Alterations in bile acid profile and pathways contribute to hepatic inflammation in cancer cachexia, a syndrome worsening the prognosis of cancer patients. As the gut microbiota impinges on host metabolism through bile acids, the current study aimed to explore the functional contribution of gut microbial dysbiosis to bile acid dysmetabolism and associated disorders in cancer cachexia. Using three mouse models of cancer cachexia (the C26, MC38 and HCT116 models), we evidenced a reduction in the hepatic levels of several secondary bile acids, mainly taurodeoxycholic (TDCA). This reduction in hepatic TDCA occurred before the appearance of cachexia. Longitudinal analysis of the gut microbiota pinpointed an ASV, identified as Xylanibacter rodentium, as a bacterium potentially involved in the reduced production of TDCA. Coherently, stable isotope-based experiments highlighted a robust decrease in the microbial 7α-dehydroxylation (7α-DH) activity with no changes in the bile salt hydrolase (BSH) activity in cachectic mice. This approach also highlighted a reduced microbial 7α-hydroxysteroid dehydrogenase (7α-HSDH) and 12α-hydroxysteroid dehydrogenase (12α-HSDH) activities in these mice. The contribution of the lower production of TDCA to cancer cachexia was explored in vitro and in vivo. In vitro, TDCA prevented myotube atrophy, whereas in vivo hepatic whole transcriptome analysis revealed that TDCA administration to cachectic mice improved the unfolded protein response and cholesterol homeostasis pathways. Coherently, TDCA administration reversed hepatic cholesterol accumulation in these mice. Altogether, this work highlights the contribution of the gut microbiota to bile acid dysmetabolism and the therapeutic interest of the secondary bile acid TDCA for hepatic cholesterol homeostasis in the context of cancer cachexia. Such discovery may prove instrumental in the understanding of other metabolic diseases characterized by microbial dysbiosis. More broadly, our work demonstrates the interest and relevance of microbial activity measurements using stable isotopes, an approach currently underused in the microbiome field.

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.

Previous studies have suggested that abnormal hepatobiliary system function may contribute to poor prognosis in patients with acute coronary syndrome (ACS) and that abnormal hepatobiliary system function may be associated with per- and polyfluoroalkyl substances (PFAS) exposure. However, there is limited evidence for this association in cardiovascular subpopulations, particularly in the ACS patients. Therefore, we performed this study to evaluate the association between plasma PFAS exposure and hepatobiliary system function biomarkers in patients with ACS. This study included 546 newly diagnosed ACS patients at the Second Hospital of Hebei Medical University, and data on 15 hepatobiliary system function biomarkers were obtained from medical records. Associations between single PFAS and hepatobiliary system function biomarkers were assessed using multiple linear regression models and restricted cubic spline model (RCS), and mixture effects were assessed using the Quantile g-computation model. The results showed that total bile acids (TBA) was negative associated with perfluorohexane sulfonic acid (PFHxS) (-7.69 %, 95 % CI: -12.15 %, -3.01 %). According to the RCS model, linear associations were found between TBA and PFHxS (P for overall = 0.003, P for non-linear = 0.234). We also have observed the association between between PFAS congeners and liver enzyme such as aspartate aminotransferase (AST) and α-l-Fucosidase (AFU), but it was not statistically significant after correction. In addition, Our results also revealed an association between prealbumin (PA) and PFAS congeners as well as mixtures. Our findings have provided a piece of epidemiological evidence on associations between PFAS congeners or mixture, and serum hepatobiliary system function biomarkers in ACS patients, which could be a basis for subsequent mechanism studies.

Xiexin Tang (XXT) is a classic Chinese medicine formula that can be used to treat Atherosclerosis (AS). This study aimed to investigate the mechanism by which XXT regulated AS lipid levels. Firstly, the mixture components of XXT were analyzed by High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Then, the AS model based on Apolipoprotein E knockout (ApoE-/-) mice was established. Cytokines related to lipid metabolism and bile acid metabolism were detected by Quantitative Real-time PCR (qRT-PCR). 16S rDNA gene sequencing was performed to analyze differential bacterial populations, and the mechanism of XXT regulation of bile acids affecting lipid metabolism was further explored by targeted metabolomics. Further, antibiotic-treated mice were used to investigate the role of gut microbiota in the anti-AS effect of XXT. The results showed that XXT attenuated the lipid levels and reversed the abnormal elevation of cytokines, such as hepatic lipid metabolism and inflammatory reaction in AS mice. XXT also repaired the gut barrier damage and reversed gut microbiota disorders in AS mice. Furthermore, the metabolic levels of bile acids were reshaped by XXT. Whereas, in the absence of gut microbiota, XXT failed to attenuate lipid levels and inhibit the expression of cytokines related to inflammation and bile acid metabolism in AS mice and failed to play a role in ultimately treating AS. In conclusion, XXT could effectively inhibit the inflammatory reaction and lipid accumulation in AS mice, and this effect was closely related to its remodeling of gut microbiota to regulate bile acid metabolism.

The combined toxic effects of microplastics (MPs) and their carried contaminants on organisms have been widely concerned; however, the health risks and its mechanism of "gut microbiota-host metabolism (bile acids, BA)" remain unknown. Herein, Xenopus tropicalis were exposured to aged polystyrene MPs carried triclosan (aPS+TCS) and single (a)PS-MPs & TCS, respectively. The bioaccumulation of TCS in the gut of X. tropicalis was significantly increased in aPS+TCS group, which was 89 % higher than that of PS+TCS group, causing more severe oxidative stress, inflammation and intestinal barrier disruption (leaky gut). The expressions of TNF-α, IL-6 and IL-10 in aPS+TCS group were enhanced by 276 % and 19 % and decreased by 81 %, respectively, compared to that in PS+TCS group. Moreover, co-exposure to aPS+TCS increased the number of Escherichia coli, and reduced levels of DCA and LCA (secondary BAs). Multiomics analysis further revealed that the intestinal toxicity of aPS+TCS to X. tropicalis was mainly influenced by the gut flora, BA metabolism and inflammation-related pathways. Co-exposure may exacerbate inflammation by increasing the blood levels of lipopolysaccharides and inhibiting secondary BA production, which are regulated by the gut microbiota-bile acid axis. This study provides new insights in the potential mechanisms of intestinal damage from pollutant-loaded aged MPs.

Metabolic-associated fatty liver disease (MAFLD) has become an increasingly prevalent liver disorder worldwide, being closely associated with obesity, metabolic syndrome, and insulin resistance. Bile acids (BAs), beyond their traditional role in lipid digestion, play a pivotal part in regulating lipid and glucose metabolism as well as inflammatory responses. Recent investigations have recognized BAs as key factors in the onset and progression of MAFLD, mainly via their interactions with nuclear receptors such as the farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor (TGR5). Additionally, active compounds derived from traditional Chinese medicine (TCM) have shown promising potential in the treatment of MAFLD. This study systematically reviews and analyzes the molecular mechanisms and recent progress in the application of TCM active ingredients for MAFLD treatment, with a focus on their regulation of BAs. These active ingredients, including saponins, flavonoids, polysaccharides, and sterols, exert therapeutic effects through diverse mechanisms, such as modulating BA synthesis and mediating receptor-signaling pathways, and are expected to restore metabolic homeostasis.

The gut microbiome refers to the collective genomes of the approximately 1,000-1,150 microbial species found in the human gut, called the gut microbiota. Changing the gut microbiota composition has been shown to affect cardiovascular health significantly. Numerous studies have demonstrated the part that gut microbiota and its metabolites play in the development and course of several illnesses, including colon cancer, heart failure, stroke, hypertension, and inflammatory bowel disease. With cardiovascular diseases responsible for more than 31% of all fatalities globally, conditions like hypertension, atherosclerosis, and heart failure are serious global health issues. Developing preventive measures to fight cardiovascular diseases requires understanding how the gut microbiota interacts with the cardiovascular system. Understanding the distinctive gut microbiota linked to cardiovascular diseases has been made possible by microbial sequencing analysis. The gut microbiota and cardiovascular diseases are closely related, and more profound knowledge of this association may result in treatment strategies and broad guidelines for enhancing cardiovascular health through gut microbiome modification. This review summarizes the role of gut microbiota in cardiovascular diseases, highlighting their influence on disease progression and potential therapeutic implications.

This study examined the different effects of high-fat and capsicum diets on the digestive organs of guinea pigs. Hartley guinea pigs (n = 24) were divided into the high-fat diet (HFD), capsicum diet (CD), and control (C) groups. Guinea pigs in the C, HFD, and CD groups received maintenance feed, high-fat, and capsicum diets, respectively. After 12 weeks of modelling, serum samples were collected for biochemical analysis. Enzyme-linked immunosorbent assay was used to quantify interleukin-1β, interleukin-6, and tumour necrosis factor-α, while haematoxylin-eosin staining was used to observe morphological changes. Blood lipid levels and inflammatory markers in the serum of guinea pigs in HFD and CD groups were significantly elevated than those in the serum of guinea pigs in the C group (P < 0.01). Inflammation and blood lipid disorders were more severe among guinea pigs in the HFD group than among those in the CD and C groups (P < 0.001). Pathological examinations revealed that high-fat and capsicum diets induce damage to the liver, stomach, gallbladder, and colon. Specifically, high-fat diets exhibited more significant effects. High-fat or capsicum diet consumption can damage the digestive organs, causing abnormal lipid metabolism; however, high-fat diets exhibit more significant effects on the digestive organs.

Bile acids are essential molecules that facilitate lipid emulsification and function as signaling molecules mediating host-microbiota interactions. They shape the gut microbial structure and function, playing a critical role in metabolic regulation via the gut-liver axis.

This study aimed to investigate the effects of exogenous bile acids, primarily hyocholic acid (HCA), on the microbiota-gut-liver metabolism in male Tan-lambs fed a high-grain diet.

Thirty six-mo-old male Tan lambs (Ovis aries) were randomly allocated into either a control group or an HCA-supplemented group (n = 15 per group). The trial lasted 84 d, including a 14-d adaptation period. On day 70, 6 lambs from each group were randomly selected for slaughtering. Rumen and ileal contents were collected for microbial profiling via 16S rRNA sequencing, and liver tissue samples were harvested for transcriptomic and metabolomic analyses.

The HCA intervention significant altered the composition and structure of ruminal and ileal bacteria. Notable increases were observed in Turicibacter species [linear discriminant analysis (LDA) score = 2.48; P < 0.05] and Muribaculaceae (LDA score = 3.75; P < 0.05) in the rumen, and Eubacterium fissicatena group (LDA score = 2.50; P < 0.05) in the ileum. Key hepatic genes and metabolites targeted by HCA were identified, including ENPP3, RFK, Ifi203, LIPG, CYP1A1, and CYP4A11, nordeoxycholic acid (log-fold change = 6.30; P < 0.005), α-muricholic acid (log-fold change = 5.60; P < 0.001), and β-muricholic acid (log-fold change = 5.60; P < 0.001).

Exogenous bile acids regulate the microbiota-gut-liver axis, influencing hepatic glycolipid metabolism in sheep. Specifically, nordeoxycholic acid demonstrates potential as a dietary intervention to promote metabolic homeostasis in ruminants. These findings highlight the potential of HCA and nordeoxycholic acid as functional feed additives or prebiotic agents for improving metabolic health in ruminants and potentially other species.

Liver transplantation (LT) is the ultimate treatment for patients with end-stage liver disease or early hepatocellular carcinoma. In the context of LT, because of the unique immunological characteristics of human liver allograft, 5%-20% of selected LT recipients can achieve operational tolerance. Nonetheless, there remains a risk of rejection in LT patients. Maintaining immune homeostasis is thus crucial for improving clinical outcomes in these patients. In mechanism, several immune cells, including dendritic cells, Kupffer cells, myeloid-derived suppressor cells, hepatic stellate cells, regulatory B cells, and CD4 + regulatory T cells (Treg), contribute to achieving tolerance following LT. In terms of Treg, it plays a role in successfully minimizing immunosuppression or achieving tolerance post-LT while also reducing the risk of rejection. Furthermore, the gut microbiome modulates systemic immune functions along the gut-liver axis. Recent studies have explored changes in the microbiome and its metabolites under various conditions, including post-LT, acute rejection, and tolerance. Certain functional microbiomes and metabolites exhibit immunomodulatory functions, such as the augmentation of Treg, influencing immune homeostasis. Therefore, understanding the mechanisms of tolerance in LT, the role of Treg in tolerance and rejection, as well as their interactions with gut microbiome, is vital for the management of LT patients.

The human gut hosts a diverse microbial community, essential for maintaining overall health. However, antibiotics, commonly prescribed for infections, can disrupt this delicate balance, leading to antibiotic-associated diarrhea, inflammatory bowel disease, obesity, and even neurological disorders. Recognizing this, probiotics have emerged as a promising strategy to counteract these adverse effects.

This review aims to offer a comprehensive overview of the latest evidence concerning the utilization of probiotics in managing antibiotic-associated side effects.

Probiotics play a crucial role in preserving gut homeostasis, regulating intestinal function and metabolism, and modulating the host immune system. These mechanisms serve to effectively alleviate antibiotic-associated adverse effects and enhance overall well-being.

The number of the patients treated with maintenance hemodialysis (HD) is increasing due to the increasing incidence of end stage renal disease (ESRD). Autologous arteriovenous fistula (AVF) is the preferable modality for long-term vascular access during HD. AVF stenosis is the main cause of AVF dysfunction in HD patients, but its mechanism has not been fully elucidated. Patients with ESRD often have various related complications due to intestinal microbiota disorders and their metabolites, and the intestinal axis reveals various metabolic disorders in patients with chronic kidney disease. This paper analyzes the correlation between intestinal axis abnormalities and AVF stenosis in patients with CKD through three axes: "gut-liver axis," "gut-brain axis," and "gut-spleen axis," to provide clinical significance for elucidating the mechanism of AVF stenosis and for the prevention and treatment of AVF stenosis.

Metabolomics describes the metabolic profile of an organism at a given time by the concentrations of its constituent metabolites. When studied over time, metabolite concentrations can help understand the dynamical evolution of a biological process. However, metabolites are involved into sequences of chemical reactions, called metabolic pathways, related to a given biological function. Accounting for these pathways into statistical methods for metabolomic data is thus a relevant way to directly express results in terms of biological functions and to increase their interpretability.

We propose a new method, phoenics, to perform differential analysis for longitudinal metabolomic data at the pathway level. In short, phoenics proceeds in two steps: First, the matrix of metabolite quantifications is transformed by a dimension reduction approach accounting for pathway information. Then, a mixed linear model is fitted on the transformed data.

This method was applied to semi-synthetic NMR data and two real NMR datasets assessing the effects of antibiotics and irritable bowel syndrome on feces. Results showed that phoenics properly controls the Type I error rate and has a better ability to detect differential metabolic pathways and to extract new impacted biological functions than alternative methods. The method is implemented in the R package phoenics available on CRAN.

Sanye Tablet (SYT), a patent traditional Chinese prescription, is commonly used in treating type 2 diabetes mellitus and hyperlipidemia. Both clinical and animal studies suggest that SYT effectively regulates lipid metabolism. However, its mode of action on hepatic steatosis has yet to be fully elucidated.

This study investigates the lipid-regulating effects and underlying mechanism of SYT in high-fat diet (HFD)-induced hepatic steatosis mice.

The inhibitory effects of SYT on developing hepatic steatosis were investigated in HFD-fed C57BL/6N mice. Biochemical markers, including total cholesterol (TC) and triglycerides (TG), were measured using specific kits. Hepatic histological alterations were determined by Hematoxylin and Eosin (H&E) and Oil Red O staining. Hepatic, fecal, and systemic bile acids (BAs) profiles were detected by UPLC-MS. mRNA and protein levels of BAs synthesis-related enzymes and critical nodes of farnesoid X receptor (FXR)/fibroblast growth factor 15 (FGF15)/fibroblast growth factor receptor 4 (FGFR4) signaling were detected. Fecal microbial composition was analyzed by 16S rRNA gene sequencing and the antimicrobial activity of SYT was further evaluated in vitro.

SYT alleviated HFD-induced hepatic steatosis by decreasing TG and TC levels, relieving hepatocyte ballooning, and promoting hepatic BAs synthesis. Moreover, SYT significantly increased the levels of taurine-conjugated BAs in the liver and feces, which in turn inhibited the FXR/FGF15/FGFR4 signaling. Consequently, the hepatic BAs synthesis-related enzyme expression was promoted to reduce lipid accumulation. Notably, SYT remodeled the gut microbiota composition of HFD-fed mice, especially inhibiting the growth of bile salt hydrolase (BSH)-producing bacteria, such as Lactobacillus murinus, Lactobacillus johnsonii, and Enterococcus faecalis.

The findings illustrated that SYT prevented hepatic steatosis by improving hepatic lipid accumulation, which is reflected in modulating the gut-liver axis. SYT corrects BAs profile, restores perturbed FXR/FGF15/FGFR4 signaling and promotes hepatic BAs synthesis, which is associated with modulation on certain BSH-producing bacteria.

The concept of the gut microbes-muscle axis underscores the impact of intestinal microbiota on the muscular system, an area that is increasingly coming to light. However, current interpretations and applications of this concept remain underdeveloped. In this review, we concluded and discussed factors, such as short-chain fatty acids, amino acids, vitamins, bile acids, antibiotics, cytokines, hormones, and extracellular vesicles that mediate gut microbes-muscle crosstalk and influence the gut microbes-muscle axis. Additionally, we examined how the gut microbes-muscle axis affects muscle mass, muscle strength, muscle metabolism, as well as muscle oxidative and immune status. Furthermore, we reviewed the influence of the microbes-muscle axis on muscle fiber type transition, muscle fat deposition, and meat quality. These insights illuminate the potential mechanisms by which the gut microbes-muscle axis operates in humans and animals. Thus, this review provides a theoretical foundation for future research and offers practical guidance for its application in biomedical and livestock industries.

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.

Type 2 diabetes mellitus is a complex disorder associated with insulin resistance and hyperinsulinaemia that is insufficient to maintain normal glucose metabolism. Changes in insulin signalling and insulin levels are thought to directly explain many of the metabolic abnormalities that occur in diabetes mellitus, such as impaired glucose disposal. However, molecules that are directly affected by abnormal insulin signalling might subsequently go on to cause secondary metabolic effects that contribute to the pathology of type 2 diabetes mellitus. In the past several years, evidence has linked insulin resistance with the concentration, composition and distribution of bile acids. As bile acids are known to regulate glucose metabolism, lipid metabolism and energy balance, these findings suggest that bile acids are potential mediators of metabolic distress in type 2 diabetes mellitus. In this Review, we highlight advances in our understanding of the complex regulation of bile acids during insulin resistance, as well as how bile acids contribute to metabolic control.

Diabetic nephropathy (DN) is a severe microvascular complication of diabetes with a complex pathogenesis.

Recent studies were reviewed to explore the role of gut microbiota and its metabolites in DN development.

Dysbiosis of gut bacteria contributes to pathological changes such as glomerular sclerosis and renal tubule injury. Microbial metabolites are involved in DN through immune and inflammatory pathways.

Understanding the relationship between gut microbiota, its metabolites, and DN may offer potential implications for DN diagnosis, prevention, and treatment. Translating this knowledge into clinical practice presents challenges and opportunities.

Lactopontin (LPN) is an important milk protein with the potential to improve bone health, however, the specific effects have not been determined. This study investigates the effects of LPN on early bone growth and development. 3-week-old SD rats (n = 16) were assigned to the control group and LPN group, receiving intragastric administration of deionized water and 15 mg/kg LPN for 30 days respectively. LPN supplementation increased body length, femur length and femur strength, improved femoral bone volume and microarchitecture, and upregulated the expression of osteoblast activity related mRNA (Bmp2, Smad8, Wnt10b and β-catenin) in the femur. The abundance of Parabacteroides in feces and the content of glycochenodeoxycholic acid (GCDCA) in serum were significantly elevated following LPN intervention. Additionally, the bile acid receptor TGR5 in the femur was activated in the LPN group, suggesting that LPN may regulate bone health via the microbiota-metabolites-bone axis. Furthermore, LPN promoted calcium absorption through transcellular and cellular bypass pathways, resulting in a significant increase in serum calcium content. These results indicate that LPN has potential application value in regulating bone metabolism during growth.

Atherosclerosis poses a significant threat to global health. This study aimed to investigate the effects of myricetin (MYR) on high-fat diet (HFD)-induced atherosclerosis in ApoE-/- mice. Our findings demonstrated that MYR treatment significantly reduced the formation of atherosclerotic plaques, particularly at a high dose of 100 mg kg-1 day-1. Additionally, MYR markedly attenuated lipid metabolism disorders in ApoE-/- mice by decreasing body weight, improving serum lipid profiles, and reducing lipid deposition. Analysis of 16S rRNA sequencing revealed that MYR treatment enhanced the abundance of probiotic g_Lachnospiraceae_NK4A136, while it reduced that of obesity-associated genera, including Rikenellaceae_RC9_gut_group and Alistipes. Metabolomic analysis and RT-qPCR tests indicated that MYR upregulated hepatic bile acid biosynthesis, evidenced by increased total bile acid levels and enhanced expression of key enzymes CYP7A1 and CYP8B1, particularly through the classical biosynthetic pathway. Spearman's correlation analysis revealed strong associations between the regulated bile acids and these aforementioned bacteria. Therefore, our results demonstrated that MYR exerts an anti-atherosclerotic effect by modulating the gut-liver axis.

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.

Takeda G protein-coupled receptor 5 (TGR5), also known as G protein-coupled bile acid receptor 1 (GPBAR1), is a cell surface receptor involved in key physiological processes, including glucose homeostasis and energy metabolism. Recent research has focused on the role of TGR5 activation in preventing or treating diabetes while also highlighting its potential impact on the progression of diabetic complications. Functional foods and edible plants have emerged as valuable sources of natural compounds that can activate TGR5, offering potential therapeutic benefits for diabetes management. Despite growing interest, studies on the activation of TGR5 by dietary bioactive compounds remain scattered. This Review aims to provide a comprehensive analysis of how dietary bioactives act as potential agents for TGR5 activation in managing diabetes and its complications. It explores the mechanisms of TGR5 activation through both direct agonistic effects and indirect pathways via modulation of the gut microbiota and bile acid metabolism.

Diclofenac (DCF) exposure is of great concern due to the ecotoxicological risk linked with a decline of vulture populations in Southeast Asia, but also because it can affect the reproduction and neurotoxicity in mammals. Otherwise, selenium (Se) is an antioxidant essential element with key roles in health and with antagonistic action against pollutants, but in some cases with a synergistic effect. To investigate the potential intertwined mechanisms between DCF, Se, and gut microbiota, gut metabolomic and gut microbiota profiles were determined in mice after DCF exposure and Se supplementation. Speciation of selenoproteins in plasma was carried out by isotopic dilution analysis to quantify the levels of selenoproteins. Significant differences in the levels of 79% of the gut metabolites were determined after DCF exposure. The most significant altered pathway in DCF and DCF-Se groups is the primary bile biosynthesis, being the only pathway altered in mice exposed to DCF, while in DCF-Se, the metabolism of galactose and linoleic acid is also altered. Moreover, specific associations between specific gut microbiota and metabolites were determined in the studied mice groups suggesting intertwined mechanisms. Selenium supplementation modulated the gut metabolic and microbiota profiles affected by DCF.

In mammalian cells cholesterol can be synthesized endogenously or obtained exogenously through lipoprotein uptake. Plasma membrane (PM) is the primary intracellular destination for both sources of cholesterol, and maintaining appropriate membrane cholesterol levels is critical for cellular viability. The endoplasmic reticulum (ER) acts as a cellular cholesterol sensor, regulating synthesis in response to cellular needs and determining the metabolic fates of cholesterol. Upon reaching the ER, cholesterol can be esterified to facilitate its incorporation into lipoproteins and lipid droplets or converted into other molecules such as bile acids and oxysterols. In recent years, it has become clear that the intracellular redistribution of lipids, including cholesterol, is critical for the regulation of various biological processes. This Review highlights physiology and mechanisms of nonvesicular (protein-mediated) intracellular cholesterol trafficking, with a focus on the role of Aster proteins in PM to ER cholesterol transport.

Cumulative studies have shown that the composition of the gut microbiome is strongly associated with the development of type 2 diabetes mellitus (T2DM). Electroacupuncture (EA) therapy has been reported to alleviate various diseases, including T2DM, by targeting specific acupuncture points and regulating metabolic homeostasis. A recent review published in the World Journal of Diabetes detailed the role of the gut microbiome in T2DM, discussing the role of therapeutic strategies developed to alleviate T2DM and its complications based on gut microbiome in ameliorating T2DM, as well as the effects of multiple diabetes medications on gut microbiome. However, the review did not elucidate the therapeutic role of EA therapy, a common non-pharmacological intervention for T2DM. This letter complemented the effect of EA therapy on glucose metabolism by adjusting the gut microbiome composition, which reveals the underlying mechanism of glucose lowering by EA therapy and provides a scientific basis for the application of EA therapy in clinical treatment.

Bile acids (BAs), not only promote the absorption of fat-soluble nutrients and regulate the metabolism of multiple substances but also have a potential role as diagnostic and prognostic indicators in a variety of diseases such as cholestasis, hepatocellular carcinoma, and diabetes mellitus. Here, a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of 50 BAs was developed and validated. Sample preparation included internal standard spiking, followed by protein precipitation, centrifugation, solvent evaporation, and reconstitution. Baseline separation of all isobaric BA species was achieved on an Ultimate XS-C18 column (5 μm, 150 mm × 4.6 mm). The method showed good linearity with high regression coefficients (>0.990) with acceptable accuracy and precision for intra-day and inter-day analyses and achieved good recovery rates for representative analytes. No apparent carryover or matrix effect was observed. The analytical method was successfully applied to the determination of the plasma BA profile in healthy subjects and patients with inflammatory bowel disease (IBD). The routine instrumentation, low sample volume, simple pretreatment, wide range of BAs, and good separation make this LC-MS/MS method suitable for use as a BA profile assay in clinical and basic research studies. This method could be poised to identify possible BA biomarkers for non-invasive early diagnosis and therapeutic evaluation of IBD.

The intricate relationship between bile acid metabolism and skeletal muscle function has emerged as a crucial area of research in metabolic health. This review synthesizes current evidence highlighting the fundamental role of bile acids as key signaling molecules in muscle homeostasis and their therapeutic potential in muscle-related disorders. Recent advances in molecular biology and metabolomics have revealed that bile acids, beyond their classical role in lipid absorption, function as essential regulators of muscle mass and function through multiple signaling pathways, particularly via the nuclear receptor FXR and membrane receptor TGR5. Clinical studies have demonstrated significant associations between altered bile acid profiles and muscle wasting conditions, while experimental evidence has elucidated the underlying mechanisms linking bile acid signaling to muscle protein synthesis, energy metabolism, and regeneration capacity. We critically examine the emerging therapeutic strategies targeting bile acid pathways, including receptor-specific agonists, microbiome modulators, and personalized interventions based on individual bile acid profiles. Additionally, we discuss novel diagnostic approaches utilizing bile acid-based biomarkers and their potential in early detection and monitoring of muscle disorders. This review also addresses current challenges in standardization and clinical translation while highlighting promising future directions in this rapidly evolving field. Understanding the bile acid-muscle axis may provide new opportunities for developing targeted therapies for age-related muscle loss and metabolic diseases.

Feeding HC diets has been found to induce metabolic dysregulation in the colon. However, the mechanisms by which changes in colonic flora and metabolites damage the colonic epithelium are poorly studied. Therefore, the present experiment used a multi-omics technique to investigate the mechanism of colonic injury induced by high-concentrate diets in lambs. Twelve male Dumont lambs were randomly split into two groups: a low-concentrate diet (LC = concentrate/forage = 30:70) group and a high-concentrate diet (HC = concentrate/forage = 70:30) group. The results showed that the HC group presented significantly increased lipopolysaccharide (LPS) concentrations in the colonic epithelium and significantly decreased serum total cholesterol (TC), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) levels (p < 0.05), which led to cavities and inflammatory cell infiltration in the colonic epithelium. The HC group had significantly lower pH and less VFAs in colon contents, as well as a significantly increased abundance of bacteria of the genera [Eubacterium]_coprostanoligenes_group, Rikenellaceae_RC9_gut_group, Treponema, Clostridia_UCG-014, Alistipes, Ruminococcus, Christensenellaceae_R-7_group, UCG-002, Bacteroidales_RF16_group and Lachnospiraceae_AC2044_group compared to the LC diet group. These microorganisms significantly increased the level of metabolites of cholic acid, chenodeoxycholic acid, LysoPA (P-16:0/0:0), methapyrilene, and fusaric acid. A transcriptome analysis showed that cytokine-cytokine receptor interaction, glutathione metabolism, and the peroxisome signaling pathway were downregulated in the colon epithelium of the lambs fed the HC diet. Therefore, the HC diet caused epithelial inflammation and oxidative damage by affecting the interaction between the microbial flora of the colon and metabolites and the host epithelium, which eventually disrupted colon homeostasis and had a negative impact on sheep health.

The intestinal epithelium represents a critical interface between the host and external environment, serving as the second largest surface area in the human body after the lungs. This dynamic barrier is sustained by specialized epithelial cell types and their complex interactions with the gut microbiota. This review comprehensively examines the recent advances in understanding the bidirectional communication between intestinal epithelial cells and the microbiome. We briefly highlight the role of various intestinal epithelial cell types, such as Paneth cells, goblet cells, and enteroendocrine cells, in maintaining intestinal homeostasis and barrier function. Gut microbiota-derived metabolites, particularly short-chain fatty acids and bile acids, influence epithelial cell function and intestinal barrier integrity. Additionally, we highlight emerging evidence of the sophisticated cooperation between different epithelial cell types, with special emphasis on the interaction between tuft cells and Paneth cells in maintaining microbial balance. Understanding these complex interactions has important implications for developing targeted therapeutic strategies for various gastrointestinal disorders, including inflammatory bowel disease, metabolic disorders, and colorectal cancer.

Kaempferol (Kae), as a homologous flavonoid, plays a pivotal role in human nutrition and disease treatment. This study endeavors to elucidate the in vivo metabolism of Kae and its potential to modulate the interplay between bile acids (BAs) and gut microbiota (GM). After Kae administration, we analyzed pharmacokinetics, BA levels, and drug metabolic enzymes (DMEs) amount using LC-MS/MS. Subsequently, we checked the gene and protein expression with qRT-PCR and western blot and studied the changes in GM using 16S rRNA sequencing, accompanying in-depth data analysis. Finally, molecular docking was employed to explore Kae's interaction with the Farnesoid X receptor (FXR). Kae enhances its own absorption and metabolic circulation in vivo by upregulating the UDP-Glucuronosyltransferases (UGTs) expression. Furthermore, Kae significantly suppressed the expression of cholesterol 7α-hydroxylase (CYP7A1) while concurrently elevating the sterol 27-hydroxylase (CYP27A1) expression, by activating the liver FXR, a nuclear transcription factor involved in the regulation of CYPs and UGTs enzymes. For BA analysis, Kae induced the upregulation of tauro-BAs by attenuating the activity of bile salt hydrolases (BSH), which correlated with shifts in the GM composition. Specifically, Kae increased the abundance of beneficial bacteria such as Bacteroides acidifaciens and Bifidobacterium choerinum, while reduced populations of species associated with BSH deconjugation. The study indicates that Kae may serve as a prebiotic, modulating the BA-GM interaction to confer nutritional and therapeutic advantages.

Branched-chain amino acids (BCAAs) including leucine, isoleucine and valine have been linked with metabolic and cardiovascular diseases. BCAAs homeostasis is tightly controlled by their catabolic pathway. BCKA dehydrogenase (BCKD) complex is the rate-limiting step for BCAA catabolism. Mitochondrial phosphatase 2C (PP2Cm) dephosphorylates the BCKD E1alpha subunit and activates BCKD complex. Deficiency of PP2Cm impairs BCAA catabolism, leading to higher plasma BCAA concentrations. Emerging evidence shows that bile acids are key regulators of glucose, lipid and energy metabolism. In this study, we investigated whether a direct link existed between BCAAs and bile acids metabolism. Wild-type mice were fed with normal-BCAA or high-BCAA diet, while PP2Cm deficiency mice were fed with normal chow for 14 weeks. The mice were fasted for 6 h before tissue harvest to exclude metabolic changes due to immediate food intake. We showed that the bile acids in tissues and feces were significantly elevated in wild-type mice fed with high-BCAA diet as well as in PP2Cm deficiency mice fed with normal chow. These mice displayed significantly increased expression of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme of bile acid synthesis in liver, and 7α-hydroxy-4-cholesten-3-one (C4), a freely diffusible metabolite downstream of CYP7A1 in plasma. BCAAs induced Cyp7a1 expression in cultured hepatocytes. In mouse liver and cultured hepatocytes, we demonstrated that elevated BCAAs inhibited fibroblast growth factor 21 (FGF21) expression and ERK signaling pathway. Direct inhibition of ERK by U0126 (800 nM) markedly induced Cyp7a1 expression in cultured hepatocytes. Moreover, the induced Cyp7a1 expression and inhibitory effects of BCAAs on ERK signaling pathway were abolished by treatment with recombinant FGF21 protein in mouse liver and cultured hepatocytes. Collectively, this study demonstrates a direct link between BCAAs and bile acid synthesis. BCAAs promotes Cyp7a1 expression and bile acid synthesis in liver via inhibiting FGF21-ERK signaling pathway. BCAAs-regulated bile acid synthesis and homeostasis may contribute to developing novel therapeutic strategies for the treatment of metabolic disorders.

Diabetes represents a global health crisis that necessitates advancements in prevention, treatment, and management. Beyond glucose regulation, addressing weight management and associated complications is imperative. This study introduces an oral nanoparticle formulation designed to simultaneously control blood glucose, obesity, and metabolic dysfunction. These nanoparticles, based on poly (zwitterion-cholic acid), incorporate a polyzwitterion component to enhance permeation through the mucus layer and prolong drug residence. Furthermore, bile acid polymers not only regulate lipid metabolism but also ameliorate obesity-associated inflammation in adipose and liver tissues. In vivo experiments demonstrated significant hypoglycemic effects in healthy, type I diabetic, and type II diabetic mice. Notably, the nanocarriers significantly reduced body weight gain, ameliorated inflammation in adipose and liver tissues, and modulated lipid metabolism in the liver of db/db mice. Our study elucidates a comprehensive strategy for addressing glycemic control and diabetes-related complications, offering a promising approach for diabetes prevention and treatment.

Sepsis is a severe, often life-threatening form of organ dysfunction that arises from an inappropriately regulated host response to infectious pathogen exposure. As the largest gland in the body, the liver serves as a regulatory hub for metabolic, immune, and detoxification activity. It is also an early sepsis target organ such that hepatic dysfunction is observed in 34-46% of patients with sepsis. The precise mechanisms that give rise to sepsis-induced liver injury, however, remain incompletely understood. Based on the research conducted to date, dysregulated systemic inflammation, microbial translocation, microcirculatory abnormalities, cell death, metabolic dysfunction, and liver inflammation may all contribute to the liver damage that can arise in the context of septicemia. This review was developed to provide an overview summarizing the potential mechanisms underlying sepsis-induced liver injury, informing the selection of potential targets for therapeutic intervention and providing a framework for the alleviation of patient symptoms and the improvement of prognostic outcomes.

Acute lymphoblastic leukemia (ALL) poses challenges in adult patients, considering its heterogeneous nature and often suboptimal treatment outcomes. Here, we performed a study on 201 newly diagnosed adult ALL cases (age ≥ 15 y) to generate intracellular and dynamic serum metabolomic profiles. Our findings revealed a predominant increase in bile acid (BA) metabolites in serum, alongside metabolic rewiring that supported highly proliferative states and actively metabolic signaling, such as enriched nucleotide metabolism in leukemic blasts. By integrating intracellular metabolomics and transcriptomics, we constructed the Comprehensive Metabolic Information Dataset (CMID), which facilitated the development of a clustering system to supplement current risk stratification. Furthermore, we explored potential metabolic interventions targeting the serum BA profile and energy metabolism in blasts. The combined use of simvastatin with vincristine and dexamethasone regimen demonstrated a synergistic therapeutic effect in a murine ALL model, effectively lowering key BA levels in serum and suppressing the infiltration of leukemic blasts in the liver. In light of the enhanced intracellular redox metabolism, combining FK866 (a nicotinamide phosphoribosyltransferase inhibitor) and venetoclax significantly prolonged survival in a patient-derived xenograft ALL model. Our findings, along with the resulting resources (http://www.genetictargets.com/MALL), provide a framework for the metabolism-centered management of ALL.