Excessive intake of dietary fats is strongly associated with an increased risk of various chronic diseases, such as obesity, diabetes, hepatic metabolic disorders, cardiovascular disease, chronic intestinal inflammation, and certain cancers. A significant portion of the adverse effects of high-fat diet on disease risk is mediated through modifications in the gut microbiota. Specifically, high-fat diets are linked to reduced microbial diversity, an overgrowth of gram-negative bacteria, an elevated Firmicutes-to-Bacteroidetes ratio, and alterations at various taxonomic levels. These microbial alterations influence the intestinal metabolism of small molecules, which subsequently increases intestinal permeability, exacerbates inflammatory responses, disrupts metabolic functions, and impairs signal transduction pathways in the host. Consequently, diet-induced changes in the gut microbiota play a crucial role in the initiation and progression of chronic diseases. This review explores the relationship between high-fat diets and gut microbiota, highlighting their roles and underlying mechanisms in the development of chronic metabolic diseases. Additionally, we propose probiotic interventions may serve as a promising adjunctive therapy to counteract the negative effects of high-fat diet-induced alterations in gut microbiota composition.

Childhood obesity is a considerable public health issue. Recent research has shown that alterations in gut microbiota can have an impact on developing obesity and other metabolic health problems in children. This study aimed to investigate whether the characteristics of gut microbiota in obese children and adolescents are associated with the severity of obesity and any metabolic complications.

During May 2022 to May 2023, a total of 56 children and adolescents with obesity, aged 6-18 years, were recruited at Thammasat Hospital, situated in provincial Pathumthani in central Thailand. Participants were allocated into two groups, characterized by the severity of their obesity. Demographic data, body composition, along with resting energy expenditures were determined. Serum samples were collected for the metabolic profile and inflammatory markers. Fecal samples were obtained for gut microbiota analysis via 16S rRNA Illumina. The obese group exhibited notably greater relative abundance of Actinobacteriota in comparison to the severely obese group, along with a lower abundance of Bacteroidota. There were no statistically significant differences in the relative abundance of Firmicutes and the Firmicutes to Bacteroidota ratio between the two cohorts. Bacteroidota positively correlated with FMI, while Actinobacteriota showed a negative correlation with FMI.

The data gathered from this study illustrated that children and adolescents with obesity and severe obesity in Thailand showed differences in the relative abundance of Actinobacteriota and Bacteroidota. Certain microbiome taxa showed correlations with various body and metabolic parameters.

Emerging science supports the role of lipid metabolism disorders in the occurrence and development of chronic diseases. Dietary intervention has been shown to be an effective strategy for regulating lipid metabolism. Recent studies showed that perilla is rich in various effective ingredients, including fatty acids, flavonoids, and phenolic acids. These ingredients exhibit a myriad of benefits, notably enhancing intestinal health and helping to manage metabolic diseases. Perilla oil stands out as a promising agent for regulating lipid metabolism, underscoring its potential for various health applications. This review introduces the active ingredients in perilla and provides a systematic overview of the mechanism by which perilla oil regulates lipid metabolism to expand its application value. Further research should focus on exploring the dose effect and absorption efficiency of perilla oil in clinical applications.

Recent studies suggest an association between the expansion of Prevotella copri and the disease severity in children with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to investigate the causative role and molecular mechanisms of P. copri in pediatric MASLD.

C57BL/6 J mice aged 3 weeks were fed a high-fat diet (HFD) and orally administered with P. copri for 5 weeks. We assessed the key features of MASLD and the gut microbiota profile. By untargeted metabolomics on mouse fecal samples and the supernatant from P. copri culture, we identified P. copri-derived metabolite and tested its effects in vitro.

In HFD-fed mice, administration of P. copri significantly promoted liver steatosis. Genes associated with inflammation and fibrosis were significantly upregulated in the livers from the HFD + P. copri group compared with those in the livers from the HFD group. In addition, P. copri reduced gut microbial diversity, increased the proportion of Firmicutes and decreased Bacteroidota. Importantly, 5-aminopentanoic acid (5-AVA) was significantly enriched in both mouse feces from the HFD + P. copri group and the culture supernatant of P. copri. In vitro, 5-AVA aggravated palmitic acid-induced lipid accumulation in HepG2 cells and primary mouse hepatocytes. Mechanistically, P. copri-produced 5-AVA exacerbated hepatic steatosis by promoting lipogenesis and fatty acid uptake, while also reducing hepatic very-low-density lipoprotein export.

Our findings demonstrated that P. copri promotes liver steatosis in HFD-fed juvenile mice through its metabolite 5-AVA, suggesting its potential as a therapeutic target for the management of pediatric MASLD.

A number of rodent studies have investigated the effects of alcohol (ethanol) administration on the catecholaminergic neurotransmitters, norepinephrine (NE) and dopamine (DA). These studies suggest that presentation of alcohol to mice or rats can alter brain levels of NE and DA, in various subregions. Other studies have presented the hypothesis that there may be an unidentified pathway in rodents, and other organisms, that actually transforms ethanol to NE or DA. Here, this paper investigates the hypothesis in male CD-1 mice.

Experimental mice were systemically injected with an intoxicating dose of stable isotope-labeled carbon 13 (C13) ethanol (ethanol-1-13C, 20% v/v, 1.5 g/kg, ip), and brain samples (hippocampus and brainstem) were collected two hours post-injection. Two other groups of mice received normal unlabeled carbon 12 (C12) ethanol or a water (Control) injection, respectively.

Although we had difficulty detecting the two neurotransmitters (especially C13 NE) due to their very low concentrations, high-resolution mass spectrometry analysis suggests that C12 ethanol selectively boosted hippocampal C12 NE, and C13 ethanol likewise boosted hippocampal C13 NE. We did not observe effects on DA.

These data provide preliminary information on whether there is a novel biosynthetic pathway in mice that converts alcohol to catecholamines in select brain regions, where the ethanol molecule would presumably help form the ethanolamine side chain of NE. There are, however, alternative interpretations of these findings, including that acute alcohol administration modulates catecholamine release, reuptake, metabolism, or canonical biosynthesis.

Schisandra chinensis is used as a traditional Chinese medicine to treat a variety of diseases. Schisandra chinensis lignans (SCL) are one of the most active components extracted from Schisandrae chinensis fructus, exhibit a broad array of pharmacological properties, especially anti-inflammatory and hepatic lipid-lowering effects, suggesting SCL may have potential anti-nonalcoholic steatohepatitis (NASH) ability. However, the therapeutic efficacy of SCL against NASH and the underlying mechanism of this action remains unclear.

In the current study, we aimed to investigate the anti-NASH action of SCL and explore the underlying mechanism in vitro and in vivo. We also assess the involvement of the gut-liver axis in the anti-NASH effects of SCL.

Palmitic acid (PA)-treated HepG2 cells, mouse primary hepatocytes (MPHs) and methionine-choline deficient (MCD) diet-fed mice were selected as NASH models. ORO staining and qRT-PCR were performed to assess hepatic steatosis and inflammatory responses, respectively. Masson's trichrome staining was used to detect the liver fibrosis. Protein expression was detected by Western blotting or immunohistochemistry. The changes of gut microbiota were analyzed using 16S rDNA sequencing in mice. The levels of metabolites in liver and feces were measured by metabolomics.

The results showed that SCL treatment alleviated steatosis and inflammation in palmitic acid (PA)-treated HepG2 cells and mouse primary hepatocytes (MPHs). SCL treatment suppressed the phosphorylation of key components involved in NF-κB signaling and enhanced the expression of fatty acid oxidation (FAO)-related enzymes (e.g. CPT1, HMGCS2, and ACOX1) in PA-treated HepG2 cells. SCL could ameliorate hepatic steatosis and inflammation in NASH mice. SCL also ameliorated intestinal barrier injury and restructured the gut microbiota in NASH mice. SCL also modulated hepatic and colonic bile acid metabolism via FXR signaling.

These findings indicate that SCL treatment ameliorates hepatic inflammation and steatosis in NASH mice, potentially though to the suppression of NF-κB signaling and the promotion of fatty acid β-oxidation. Moreover, SCL could restore gut microbiota-mediated bile acid homeostasis via activation of FXR/FGF15 signaling. Our study presents a pharmacological rationale for using SCL in the management of NASH.

The transition from breastmilk to complementary foods is critical for maturing the colonic microbiota of infants. Dietary choices at weaning can lead to long-lasting microbial changes, potentially influencing health later in life. However, the weaning phase remains underexplored in colonic microbiome research, and the current understanding of how complementary foods impact the infant's colonic microbiota is limited. To address this knowledge gap, this study assessed the influence of 13 food ingredients on the in vitro microbial composition and production of organic acids by the faecal microbiota in New Zealand infants aged 5 to 11 months. To better represent real feeding practices, ingredients were combined with infant formula, other complementary foods, or both infant formula and other foods. Among the individual food ingredients, fermentation with peeled kūmara (sweet potato) increased the production of lactate and the relative abundance of the genus Enterococcus. Fermentation with blackcurrants, strawberries, or raspberries enhanced acetate and propionate production. Additionally, fermentation with blackcurrants increased the relative abundance of the genus Parabacteroides, while raspberry fermentation increased the relative abundance of the genera Parabacteroides and Eubacterium. When combined with infant formula or with blackcurrants, fermenting black beans increased butyrate production and stimulated the relative abundance of Clostridium sensu stricto 1. These foods are promising candidates for future clinical trials.

Gut microbiota has a crucial role in the pathophysiology of metabolic-associated steatotic liver disease (MASLD), influencing various metabolic mechanisms and contributing to the development of the disease. Dietary interventions targeting gut microbiota have shown potential in modulating microbial composition and mitigating MASLD progression. In this context, the integration of multi-omics analysis and artificial intelligence (AI) in personalized nutrition offers new opportunities for tailoring dietary strategies based on individual microbiome profiles and metabolic responses. The use of chatbots and other AI-based health solutions offers a unique opportunity to democratize access to health interventions due to their low cost, accessibility, and scalability. Future research should focus on the clinical validation of AI-powered dietary strategies, integrating microbiome-based therapies and precision nutrition approaches. Establishing standardized protocols and ethical guidelines will be crucial for implementing AI in MASLD management, paving the way for a more personalized, data-driven approach to disease prevention and treatment.

The mechanistic role of gut microbiota in metabolic dysfunction-associated steatotic liver disease (MASLD) and chronic kidney disease (CKD) is increasingly recognized. Despite their close association, comparative data regarding gut dysbiosis in these disorders are limited. This study included 22 healthy controls and 180 patients (90 MASLD, 60 CKD, and 30 both diseases with sex- and age-matched). Fecal bacterial 16 S ribosomal RNA sequencing and butyryl-CoA: acetate CoA transferase (BCoAT) gene expression were analyzed. Plasma intestinal fatty acid binding protein (I-FABP), representing intestinal barrier dysfunction, was assessed using the ELISA method. Our data showed that alpha and beta diversities of gut microbiota differed between MASLD and healthy controls. However, only beta diversities were different between CKD and healthy individuals. The MASLD and CKD groups displayed fewer SCFA-producing genera, particularly Bifidobacterium, than healthy controls. Fecal BCoAT levels were inversely correlated with eGFR and I-FABP levels. Patients with CKD had significantly enriched pathogenic bacteria, reduced BCoAT, and increased I-FABP levels versus MASLD. Combining significant bacterial genera discriminated MASLD from CKD with high diagnostic accuracy (AUC of 0.90). Among patients with both diseases, gut microbial alterations showed mixed characteristics of MASLD and CKD. These data highlighted the shared and distinct gut dysbiosis and related biomarkers, which could provide a better understanding of MASLD and CKD pathogenesis.

Exposure to chemical pollutants and their effects on the gut microbiome during early life are scarce, especially the effects of mixed exposures. Plasma pollutants levels were measured using gas chromatography -triple quadrupole mass spectrometer (GC-MS/MS) among 304 infants in the neonatal ward at Hunan Children's hospital, China, and gut microbiota was derived from 16S rRNA sequencing. We assessed exposure and alpha diversity using generalized linear models, and variation in beta diversity (Bray-Curtis), taxa abundance (MaAsLin2), and employed Bayesian kernel machine regression (BKMR) to investigate the association of pollutants mixture with alpha diversity and taxa. PBDE-99 was positively associated with the Chao1 index (β = 4.29, 95%CI:1.54,7.03). Exposure to the pesticides trifluralin, γ-BHC, and methidathion significantly affected beta diversity (all PFDR < 0.05). PBDE-100, β-BHC, phosalone, methiamitron, fenpropathrin, δ-BHC, and o,p'-DDT were associated with changes in taxa abundance, including negative associations [e.g., Staphylococcus, Bacteroides, Bifidobacterium, and Corynebacterium] and positive associations [e.g., Acinetobacter and Pseudomonas]. An interaction between o,p'-DDT and δ-BHC on Pseudomonas was also found in BKMR models. Our findings suggest that chemical pollutants are associated with gut microbiome changes in hospitalized infants, providing new insights into the mechanisms of chemical pollutants toxicity. Further validation is necessary to confirm these associations and explore their long-term health effects.

The microbiota in humans consists of trillions of microorganisms that are involved in the regulation of the gastrointestinal tract and immune and metabolic homeostasis. The gut microbiota (GM) has a prominent impact on the pathogenesis of metabolic syndrome (MetS). This process is reciprocal, constituting a crosstalk process between the GM and MetS. In this review, GM directly or indirectly inducing MetS via the host-microbial metabolic axis has been systematically reviewed. Additionally, the specifically altered GM in MetS are detailed in this review. Moreover, short-chain fatty acids (SCFAs), as unique gut microbial metabolites, have a remarkable effect on MetS, and the role of SCFAs in MetS-related diseases is highlighted to supplement the gaps in this area. Finally, the existing therapeutics are outlined, and the superiority and shortcomings of different therapeutic approaches are discussed, in hopes that this review can contribute to the development of potential treatment strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as the leading cause of chronic liver disease worldwide, reflecting the global epidemics of obesity, metabolic syndrome, and type 2 diabetes. Beyond its strong association with excess adiposity, MASLD encompasses a heterogeneous population that includes individuals with normal body weight ("lean MASLD") highlighting the complexity of its pathogenesis. This disease results from a complex interplay between genetic susceptibility, epigenetic modifications, and environmental factors, which converge to disrupt metabolic homeostasis. Adipose tissue dysfunction and insulin resistance trigger an overflow of lipids to the liver, leading to mitochondrial dysfunction, oxidative stress, and hepatocellular injury. These processes promote hepatic inflammation and fibrogenesis, driven by cross talk among hepatocytes, immune cells, and hepatic stellate cells, with key contributions from gut-liver axis perturbations. Recent advances have unraveled pivotal molecular pathways, such as transforming growth factor-β signaling, Notch-induced osteopontin, and sphingosine kinase 1-mediated responses, that orchestrate fibrogenic activation. Understanding these interconnected mechanisms is crucial for developing targeted therapies. This review integrates current knowledge on the pathophysiology of MASLD, emphasizing emerging concepts such as lean metabolic dysfunction-associated steatohepatitis (MASH), epigenetic alterations, hepatic extracellular vesicles, and the relevance of extrahepatic signals. It also discusses novel therapeutic strategies under investigation, aiming to provide a comprehensive and structured overview of the evolving MASLD landscape for both basic scientists and clinicians.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a series of obesity-related metabolic liver diseases, ranging from relatively benign hepatic steatosis to metabolic-associated steatohepatitis (MASH). With the changes in lifestyle, its incidence and prevalence have risen to epidemic proportions globally. In recent years, an increasing amount of evidence has indicated that the hepatic microenvironment is involved in the pathophysiological processes of MASH-induced liver fibrosis and the formation of hepatocellular carcinoma (HCC). The hepatic microenvironment is composed of various parenchymal and non-parenchymal cells, which communicate with each other through various factors. In this review, we focus on the changes in hepatocytes, cholangiocytes, liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), Kupffer cells (KC), dendritic cells (DC), neutrophils, monocytes, T and B lymphocytes, natural killer cells (NK), natural killer T cells (NKT), mucosal-associated invariant T cells (MAIT), γδT cells, and gut microbiota during the progression of MASLD. Furthermore, we discuss promising therapeutic strategies targeting the microenvironment of MASLD-MASH-HCC.

Background/Objectives: Childhood obesity is a growing global concern linked to metabolic disorders such as nonalcoholic fatty liver disease (NAFLD). Small intestinal bacterial overgrowth (SIBO) may exacerbate these conditions by promoting systemic inflammation and metabolic dysfunction. This review evaluates the prevalence of SIBO in obese children, its association with inflammatory and metabolic markers, and the efficacy of diagnostic and therapeutic strategies. Methods: A systematic search of PubMed, Scopus, and Web of Science (2010-present) was conducted using Boolean operators: ('small intestinal bacterial overgrowth' OR 'SIBO') AND 'prevalence' AND ('low-grade inflammatory markers' OR 'metabolic status') AND 'gut microbiome' AND 'dysbiosis' AND 'obese children'. Results: The data show that SIBO is frequently observed in obese pediatric populations and is associated with gut dysbiosis, impaired nutrient absorption, and reduced production of short-chain fatty acids. These changes contribute to increased intestinal permeability, endotoxemia, and chronic low-grade inflammation. Several microbial taxa have been proposed as biomarkers and therapeutic targets. Diagnostic inconsistencies persist, but treatments such as probiotics, prebiotics, dietary interventions, and selective antibiotics show potential, pending further validation. Conclusions: Early identification and treatment of SIBO with tailored strategies may help reduce metabolic complications and improve outcomes in children with obesity.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex metabolic disorder characterized by hepatic lipid accumulation and subsequent inflammation. This condition is closely linked to metabolic syndrome and obesity, with its prevalence rising due to sedentary lifestyles and high-calorie diets. The pathogenesis of MAFLD involves multiple factors, including insulin resistance, lipotoxicity, oxidative stress, and inflammatory responses. The gut microbiota plays a crucial role in MAFLD development, with dysbiosis contributing to liver inflammation through various mechanisms, such as enhanced intestinal permeability and the translocation of bacterial products like lipopolysaccharide (LPS). Microbial metabolites, including short-chain fatty acids (SCFAs) and bile acids, influence hepatic function and immune responses, with potential implications for disease progression. Specific gut microbiome signatures have been identified in MAFLD patients, offering potential diagnostic and therapeutic targets. Moreover, gut-derived toxins, such as endotoxins, lipopolysaccharides, trimethylamine-N-oxide and bacterial metabolites, significantly influence liver damage and inflammation, highlighting the complex interplay between the gut microbiome and hepatic health. This review comprehensively examines the complex interplay between the gut microbiota and MAFLD, focusing on underlying pathogenic mechanisms, potential biomarkers, and emerging microbiome-targeted therapeutic strategies for disease management.

The development and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) in children are closely related to alterations of gut microbiota. This study aims to investigate changes in the gut microbiota signature and microbial metabolites in children with MASLD. We collected fecal samples from children and adolescents aged 6-16 years, and the presence of MASLD was diagnosed by ultrasound. We performed 16S ribosomal DNA sequencing and targeted metabolomics in 36 and 25 subjects, consisting of healthy controls, children with obesity, and children with MASLD. The α-diversity was significantly lower in children with obesity and MASLD compared with healthy controls. Linear discriminant analysis of effect size analysis identified Anaerostipes and A. hadrus as the top biomarkers differentiating the obesity group from the MASLD group. In MASLD patients with high alanine aminotransferase values (≥50 U/L for boys and 44 U/L for girls), we observed a decrease in the gut microbiota health index. MASLD patients with high shear wave elastography (E) values (≥6.2 kPa) showed an increased abundance of Ruminococcus torques, which was positively correlated with the levels of deoxycholic acid (DCA) and E values. Importantly, the mediation analysis identified positive associations between R. torques and clinical indicators of MASLD that were mediated by DCA. Overall, our study suggests that gut microbiota and metabolites are significantly altered in children with MASLD, and targeting R. torques may offer potential benefits for disease management.IMPORTANCEThis study investigated alterations in the gut microbiota signature and microbial metabolites in children with metabolic dysfunction-associated steatotic liver disease (MASLD). We found that an increased abundance of Ruminococcus torques was associated with increased levels of deoxycholic acid and the progression of MASLD, suggesting that R. torques may serve as a novel clinical target in pediatric MASLD.

The incidence of acute liver injury is increasing and poses a significant threat to human health. Ganoderma lucidum spore oil (GLSO), a lipid substance extracted from Ganoderma lucidum spore powder using supercritical CO2 technology, has been investigated for its potential to prevent acute liver injury. However, the specific mechanism underlying the protective effects of GLSO remains incompletely understood. In this study, we investigated the preventive effect of GLSO on acute liver injury in rats, focusing on the gut microbiome and serum metabolomics. GLSO effectively alleviated liver dysfunction and reduced inflammation, leading to the prevention of acute liver injury in rats. Serum metabolomics analysis revealed that GLSO primarily modulated lipid metabolic pathways related to glycerophospholipid metabolism and sphingolipid metabolism. Specifically, GLSO decreased the levels of metabolites such as lysophosphatidylcholine (LPC), glycerophosphatidylcholine (GPC), and sphinganine 1-phosphate (SA1P), while increasing the levels of phosphatidylglycerol (PG) and digalactosylceramide (DGC). Gut microbiomics data indicated that GLSO effectively regulated the composition of the gut microbiota in rats with acute liver injury. Specifically, it increased the abundance of Firmicutes and decreased the abundance of Proteobacteria. Mantel test correlation analysis revealed a close relationship between gut microbial Burkholderiales and lipid metabolites in GLSO-mediated prevention of acute liver injury. GLSO exerts its preventive effects on acute liver injury by remodeling the gut microbiota and regulating lipid metabolism. These findings provide novel insights and potential directions for the development of new drugs targeting acute liver injury.

Mycotoxins perturb the gut microbiota performance. Bioactive compounds have been recently used as a new food strategy to diminish mycotoxins bioaccessibility and prevent their toxic effects on human and animal health. Male and female Wistar rats were exposed orally to twelve different diets containing aflatoxin B1 (AFB1) and/or ochratoxin A (OTA) with or without fermented whey (FW) and pumpkin (P) for 28 days. Fecal microbiota using 16S rRNA gene sequencing and subsequent metagenomics analysis were analyzed to study the effect of 28-day exposure through diet of contaminated and enriched feed. QIIME 2 microbiome analysis package (version 2024.5) was used to analyze the demultiplexed data. Mycotoxins-functional ingredients combination contributed more to microbial phylogenetic faith α-diversity rather than the functional ingredients alone, while the same combination reported a microbial α-diversity enhancement in comparison to the mycotoxins alone. Proteobacteria phylum was reduced in rat samples fed with contaminated diets (AFB1, OTA, and AFB1+OTA), while there was an increase-although not in all groups-when adding the functional ingredients. The main difference between the sexes was found in FW+AFB1+OTA group, with males (25%) showing higher % of Proteobacteria than females (1.86%). Phylogenetic diversity faith only focuses on microbial genetic (dis)similarity, not considering the biological function. Morganella morganii, a Proteobacteria found in some groups presents anticancer activity, but it is also related to inflammatory bowel disease and colorectal cancer. To sum up, both mycotoxins and functional ingredients trigger changes in the microbiota profile of Wistar rats in a sex-specific manner.

Hepatocellular carcinoma (HCC) is closely linked to alterations in the gut microbiota. This dysbiosis is characterized by significant changes in the microbial population, which correlate with the progression of HCC. Gut dysbiosis ultimately promotes HCC development in several ways: it damages the integrity of the gut-vascular barrier (GVB), alters the tumor microenvironment (TME), and even affects the intratumoral microbiota. Subsequently, intratumoral microbiota present a characteristic profile and play an essential role in HCC progression mainly by causing DNA damage, mediating tumor-related signaling pathways, altering the TME, promoting HCC metastasis, or through other mechanisms. Both gut microbiota and intratumoral microbiota have dual effects on HCC progression; a comprehensive understanding of their complex biological roles will provide a theoretical foundation for potential clinical applications in HCC treatment.

Background and Aims: Chronic kidney disease (CKD) is a recognized extra-hepatic disease of nonalcoholic fatty liver disease (NAFLD). With the redefinition of NAFLD as metabolic dysfunction-associated steatotic liver disease (MASLD), the importance of cardiovascular metabolic factors in MASLD has been highlighted. However, whether MASLD remains independently associated with the prevalence of CKD is yet to be determined. Method: We analyzed data from 6567 non-pregnant adults from the National Health and Nutrition Examination Survey 2017-2020. MASLD was identified using liver ultrasound transient elastography and five cardiovascular risk factors. Multivariate logistic regression, subgroup analysis, and restricted cubic splines were employed to explore the associations and interactions within the data. Results: The prevalence of CKD across MASLD subgroups with different combinations of cardiometabolic risk factors varied. Univariate regression analysis indicated a significant association between MASLD and CKD (OR: 1.68, p < 0.001). This association was not significant after adjusting for diabetes (OR: 0.94, p = 0.74) or insulin resistance (OR: 1.00, p = 0.98) and was not significant in the fully adjusted model (OR: 0.87, p = 0.64). Subgroup analysis confirmed insulin resistance as a modifier in the MASLD-CKD relationship (p for interaction = 0.02). Multivariate analysis revealed that liver stiffness measurements (LSMs) were independently associated with CKD. LSM values showed an S-shaped correlation with CKD, with risk increasing above the 8.612 kPa threshold. Conclusions: This study suggests that the direct relationship between MASLD and CKD diminished when accounting for insulin resistance. Nevertheless, liver fibrosis emerges as an independent CKD risk factor, emphasizing the critical need for targeted CKD screening among MASLD patients, particularly those with insulin resistance or advanced fibrosis.

Endogenous ethanol production, or auto-brewery syndrome (ABS), is a rare condition of the human alimentary canal that results in intoxication without alcohol consumption. Despite its clinical significance, ABS remains largely undiagnosed because of a lack of awareness among clinicians. Published cases have reported extensive biopsychosocial comorbidities accompanying delayed diagnosis and incomplete management; these include social rejection and family separation, court-ordered alcohol rehabilitation and psychiatric admission, legal and employment ramifications, and deteriorating mental health and suicidality. In this mini review, we aim to educate and enlighten clinicians by discussing literature findings pertaining to the pathophysiological mechanisms of gut dysbiosis due to overgrowth of Saccharomyces cerevisiae, E. coli and Klebsiella, impaired intestinal barrier function, and dysregulation of the hypothalamic-pituitary-adrenal axis. Furthermore, we discuss recently discovered associations with sleep quality and mood disorders and explore the medical sequelae of metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatohepatitis. Drawing on these data, we propose protocols for initial care in the emergency room, subsequent critical care, diagnostic testing with glucose challenge testing, and definitive microbiological testing during the acute phase of illness. We also present an empirical treatment outline while awaiting confirmation of causative organisms and sensitivities.

Given the increasing prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and non-alcoholic steatohepatitis (NASH), there is a critical need for accurate non-invasive early diagnostic markers.

This study aimed to validate NLRP3-related RNA signatures (EP300, CPN60, and ITGB1 mRNAs, miR-6881-5p, and LncRNA-RABGAP1L-DT-206) using an integrated molecular approach and advanced machine-learning algorithms to identify robust biomarkers for early diagnosis of NASH.

A cohort of 237 participants (117 Healthy controls, 60 MAFLD, 120 NASH) was utilized. Twenty-five demographic, clinical, and molecular features were collected from each participant. Various machine learning models were trained on the dataset.

The Random Forest algorithm emerged as the most effective classifier. The model identified nine key features: EP300 mRNA, CPN60 mRNA, AST, D. bilirubin, Albumin, GGT, HbA1c, HOMA-IR, and BMI, achieving an impressive 97 % accuracy in distinguishing NASH from non-NASH cases.

The integration of molecular, clinical, and demographic data with machine learning algorithms provides a highly accurate method for the early diagnosis of NASH. This model holds promise for early detection in individuals at risk of progressing to cirrhosis or liver cancer and may aid in identifying new therapeutic targets for managing NASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of liver disease worldwide, and our understanding of its pathogenesis continues to evolve. MASLD progresses from steatosis to steatohepatitis, fibrosis, and cirrhosis, and this Review explores how the gut microbiome and their metabolites contribute to MASLD pathogenesis. We explore the complexity and importance of the intestinal barrier function and how disruptions of the intestinal barrier and dysbiosis work in concert to promote the onset and progression of MASLD. The Review focuses on specific bacterial, viral, and fungal communities that impact the trajectory of MASLD and how specific metabolites (including ethanol, bile acids, short chain fatty acids, and other metabolites) contribute to disease pathogenesis. Finally, we underscore how knowledge of the interaction between gut microbes and the intestinal barrier may be leveraged for MASLD microbial-based therapeutics. Here, we include a discussion of the therapeutic potential of prebiotics, probiotics, postbiotics, and microbial-derived metabolites.

The gut microbiota (GM) is a highly dynamic ecology whose density and composition can be influenced by a wide range of internal and external factors. Thus, "How do GM, which can have commensal, pathological, and mutualistic relationships with us, affect human health?" has become the most popular research issue in recent years. Numerous studies have demonstrated that the trillions of microorganisms that inhabit the human body can alter host physiology in a variety of systems, such as metabolism, immunology, cardiovascular health, and neurons. The GM may have a role in the development of a number of clinical disorders by producing bioactive peptides, including neurotransmitters, short-chain fatty acids, branched-chain amino acids, intestinal hormones, and secondary bile acid conversion. These bioactive peptides enter the portal circulatory system through the gut-liver axis and play a role in the development of chronic liver diseases, cirrhosis, and hepatic encephalopathy. This procedure is still unclear and quite complex. In this study, we aim to discuss the contribution of GM to the development of liver diseases, its effects on the progression of existing chronic liver disease, and to address the basic mechanisms of the intestinal microbiota-liver axis in the light of recent publications that may inspire the future.

Non-alcoholic steatohepatitis (NASH), characterized by severe fatty liver-associated inflammation and hepatocellular damage, is a major precursor to cirrhosis and hepatocellular carcinoma. While the exact pathogenesis of NASH remains unclear, gut microbiota dysbiosis has been implicated as a key factor contributing to endotoxin translocation and chronic liver inflammation. Recent studies have highlighted the therapeutic potential of bovine colostrum-derived extracellular vesicles (BCEVs) in modulating gut microbiota and enhancing gut barrier function, but their effects on NASH remain largely unexplored. To investigate the potential protective effects of BCEVs against NASH, 8-wk-old mice were fed a NASH-inducing diet for 3 wks while concurrently receiving oral BCEV administration. BCEV treatment markedly ameliorated hepatic steatosis, fibrosis, and inflammation. Transcriptomic analyses demonstrated a notable reduction in lipid metabolism, bacterial response, and inflammatory pathways in the intestine, as well as reduced expression of inflammation- and fibrosis-related pathways in the liver. Gut microbiota profiling revealed an increased abundance of Akkermansia, accompanied by enhanced cholesterol excretion. Furthermore, BCEV treatment promoted the production of tight junction proteins and mucin in the gut, reinforcing intestinal barrier integrity. These findings suggest that BCEVs promote the proliferation of Akkermansia, which in turn prevents endotoxin translocation to the liver. This reduction in endotoxin leakage alleviates hepatic inflammation and fibrosis. Overall, this study highlights the therapeutic potential of BCEVs as a novel strategy for managing NASH by targeting the gut-liver axis through the modulation of gut microbiota and barrier function.

Numerous factors are involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), which are responsible for its development and progression as an independent entity, but also thanks to their simultaneous action. This is explained by the hypothesis of multiple parallel hits. These factors are insulin resistance, lipid metabolism alteration, oxidative stress, endoplasmic reticulum stress, inflammatory cytokine liberation, gut microbiota dysbiosis or gut-liver axis activation. This is a systematic review which has an aim to show the connection between intestinal microbiota and the role of its disbalance in the development of NAFLD. The gut microbiota is made from a wide spectrum of microorganisms that has a systemic impact on human health, with a well-documented role in digestion, energy metabolism, the stimulation of the immune system, synthesis of essential nutrients, etc. It has been shown that dysbiosis is associated with all three stages of chronic liver disease. Thus, the modulation of the gut microbiota has attracted research interest as a novel therapeutic approach for the management of NAFLD patients. The modification of microbiota can be achieved by substantial diet modification and the application of probiotics or prebiotics, while the most radical effects are observed by fecal microbiota transplantation (FMT). Given the results of FMT in the context of metabolic syndrome (MetS) and NAFLD in animal models and scarce pilot studies on humans, FMT seems to be a promising treatment option that could reverse intestinal dysbiosis and thereby influence the course of NAFLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a condition wherein excessive fat accumulates in the liver, leading to inflammation and potential liver damage. In this narrative review, we evaluate the tissue microbiota, how they arise and their constituent microbes, and the role of the intestinal and hepatic microbiota in MASLD. The history of bacteriophages (phages) and their occurrence in the microbiota, their part in the potential causation of MASLD, and conversely, "phage therapy" for antibiotic resistance, obesity, and MASLD, are all described. The microbiota metabolism of bile acids and dietary tryptophan and histidine is defined, together with the impacts of their individual metabolites on MASLD pathogenesis. Both periodontitis and intestinal microbiota dysbiosis may cause MASLD, and how individual microorganisms and their metabolites are involved in these processes is discussed. Novel treatment opportunities for MASLD involving the microbiota exist and include fecal microbiota transplantation, probiotics, prebiotics, synbiotics, tryptophan dietary supplements, intermittent fasting, and phages or their holins and endolysins. Although FDA is yet to approve phage therapy in clinical use, there are multiple FDA-approved clinical trials, and this may represent a new horizon for the future treatment of MASLD.

This study explores the relationship between gout and metabolic dysfunction-associated steatotic liver disease (MASLD), two metabolic conditions linked to worsening health outcomes. While hyperuricemia's association with MASLD is established, the specific connection between gout and MASLD remains less explored. Using data from the UK Biobank, the study employs COX proportional hazard models, multi-state survival analysis, and Mendelian randomization to assess the independent and mutual risks of gout and MASLD. Findings indicate a mutual risk increase: male gout patients, those younger than 60, and those with high BMI are particularly susceptible to MASLD, while female MASLD patients are at heightened risk for gout. Shared risk factors for both conditions include high BMI, hypertension, diabetes, and hyperuricemia. The study further identifies a bidirectional causal link, with gout leading to MASLD, mediated by gut microbiota Ruminococcaceae and proteins like IL-2 and GDF11, implicating specific metabolic pathways. The findings highlight a clinical and mechanistic correlation, emphasizing the need for targeted interventions to address these overlapping metabolic pathways in future treatments.

The gut microbiota plays an important role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, we aimed to evaluate the role of the butyrate-producing bacterium Faecalibacterium prausnitzii in MASLD and whether supplementation with butyrate-producing bacteria, in particular Faecalibacterium prausnitzii, can ameliorate diet-induced steatohepatitis in mice. The relative abundance of the genus Faecalibacterium and its most abundant strain Faecalibacterium prausnitzii was determined by 16S rRNA sequencing and quantitative polymerase chain reaction (qPCR), respectively, in 95 participants with MASLD and 19 healthy control subjects. Butyrate and butyrate-producing bacteria (Faecalibacterium prausnitzii and Coprococcus comes) were gavaged to C57BL/6 mice fed a steatohepatitis-inducing diet. The fecal relative abundance of Faecalibacterium and Faecalibacterium prausnitzii was decreased in subjects with MASLD versus healthy controls and lower in individuals with MASLD and stage 3-4 fibrosis versus those with stage 0-2 fibrosis. Sodium-butyrate supplementation improved hepatic steatosis in mice on high-fat diet (HFD). Gavage of various butyrate-producing bacteria including Faecalibacterium prausnitzii and Coprococcus comes isolated from humans did not improve HFD-induced liver disease in mice. Although the abundance of Faecalibacterium prausnitzii is associated with MASLD severity in humans, its gavage to mice does not improve experimental diet-induced liver disease.

To examine the relationship between early childhood adiposity, adolescent lifestyles, gut microbiota and steatotic liver disease (SLD) development in adolescents using data from a prospective, longitudinal cohort study.

We included 69 adolescents (14-17 years old) with SLD and 69 adolescents without SLD, matched for BMI-z scores, sex, and age, from the 13-year longitudinal cohort the "Growth and Obesity Cohort Study". Anthropometric data between the ages of 4 and 17 and lifestyle parameters (including diet and physical activity) at 14-17 years old were evaluated. Fecal samples were collected and microbiome composition and function were assessed using 16S ribosomal RNA amplicon sequencing.

Principal component analysis demonstrated dietary intake factors and childhood adiposity factors expanding the distribution variation between case and control groups, respectively. Lower odds of developing SLD during adolescence was associated with higher levels of daily fiber intake during adolescence (adjusted odds ratio = 0.91) and lower childhood adiposity (triceps skinfold at 5 years of age, suprailiac skinfold at 8 and 11 years of age, and waist-to-hip ratio at age 5-9 years). SLD was associated with a lower abundance of specific microbial species, such as Bacteroides vulgatus, which was higher in the control group compared to the case group (control/case abundance ratio = 18.71). B. vulgatus abundance also positively correlated with dietary fiber intake and inversely correlated with childhood adiposity.

Adiposity in early childhood and a low dietary fiber intake may contribute to the pathogenesis of SLD during adolescence, possibly through alterations to the intestinal microbiome; these findings could inform early disease markers and targets for intervention.

Immune dysregulation-induced inflammation serves as a driving force in the progression of metabolic dysfunction-associated steatohepatitis (MASH), while the underlying cellular and molecular mechanisms remain largely uncharted. A Western diet (WD) is employed to construct mouse models of metabolic dysfunction associated steatotic liver disease (MASLD) or MASH. Mass cytometry identifies a c-kit+ cDC1 subset whose frequency is reduced in the livers of mice and patients with MASH compared with healthy controls. Adoptive cell transfer of c-kit+ cDC1 protects the progression of MASH. Moreover, analysis of gut microbe sequence shows that WD-fed mice and MASLD/MASH patients exhibit gut microbiota dysbiosis, with an elevated abundance of H2S-producing Desulfovibrio_sp. Transplanting of MASH-derived fecal flora, Desulfovibrio_sp., or injecting H2S intraperitoneally into MASLD mice decreases the c-kit+cDC1 population and exacerbates liver inflammation. Mechanistically, H2S induces autophagic cell death of cDC1 in a c-kit-dependent manner in cDC-specific c-kit-/- and Atg5-/- mice. We thus uncover that microbiota-derived H2S triggers the autophagic cell death of c-kit+ cDC1 and ignites the liver inflammatory cascade in MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects around 30% of the global population. Studies suggest that MASLD is associated with compromised brain health and cognitive dysfunction, initiating a growing interest in exploring the liver-brain axis mechanistically within MASLD pathophysiology. With the prevalence of MASLD increasing at an alarming rate, leaving a large proportion of people potentially at risk, cognitive dysfunction in MASLD is a health challenge that requires careful consideration and awareness. This Review summarises the current literature on cognitive function in people with MASLD and discusses plausible causes for its impairment. It is likely that a multifaceted spectrum of factors works collectively to affect cognition in patients with MASLD. We describe the role of inflammation, vascular disease, and brain ageing and neurodegeneration as possible key players. This Review also highlights the need for future studies to identify the optimal test for diagnosing cognitive dysfunction in patients with MASLD, to examine the correlation between MASLD progression and the severity of cognitive dysfunction, and to evaluate whether new MASLD-targeted therapies also improve brain dysfunction.

Alcohol is generally believed to be metabolized in the liver by alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and to a much lesser extent cytochrome P450 2E1 (CYP2E1) and other enzymes. Recent studies suggest that gut also play important roles in the promotion of alcohol metabolism. ADH, ALDH, and CYP2E1 have several polymorphisms that markedly impact alcohol metabolism. These alcohol-metabolizing enzymes not only affect alcohol-associated liver disease (ALD), but may also modulate the pathogenesis of other liver diseases and cancer in the absence of alcohol consumption. In this review, we discuss alcohol metabolism and the roles of alcohol-metabolizing enzymes in the pathogenesis of ALD, metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction and alcohol-associated liver disease, viral hepatitis, and liver cancer. We also discuss how alcohol-metabolizing enzymes may affect endogenous ethanol production, and how ethanol metabolism in the gut affects liver disease and cancer. Directions for future research on the roles of alcohol-metabolizing enzymes in liver disease and cancer are also elaborated.

Acute-on-chronic liver failure (ACLF) is a severe condition in patients with decompensated liver cirrhosis, marked by high short-term mortality. Recent experimental and clinical evidence has linked intestinal dysfunction to both the initiation of ACLF as well as disease outcome. This review discusses the significant role of the gut-liver axis in ACLF pathogenesis, highlighting recent advances. Gut mucosal barrier disruption, gut dysbiosis, and bacterial translocation emerge as key factors contributing to systemic inflammation in ACLF. Different approaches of therapeutically targeting the gut-liver axis via farnesoid X receptor agonists, nonselective beta receptor blockers, antibiotics, and probiotics are discussed as potential strategies mitigating ACLF progression. The importance of understanding the distinct pathophysiology of ACLF compared with other stages of liver cirrhosis is highlighted. In conclusion, research findings suggest that disruption of intestinal integrity may be an integral component of ACLF pathogenesis, paving the way for novel diagnostic and therapeutic approaches to manage this syndrome more effectively.

Symbiotic microbiota plays a crucial role in the education, development, and maintenance of the host immune system, significantly contributing to overall health. Through the gut-liver axis, the gut microbiota and liver have a bidirectional relationship that is becoming increasingly evident as more research highlights the translocation of the gut microbiota and its metabolites. The focus of this narrative review is to examine and discuss the importance of the gut-liver axis and the enterohepatic barrier in maintaining overall health. Additionally, we emphasize the crucial role of the gut microbiome in liver diseases and explore potential therapeutic strategies for liver diseases by manipulating the microbiota.

The gut microbiota plays a pivotal role in influencing the metabolism and immune responses of the body. A balanced microbial composition promotes metabolic health through various mechanisms, including the production of beneficial metabolites, which help regulate inflammation and support immune functions. In contrast, imbalance in the gut microbiota, known as dysbiosis, can disrupt metabolic processes and increase the risk of developing diseases, such as obesity, type 2 diabetes, and inflammatory disorders. The composition of the gut microbiota is dynamic and can be influenced by environmental factors such as diet, medication, and the consumption of live bacteria. Since the early 1900s, bacteria isolated from food and have been used as probiotics. However, the human gut also offers an enormous reservoir of bacterial strains, and recent advances in microbiota research have led to the discovery of strains with probiotic potentials. These strains, derived from a broad spectrum of microbial taxa, differ in their ecological properties and how they interact with their hosts. For most probiotics bacterial structural components and metabolites, such as short-chain fatty acids, contribute to the maintenance of metabolic and immunological homeostasis by regulating inflammation and reinforcing gut barrier integrity. Metabolites produced by probiotic strains can also be used for bacterial cross-feeding to promote a balanced microbiota. Despite the challenges related to safety, stability, and strain-specific properties, several newly identified strains offer great potential for personalized probiotic interventions, allowing for targeted health strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as nonalcoholic fatty liver disease) is a chronic liver disease affecting over a billion individuals worldwide. MASLD can gradually develop into more severe liver pathologies, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and liver malignancy. Notably, although being a global health problem, there are very limited therapeutic options against MASLD and its related diseases. While a thyroid hormone receptor agonist (resmetirom) is recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in MASLD and MASH incidence, it is urgent to develop novel and effective therapeutic strategies against these prevalent liver diseases. In this article, the pathogenic mechanisms of MASLD and MASH, including insulin resistance, dysregulated nuclear receptor signaling, and genetic risk factors (eg, patatin-like phospholipase domain-containing 3 and hydroxysteroid 17-β dehydrogenase-13), are introduced. Various therapeutic interventions against MASH are then explored, including approved medication (resmetirom), drugs that are currently in clinical trials (eg, glucagon-like peptide 1 receptor agonist, fibroblast growth factor 21 analog, and PPAR agonist), and those failed in previous trials (eg, obeticholic acid and stearoyl-CoA desaturase 1 antagonist). Moreover, given that the role of gut microbes in MASLD is increasingly acknowledged, alterations in the gut microbiota and microbial mechanisms in MASLD development are elucidated. Therapeutic approaches that target the gut microbiota (eg, dietary intervention and probiotics) against MASLD and related diseases are further explored. With better understanding of the multifaceted pathogenic mechanisms, the development of innovative therapeutics that target the root causes of MASLD and MASH is greatly facilitated. The possibility of alleviating MASH and achieving better patient outcomes is within reach. SIGNIFICANCE STATEMENT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, and it can progress to more severe pathologies, including steatohepatitis, cirrhosis, and liver cancer. Better understanding of the pathogenic mechanisms of these diseases has facilitated the development of innovative therapeutic strategies. Moreover, increasing evidence has illustrated the crucial role of gut microbiota in the pathogenesis of MASLD and related diseases. It may be clinically feasible to target gut microbes to alleviate MASLD in the future.

The experiment aimed to study the effect of dietary metabolizable energy (ME) and crude protein (CP) on laying performance, egg quality, serum routine biochemical and lipid metabolism indicators, the apparent digestibility of nutrients, and fecal microbiota of Taihe Silky Fowl (TSF) during the peak laying period.

A total of 540 26-week-old TSF female fowls were randomly allocated to 9 groups with 5 replicates per group and 12 fowls per replicate. The fowls were fed with a 3×3 factorial arrangement of treatments diets (ME:10.88,11.30, or 11.72 MJ/kg; CP: 15, 16, or 17%).

With the increasing CP level, the egg weight (p = 0.023), egg production (p = 0.047), and egg mass (p = 0.022) enhanced, while the feed conversion rate (FCR) (p = 0.023) decreased. As the ME levels grew, the average daily feed intake (p<0.001) and FCR (p = 0.045) decreased. With enhanced ME, the triglycerides (p = 0.037), total cholesterol (p = 0.041), and high-density lipoprotein cholesterol (p = 0.028) increased, whereas the low-density serum lipoprotein cholesterol (p = 0.039) decreased. The apparent digestibility of CP increased as the ME level increased (p = 0.029) and as the CP level decreased (p = 0.027). At the same time, the apparent digestibility of gross energy increased as the ME level increased (p = 0.018). Different levels of ME or CP changed the composition of fecal microbiota, 17% CP increased the abundance of Bifidobacterium.

It is suggested that 10.88 MJ/kg dietary ME and 17% CP level are suitable for the nutritional requirements of TSF during the peak laying period.

The human gut microbiome plays a crucial role in regulating intestinal and systemic health, impacting host immune response and metabolic function. Dysbiosis of the gut microbiome is linked to various diseases, including steatotic liver diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD), a chronic liver disease characterized by excess hepatic lipid content and impaired metabolism, is the leading cause of liver disease worldwide. Among the gut microbes, Ruminococcus gnavus (R. gnavus) has garnered attention for its association with inflammatory and metabolic diseases. While R. gnavus abundance correlates to liver fat accumulation, further research is needed to identify a causal role or therapeutic intervention in steatotic liver disease. This review surveys our current understanding of R. gnavus in the development and progression of steatotic liver diseases, highlighting its potential mechanisms through metabolite secretion, and emphasizes the need for comprehensive microbiome analyses and longitudinal studies to better understand R. gnavus' impact on liver health. This knowledge could pave the way for targeted interventions aimed at modulating gut microbiota to treat and prevent MASLD and its comorbidities.

The liver acts as a central metabolic hub, integrating signals from the gastrointestinal tract and adipose tissue to regulate carbohydrate, lipid, and amino acid metabolism. Gut-derived metabolites, such as acetate and ethanol and non-esterified fatty acids from white adipose tissue (WAT), influence hepatic processes, which rely on mitochondrial function to maintain systemic energy balance. Metabolic dysregulation from obesity, insulin resistance, and type 2 diabetes disrupt these pathways, leading to metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). This review explores the metabolic fluxes within the gut-adipose tissue-liver axis, focusing on the pivotal role of de novo lipogenesis (DNL), dietary substrates like glucose and fructose, and changes in mitochondrial function during MASLD progression. It highlights the contributions of white adipose tissue insulin resistance and impaired mitochondrial dynamics to hepatic lipid accumulation. Further understanding how the interplay between substrate flux from the gastro-intestinal tract integrates with adipose tissue and intersects with structural and functional alterations to liver mitochondria will be important to identify novel therapeutic targets and advance the treatment of MASLD and MASH.

Mongolian Medicine Qiqirigan-8 (MMQ-8) is a traditional Mongolian medicine formula used to treat fatty liver disease. However, the material basis and in vivo metabolic process of the therapeutic effect of MMQ-8 on non-alcoholic fatty liver disease (NAFLD) remain unclear.

The chemical composition of MMQ-8 was determined using Ultra-high-performance liquid chromatography-quadrupole Exactive Mass spectrometry analysis (UHPLC-QE-MS). C57BL/6J mice were fed a choline-deficient diet for 12 weeks to induce a NAFLD model. Hematoxylin and Eosin (H&E)-staining, combined with serum biochemical indexes, was used to observe liver appearance and characterize the pathological changes and functions of the liver. HE staining and Alcian Blue-Phosphoric Acid Schiff (AB-PAS) staining of the colon, along with ZO-1 immunofluorescence expression in the colon were used to reveal the effect of MMQ-8 on the disruption of the intestinal epithelial mucosal barrier in the NAFLD. The expression of intestinal tight junction genes was analyzed by qRT-PCR to observe the protective effect of MMQ-8 against intestinal epithelial mucosal barrier disruption. Fecal metagenomics and serum non-targeted metabolomics were used to reveal the effects of MMQ-8 on the gut microbiota and metabolism in mice with NAFLD. Finally, we emphasize the interaction between gut microbiota and metabolites through Spearman correlation coefficient analysis.

Mongolian Medicine Qiqirigan-8 contains 17 active ingredients, which can reduce hepatic steatosis and lobular inflammation in mice with NAFLD, and have protective effects against liver injury. MMQ-8 reduced the infiltration of inflammatory cells in the colon epithelium of model mice while restoring the number of goblet cells. MMQ-8 significantly enhanced ZO-1 protein expression in the colon, as well as the mRNA expression of both ZO-1 and Occludin. Fecal metagenomics results showed that MMQ-8 reduced the Bacillota/Bacteroidota ratio in NAFLD mice. Increased the abundance of beneficial bacteria such as Porphyromonadaceae, Prevotella, and Bacteroidota. and suppressed the abundance of dysfunctional bacteria, such as Bacillota, Acetatifactor, and Erysipelotrichaceae. Furthermore, metabolomics studies revealed that MMQ-8 intervention significantly regulated the expression of metabolites related to glutathione metabolism, butyric acid metabolism, sphingolipid metabolism, and glycerophospholipid metabolism in NAFLD mice compared to the model group. These metabolic pathways play key roles in NAFLD. According to Spearman's correlation coefficient analysis, up-regulation of Porphyromonadaceae, Prevotella, and Bacteroidota after MMQ-8 intervention was negatively correlated with LPC levels in glycerophospholipid metabolic pathways, while positively correlated with PC levels. In contrast, the relationship between Bacillota and Acetatifactor, which were down-regulated after MMQ-8 intervention, was the opposite. In addition, the up-regulation of Porphyromonadaceae, Prevotella, and Bacteroidota after MMQ-8 intervention was positively correlated with fumaric acid, 2-oxoglutaric acid, adenosine, and L-glutathione levels, while those down-regulated after MMQ-8 intervention were positively correlated with the levels of Bacillota, Acetatifactor were negatively correlated with all the above metabolites. Thus, glutathione metabolism, butyric acid metabolism, sphingolipid metabolism, glycerophospholipid metabolism and gut microbial ecosystem are tightly intertwined in this process.

In summary, these findings indicate that MMQ-8 has a synergistic anti-NAFLD effect through its multi-component, multi-target, gut microbiota-modulating and multi metabolic pathway characteristics. The host's regulation of specific gut microbiota and involvement in multiple metabolic pathways may be one of the important mechanisms by which MMQ-8 exerts its therapeutic effects on NAFLD. It is worth noting that metabolic pathways such as glutathione metabolism, butyric acid metabolism, sphingolipid metabolism, glycerophospholipid metabolism, and the gut microbiota ecosystem are closely intertwined in this process.