 1.37; 95% CI 1.05-1.80), relative to normal stools. A significant interaction between BMF and age was observed. No significant associations were found between stool consistency or BMF and advanced liver fibrosis. Sensitivity analyses confirmed the robustness of these findings.

This cross-sectional study demonstrates that a BMF of 3-6 BMs/week and hard stools are associated with a reduced risk of MAFLD, whereas a BMF of more than once/day and loose stools are linked to an increased risk of MAFLD. Moreover, no significant associations were observed between stool consistency, BMF, and advanced fibrosis among individuals diagnosed with MAFLD.

Not applicable.

Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by bile acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in liver disease models while significantly mitigating the itch side effects.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a wide spectrum of liver injuries, ranging from hepatic steatosis, metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis to MASLD-associated hepatocellular carcinoma (MASLD-HCC). Recent studies have highlighted the bidirectional impacts between host genetics/epigenetics and the gut microbial community. Host genetics influence the composition of gut microbiome, while the gut microbiota and their derived metabolites can induce host epigenetic modifications to affect the development of MASLD. The exploration of the intricate relationship between the gut microbiome and the genetic/epigenetic makeup of the host is anticipated to yield promising avenues for therapeutic interventions targeting MASLD and its associated conditions. In this review, we summarise the effects of gut microbiome, host genetics and epigenetic alterations in MASLD and MASLD-HCC. We further discuss research findings demonstrating the bidirectional impacts between gut microbiome and host genetics/epigenetics, emphasising the significance of this interconnection in MASLD prevention and treatment.

Multiply adverse effects including declines in production performance and excessive fat deposition were noticed with the extension of the laying cycle in hens, which are pertinent to animal welfare and human food safety. This study aimed to investigate the effect of dietary supplementation of bile acids (BAs) on production performance and lipid metabolism in late-phase laying hens. A total of 144 70-week-old hens were distributed into three treatments with eight replicates per treatment, including the basal diet with 0 (Ctrl), 95.01 (Low-BA), and 189.99 mg/kg (High-BA) of porcine BAs, respectively. The test period was from 70 to 75 weeks. The supplementation of BAs did not significantly alter laying performance during the trial, whereas it increased (p < 0.05) the total follicles compared to the Ctrl diet. The eggs from the hens fed the BA diet exhibited increased (p > 0.05) relative weight of eggshell and yolk color than those that consumed the Ctrl diet. There were no significant changes following BA treatment regarding the serum lipid profile. Dietary BA treatment reduced the total triglyceride in livers to different extents, resulting in the decreased diameter and area of vacuoles in liver tissues. The low-dose BA treatment decreased the mRNA levels of fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD), while promoting the expression of lipoprotein lipase (LPL) compared to the Ctrl group (both p < 0.05). Of note, the expressions of farnesoid X receptor (FXR), apical sodium-dependent bile acid transporter (ASBT), and ileum bile acid-binding protein (IBABP) were notably downregulated (p < 0.05) by the low-dose BA treatment. Dietary BA treatment had no apparent effects on laying performance, whereas it increased the follicle frequency, eggshell weight, and yolk color. Moreover, a diet containing 95.01 mg/kg of BAs depressed ileal BA resorption and hepatic fatty deposition by reducing lipogenesis and promoting lipolysis, which may have a beneficial effect on the liver in late-phase layers.

Acute kidney injury (AKI), a common complication of sepsis, might be caused by overactivated inflammation, mitochondrial damage, and oxidative stress. However, the mechanisms underlying sepsis-induced AKI (SAKI) have not been fully elucidated, and there is a lack of effective therapies for AKI. To this end, this study aimed to investigate whether obeticholic acid (OCA) has a renoprotective effect on SAKI and to explore its mechanism of action. Through bioinformatics analysis, our study confirmed that the mitochondria might be a critical target for the treatment of SAKI. Thus, a septic rat model was established by cecal ligation puncture (CLP) surgery. Our results showed an evoked inflammatory response via the NF-κB signaling pathway and NLRP3 inflammasome activation in septic rats, which led to mitochondrial damage and oxidative stress. OCA, an Farnesoid X Receptor (FXR) agonist, has shown anti-inflammatory effects in numerous studies. However, the effects of OCA on SAKI remain unclear. In this study, we revealed that pretreatment with OCA can inhibit the inflammatory response by reducing the synthesis of proinflammatory factors (such as IL-1β and NLRP3) via blocking NF-κB and alleviating mitochondrial damage and oxidative stress in the septic rat model. Overall, this study provides insight into the excessive inflammation-induced SAKI caused by mitochondrial damage and evidence for the potential use of OCA in SAKI treatment.

Bile acid (BA) signaling dysregulation is an important etiology for the development of metabolic dysfunction-associated steatotic liver disease (MASLD). As diverse signaling molecules synthesized in the liver by pathways initiated with CYP7A1 and CYP27A1, BAs are endogenous modulators of farnesoid x receptor (FXR). FXR activation is crucial in maintaining BA homeostasis, regulating lipid metabolism, and suppressing inflammation. Additionally, BAs interact with membrane receptors and gut microbiota to regulate energy expenditure and intestinal health. Complex modulation of BAs in vivo and the lack of suitable animal models impede our understanding of the functions of individual BAs, especially during MASLD development. Previously, we determined that acute feeding of individual BAs differentially affects lipid, inflammation, and oxidative stress pathways in a low-BA mouse model, Cyp7a1/Cyp27a1 double knockout (DKO) mice. Currently, we investigated to what degree cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) at physiological concentrations impact MASLD development in DKO mice. The results showed that these 3 BAs varied in the ability to activate hepatic and intestinal FXR, disrupt lipid homeostasis, and modulate inflammation and fibrosis. Additionally, UDCA activated intestinal FXR in these low-BA mice. Significant alterations in lipid uptake and metabolism in DKO mice following CA and DCA feeding indicate differences in cholesterol and lipid handling across genotypes. Overall, the DKO were less susceptible to weight gain, but more susceptible to MASH diet induced inflammation and fibrosis on CA and DCA supplements, whereas WT mice were more vulnerable to CA-induced fibrosis on the control diet.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD)-previously described as nonalcoholic fatty liver disease-continues to rise globally. Despite this, therapeutic measures for MASLD remain limited. Recently, there has been a growing interest in the gut microbiome's role in the pathogenesis of MASLD. Understanding this relationship may allow for the administration of therapeutics that target the gut microbiome and/or its metabolic function to alleviate MASLD development or progression. This review will discuss the interplay between the gut microbiome's structure and function in relation to the development of MASLD, assess the diagnostic yield of gut microbiome-based signatures as a noninvasive tool to identify MASLD severity, and examine current and emerging therapies targeting the gut microbiome-liver axis.

Oleanolic acid (OA) is a naturally occurring pentacyclic triterpene compound that has been reported to cause cholestatic liver injury. However, the regulation and pathogenic role of bile acids in OA-induced development of cholestatic liver injury remains largely unclear. Farnesoid X receptor (FXR) is a metabolic nuclear receptor that plays an important role in bile acid homeostasis in the liver by regulating efflux transporters bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2). The aim of this study was to investigate the effect of OA on hepatocyte tight junction function and determine the role of FXR, BSEP, and MRP2 in the mechanism of impairment of transport of bile acids induced by OA. Both in vivo and in vitro models were used to characterize the OA-induced liver injury. The liquid chromatography-tandem mass spectrometry (LC-MS) was employed to characterize the efflux function of the transporters, and the results showed that OA caused a blockage of bile acids efflux. OA treatment resulted in decreased expression levels of the tight junction proteins zonula occludens-1 and occludin. Immunofluorescence results showed that OA treatment significantly reduced the number of bile ducts and the immunofluorescence intensity. Pretreatment with agonists of FXR and MRP2, respectively, in animal experiments attenuated OA-induced liver injury, while pretreatment with inhibitors of BSEP and MRP2 further aggravated OA-induced liver injury. These results suggest that OA inhibits FXR-mediated BSEP and MRP2, leading to impaired bile acid efflux and disruption of tight junctions between liver cells, resulting in liver damage.

Bile acids are increasingly appearing in the spotlight owing to their novel impacts on various host processes. Similarly, there is growing attention on members of the microbiota that are responsible for bile acid modifications. With recent advances in technology enabling the discovery and continued identification of microbially conjugated bile acids, the chemical complexity of the bile acid landscape in the body is increasing at a rapid pace. In this Review, we summarize our current understanding of how bile acids and the gut microbiota interact to modulate immune responses during homeostasis and disease, with a particular focus on the gut.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading indication for liver transplantation (LT), but also occurs after LT. The prevalence of de novo MASLD (dnMASLD) after LT, based on both surveillance (svLbx) and indication biopsies (indLbx), is unknown. Furthermore, the impact of the distinct cardiometabolic risk factors on histological disease activity has not been assessed. We aimed to evaluate the prevalence of dnMASLD and the association between the cardiometabolic risk factors and histological disease activity.

We performed a retrospective single-center study in a LT cohort with indLbx and svLbx. Patients with NAFLD before LT were excluded.

We analyzed 249 patients who underwent either svLbx or indLbx. Forty-eight (19.2%) had either dnMASLD (n = 26/249, 10.4%) or metabolic dysfunction associated steatohepatitis (dnMASH) (n = 22/249, 8.8%). Although dnMASLD/dnMASH was more frequent in indLbx (35.1%, p < 0.01), still 16.5% of patients with svLbx had dnMASLD/dnMASH. While overweight (p < 0.01) and diabetes (p = 0.01) were more frequent in patients with dnMASH, only overweight was associated with histological disease activity in the multivariate analysis. No impact of dnMASLD on the overall survival was observed.

While dnMASLD is more frequent in patients with indLBX, it also occurs in 16.5% of patients without signs of graft dysfunction. Overweight has the strongest impact on histological disease activity and should be monitored carefully after LT.

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.

Sterol 12α-hydroxylase (CYP8B1) is the unique P450 enzyme with sterol 12-oxidation activity, playing an exclusive role in 12α-hydroxylating intermediates along the bile acid (BA) synthesis pathway. Despite the long history of BA metabolism studies, it is unclear whether CYP8B1 catalyzes 12α-hydroxylation of C27 BAs, the key intermediates shuttling between mitochondria and peroxisomes. This work provides robust in vitro evidence that both microsomal and recombinant CYP8B1 enzymes catalyze the 12α-hydroxylation of dihydroxycoprostanic acid (DHCA) into trihydroxycoprostanic acid (THCA). On the one hand, DHCA 12α-hydroxylation reactivity is conservatively detected in liver microsomes of both human and preclinical animals. The reactivity of human tissue fractions conforms well with the selectivity of CYP8B1 mRNA expression, while the contribution of P450 enzymes other than CYP8B1 is excluded by reaction phenotyping in commercial recombinant enzymes. On the other hand, we prepared functional recombinant human CYP8B1 proteins according to a recently published protocol. Titration of the purified CYP8B1 proteins with either C4 (7α-hydroxy-4-cholesten-3-one) or DHCA yields expected blue shifts of the heme Soret peak (type I binding). The recombinant CYP8B1 proteins efficiently catalyze 12α-hydroxylation of both DHCA and C4, with substrate concentration occupying half of the binding sites of 3.0 and 1.9 μM and kcat of 3.2 and 2.6 minutes-1, respectively. In summary, the confirmed role of CYP8B1 in 12α-hydroxylation of C27 BAs has furnished the forgotten passageway in the BA synthesis pathway. The present finding might have opened a new window to consider the biology of CYP8B1 in glucolipid metabolism and to evaluate CYP8B1 inhibition as a therapeutic approach of crucial interest for metabolic diseases. SIGNIFICANCE STATEMENT: The academic community has spent approximately 90 years interpreting the synthesis of bile acids. However, the 12α-hydroxylation of intermediates catalyzed by CYP8B1 is not completely mapped on the classic pathway, particularly for the C27 bile acids, the pivotal intermediates shuttling between mitochondria and peroxisomes. This work discloses the forgotten 12α-hydroxylation pathway from dihydroxycoprostanic acid into trihydroxycoprostanic acid. The present finding may facilitate evaluating CYP8B1 inhibition as a therapeutic approach of crucial interest for metabolic diseases.