Search Results (41)

Background/Objectives: Hepatic cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are major global health concerns due to rising incidence and limited therapeutic success. While traditional risk factors include chronic liver disease and environmental exposures, recent evidence underscores the significance of genetic alterations and gut microbiota in liver cancer development and progression. This review aims to integrate emerging knowledge on the interplay between host genomic changes and gut microbial dynamics in the pathogenesis and treatment of hepatic cancers. Methods: We conducted a comprehensive review of current literature on genetic and epigenetic drivers of HCC and CCA, focusing on commonly mutated genes such as TP53, CTNNB1, TERT, IDH1/2, and FGFR2. In parallel, we evaluated studies addressing the gut–liver axis, including the roles of dysbiosis, microbial metabolites, and immune modulation. Key clinical and preclinical findings were synthesized to explore how host–microbe interactions influence tumorigenesis and therapeutic response. Results: HCC and CCA exhibit distinct but overlapping genomic landscapes marked by recurrent mutations and epigenetic reprogramming. Alterations in the gut microbiota contribute to hepatic inflammation, genomic instability, and immune evasion, potentially enhancing oncogenic signaling pathways. Furthermore, microbiota composition appears to affect responses to immune checkpoint inhibitors. Emerging therapeutic strategies such as probiotics, fecal microbiota transplantation, and precision oncology based on mutational profiling demonstrate potential for personalized interventions. Conclusions: The integration of host genomics with microbial ecology provides a promising paradigm for advancing diagnostics and therapies in liver cancer. Targeting the gut–liver axis may complement genome-informed strategies to improve outcomes for patients with HCC and CCA. Full article

Background/Objectives: High-fat-diet (HFD) consumption drives chronic liver injury via gut dysbiosis and metabolic disturban. Apple cider vinegar, rich in polyphenols and organic acids, shows potential in metabolic regulation. This study aimed to investigate whether apple cider vinegar powder (ACVP) alleviates HFD-induced liver injury by modulating the gut–liver axis. Methods: For 12 weeks, C57BL/6 J mice received daily ACVP gavage while being fed a HFD. A series of biological assessments were conducted, including systemic metabolic evaluations (body weight, serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST), and lipid/glucose levels), hepatic steatosis (hematoxylin and eosin (H&E) staining), intestinal microbiome characterization (16S rRNA gene genomic analysis), and comprehensive metabolite profiling of cecal contents (non-targeted metabolomics). Pearson correlation networks integrated multi-omics data. Results: ACVP attenuated HFD-induced weight gain by 26.3%, hepatomegaly and dyslipidemia, as well as reduced hepatic lipid vacuoles and serum ALT (48%)/AST (21.5%). ACVP restored gut microbiota diversity, enriching Muribaculaceae. Cecal metabolomics identified 38 HFD-perturbed metabolites reversed by ACVP, including indolelactate, hyocholate, and taurocholic acid. the Kyoto encyclopedia of genes and genomes (KEGG) analysis revealed ACVP-mediated recovery of linoleic acid metabolism. Correlation networks linked Akkermansia to anti-inflammatory metabolites (e.g., trans-ferulic), while Desulfobacterota correlated with pro-inflammatory oxylipins (e.g., 12,13-dihydroxy-9Z-octadecenoic acid (DHOME)). Conclusions: ACVP mitigates HFD-induced liver injury by remodeling gut microbiota, restoring microbial metabolites, and enhancing gut–liver crosstalk. 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

Background/Objectives: Xanthoceras sorbifolium oil (XSO), containing nervonic acid and unsaturated fatty acids (93%), exhibits lipid-lowering potential; yet, its mechanisms involving gut–liver crosstalk remain unclear. This study investigated XSO’s anti-hyperlipidemic effects and gut microbiota interactions. Methods: Forty-eight Sprague Dawley male rats were divided into: normal control (NC), high-fat diet (HFD), XSO prevention (XOP, 1.4 mL/kg pre-HFD), and XSO treatment (XOT, post-HFD). Serum lipids, fecal short-chain fatty acids (SCFAs), gut microbiota (16S rRNA), and lipidomics (UPLC-MS/MS) were analyzed after 12 weeks. Results: XOP significantly reduced serum total cholesterol (TC, 26.8%), triglycerides (TG, 35.9%), and low-density lipoprotein cholesterol (LDL-C, 45.9%) versus HFD (p < 0.05), while increasing high-density lipoprotein cholesterol (HDL-C, 7.98%). XOP showed enhanced hepatoprotection (AST↓ 32.6%, p < 0.01). Although XSO elevated fecal acetate (1.5-fold) and butyrate (1.3-fold), these changes lacked significance (p > 0.05). The analysis of gut microbiota showed that the pro-inflammatory Coriobacteriaceae and Erysipelibacteriaceae were reduced at the family level in the XOP group (p < 0.05). Lipidomics identified 69 differential metabolites: XSO downregulated atherogenic cholesteryl esters and triglycerides, upregulated six phosphatidylethanolamines, and modulated aberrant lysophosphatidylcholines. Conclusions: XSO alleviates hyperlipidemia through direct modulation of lipid metabolism pathways and suppression of pro-inflammatory gut microbiota. While its prebiotic potential warrants further validation, these findings highlight XSO as a functional dietary adjunct for improving lipid homeostasis and mitigating cardiovascular risks. XSO alleviates hyperlipidemia through direct modulation of lipid metabolism pathways and suppression of pro-inflammatory gut microbiota, while its prebiotic potential warrants further validation. These findings support XSO as a dietary adjunct for lipid homeostasis improvement, offering a nutritional strategy for early-stage cardiovascular risk management. Full article

Adipose tissue was previously regarded as a dormant organ for lipid storage until the identification of adiponectin and leptin in the early 1990s. This revelation unveiled the dynamic endocrine function of adipose tissue, which has expanded further. Adipose tissue has emerged in recent decades as a multifunctional organ that plays a significant role in energy metabolism and homeostasis. Currently, it is evident that adipose tissue primarily performs its function by secreting a diverse array of signaling molecules known as adipokines. Apart from their pivotal function in energy expenditure and metabolism regulation, these adipokines exert significant influence over a multitude of biological processes, including but not limited to inflammation, thermoregulation, immune response, vascular function, and insulin sensitivity. Adipokines are pivotal in regulating numerous biological processes within adipose tissue and facilitating communication between adipose tissue and various organs, including the brain, gut, pancreas, endothelial cells, liver, muscle, and more. Dysregulated adipokines have been implicated in several metabolic diseases, like obesity and diabetes, as well as cardiovascular diseases. In this article, we attempted to describe the significance of adipokines in developing metabolic and cardiovascular diseases and highlight their role in the crosstalk between adipose tissues and other tissues and organs. Full article

The intricate interplay between the gut microbiota and polyphenols has emerged as a captivating frontier in understanding and potentially harnessing the therapeutic potential of these bioactive compounds. Phenolic compounds, renowned for their antioxidant, anti-inflammatory, antidiabetic, and anticancer properties, are subject to intricate transformations within the gut milieu, where the diverse microbial ecosystem exerts profound effects on their metabolism and bioavailability. Conversely, polyphenols exhibit a remarkable capacity to modulate the composition and activity of the gut microbiota, fostering a bidirectional relationship that extends beyond mere nutrient processing. This symbiotic interaction holds significant implications for human health, particularly in cardiometabolic diseases such as diabetes mellitus, metabolic-dysfunction-associated steatotic liver disease, and cardiovascular disease. Through a comprehensive exploration of molecular interactions, this narrative review elucidates the reciprocal dynamics between the gut microbiota and polyphenols, unveiling novel avenues for therapeutic intervention in cardiometabolic disorders. By unravelling the intricate cross-talk between these two entities, this review underscores the multifaceted roles of polyphenols in overall health and the pivotal role of gut microbiota modulation as a promising therapeutic strategy in mitigating the burden of cardiometabolic diseases. Full article

Multiple organs and tissues coordinate to respond to dietary and environmental challenges. It is interorgan crosstalk that contributes to systemic metabolic homeostasis. The liver and brain, as key metabolic organs, have their unique dialogue to transmit metabolic messages. The interconnected pathogenesis of liver and brain is implicated in numerous metabolic and neurodegenerative disorders. Recent insights have positioned the liver not only as a central metabolic hub but also as an endocrine organ, capable of secreting hepatokines that transmit metabolic signals throughout the body via the bloodstream. Metabolites from the liver or gut microbiota also facilitate a complex dialogue between liver and brain. In parallel to humoral factors, the neural pathways, particularly the hypothalamic nuclei and autonomic nervous system, are pivotal in modulating the bilateral metabolic interplay between the cerebral and hepatic compartments. The term “liver–brain axis” vividly portrays this interaction. At the end of this review, we summarize cutting-edge technical advancements that have enabled the observation and manipulation of these signals, including genetic engineering, molecular tracing, and delivery technologies. These innovations are paving the way for a deeper understanding of the liver–brain axis and its role in metabolic homeostasis. Full article

Exploring the intricate crosstalk between dietary prebiotics and the specific intestinal microbiome (SIM) is intriguing in explaining the mechanisms of current successful dietary interventions, including the Mediterranean diet and high-fiber diet. This knowledge forms a robust basis for developing a new natural food therapy. The SIM diet can be measured and evaluated to establish a reliable basis for the management of metabolic diseases, such as diabetes, metabolic (dysfunction)-associated fatty liver disease (MAFLD), obesity, and metabolic cardiovascular disease. This review aims to delve into the existing body of research to shed light on the promising developments of possible dietary prebiotics in this field and explore the implications for clinical practice. The exciting part is the crosstalk of diet, microbiota, and gut–organ interactions facilitated by producing short-chain fatty acids, bile acids, and subsequent metabolite production. These metabolic-related microorganisms include Butyricicoccus, Akkermansia, and Phascolarctobacterium. The SIM diet, rather than supplementation, holds the promise of significant health consequences via the prolonged reaction with the gut microbiome. Most importantly, the literature consistently reports no adverse effects, providing a strong foundation for the safety of this dietary therapy. Full article

The functions of the gut are closely related to those of many other organs in the human body. Indeed, the gut microbiota (GM) metabolize several nutrients and compounds that, once released in the bloodstream, can reach distant organs, thus influencing the metabolic and inflammatory tone of the host. The main microbiota-derived metabolites responsible for the modulation of endocrine responses are short-chain fatty acids (SCFAs), bile acids and glucagon-like peptide 1 (GLP-1). These molecules can (i) regulate the pancreatic hormones (insulin and glucagon), (ii) increase glycogen synthesis in the liver, and (iii) boost energy expenditure, especially in skeletal muscles and brown adipose tissue. In other words, they are critical in maintaining glucose and lipid homeostasis. In GM dysbiosis, the imbalance of microbiota-related products can affect the proper endocrine and metabolic functions, including those related to the gut–liver–pancreas axis (GLPA). In addition, the dysbiosis can contribute to the onset of some diseases such as non-alcoholic steatohepatitis (NASH)/non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), and type 2 diabetes (T2D). In this review, we explored the roles of the gut microbiota-derived metabolites and their involvement in onset and progression of these diseases. In addition, we detailed the main microbiota-modulating strategies that could improve the diseases’ development by restoring the healthy balance of the GLPA. Full article

The movement of organic anionic drugs across cell membranes is partly governed by interactions with SLC and ABC transporters in the intestine, liver, kidney, blood–brain barrier, placenta, breast, and other tissues. Major transporters involved include organic anion transporters (OATs, SLC22 family), organic anion transporting polypeptides (OATPs, SLCO family), and multidrug resistance proteins (MRPs, ABCC family). However, the sets of molecular properties of drugs that are necessary for interactions with OATs (OAT1, OAT3) vs. OATPs (OATP1B1, OATP1B3) vs. MRPs (MRP2, MRP4) are not well-understood. Defining these molecular properties is necessary for a better understanding of drug and metabolite handling across the gut–liver–kidney axis, gut–brain axis, and other multi-organ axes. It is also useful for tissue targeting of small molecule drugs and predicting drug–drug interactions and drug–metabolite interactions. Here, we curated a database of drugs shown to interact with these transporters in vitro and used chemoinformatic approaches to describe their molecular properties. We then sought to define sets of molecular properties that distinguish drugs interacting with OATs, OATPs, and MRPs in binary classifications using machine learning and artificial intelligence approaches. We identified sets of key molecular properties (e.g., rotatable bond count, lipophilicity, number of ringed structures) for classifying OATs vs. MRPs and OATs vs. OATPs. However, sets of molecular properties differentiating OATP vs. MRP substrates were less evident, as drugs interacting with MRP2 and MRP4 do not form a tight group owing to differing hydrophobicity and molecular complexity for interactions with the two transporters. If the results also hold for endogenous metabolites, they may deepen our knowledge of organ crosstalk, as described in the Remote Sensing and Signaling Theory. The results also provide a molecular basis for understanding how small organic molecules differentially interact with OATs, OATPs, and MRPs. Full article

The gut microbiota is a complex system, playing a peculiar role in regulating innate and systemic immunity. Increasing evidence links dysfunctional gut microbiota to metabolic dysfunction-associated steatotic liver disease (MASLD) due to the activation of multiple pathways in the gut and in the liver, including those mediated by Toll-like receptors (TLRs), that sustain hepatic inflammation. Thus, many efforts have been made to unravel the role of microbiota-associated dysfunction in MASLD, with the final aim of finding novel strategies to improve liver steatosis and function. Moreover, recent evidence underlines the role of adipose tissue in sustaining hepatic inflammation during MASLD development. In this review, we focus on the recently discovered strategies proposed to improve the alteration of gut microbiota observed in MASLD patients, with a particular insight into those known to modulate gut microbiota-associated dysfunction and to affect the complex crosstalk between the gut, the adipose tissue, and the liver. Full article

Adipokines are essential mediators produced by adipose tissue and exert multiple biological functions. In particular, adiponectin, leptin, resistin, IL-6, MCP-1 and PAI-1 play specific roles in the crosstalk between adipose tissue and other organs involved in metabolic, immune and vascular health. During obesity, adipokine imbalance occurs and leads to a low-grade pro-inflammatory status, promoting insulin resistance-related diabetes and its vascular complications. A causal link between obesity and gut microbiota dysbiosis has been demonstrated. The deregulation of gut bacteria communities characterizing this dysbiosis influences the synthesis of bacterial substances including lipopolysaccharides and specific metabolites, generated via the degradation of dietary components, such as short-chain fatty acids, trimethylamine metabolized into trimethylamine-oxide in the liver and indole derivatives. Emerging evidence suggests that these bacterial metabolites modulate signaling pathways involved in adipokine production and action. This review summarizes the current knowledge about the molecular links between gut bacteria-derived metabolites and adipokine imbalance in obesity, and emphasizes their roles in key pathological mechanisms related to oxidative stress, inflammation, insulin resistance and vascular disorder. Given this interaction between adipokines and bacterial metabolites, the review highlights their relevance (i) as complementary clinical biomarkers to better explore the metabolic, inflammatory and vascular complications during obesity and gut microbiota dysbiosis, and (ii) as targets for new antioxidant, anti-inflammatory and prebiotic triple action strategies. Full article

Metabolism-associated fatty liver disease (MAFLD) is a multifaceted disease that involves complex interactions between various organs, including the gut and heart. It is defined by hepatic lipid accumulation and is related to metabolic dysfunction, obesity, and diabetes. Understanding the intricate interplay of the gut–liver–heart crosstalk is crucial for unraveling the complexities of MAFLD and developing effective treatment and prevention strategies. The gut–liver crosstalk participates in the regulation of the metabolic and inflammatory processes through host–microbiome interactions. Gut microbiota have been associated with the development and progression of MAFLD, and its dysbiosis contributes to insulin resistance, inflammation, and oxidative stress. Metabolites derived from the gut microbiota enter the systemic circulation and influence both the liver and heart, resulting in the gut–liver–heart axis playing an important role in MAFLD. Furthermore, growing evidence suggests that insulin resistance, endothelial dysfunction, and systemic inflammation in MAFLD may contribute to an increased risk of cardiovascular disease (CVD). Additionally, the dysregulation of lipid metabolism in MAFLD may also lead to cardiac dysfunction and heart failure. Overall, the crosstalk between the liver and heart involves a complex interplay of molecular pathways that contribute to the development of CVD in patients with MAFLD. This review emphasizes the current understanding of the gut–liver–heart crosstalk as a foundation for optimizing patient outcomes with MAFLD. Full article

Bile acids (BAs), endogenous acidic steroids synthetized from cholesterol in the liver, play a key role in the gut–liver axis physiopathology, including in hepatotoxicity, intestinal inflammatory processes, and cholesterol homeostasis. Faecal Oxo-BAs, relatively stable intermediates of oxidation/epimerization reactions of the BA hydroxyls, could be relevant to investigating the crosstalk in the liver–gut axis and the relationship between diseases and alterations in microbiota composition. A paucity of information currently exists on faecal BA profiles in dogs with and without chronic inflammatory enteropathy (CIE). Comprehensive assessment of 31 molecules among faecal BAs and related microbiota metabolites was conducted with high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Odds ratios (ORs) for associations of BAs with CIE were estimated using logistic regression. Principal component analysis was performed to find differences between the control and pathological dogs. Higher levels of primary BAs and muricholic acids, and lower levels of secondary BAs were found in pathological dogs. Higher concentrations in faecal oxo-metabolites were associated with the absence of CIE (OR < 1). This study shows a marked difference in faecal BA profiles between dogs with and without CIE. Further research will be needed to better understand the role of oxo-BAs and muricholic acids in CIE dogs. Full article

Recently the roles of gut microbiota are highly regarded in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The intestinal bacteria regulate the metabolism of bile acids depending on bile salt hydrolase (BSH), 7-dehydroxylation, hydroxysteroid dehydrogenase (HSDH), or amide conjugation reaction, thus exerting effects on NAFLD development through bile acid receptors such as farnesoid X receptor (FXR), Takeda G-protein-coupled bile acid protein 5 (TGR5), and vitamin D receptor (VDR), which modulate nutrient metabolism and insulin sensitivity via interacting with downstream molecules. Reversely, the composition of gut microbiota is also affected by the level of bile acids in turn. We summarize the mutual regulation between the specific bacteria and bile acids in NAFLD and the latest clinical research based on microbiota and bile acids, which facilitate the development of novel treatment modalities in NAFLD. Full article