Secondary bile acids, lithocholic acid and deoxycholic acid (LCA and DCA), are dehydroxylated derivatives of primary bile acids. However, in addition to LCA and DCA the intestinal microbiota produced a variety of poorly characterized metabolites. Allo-LCA, a LCA metabolite, acts as a dual GPBAR1 agonist and RORγt inverse agonist and modulates intestinal immunity, although is not yet known whether allo-LCA exerts regulatory functions outside the intestine. In the present study we have therefore investigated whether administration of allo-LCA, 10 mg/kg/day, to mice administered a high fat/high fructose diet (HFD-F) and carbon tetrachloride (Ccl4), a model for metabolic dysfunction-associated steatohepatitis (MASH), protects from development of liver damage. In vitro allo-LCA functions as GPBAR1 agonist and RORγt inverse agonist and prevents macrophages M1 polarization and Th17 polarization of CD4 cells. In vivo studies, while exposure to a HFD-F/Ccl4 promoted insulin resistance and development of a pro-atherogenic lipid profile and liver steatosis and fibrosis, allo-LCA reversed this pattern by improving insulin sensitivity and liver lipid accumulation. The liver transcriptomic profile demonstrated that allo-LCA reversed the dysregulation of multiple pathways associated with immunological, inflammatory and metabolic signaling. Allo-LCA also restored bile acid homeostasis, reversing HFD/Ccl4-induced shifts in bile acid pool composition and restored adipose tissue histopathology and function by reducing the expression of leptin and resistin, two pro-inflammatory adipokines, and restored a healthier composition of the intestinal microbiota. In conclusion, present results expand on the characterization of entero-hepatic signaling and suggest that allo-LCA, a microbial metabolite, might have therapeutic potential in liver diseases.

Human CYP1A1 and CYP1B1 are two important enzymes for the hydroxylation of estrogens. In this study, we aimed to investigate the potential role for FXR receptor in the regulation of CYP1A1 and CYP1B1 expressions and activities. First, pharmacokinetic analysis was conducted in male wild-type and Fxr-/- mice after intraperitoneal dosing of exogenous estradiol. In vitro microsomal Cyp1a1 and Cyp1b1 activities were probed using their substrates estradiol, phenacetin, and melatonin. The regulatory effects of FXR on these two enzymes were explored using female Fxr-/- mice, mouse 4T1 and human MCF-7 cell lines. As a result, Fxr-deficiency significantly changed the plasma concentration-time curve and exposure (AUC0-2 h) of estradiol, and the metabolism ratios of its hydroxylated metabolites. Global deletion of Fxr led to significant down-regulation of Cyp1a1 and Cyp1b1 mRNA and protein in major organs (liver, lung, kidney, stomach, small intestine). Overexpression of Fxr in mouse 4T1 cells resulted in increased levels of Cyp1a1 and Cyp1b1 mRNA and protein, whereas Fxr knockdown caused down-regulation of Cyp1a1 and Cyp1b1 expression. In human MCF-7 cells, there was a similar regulatory trend of FXR towards CYP1A1 and CYP1B1 as well as those in mouse 4T1 cells. In vitro incubation assays also supported these results. Based on luciferase reporter and electrophoretic mobility shift assays, Fxr directly activated Cyp1a1 and Cyp1b1 via their specific binding to (-488 ∼ -477 bp) and (-1475 ∼ -1460 bp) regions in their promoters, respectively. Therefore, FXR transcriptionally regulates the expression of CYP1A1 and CYP1B1, impacting the in vitro metabolism and pharmacokinetics of their substrates.

Oat β-glucan has demonstrated an anti-obesity effect against high fat diet. However, its precise regulatory mechanism remains unclear. The anti-obesity effect was related to the structural characteristics. In this study, different molecular weight oat β-glucans were investigated, and yeast glucan was taken as the positive control. Compared with the low molecular weight oat β-glucan, the higher molecular weight β-glucan presented a superior anti-obesity effect, which might be attributed to its viscosity and fermentability. Oat β-glucan effectively modulated microbiota in both the large and small intestines. Correlation analysis revealed that ileal bacteria played a more critical role in lipid metabolism. Most bile acids are recycled in the distal ileum, and bile acid metabolism influences lipid metabolism. Consequently, the impact of oat β-glucan on bile acid metabolism was assessed. Oat β-glucan intervention reduced the abundance of Faecalibaculum, while increasing the abundance of Lactobacillus and Bifidobacterium. These microbiota alterations contributed to an increase in 7-ketodeoxycholic acid, which was identified as a Farnesoid X receptor (FXR) antagonist in cell experiments. Inactivation of ileal FXR-fibroblast growth factor 15 (FGF15) signaling by 7-ketodeoxycholic acid led to enhanced bile acid synthesis via the alternative pathway. Furthermore, upregulated cytochrome P450 family 27 subfamily A member 1 (CYP27A1) promoted chenodeoxycholic acid production, which subsequently activated hepatic FXR and further accelerated hepatic lipolysis through the peroxisome proliferator-activated receptor α (PPARα)-carnitine palmitoyltransferase 1 A (CPT1A) pathway. These findings provide new evidence that oat β-glucan exerts anti-obesity effects by modulating bile acid metabolism.

The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.

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.

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.

Drug-induced liver injury (DILI), caused by chemical drugs and traditional Chinese medicine, often leads to severe outcomes like liver failure due to a lack of early detection markers. Farnesoid X receptor (FXR), a key regulator of bile acid (BA) and cholesterol metabolism, is a potential therapeutic target. This study investigates the pathogenesis, markers, and treatment strategies for DILI, focusing on the hepatoprotective effects of geniposidic acid (GPA) from Gardenia jasminoides J. Ellis. Using cellular and animal models of acute and chronic DILI induced by acetaminophen and triptolide, we explored GPA's mechanisms in BA and cholesterol metabolism. Lipidomic and BA analyses revealed that GPA alleviates DILI by enhancing bile acid synthesis and transport via FXR activation. Experiments using AAV-shFXR, Fxr- / - mice and molecular assays demonstrated that GPA targets Ser332 and His447 on FXR ligand-binding domain, promoting FXR nuclear translocation and initiating cytochrome P450 proteins (CYPs) transcriptional activation for BA metabolism. Additionally, miRNA sequencing and RNA-pulldown assays showed that GPA-activated FXR upregulates miR-19a-3p, binding to LXR 3'UTR to inhibit cholesterol production. These findings reveal the GPA-FXR "structure-target" relationship, highlighting a dual mechanism in which GPA promotes CYPs-mediated bile acid metabolism and miR-19a-3p-mediated cholesterol synthesis inhibition, providing a basis for FXR-targeted DILI therapies.

Small-molecule pectin (SMP) extracted from the leaves of Premna ligustroides Hemsl, with a molecular weight range of 5000-35,000 Da, has demonstrated anti-inflammatory and lipid-lowering properties in vitro. This study explored the effects of SMP on hypercholesterolemia in mice, with a focus on inflammation, lipid profiles, and cholesterol metabolism. Mice received SMP at doses of 607, 303, and 152 mg/kg body weight. Key biomarkers were assessed, including serum lipid levels, inflammatory factors in serum and liver, oxidative stress markers, short-chain fatty acids in cecal contents, cecal microbiota composition, and cholesterol metabolism-related gene expression. The results showed that SMP treatment normalized total cholesterol and alanine aminotransferase levels. In the medium-dose group, interleukin (IL)-1β and IL-18 levels decreased by 35.08 % and 29.90 %, respectively, compared to the model group. Serum malondialdehyde levels declined by 52.35 %, while superoxide dismutase levels increased by 18.48 %. Tumor necrosis factor-α and IL-6 levels were reduced by 44.13 % and 89.32 %, respectively. Additionally, SMP promoted the growth of beneficial bacteria, such as Muribaculum and Akkermansia, while suppressing harmful bacteria, including Acetatifactor. These microbiota changes were associated with elevated propionic acid levels and regulation of the CYP7A1/FXR/SREBP-2/LDLR signaling pathway. These findings underscore SMP's potential to improve cholesterol metabolism and mitigate inflammation, positioning it as a promising dietary intervention for the management of hypercholesterolemia.

The normal development and growth of bones are critical for poultry health. With the rapid increase in poultry growth rates achieved over the last few decades, juvenile meat-type poultry exhibit a high incidence of leg weakness and lameness. These issues are significant contributors to poor animal welfare and substantial economic losses. Understanding the potential etiology of bone problems in poultry will aid in developing treatments for bone diseases. The gut microbiota represents the largest micro-ecosystem in animals and is closely related to many metabolic disorders, including bone disease. It achieves this by secreting secondary metabolites and coordinating with various tissues and organs through the circulatory system, which leads to the concept of the gut-X axis. Given its importance, modulating gut microbiota to influence the gut-X axis presents new opportunities for understanding and developing innovative therapeutic approaches for poultry bone diseases. In light of the extensive literature on this topic, this review focuses on the effects of gut microbiota on bone density and strength in poultry, both directly and indirectly, through the regulation of the gut-X axis. Our aim is to provide scientific insights into the bone health problems faced by poultry.

Atherosclerosis is the leading cause of cardiovascular disease-related morbidity and mortality. The traditional Chinese medicine Qingre Sanjie Formula (QRSJF), composed of Prunellae Spica, Sargassum, Fritillariae Thunbergii Bulbus, Leonuri Herba, and Forsythiae Fructus, has shown efficacy in treating cardiovascular diseases, although its mechanisms are unclear.

This study aimed to explore the protective effects of QRSJF against atherosclerosis and the mechanisms involved.

The composition of QRSJF was analyzed using Ultra Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry. An 8-week high-fat diet (HFD)-induced atherosclerosis model was established in ApoE-/- mice. Following model induction, mice received 12 weeks of QRSJF treatment at high- and low doses (3.16 and 1.58 g drug/kg/day, respectively) via oral gavage, while simvastatin (2.6 mg/kg/day) as the positive control. Various techniques, including biochemical assays, vascular ultrasonography, histopathology, untargeted metabolomics, and molecular biology techniques were utilized to evaluate therapeutic effects. The underlying mechanism was investigated in vitro using free fatty acids -induced HepG2 cells.

Both low- and high-dose QRSJF effectively attenuated dyslipidemia and decreased serum inflammatory cytokine levels in HFD-fed ApoE-/- mice. In addition, QRSJF alleviated atherosclerotic plaque formation, reduced arterial narrowing, and enhanced plaque stability. Plasma and liver metabolomic analyses further identified that ABC (ATP binding cassette) subfamily transporters and bile acid metabolism as key pathways through which QRSJF ameliorates atherosclerosis. QRSJF also alleviated liver lipid accumulation and increased the expression of liver proteins, including scavenger receptor class B type 1, low-density lipoprotein receptor, ABC subfamily A member 1, cholesterol 7α-hydroxylase (CYP7A1), ABC transporter G5/G8 (ABCG5/G8), bile salt output pump, and liver X receptor alpha (LXR-α). In vitro, QRSJF activated LXR-α expression in HepG2 cells, thereby enhancing the expression of the downstream targets, CYP7A1 and ABCG5/8, and reducing free fatty acid-induced lipid accumulation. Notably, the beneficial effects of QRSJF were abrogated by the LXR-α inhibitor GSK2033.

QRSJF improves dyslipidemia and reduces atherosclerotic plaque in ApoE-/- mice by activating the LXR-α/ABCG5/G8 pathway. This facilitates cholesterol transport to the liver and promotes bile acid synthesis and cholesterol excretion into the bile and intestine, thereby exerting anti-atherosclerotic effects.

Although an association between gut microbiota and cholestatic liver disease (CLD) has been reported, the precise functional roles of these microbes in CLD pathogenesis remain largely unknown.

To explore the function of gut microbes in CLD pathogenesis and the effects of gut microbiota on intestinal barrier and bile acid (BA) metabolism in CLD.

Male C57BL/6J mice were fed a 0.05% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet for 2 weeks to induce CLD. The sterile liver tissues of mice were then meticulously harvested, and bacteria in homogenates were identified through culture methods. Furthermore, 16S ribosomal DNA sequencing was employed to analyze sterile liver samples collected from eight patients with primary biliary cholangitis (PBC) and three control individuals with hepatic cysts. The functional roles of the identified bacteria in CLD pathogenesis were assessed through microbiota transfer experiments, involving the evaluation of changes in intestinal permeability and BA dynamics.

Ligilactobacillus murinus (L. murinus) and Lactococcus garvieae (L. garvieae) were isolated from the bacterial culture of livers from CLD mice. L. murinus was prevalently detected in PBC patients and controls, whereas L. garvieae was detected only in patients with PBC but not in controls. Mice inoculated with L. garvieae exhibited increased susceptibility to experimental CLD, with both in vitro and in vivo indicating that L. garvieae disrupted the intestinal barrier function by down-regulating the expression of occludin and zonula occludens-1. Moreover, L. garvieae administration significantly upregulated the expression of the apical sodium-dependent BA transporter in the terminal ileum and increased serum BA levels.

L. garvieae contributes to excessive BA-induced hepatobiliary injury and liver fibrosis by increasing intestinal permeability and enhancing BA reabsorption.

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.

Previous research has identified bile acids (BAs) as a valuable supplement for animal feed, especially in the poultry industry. However, there is limited research on the use of bile acids as a preventative measure against intestinal inflammation in broilers. This study aims to investigate the impact of dietary BAs on LPS-triggered intestinal inflammation in broilers. 180 Arbor Acres broilers were randomly divided into four group: (1) broilers receiving a standard diet (Con group); (2) broilers from the Con category subjected to LPS challenge (LPS group); (3) broilers on a diet supplemented with BAs compound and exposed to LPS (BA+LPS group); and (4) broilers on a diet enriched with lithocholic acid (LCA) and challenged with LPS (LCA + LPS group).The results showed that the LPS challenge caused a notable rise in liver mass, plasma AST concentrations, and levels of inflammatory cytokines (P < 0.05). BAs compounds or LCA improved intestinal morphological damage, inflammation response and bile acid metabolism (P < 0.05). Furthermore, analysis of 16S rRNA gene sequences revealed that supplementation with BAs compounds or LCA mitigated the reduction in bacterial diversity, while also increasing the abundance of operational taxonomic units (OTUs) associated with Bacteroides and Bifidobacterium. Additionally, the increased abundance of Candidatus_Arthromitus due to BAs compound or LCA supplementation showed a significant negative correlation with the concentrations of intestinal inflammatory cytokines (P < 0.05). These results suggest that the supplementation of BAs compound or LCA has the potential to alleviate intestinal inflammation and regulate gut microbiota in broilers subjected to LPS challenge.

Nonalcoholic steatohepatitis (NASH) poses significant health risks; however, effective treatment options remain scarce. Yinchen-Gancao decoction (YG, a formula composed of Traditional Chinese Medicine Artemisia capillaris Thunb. and Glycyrrhiza uralensis Fisch.) ameliorated symptoms in NASH mouse models. However, the underlying mechanisms have not been elucidated.

This study aimed to assess the therapeutic efficacy of YG and explore the underlying mechanisms.

YG was prepared and characterized, and then orally administered to high-fat diet (HFD) or high-fat high-sugar diet (HFHS) induced mice. Histopathological examinations and biochemical analyses were performed to evaluate the therapeutic effects. Fxr-/- mice were used to investigate the role of farnesoid X receptor (FXR) in the therapeutic effects of YG. The mechanism of action was explored by quantitative real-time PCR (RT-qPCR), western blotting, molecular docking, and cellular thermal shift assay (CETSA).

YG improved liver histopathology and biochemical parameters in wild-type mice but only improved alanine aminotransferase (ALT) in Fxr-/- mice. YG upregulated FXR with Chlorogenic acid (CGA) identified as a bioactive constituent. In wild-type (WT) mice, YG downregulated de novo lipogenesis (DNL), fatty acid (FA) uptake, and upregulated FA β-oxidation. However, these effects were absent in the Fxr-/- mice. YG inhibited hepatic inflammation and endoplasmic reticulum stress (ERS) in both WT and Fxr-/- mice.

Our study supported the use of YG as a promising therapeutic agent to attenuate NASH. Its mechanism of action involved the reduction of hepatic lipid accumulation (FXR-dependent) and the inhibition of hepatic inflammation and ERS.

Advanced glycation end products (AGEs) in processed foods are closely linked to intestinal injury. However, the long-term effects of exposure to free Nɛ-carboxymethyl lysine (CML), a prevalent AGE molecule, on intestinal barrier integrity have been rarely evaluated. This study investigated the temporal effects of CML exposure on intestinal barrier permeability in C57BL/6N mice at diet-related doses over 12, 14, and 16 weeks. No significant changes were observed at 12 weeks, but CML exposure significantly increased intestinal permeability at 14 and 16 weeks, accompanied by elevated serum LPS levels, colonic histological damage, and reduced tight junction protein expression at 16 weeks. CML exposure also altered gut microbiota composition and intestinal bile acid (BA) profiles, specifically reducing TDCA, GDCA, and GCDCA levels. Given the important role of colonic BA receptor signaling in maintaining the intestinal barrier integrity, the impact of CML on BA receptor signaling was assessed. CML exposure significantly downregulated BA receptor TGR5-YAP signaling in mice, while no significant effects were observed in vitro, suggesting that the changes observed in TGR5-YAP signaling in vivo may not result from the direct effects of CML. Spearman's correlation analysis revealed strong associations between altered gut microbiota, BA levels, TGR5-YAP signaling, and intestinal barrier injury. This study highlighted the chronic health risks of long-term CML intake and provided new insights into the links between CML-induced intestinal toxicity, gut microbiota, BA profiles, and BA receptor signaling.

Hibernation is a necessary means for animals to maintain survival while coping with low temperatures and food shortages. While most studies have largely focused on mammalian hibernation, its reptilian equivalent has been less studied. In order to provide insights into the energy metabolism and potential microbial regulatory mechanisms in hibernating snakes, the serum, liver, gut content samples were measured by multi-omic methods. Here we show the active snakes have more vigorous lipid metabolism, whereas snakes in hibernation groups have higher sphingolipid metabolism. Furthermore, the results indicate that the potential energy supply pathway was gluconeogenesis. Microbial analysis reveals that Proteobacteria and Firmicutes showed dynamic changes with the transformation among active, pre-hibernation and hibernation periods. The correlation analysis reveals the potential role of Romboutsia, Providencia and Vagococcus in regulating above metabolism by producing certain metabolites. The results advance the understanding of the complex energy-saving strategy in hibernating poikilotherms.

Dietary interventions have been shown to improve gut health by altering the gut flora, preventing obesity, and mitigating inflammatory disorders. This study investigated the benefits of a rice starch-konjac glucomannan (ERS-KGM) complex, produced via screw extrusion, for gut health and obesity prevention. Analyzed through in vitro starch digestion, scanning electron microscopy, and structural analysis, the ERS-KGM complex exhibited a notable increase in resistant starch content due to its well-ordered structure. When administered to mice on a high-fat diet for 8 weeks, the ERS-KGM complex significantly reduced body weight, white adipose tissue mass, adipocyte size, and food intake while increasing water consumption. It also improved glucose metabolism, insulin sensitivity, and lipid profiles by lowering serum triglycerides and total glycerol content. Enhanced metabolic biomarkers and enzyme activities were observed, specifically involving glycerophospholipid metabolism. It decreased the activities of aldehyde dehydrogenase, lactate dehydrogenase, and amino acid transaminase while increasing antioxidant enzymes like glutathione peroxidase and superoxide dismutase. Additionally, it elevated glycogen and positively altered gut microbiota by enriching Firmicutes, Desulfobacterota, and Bifidobacterium. This change enhanced the ability to degrade specific compounds and elevated the concentrations of short-chain fatty acids in feces. These findings suggest that the ERS-KGM complex could serve as a dietary supplement for obesity prevention.

Bile acids (BAs) affect the growth of potentially pathogenic commensals, including those from the Enterobacteriaceae family, which are frequently overrepresented in inflammatory bowel disease (IBD). BAs are normally reabsorbed in the ileum for recycling and are often increased in the colonic lumina of patients with IBD, including those with Crohn's disease (CD). Here, we investigated the influence of BAs on gut colonization by Enterobacteriaceae. We found increased abundance of Enterobacteriaceae in the colonic mucosae of patients with CD with a concomitant decrease in the transporters that resorb BAs in the ileum. The increase in Enterobacteriaceae colonization was greater in the colons of patients who had undergone terminal ileum resection compared with those with intact ileum, leading us to hypothesize that BAs promote intestinal colonization by Enterobacteriaceae. Exposure of human colonic epithelial cell lines to BAs reduced mitochondrial respiration, increased oxygen availability, and enhanced the epithelial adherence of several Enterobacteriaceae members. In a publicly available human dataset, mucosal Enterobacteriaceae was negatively associated with the expression of genes related to mitochondrial function. In a murine model, increased intestinal BA availability enhanced colonization by Escherichia coli in a manner that depended on bacterial respiration. Together, our findings demonstrate that BAs reduce mitochondrial respiration in the colon, leading to an increase in oxygen availability that facilitates Enterobacteriaceae colonization. This identification of BAs as facilitators of host-commensal interactions may be relevant to multiple intestinal diseases.

High sugar, high-fat diets and unhealthy lifestyles have led to an epidemic of obesity and obesity-related metabolic diseases, seriously placing a huge burden on socio-economic development. A deeper understanding and elucidation of the specific molecular biological mechanisms underlying the onset and development of obesity has become a key to the treatment of metabolic diseases. Recent studies have shown that the changes of bile acid composition are closely linked to the development of metabolic diseases. Bile acids can not only emulsify lipids in the intestine and promote lipid absorption, but also act as signaling molecules that play an indispensable role in regulating bile acid homeostasis, energy expenditure, glucose and lipid metabolism, immunity. Disorders of bile acid metabolism are therefore important risk factors for metabolic diseases. The farnesol X receptor, a member of the nuclear receptor family, is abundantly expressed in liver and intestinal tissues. Bile acids act as endogenous ligands for the farnesol X receptor, and erroneous FXR signaling triggered by bile acid dysregulation contributes to metabolic diseases, including obesity, non-alcoholic fatty liver disease and diabetes. Activation of FXR signaling can reduce lipogenesis and inhibit gluconeogenesis to alleviate metabolic diseases. It has been found that intestinal FXR can regulate hepatic FXR in an organ-wide manner. The crosstalk between intestinal FXR and hepatic FXR provides a new idea for the treatment of metabolic diseases. This review focuses on the relationship between bile acids and metabolic diseases and the current research progress to provide a theoretical basis for further research and clinical applications.

The interplay between the dysbiotic microbiota and bile acids is a critical determinant for development of a dysregulated immune system in inflammatory bowel disease (IBD). Here we have investigated the fecal bile acid metabolome, gut microbiota composition, and immune responses in IBD patients and murine models of colitis and found that IBD associates with an elevated excretion of primary bile acids while secondary, allo- and oxo- bile acids were reduced. These changes correlated with the disease severity, mucosal expression of pro-inflammatory cytokines and chemokines, and reduced inflow of anti-inflammatory macrophages and Treg in the gut. Analysis of bile acids metabolome in the feces allowed the identification of five bile acids: 3-oxo-DCA, 3-oxo-LCA, allo-LCA, iso-allo-LCA and 3-oxo-UDCA, whose excretion was selectively decreased in IBD patients and diseased mice. By transactivation assay and docking calculations all five bile acids were shown to act as GPBAR1 agonists and RORγt inverse agonists, skewing Th17/Treg ratio and macrophage polarization toward an M2 phenotype. In a murine model of colitis, administration of 3-oxo-DCA suffices to reverse colitis development and intestinal dysbiosis in a GPBAR1-dependent manner. In vivo administration of 3-oxo-DCA to colitic mice also reverses disease severity and RORγt activation induced by a RORγt agonist and IL-23, a Th17 inducing cytokine. These results demonstrated that intestinal excretion of 3-oxoDCA, a dual GPBAR1 agonist and RORγt inverse agonist, is reduced in IBD and in models of colitis and its restitution protects against colitis development, highlighting a potential role for this agent in IBD management.

The circadian syndrome is linked with chronic diseases such as stroke, kidney stones, and overactive bladder. However, the relationship between circadian syndrome and gallstones is poorly understood. In this study, we aim to investigate whether circadian syndrome is associated with gallstones in a population-based study.

Using data from the National Health and Nutrition Examination Survey (NHANES) database spanning from 2017 to 2020, a cross-sectional study with 2913 participants was performed to assess the relationship between circadian syndrome and gallstones. Univariate and two adjusted multivariate regression models were used to examine the connection between circadian syndrome and gallstones incidence. Smoothed curve fitting using the generalized additive model (GAM) was used to describe the nonlinear relationship. Subgroup analyses were also performed to investigate potential variations in the relationship between circadian syndrome and the risk of developing gallstones.

The findings indicated a positive association of circadian syndrome with gallstones, with model 2 showing a 117% increase in risk (OR = 2.17, 95% CI 1.43, 3.29). In model 3, the incidence of gallstones increased by 76% (OR = 1.76, 95% CI 0.91, 3.43). However, there was no significant relationship between the number of circadian syndrome components and the risk of gallstones. Smooth curve fitting based on the GAM further demonstrated linear relationships between CircS and the risk of gallstones. Subgroup analyses further demonstrated statistically significant associations between circadian syndrome and the prevalence of gallstones among individuals who were non-smokers.

Circadian syndrome was positively associated with the prevalence of gallstones, particularly among non-smoking participants.

Bile acids (BAs) play a crucial role in lipid metabolism of children. However, the association between per- and polyfluoroalkyl substance (PFAS) exposure and BAs in children is scarce. To address this need, we selected 252 children from the Maoming Birth Cohort and measured 32 PFAS, encompassing short- and long-chain perfluorocarboxylic acids (PFCAs) and perfluorosulfonic acids (PFSAs) in the cord blood. Additionally, we analyzed nine primary and eight secondary BAs in the serum of three-year-old children. Generalized linear models with FDR-adjusted and Bayesian kernel machine regression (BKMR) were used to explore the associations of individual and mixture effects of PFAS and BAs. We found negative associations between cord blood long-chain PFCAs exposure and serum primary BAs in three-year-old children. For example, one ln-unit (ng/mL) increase of perfluoro-n-tridecanoic acid (PFTrDA), perfluoro-n-undecanoic acid (PFUnDA) and perfluoro-n-decanoic acid (PFDA) were associated with decreased taurochenodeoxycholic acid, with estimated percentage change of -24.28% [95% confidence interval (CI): -36.75%, -9.35%], -25.84% (95% CI: -39.67%, -8.83%), and -22.97% (95% CI: -34.45%, -9.47%) respectively. Notably, the observed associations were more pronounced in children with lower vegetable intake. Additionally, the BKMR model also demonstrated a monotonical decline in primary BAs as the PFAS mixture increased. We provided the first evidence of the association between intrauterine exposure to PFAS and its mixture with BAs in children. Further large-sample-size studies are needed to verify this finding.

Although multiple approaches have been suggested, treating mild-to-severe fibrosis in the context of metabolic dysfunction associated with liver disease (MASLD) remains a challenging area in drug discovery. Pathogenesis of liver fibrosis is multifactorial, and pathogenic mechanisms are deeply intertwined; thus, it is well accepted that future treatment requires the development of multitarget modulators. Harnessing the 3,4,5-trisubstituted isoxazole scaffold, previously described as a key moiety in Farnesoid X receptor (FXR) agonism, herein we report the discovery of a novel class of hybrid molecules endowed with dual activity toward FXR and the leukemia inhibitory factor receptor (LIFR). Up to 27 new derivatives were designed and synthesized. The pharmacological characterization of this series resulted in the identification of 3a as a potent FXR agonist and LIFR antagonist with excellent ADME properties. In vitro and in vivo characterization identified compound 3a as the first-in-class hybrid LIFR inhibitor and FXR agonist that protects against the development of acute liver fibrosis and inflammation.

Bile acids (BAs) exert a profound influence on the body's pathophysiology by intricately shaping the composition of gut bacteria. However, the complex interplay between BAs and gut microbiota has impeded a systematic exploration of their impact on intestinal bacteria. Initially, we investigated the effects of 21 BAs on the growth of 65 gut bacterial strains in vitro. Subsequently, we examined the impact of BAs on the overall composition of intestinal bacteria, both in vivo and in vitro. The results unveiled distinct effects of various BAs on different intestinal strains and their diverse impacts on the composition of gut bacteria. Mechanistically, the inhibition of intestinal strains by BAs occurs through the accumulation of these acids within the strains. The intracellular accumulation of deoxycholic acid (DCA) significantly influenced the growth of intestinal bacteria by impacting ribosome transcription and amino-acid metabolism. The metabolomic analysis underscores the pronounced impact of DCA on amino-acid profiles in both in vivo and in vitro settings. This study not only elucidates the effects of BAs on a diverse range of bacterial strains and their role in shaping the gut microbiota but also reveals underlying mechanisms essential for understanding and maintaining a healthy gut microbiota.

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

Since its first outbreak in 2020, the pandemic caused by the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) has caused the death of almost 7 million people worldwide. Vaccines have been fundamental in disease prevention and to reduce disease severity especially in patients with comorbidities. Nevertheless, treatment of COVID-19 has been proven difficult and several approaches have failed to prevent disease onset or disease progression, particularly in patients with comorbidities. Interrogation of drug data bases has been widely used since the beginning of pandemic to repurpose existing drugs/natural substances for the prevention/treatment of COVID-19. Steroids, including bile acids such as ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) have shown to be promising for their potential in modulating SARS-CoV-2/host interaction. Bile acids have proven to be effective in preventing binding of spike protein with the Angiotensin Converting Enzyme II (ACE2), thus preventing virus uptake by the host cells and inhibiting its replication, as well as in indirectly modulating immune response. Additionally, the two main bile acid activated receptors, GPBAR1 and FXR, have proven effective in modulating the expression of ACE2, suggesting an indirect role for these receptors in regulating SARS-CoV-2 infectiveness and immune response. In this review we have examined how the potential of bile acids and their receptors as anti-COVID-19 therapies and how these biochemical mechanisms translate into clinical efficacy.

Bile acids are microbial metabolites that can impact infection of enteric and hepatitis viruses, but their functions during systemic viral infection remain unclear. Here we show that elevated levels of the secondary bile acid taurolithocholic acid (TLCA) are associated with reduced fatality rates and suppressed viraemia in patients infected with severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne haemorrhagic fever virus. TLCA inhibits viral replication and mitigates host inflammation during SFTSV infection in vitro, and indirectly suppresses SFTSV-mediated induction of ferroptosis by upregulating fatty acid desaturase 2 via the TGR5-PI3K/AKT-SREBP2 axis. High iron and ferritin serum levels during early infection were correlated with decreased TLCA levels and fatal outcomes in SFTSV-infected patients, indicating potential biomarkers. Furthermore, treatment with either ferroptosis inhibitors or TLCA protected mice from lethal SFTSV infection. Our findings highlight the therapeutic potential of bile acids to treat haemorrhagic fever viral infection.

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic disorders characterized by dysregulated immune response and persistent inflammation. Recent studies suggest that bile acid receptors, particularly GPBAR1, and the transcription factor RORγt play critical roles in modulating intestinal inflammation. This study evaluates the therapeutic potential of PBT002, a dual GPBAR1 agonist and RORγt inverse agonist, in IBD models. The effects of PBT002 were assessed through in vitro and in vivo experiments. Macrophages and T lymphocytes obtained from the buffy coat were exposed to PBT002 to evaluate its immunomodulatory activity. The beneficial effects in vivo were evaluated in mouse models of colitis induced by TNBS, DSS or DSS + IL-23 using also a Gpbar1 knock-out male mice. PBT002 exhibited an EC50 of 1.2 µM for GPBAR1 and an IC50 of 2.8 µM for RORγt. In in vitro, PBT002 modulated macrophage polarization towards an anti-inflammatory M2 phenotype and reduced Th17 cell markers while increasing Treg markers. In the TNBS-induced colitis model, PBT002 reduced weight loss, CDAI, and colon damage, while it modulated cytokine gene expression towards an anti-inflammatory profile. In GPBAR1-/-, the anti-inflammatory effects of PBT002 were attenuated, indicating partial GPBAR1 dependence. RNA sequencing revealed significant modulation of inflammatory pathways by PBT002. In DSS+IL-23 induced colitis, PBT002 mitigated disease exacerbation, reducing pro-inflammatory cytokine levels and immune cell infiltration. In conclusion, PBT002, a GPBAR1 agonist and RORγt inverse agonist, modulates both the innate and adaptive immune responses to reduce inflammation and disease severity in models of IBD.

Hearing loss places a significant burden on our aging population. However, there has only been limited progress in developing therapeutic techniques to effectively mediate this condition. This review will outline several of the most commonly utilized practices for the treatment of sensorineural hearing loss before exploring more novel techniques currently being investigated via both in vitro and in vivo research. This review will place particular emphasis on novel gene-delivery technologies. Primarily, it will focus on techniques used to deliver genes that have been shown to encourage the proliferation and differentiation of sensory cells within the inner ear and how these technologies may be translated into providing clinically useful results for patients.

Bile acids (BAs) are steroidal molecules that play important roles in nutrient absorption, distribution, and excretion. They also act on specific receptors implicated in various metabolic and inflammatory diseases demonstrating their importance as potential drug candidates. Accordingly, there has been a concerted effort to develop new BA derivatives to probe structure-activity relationships with the goal of discovering BA analogues with enhanced pharmacological properties. Among the many steroidal derivatisations reported, the formation of endocyclic azasteroids appeals due to their potential to deliver altered biological responses with minimal change to the steroidal superstructure. Here, we report the synthesis of 3-aza-obeticholic acid (6) via a regioconvergent route. Ammoniolysis of lactones, formed from an m-CPBA-mediated Baeyer-Villiger reaction on a 3-keto-OCA derivative, furnished protected intermediate amido-alcohols which were separately elaborated to amino-alcohols via Hofmann degradation with BAIB. Upon individual N-Boc-protection, these underwent annulation to the 3-aza-A-ring when subjected to either mesylation or a Dess-Martin oxidation/hydrogenation sequence. Global deprotection of the 3-aza-intermediate delivered 3-aza-OCA in ten steps and an overall yield of up to 19%.

The gut microbiome plays pivotal roles in various physiological and pathological processes, with key metabolites including short chain fatty acids (SCFAs), bile acids (BAs), and tryptophan (TRP) derivatives gaining significant attention for their diverse physiological roles. However, quantifying these metabolites presents challenges due to structural similarity, low abundance, and inherent technical limitations in traditional detection methods. In this study, we developed a precise and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method utilizing a chemical isotope derivatization technique employing 4-(aminomethyl)-N,N-dimethylaniline-d0/d6 (4-AND-d0/d6) reagents to quantify 37 typical gut microbiome-derived metabolites. This method achieved an impressive 1500-fold enhancement in sensitivity for detecting metabolites, compared to methods using non-derivatized, intact molecules. Moreover, the quantitative accuracy of our chemical isotope derivatization strategy proved comparable to the stable isotope labeled internal standards (SIL-IS) method. Subsequently, we successfully applied this newly developed method to quantify target metabolites in plasma, brain, and fecal samples obtained from a neonatal hypoxic-ischemic encephalopathy (HIE) rat model. The aim was to identify crucial metabolites associated with the progression of HIE. Overall, our sensitive and reliable quantification method holds promise in elucidating the role of gut microbiome metabolites in the pathogenesis of various diseases.

Bile acids are crucial for lipid metabolism and their composition and metabolism differ among species. However, there have been no data on the differences in the composition and metabolism of bile acids between aquatic larvae and terrestrial adults of amphibians. This study explored the differences in composition and metabolism of bile acid between Bufo gargarizans larvae and adults. The results demonstrated that adult liver had a lower total bile acid level and a higher conjugated/total bile acid ratio than larval liver. Meanwhile, histological analysis revealed that the larvae showed a larger cross-sectional area of bile canaliculi lumen compared with the adults. The transcriptomic analysis showed that B. gargarizans larvae synthesized bile acids through both the alternative and the 24-hydroxylase pathway, while adults only synthesized bile acids through the 24-hydroxylase pathway. Moreover, bile acid regulator-related genes FXR and RXRα were highly expressed in adult, whereas genes involved in bile acid synthesis (CYP27A1 and CYP46A1) were highly expressed in larvae. The present study will provide valuable insights into understanding metabolic disorders and exploring novel bile acid-based therapeutics.

Amelioration of hypercholesterolemia is essential for the treatment of atherosclerotic cardiovascular disease. Sodium sulphate is the effective component of mirabilite, which has been used in traditional Chinese medicine for the treatment of various diseases. In the present study, C57BL/6 mice were fed with a high-cholesterol diet (HCD) for 7 weeks and were treated with sodium sulphate in the last three of those weeks. Sodium sulphate significantly reduced the total cholesterol level and the low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio in the serum of mice fed the HCD. In addition, cytochrome P450 7a1 and 39a1 were significantly upregulated in the livers of mice treated with sodium sulphate. Furthermore, tribbles pseudokinase 3 expression was significantly increased in the livers of mice fed the HCD, but was significantly reduced by sodium sulphate treatment. In terms of the insulin signaling pathway, the ratio of phosphorylated AKT to total AKT in the livers of mice fed the HCD was significantly lower compared with that of control mice fed a normal diet, but was significantly increased by sodium sulphate treatment. Sodium sulphate treatment also reduced the levels of fibroblast growth factor (FGF)15 in the ileum and inhibited the FGF15/FGF receptor 4-Klotho β/c-Jun N-terminal kinase/c-Jun signaling pathway in the livers of mice fed the HCD. In addition, sodium sulphate changed the composition of the gut microbiota of mice fed the HCD. In conclusion, sodium sulphate may mitigate hypercholesterolemia and hepatic insulin resistance in mice fed an HCD.

Previous epidemiological studies have repeatedly found per- and polyfluoroalkyl substances (PFAS) exposure associated with higher circulating cholesterol, one of the greatest risk factors for development of coronary artery disease. The main route of cholesterol catabolism is through its conversion to bile acids, which circulate between the liver and ileum via enterohepatic circulation. Patients with coronary artery disease have decreased bile acid excretion, indicating that PFAS-induced impacts on enterohepatic circulation may play a critical role in cardiovascular risk.

Using a mouse model with high levels of low-density and very low-density lipoprotein (LDL and VLDL, respectively) cholesterol and aortic lesion development similar to humans, the present study investigated mechanisms linking exposure to a PFAS mixture with increased cholesterol.

Male and female L d l r - / - mice were fed an atherogenic diet (Clinton/Cybulsky low fat, 0.15% cholesterol) and exposed to a mixture of 5 PFAS representing legacy, replacement, and emerging subtypes (i.e., PFOA, PFOS, PFHxS, PFNA, GenX), each at a concentration of 2 mg / L , for 7 wk. Blood was collected longitudinally for cholesterol measurements, and mass spectrometry was used to measure circulating and fecal bile acids. Transcriptomic analysis of ileal samples was performed via RNA sequencing.

After 7 wk of PFAS exposure, average circulating PFAS levels were measured at 21.6, 20.1, 31.2, 23.5, and 1.5 μ g / mL in PFAS-exposed females and 12.9, 9.7, 23, 14.3, and 1.7 μ g / mL in PFAS-exposed males for PFOA, PFOS, PFHxS, PFNA, and GenX, respectively. Total circulating cholesterol levels were higher in PFAS-exposed mice after 7 wk (352 mg / dL vs. 415 mg / dL in female mice and 392 mg / dL vs. 488 mg / dL in male mice exposed to vehicle or PFAS, respectively). Total circulating bile acid levels were higher in PFAS-exposed mice (2,978  pg / μ L vs. 8,496  pg / μ L in female mice and 1,960  pg / μ L vs. 4,452  pg / μ L in male mice exposed to vehicle or PFAS, respectively). In addition, total fecal bile acid levels were lower in PFAS-exposed mice (1,797  ng / mg vs. 682  ng / mg in females and 1,622  ng / mg vs. 670  ng / mg in males exposed to vehicle or PFAS, respectively). In the ileum, expression levels of the apical sodium-dependent bile acid transporter (ASBT) were higher in PFAS-exposed mice.

Mice exposed to a PFAS mixture displayed higher circulating cholesterol and bile acids perhaps due to impacts on enterohepatic circulation. This study implicates PFAS-mediated effects at the site of the ileum as a possible critical mediator of increased cardiovascular risk following PFAS exposure. https://doi.org/10.1289/EHP14339.

Bile acids (BAs) are synthesized by the host liver from cholesterol and are delivered to the intestine, where they undergo further metabolism by gut microbes and circulate between the liver and intestines through various transporters. They serve to emulsify dietary lipids and act as signaling molecules, regulating the host's metabolism and immune homeostasis through specific receptors. Therefore, disruptions in BA metabolism, transport, and signaling are closely associated with cholestasis, metabolic disorders, autoimmune diseases, and others. Botanical triterpenoids and steroids share structural similarities with BAs, and they have been found to modulate BA metabolism, transport, and signaling, potentially exerting pharmacological or toxicological effects. Here, we have updated the research progress on BA, with a particular emphasis on new-found microbial BAs. Additionally, the latest advancements in targeting BA metabolism and signaling for disease treatment are highlighted. Subsequently, the roles of botanical triterpenoids in BA metabolism, transport, and signaling are examined, analyzing their potential pharmacological, toxicological, or drug interaction effects through these mechanisms. Finally, a research paradigm is proposed that utilizes the gut microbiota as a link to interpret the role of these important natural products in BA signaling.

Iron is a vital trace element for our bodies and its imbalance can lead to various diseases. The progression of metabolic-associated fatty liver disease (MAFLD) is often accompanied by disturbances in iron metabolism. Alisma orientale extract (AOE) has been reported to alleviate MAFLD. However, research on its specific lipid metabolism targets and its potential impact on iron metabolism during the progression of MAFLD remains limited. To establish a model of MAFLD, mice were fed either a standard diet (CON) or a high-fat diet (HFD) for 9 weeks. The mice nourished on the HFD were then randomly assigned to the HF group and the HFA group, with the HFA group receiving AOE by gavage on a daily basis for 13 weeks. Supplementation with AOE remarkably reduced overabundant lipid accumulation in the liver and restored the iron content of the liver. AOE partially but significantly reversed dysregulated lipid metabolizing genes (SCD1, PPAR γ, and CD36) and iron metabolism genes (TFR1, FPN, and HAMP) induced by HFD. Chromatin immunoprecipitation assays indicated that the reduced enrichment of FXR on the promoters of SCD1 and FPN genes induced by HFD was significantly reversed by AOE. These findings suggest that AOE may alleviate HFD-induced disturbances in liver lipid and iron metabolism through FXR-mediated gene repression.