Search Results (257)

Next-generation sequencing has overturned the dogma of biliary sterility, revealing low-biomass microbiota along the gut–biliary axis with metabolic and immunologic effects. This review synthesizes evidence on composition, function, and routes of colonization across benign and malignant disease. In cholelithiasis, Proteobacteria- and Firmicutes-rich consortia provide β-glucuronidase, phospholipase A₂, and bile salt hydrolase, driving bile supersaturation, nucleation, and recurrence. In primary sclerosing cholangitis, primary biliary cholangitis, and autoimmune hepatitis, intestinal dysbiosis and disturbed bile acid pools modulate pattern recognition receptors and bile acid signaling (FXR, TGR5), promote Th17 skewing, and injure cholangiocytes; bile frequently shows Enterococcus expansion linked to taurolithocholic acid. Distinct oncobiomes characterize cholangiocarcinoma subtypes; colibactin-positive Escherichia coli and intratumoral Gammaproteobacteria contribute to DNA damage and chemoresistance. In hepatocellular carcinoma, intratumoral microbial signatures correlate with tumor biology and prognosis. We critically appraise key methodological constraints—sampling route and post-sphincterotomy contamination, antibiotic prophylaxis, low biomass, and heterogeneous analytical pipelines—and outline a translational agenda: validated microbial/metabolomic biomarkers from bile, tissue, and stent biofilms; targeted modulation with selective antibiotics, engineered probiotics, fecal microbiota transplantation, and bile acid receptor modulators. Standardized protocols and spatial, multi-omic prospective studies are required to enable risk stratification and microbiota-informed therapeutics. Full article

Type 2 diabetes (T2D) is a complex metabolic disease characterized by chronic hyperglycemia due to insulin resistance and inadequate insulin secretion. Beyond the classically implicated organs, emerging evidence highlights the gut as a central player in T2D pathophysiology through its interactions with metabolic organs. The gut hosts trillions of microbes and enteroendocrine cells that influence inflammation, energy homeostasis, and hormone regulation. Disruptions in gut homeostasis (dysbiosis and increased permeability) have been linked to obesity, insulin resistance, and β-cell dysfunction, suggesting multifaceted “Gut-X axes” contribute to T2D development. We aimed to comprehensively review the evidence for gut-mediated crosstalk with the pancreas, endocrine system, liver, and kidneys in T2D. Key molecular mechanisms (incretins, bile acids, short-chain fatty acids, endotoxins, etc.) were examined to construct an integrated model of how gut-derived signals modulate metabolic and inflammatory pathways across organs. We also discuss clinical implications of targeting Gut-X axes and identify knowledge gaps and future research directions. A literature search (2015–2025) was conducted in PubMed, Scopus, and Web of Science, following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews). Over 150 high-impact publications (original research and review articles from Nature, Cell, Gut, Diabetologia, Lancet Diabetes & Endocrinology, etc.) were screened. Data on gut microbiota, enteroendocrine hormones, inflammatory mediators, and organ-specific outcomes in T2D were extracted. The GRADE framework was used informally to prioritize high-quality evidence (e.g., human trials and meta-analyses) in formulating conclusions. T2D involves perturbations in multiple Gut-X axes. This review first outlines gut homeostasis and T2D pathogenesis, then dissects each axis: (1) Gut–Pancreas Axis: how incretin hormones (GLP-1 and GIP) and microbial metabolites affect insulin/glucagon secretion and β-cell health; (2) Gut–Endocrine Axis: enteroendocrine signals (e.g., PYY and ghrelin) and neural pathways that link the gut with appetite regulation, adipose tissue, and systemic metabolism; (3) Gut–Liver Axis: the role of microbiota-modified bile acids (FXR/TGR5 pathways) and bacterial endotoxins in non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance; (4) Gut–Kidney Axis: how gut-derived toxins and nutrient handling intersect with diabetic kidney disease and how incretin-based and SGLT2 inhibitor therapies leverage gut–kidney communication. Shared mechanisms (microbial SCFAs improving insulin sensitivity, LPS driving inflammation via TLR4, and aryl hydrocarbon receptor ligands modulating immunity) are synthesized into a unified model. An integrated understanding of Gut-X axes reveals new opportunities for treating and preventing T2D. Modulating the gut microbiome and its metabolites (through diet, pharmaceuticals, or microbiota therapies) can improve glycemic control and ameliorate complications by simultaneously influencing pancreatic islet function, hepatic metabolism, and systemic inflammation. However, translating these insights into clinical practice requires addressing gaps with robust human studies. This review provides a state-of-the-art synthesis for researchers and clinicians, underlining the gut as a nexus for multi-organ metabolic regulation in T2D and a fertile target for next-generation therapies. Full article

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder specific to pregnancy, typically presenting in the third trimester. It is characterized by pruritus, elevated serum bile acids, and abnormal liver function tests. While maternal symptoms resolve postpartum, ICP poses significant risks to fetal health, including spontaneous preterm labor, meconium-stained amniotic fluid, and stillbirth. This review aims to synthesize current knowledge on the pathogenesis, diagnosis, and management and highlight emerging research and possible therapy directions in ICP. A comprehensive review of recent literature was conducted, focusing on molecular mechanisms, clinical management guidelines, fetal outcomes, and novel therapeutics under investigation. Ursodeoxycholic acid (UDCA) remains the primary pharmacologic treatment of intrahepatic cholestasis of pregnancy; however, its effect on perinatal outcomes is debated. Investigational therapies—including Volixibat, FXR agonists, 4-phenylbutyrate, and NorUDCA—are under exploration. These emerging therapies hold the potential to improve both maternal symptoms and perinatal outcomes by addressing the underlying pathophysiology of ICP more effectively than current standard treatment. Additionally, emerging biomarkers and machine-learning tools hold promise for improved diagnosis and personalized care. ICP continues to pose diagnostic and therapeutic challenges. While maternal outcomes are generally favorable, optimizing fetal safety requires timely diagnosis, stratified risk assessment, and evidence-based delivery planning. Future research should prioritize identifying predictive biomarkers, refining treatment algorithms, and assessing long-term outcomes for both mothers and offspring. Special attention should also be given to the investigation of novel therapeutic targets. Full article

The nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), and farnesoid X receptor (FXR) regulate the hepatic metabolism of androstenone, a testicular steroid that accumulates in the fat of intact male pigs and causes boar taint. This study evaluated natural product-derived compounds and conventional agonists targeting these nuclear receptors for their effects on androstenone metabolism in primary hepatocytes from slaughter-weight boars, to assess their potential as treatments for boar taint. Cells were incubated with natural products, conventional agonists, or dimethyl sulfoxide (DMSO; control), then being treated with androstenone. Culture media and cells were analyzed to assess changes in androstenone metabolism and gene expression. UGT1A6 was upregulated by treatments targeting both PXR and CAR and downregulated by FXR agonists. Additionally, PGC1α and NR2F1 were downregulated by compounds targeting PXR/CAR, while FXR and NR0B2 were upregulated and HNF4α downregulated by treatments acting on FXR. The natural products diallyl sulfide (DAS) and (Z)-guggulsterone (GUG) increased overall androstenone metabolism (DAS, GUG) and the production of Phase I androstenol metabolites (DAS), but only in hepatocyte culture replicates that responded positively to these treatments. Although gene expression was similar between positive-response and negative/non-responsive replicates following treatments, negative/non-responsive replicates for several treatments had higher basal expression of UGT2B31, UGT2A1, and SIRT1 and lower basal expression of FXR, PXR, and NR0B1 compared to positive-response replicates. These findings suggest that DAS and GUG may be promising treatments for boar taint, specifically in animals with lower basal rates of androstenone metabolism and higher expression of key nuclear receptors. Full article

Background/Objectives: This study investigates the therapeutic potential of camel milk-derived extracellular vesicles (CM-EVs) for treating colonic damage caused by high-altitude hypoxia, supporting the WHO’s “Food as Medicine” initiative. Methods: Using a 5500 m mouse model, researchers induced colonic injury and treated it with oral CM-EVs for 15 days, comparing results to whole camel milk. Results: CM-EVs outperformed whole milk, significantly improving colon health by restoring barrier integrity and reducing disease activity index (DAI) (p < 0.01). They boosted beneficial bacteria like Lactobacillus and Bifidobacterium and decreased Enterobacteriaceae (p < 0.01). Metabolic analysis showed restored bile acid balance and amino acid modulation via the FXR/NF-κB pathway, reducing TLR4/MyD88-mediated inflammation and oxidative stress (p < 0.01). Fecal microbiota transplantation in the CM-EVs group notably decreased DAI and increased colon length (p < 0.05). Conclusions: CM-EVs repair mucosal damage, balance microbiota, and regulate metabolism to combat hypoxia-induced colonic damage, suggesting their potential as nutraceuticals and altitude-adaptive foods. This showcases nanotechnology’s role in enhancing traditional dietary benefits via precision nutrition. Full article

The progression of type 2 diabetes mellitus (T2DM) is shaped by a multifaceted interplay among genetic, behavioral, and environmental factors, alongside gut dysbiosis. Cinnamon, being abundant in polyphenols and flavonoids, shows significant antioxidant effects. Studies have substantiated that cinnamon contributes to the management of glucose and lipid metabolism. However, the anti-diabetic efficacy of cinnamon is not completely understood. The objective of this research was to clarify the anti-diabetic mechanism associated with cinnamon extract through a combination of chemical profiling, network pharmacology, and in vivo investigations. The results indicated that 32 chemical ingredients, including quercetin, were identified through UPLC-Q-TOF-MS. Network pharmacology revealed that 471 targets related to 14 compounds were screened. The analysis of GO enrichment revealed that the primary pathways were notably enhanced in the metabolism of insulin and glucose. In vivo analyses showed that cinnamon could effectively alleviate hyperglycemia, insulin resistance, and lipid metabolism abnormalities via increased relative abundance of Akkermansia and Ligilactobacillus at the genus level and a decreased Firmicutes/Bacteroidetes ratio at the phylum level. Moreover, cinnamon reduced the serum levels of lipopolysaccharide (LPS) and proinflammatory cytokines (IL-6 and TNF-α) and significantly increased the colon Zonula occludens-1 (ZO-1) and occludin protein levels. It was also observed that cinnamon improved the fecal SCFA levels (acetic, propionic, butyric, valeric and caproic acid), while also modifying the bile acid (BA) profile and increasing the conjugated-to-unconjugated BA ratio. The Western blotting analysis further demonstrated that cinnamon activated intestinal FXR/FGF15 and hepatic PI3K/AKT signaling pathways. In summary, the finding confirmed that cinnamon ameliorated glucose and lipid metabolism disorders by safeguarding the intestinal barrier and modulating the gut microbiota and metabolites, thereby activating intestinal FXR/FGF15 and hepatic PI3K/AKT signaling pathways. Full article

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic condition characterized by hepatic lipid deposits, insulin resistance, and inflammation which may progress to non-alcoholic steatohepatitis (NASH) and fibrosis. Protein kinases play an important role in NAFLD development by regulating metabolic and inflammatory pathways. Mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), AMP-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K)/AKT, and mechanistic target of rapamycin (mTOR) are all involved in NAFLD and NASH progression. Emerging evidence indicates that Farnesoid X Receptor (FXR) agonists have therapeutic potential by modulating bile acid metabolism, lipid balance, and inflammatory responses. This review examines the mechanistic interplay between FXR agonists and important protein kinases in NAFLD and NASH. FXR agonists activate AMPK, which promotes fatty acid oxidation and reduces hepatic steatosis. They also regulate MAPK signaling, which reduces c-Jun NH2-terminal kinase (JNK)- and p38 MAPK-mediated inflammation. Furthermore, FXR agonists activate the PI3K/AKT pathway, enhancing insulin sensitivity and modulating mTOR signaling to reduce hepatic fibrosis. Clinical studies in NAFLD/NASH indicate that FXR agonists confer metabolic and anti-inflammatory benefits, although optimizing efficacy and minimizing adverse effects remain challenging. Future studies should focus on combination therapies targeting FXR alongside specific kinases to improve therapeutic outcomes. This review highlights the potential of FXR agonists to modulate protein kinase signaling, opening new avenues for targeted NAFLD/NASH therapy. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly NAFLD, is the most prevalent chronic liver disease worldwide. Strongly linked to obesity, type 2 diabetes, and metabolic syndrome, MASLD poses a growing health burden. Despite its high prevalence and risk of progression, no pharmacological treatment is currently approved. This narrative review provides an overview of emerging pharmacological treatments under clinical investigation, with a particular focus on agents recently evaluated in randomized clinical trials. A systematic search of the ClinicalTrials.gov database through to April 2025 was conducted to identify relevant studies. Investigational drugs were categorized by their molecular mechanisms, and data on efficacy, safety, and clinical development phases were summarized. The most extensively studied drug classes include GLP-1 receptor agonists, PPAR agonists, and FXR agonists, as well as inhibitors of ACC and DGAT. These therapies have shown promising effects on hepatic steatosis, liver enzyme levels, and metabolic markers and may be introduced into clinical practice in the near future. Full article

Background/Objectives: Gypenosides (Gps) are the main active compounds of Gynostemma and show promise in managing diabetes; nevertheless, the mechanism by which Gps exert anti-diabetic effects is still not fully understood. The aim of this study is to clarify the molecular mechanisms of Gps in ameliorating glucose dysregulation. Methods: Qualitative and quantitative analyses on the chemical components of Gps were performed, respectively. Type 2 diabetes mellitus mouse models were established, and the mice were subsequently treated with Gps at doses of 200, 100, or 50 mg/kg for 4 weeks. Biochemical markers were measured. Histopathological assessments of hepatic and colonic tissues were conducted. The compositions of the intestinal microbiota, short-chain fatty acids (SCFAs), and bile acids (BAs) in fecal samples were analyzed. Western blotting was applied to examine the activation of relevant signaling pathways. Results: Gps have potent regulatory effects on metabolic homeostasis by improving glucose and lipid profiles and alleviating hepatic tissue damage. Treatment with Gps significantly reduced serum levels of lipopolysaccharides and key pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor-α). Moreover, Gps enhanced the integrity of the gut barrier by upregulating the level of tight junction proteins (ZO-1 and occludin). Microbiota profiling revealed that Gps markedly increased microbial diversity and richness, decreased the ratio of Firmicutes/Bacteroidetes, and elevated Bacteroidia abundance from the phylum to the genus level. Targeted metabolomics further demonstrated that Gps modulated gut microbial metabolites by promoting SCFA production and reshaping BA profiles. Specifically, Gps elevated the primary-to-secondary BA ratio while reducing the 12α-hydroxylated to non-12α-hydroxylated BA ratio. Mechanistically, Western blotting demonstrated that Gps triggered the hepatic PI3K/AKT pathway and the intestinal BA/FXR/FGF15 axis, suggesting the coordinated regulation of metabolic and gut–liver axis signaling pathways. Conclusions: Gps significantly ameliorate hyperglycemia and hyperlipidemia through a multifaceted mechanism involving gut microbiota modulation, the restoration of intestinal barrier function, and the regulation of microbial metabolites such as SCFAs and BAs. These findings offer novel insights into their mechanism of action via the gut–liver axis. Full article

Metabolic dysregulation involving glucose and lipids is closely associated with chronic diseases such as type 2 diabetes mellitus. Emerging evidence highlights the regulatory role of bile acid (BA)–gut microbiota interactions in these metabolic disorders. The gut microbiota orchestrates the biotransformation of primary BAs into bioactive secondary BAs, which function as endocrine signaling molecules by activating the nuclear farnesoid X receptor (FXR) and G protein-coupled membrane receptor (TGR5), forming a communication network essential for metabolic homeostasis. BAs also reciprocally modulate gut microbiota composition. This BA–gut microbiota co-metabolism has emerged as a promising therapeutic target for lipid metabolism disorders. This comprehensive review examines the bidirectional interplay between gut microbiota and BA metabolism, focusing on microbial transformation of BAs, host–microbial co-regulatory pathways and mechanisms of BA metabolism, and the therapeutic implications of modulating the gut microbiota–BA axis in addressing glucose and lipid metabolism disorders. The synthesis of current evidence aims to elucidate the intricate crosstalk between microbial ecology and host metabolism mediated by BA signaling pathways, thereby exploring novel therapeutic intervention strategies. Full article

Elderly individuals infected with SARS-CoV-2 are at higher risk of developing cytokine storms and severe outcomes, yet specific biomarkers remain unclear. In this study, we investigated the alteration of primary bile acid metabolism in elderly patients with severe COVID-19 using untargeted metabolomics (n = 31), followed by targeted metabolomics to compare patients with disease progression (n = 16) to those without (n = 48). Significant reductions in chenodeoxycholic acid (CDCA) and glycochenodeoxycholic acid (GCDCA) levels were identified in severe cases, with GCDCA levels at admission correlating strongly with peak inflammatory markers. In vitro, CDCA, GCDCA, and their receptors, Farnesoid X Receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5), effectively inhibited the inflammatory response induced by SARS-CoV-2. NOD-like receptor pathway, activated by SARS-CoV-2, may modulate inflammatory cytokines under the treatment of CDCA, GCDCA, and TGR5. CDCA and GCDCA levels at admission predicted disease progression, suggesting their potential as biomarkers for severe COVID-19 in the elderly and highlighting their regulatory role in inflammation, pointing to new therapeutic avenues. Full article

Objective: Yinchenhao decoction (YCHD), a classical herbal formula comprising Artemisia capillaris, Gardenia jasminoides, and Rheum palmatum, has been clinically used for over 1000 years to treat cholestasis. However, its mechanism of action remains undefined. This study aimed to elucidate YCHD’s therapeutic mechanisms against cholestasis, with a focus on the gut microbiota-mediated regulation of the farnesoid X receptor (FXR)–fibroblast growth factor 15 (FGF15) pathway. Methods: An alpha-naphthyl isothiocyanate (ANIT)-induced cholestasis mouse model was established. Mice received YCHD (3/9 g/kg) for 7 days. 16S rRNA sequencing, targeted LC/MS (bile acid (BA) quantification), untargeted GC/MS (fecal metabolite detection), qPCR/Western blot (FXR pathway analysis), fecal microbiota transplantation (FMT), and antibiotic depletion were employed to dissect the gut–liver axis interactions. Results: YCHD alleviated cholestatic liver injury by reducing serum biomarkers, restoring BA homeostasis via FXR-FGF15 activation, and suppressing hepatic Cyp7a1-mediated BA synthesis. It remodeled gut microbiota, enriched FXR-activating secondary BAs (CDCA, DCA, CA), and restored the intestinal barrier integrity. Antibiotic cocktail abolished YCHD’s efficacy, while FMT from YCHD-treated mice enhanced its therapeutic effects, confirming microbiota dependency. Conclusions: YCHD mitigates cholestasis through gut microbiota-driven FXR activation and direct hepatobiliary regulation. These findings bridge traditional medicine and modern pharmacology, highlighting microbiome modulation as a therapeutic strategy for cholestatic liver diseases. Full article

Bile acids (BAs), essential for lipid metabolism and fat-soluble vitamin absorption, also act as signaling molecules that regulate immune homeostasis. This review focuses on the roles of four key BA-activated receptors, farnesoid X receptor (FXR), G protein-coupled bile acid receptor 1 (GPBAR1), liver X receptors (LXRs), and vitamin D receptor (VDR), in modulating the functions of monocytes-macrophages, and dendritic cells (DCs). The biological synthesis, transport, and metabolism of BAs were discussed and highlighted the feedback mechanisms regulating the synthesis and enterohepatic circulation of BAs. Each receptor’s role in shaping immune responses is detailed, including their function in inflammation, apoptosis, phagocytosis, and pathogen clearance. FXR and GPBAR1 activation generally exhibits anti-inflammatory effects, while LXR and VDR modulate a more nuanced interplay between immune responses and lipid homeostasis. We also explored the cross-talk between BA-activated receptors and Toll-like receptors, providing a comprehensive understanding of the complex interplay between BA signaling and innate immunity. This review culminates by highlighting the therapeutic potential of targeting these receptors for the treatment of inflammatory and autoimmune diseases. Full article

Peroxisome proliferator-activated receptor α (PPARα, encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are the two prominent nutrient-sensing nuclear receptors essential for maintaining hepatic metabolism during fasting and fed states, respectively. These nuclear receptors comprehensively regulate the transcription of numerous genes involved in fatty acid oxidation (FAO), ketogenesis, bile acid (BA) biosynthesis, and other metabolic processes critical for liver energy homeostasis. These receptors have been shown to have opposite impacts on autophagy, which is triggered by PPARα activation but inhibited by FXR activation. Recent studies have further revealed that liver-specific genetic ablation of key autophagic genes tremendously impairs the activation of these nuclear receptors, thereby profoundly affecting hepatic metabolism in both fasting and feeding states. This review explores the roles and mechanisms of PPARα and FXR in regulating liver metabolism and autophagy, highlighting the necessity of basal autophagic activity in ensuring the proper signaling of these nutrient-sensing nuclear receptors. Finally, we examine the potential therapeutic strategies that leverage the interplay between PPARα, FXR, and autophagy for the treatment of metabolic liver disorders. We also delve into the clinical implications of this complex relationship, emphasizing its significance for translational medicine and future therapeutic interventions. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a global health burden, however, therapeutic advancements remain hindered by incomplete insights on mechanisms and suboptimal clinical interventions. This review focused on the transcription factors (TFs) associated with the gut–liver axis, emphasizing their roles as molecular interpreters of systemic crosstalk in MAFLD. We delineate how TF networks integrate metabolic, immune, and gut microbial signals to manage hepatic steatosis, inflammation, and fibrosis. For instance, metabolic TFs such as peroxisome proliferator-activated receptor α (PPARα) and farnesoid X receptor (FXR) are responsible for regulating lipid oxidation and bile acid homeostasis, while immune-related TFs like signal transducer and activator of transcription 3 (STAT3) modulate inflammatory cascades involving immune cells. Emerging evidence highlights microbiota-responsive TFs, like hypoxia-inducible factor 2α (HIF2α) and aryl hydrocarbon receptor (AHR), linking microbial metabolite signaling to hepatic metabolic reprogramming. Critically, TF-centric therapeutic strategies, including selective TF-agonists, small molecules targeted to degrade TF, and microbiota modulation, hold considerable promise for treating MAFLD. By synthesizing these insights, this review underscores the necessity to dissect TF-mediated interorgan communication and proposes a roadmap for translating mechanism discoveries into precision therapies. Future research should prioritize the use of multi-omics approaches to map TF interactions and validate their clinical relevance to MAFLD. Full article