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Gut microbiota and the mammalian host share a symbiotic relationship, in which the host provides a suitable ecosystem for the gut bacteria to digest indigestible nutrients and produce useful metabolites. Although gut microbiota primarily reside in and influence the intestine, they also regulate liver function via absorption and subsequent transfer of microbial components and metabolites through the portal vein to the liver. Due to this transfer, the liver may be continuously exposed to gut‐derived metabolites and components. For example, short‐chain fatty acids (SCFA) produced by gut microbiota, through the fermentation of dietary fiber, can suppress inflammation via regulatory T cell induction through SCFA‐induced epigenetic mechanisms. Additionally, secondary bile acids (BA), such as deoxycholic acid, produced by gut bacteria through the 7α‐dehydroxylation of primary BAs, are thought to induce DNA damage and contribute to the remodeling of tumor microenvironments. Other substances that are also thought to influence liver function include lipopolysaccharides (components of the outer membrane of gram‐negative bacteria) and lipoteichoic acid (cell wall component of Gram‐positive bacteria), which are ligands of innate immune receptors, Toll‐like receptor‐4, and Toll‐like receptor‐2, respectively, through which inflammatory signaling is elicited. In this review, we focus on the role of gut microbiota in the liver microenvironment, describing the anatomy of the gut‐liver axis, the role of gut microbial metabolites, and the relationships that exist between gut microbiota and liver diseases, including liver cancer. The intestinal tract and the liver are anatomically and physiologically connected. Recently, this relationship between the intestine and the liver has been called the “gut‐liver axis.” Gut‐liver axis‐mediated transfer of increased secondary bile acid, deoxycholic acid, as well as lipoteichoic acid (LTA) under high‐fat diets‐fed conditions provoke DNA damage in HSCs, creating a tumor‐promoting microenvironment due to SASP induction.

Non‐alcoholic fatty liver disease (NAFLD) and alcohol‐associated liver disease (ALD) represent a spectrum of injury, ranging from simple steatosis to steatohepatitis and cirrhosis. In humans, in fact, fatty changes in the liver, possibly leading to end‐stage disease, were observed after chronic alcohol intake or in conditions of metabolic impairment. In this article, we examined the features and the pro‐inflammatory pathways leading to non‐alcoholic and alcoholic steatohepatitis. The involvement of several events (hits) and multiple inter‐related pathways in the pathogenesis of these diseases suggest that a single therapeutic agent is unlikely to be an effective treatment strategy. Hence, a combination treatment towards multiple pro‐inflammatory targets would eventually be required. Gut‐liver crosstalk is involved not only in the impairment of lipid and glucose homoeostasis leading to steatogenesis, but also in the initiation of inflammation and fibrogenesis in both NAFLD and ALD. Modulation of the gut‐liver axis has been suggested as a possible therapeutic approach since gut‐derived components are likely to be involved in both the onset and the progression of liver damage. This review summarizes the translational mechanisms underlying pro‐inflammatory signalling and gut‐liver axis in non‐alcoholic and alcoholic steatohepatitis. With a multitude of people being affected by liver diseases, identification of possible treatments and the elucidation of pathogenic mechanisms are elements of paramount importance.

Hepatocellular carcinoma (HCC) is among the most common and lethal cancers worldwide and is characterized by complex metabolic and immunological processes throughout its progression. Emerging research has underscored the critical involvement of the gut microbiota and its metabolites, particularly short-chain fatty acids (SCFAs), in regulating the hepatic immune microenvironment and contributing to the development of HCC. SCFAs play essential roles in the gut-liver axis by supporting immune homeostasis, modulating lipid metabolism and influencing immune escape mechanisms within the liver. SCFAs are not only products of gut microbiota metabolism but also key regulators of liver metabolism and immune responses. SCFAs play both positive and negative roles in HCC. SCFAs influence T-cell function and immune responses through the activation of G-protein-coupled receptors and the inhibition of histone deacetylases. The present review provided an overview of the current knowledge concerning the regulatory dual effects of SCFAs on the immune microenvironment of HCC, examines their interactions with immune cells via the gut-liver axis and evaluated their potential as adjuncts in HCC immunotherapy, with the goal of informing future therapeutic strategies.

LLKL, a new traditional Chinese medicine formula containing Edgeworthia gardneri (Wall.) Meisn., Sibiraea angustata and Crocus sativus L. (saffron), was designed to ameliorate type 2 diabetes mellitus. Despite the therapeutic benefits of LLKL, its underlying mechanisms remain elusive. This study evaluated the LLKL anti‐diabetic efficacy and its effect on gut microbiota to elucidate its mechanism of action in Zucker diabetic fatty rats. We found that administration of different LLKL concentrations (4.68, 2.34 and 1.17 g/kg/d) improved several diabetic parameters after a 6‐week treatment. Moreover, LLKL modulated gut microbiota dysbiosis, increased the expression of occluding and maintained intestinal epithelial homeostasis, leading to a reduction in LPS, TNF‐α and IL‐6 levels. Hepatic transcriptomic analysis showed that the Toll‐like receptor signalling pathway was markedly enriched by LLKL treatment. RT‐qPCR results validated that LLKL treatment decreased the expressions of TLR4, MyD88 and CTSK. Furthermore, a gene set enrichment analysis indicated that LLKL enhanced the insulin signalling pathway and inhibited glycerolipid metabolism and fatty acid metabolism, which were verified by the liver biochemical analysis. These findings demonstrate that LLKL ameliorates hyperglycaemia, modulates the gut microbiota and regulates the gut‐liver axis, which might contribute to its anti‐diabetic effect.

Food‐derived extracellular vesicles (FEVs) are nanoscale membrane vesicles obtained from dietary materials such as breast milk, plants and probiotics. Distinct from other EVs, FEVs can survive the harsh degrading conditions in the gastrointestinal tract and reach the intestines. This unique feature allows FEVs to be promising prebiotics in health and oral nanomedicine for gut disorders, such as inflammatory bowel disease. Interestingly, therapeutic effects of FEVs have recently also been observed in non‐gastrointestinal diseases. However, the mechanisms remain unclear or even mysterious. It is speculated that orally administered FEVs could enter the bloodstream, reach remote organs, and thus exert therapeutic effects therein. However, emerging evidence suggests that the amount of FEVs reaching organs beyond the gastrointestinal tract is marginal and may be insufficient to account for the significant therapeutic effects achieved regarding diseases involving remote organs such as the liver. Thus, we herein propose that FEVs primarily act locally in the intestine by modulating intestinal microenvironments such as barrier integrity and microbiota, thereby eliciting therapeutic impact remotely on the liver in non‐gastrointestinal diseases via the gut‐liver axis. Likewise, drugs delivered to the gastrointestinal system through FEVs may act via the gut‐liver axis. As the liver is the main metabolic hub, the intestinal microenvironment may be implicated in other metabolic diseases. In fact, many patients with non‐alcoholic fatty liver disease, obesity, diabetes and cardiovascular disease suffer from a leaky gut and dysbiosis. In this review, we provide an overview of the recent progress in FEVs and discuss their biomedical applications as therapeutic agents and drug delivery systems, highlighting the pivotal role of the gut‐liver axis in the mechanisms of action of FEVs for the treatment of gut disorders and metabolic diseases.

Olanzapine is associated with a high risk of hepatic steatosis as a commonly used atypical antipsychotic. In this study, we observed differential susceptibility to olanzapine‐induced fatty liver disease in both rats and patients. Notably, patients with olanzapine‐induced liver damage exhibited an altered gut microbiota composition, with Akkermansia muciniphila showing the most pronounced alteration. To explore its therapeutic potential, we administered A. muciniphila to olanzapine‐treated rats, which significantly reduced hepatic lipid accumulation and liver injury. Gut microbiome analysis revealed significant alterations in microbial diversity and composition following A. muciniphila treatment. Transcriptomic analysis further identified differentially expressed genes in the liver, highlighting the involvement of IGFBP2 and APOA1 in the protective effects of A. muciniphila . Functional validation demonstrated that overexpression of IGFBP2 and APOA1 alleviated olanzapine‐induced hepatic steatosis in both cellular and animal models. These findings suggest that A. muciniphila exerts hepatoprotective effects via the gut microbiota‐IGFBP2/APOA1‐liver axis, offering a potential microbiota‐targeted strategy to mitigate olanzapine‐induced metabolic dysfunction. Olanzapine induces hepatic steatosis with differential susceptibility observed in both rats and patients, while A. muciniphila alleviates liver lipid accumulation and injury by modulating gut microbiota and hepatic gene expression. Overexpression of IGFBP2 and APOA1 further protects against olanzapine‐induced hepatic steatosis.

Abstract Interorgan crosstalk refers to the bidirectional communication and interaction between different organs in the body. It plays a crucial role in maintaining metabolic homeostasis and is essential for proper physiological function. Dysregulation of organ crosstalk has been associated with the development of various metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is a growing health issue worldwide, affecting approximately 30% of the global population. There has been a growth in literature to address the dysregulated crosstalk between multiple extrahepatic organs and the liver; thus, many striking findings have been published. However, the underlying mechanisms remain largely obscure. In this study, we focused on the perspective of circulating proteins, metabolites, neuroendocrine signals, and extracellular vesicles, summarizing systematically how they affect extrahepatic organs and the liver in the pathogenesis of MASLD. Furthermore, particular attention is placed on the potential novel therapeutic strategies.

Background and Aims Dietary patterns and associated gut microbiota are increasingly recognized as key contributors to the development and prevention of colon polyps (CP). This study aimed to investigate whether specific dietary components and gut microbiome alterations are associated with CP incidence and severity, and to compare these patterns with other gastrointestinal or hepatic conditions. Methods Stool samples were collected from individuals with CP, healthy controls, and patients with alcoholic fatty liver disease (AFLD), metabolic‐associated fatty liver disease (MAFLD), and ulcerative colitis (UC). Gut microbiome profiling was conducted to characterize microbial composition across groups. Dietary intake data were analyzed, with a focus on nutrient profiles and potential food contaminants. CP patients were further divided into subgroups based on polyp number (single vs. multiple) for dietary pattern comparison. Results Distinct microbiota profiles were observed among groups: Bacteroidetes dominated in CP patients, Actinobacteria in AFLD, Proteobacteria in MAFLD, and Firmicutes in UC. CP‐associated microbiota were enriched in Prevotellaceae and Paraprevotellaceae. Dietary patterns linked to CP included high‐fat, ketogenic, and high‐sugar diets, as well as possible exposure to food contaminants. Patients with multiple polyps exhibited higher intake of calories, fat, and red meat, while those with single polyps consumed diets lower in calories and fat but richer in vitamins E and K. Conclusion Food intake is strongly associated with both the incidence and severity of colon polyps, likely through modulation of the gut microbiome and nutritional environment. These findings support the potential for dietary interventions targeting gut microbial composition to prevent or mitigate CP development.

T‐2 toxin, a mycotoxin that frequently causes hidden contamination in food and animal feed, poses a substantial threat to both human and animal health. Staphylococcus saprophyticus (S. saprophyticus) is an opportunistic pathogen that widely infects humans and various animals. However, the specific conditions under which it becomes pathogenic, as well as the mechanisms underlying its pathogenicity remain unknown. In this study, it is found that a sub‐cytotoxic dose of T‐2 toxin in piglet and mouse models promotes the proliferation of intestinal S. saprophyticus and facilitates its translocation to the liver. Subsequent mechanistic investigations reveal that the translocated bacterium activates the nucleotide‐binding oligomerization domain 2 (NOD2)‐microtubule‐associated protein 1 light chain 3 and NOD2‐C‐C motif chemokine ligand 2 signaling pathways in Kupffer cells (KCs), thereby provoking autophagy in KCs and recruiting monocytes to the liver, alongside the M1 polarization of hepatic macrophages. Furthermore, modulation of the intestinal microbiota by xylo‐oligosaccharides, as opposed to antibacterial agents, effectively mitigates the disruption of hepatic macrophage homeostasis. This work shows, for the first time, the pivotal role of S. saprophyticus in mycotoxin‐induced impairment of liver immune function. It reveals the interaction between opportunistic pathogens, environmental toxins, and immune homeostasis. T‐2 toxin promotes the proliferation of intestinal S. saprophyticus and facilitates its translocation to the liver in piglets and mice. The translocated bacteria trigger autophagy in Kupffer cells and recruit monocytes to the liver through the nucleotide‐binding oligomerization domain 2 (NOD2) signaling pathway, alongside the M1 polarization of hepatic macrophages. Ultimately, this disrupts the immune homeostasis of the liver.

Background and Objective The global incidence of liver diseases is on the rise, and targeting gut microbiota has become a new strategy for treating liver diseases. This study provides a comprehensive and objective analysis of the potential protective role of gut microbiota in liver disease, highlighting the need for continued research in this area. Methods After literature screening, 24 related articles were included in the study. After article quality and risk of bias assessment, data extraction and data collation were carried out, and then comprehensive analysis was carried out using stata12.0 software. Results From the perspective of microbial community, most of the microbial communities at the phylum level are risk factors; from the perspective of the top ten families, the intestinal microbial communities play an obvious harmful role in Primary Biliary Cholangitis.From the perspective of disease, the microbial communities at the genus level mostly have protective effects on Chronic Hepatitis B ,Fatty Liver;and Primary Liver Cancer. Conclusion Gut microbiota plays a significant role in the occurrence of liver diseases, and different bacterial levels play different roles in the disease.