The developmental origin of health and disease hypothesis shows that early adverse exposures can have lifelong health effects. Thus, the aim of this study was to analyze the impact of choline intake during pregnancy and/or lactation on gene expression profiles in the liver of 24-day-old male rat offspring from dams with non-alcoholic fatty liver disease (NAFLD).

Phenotypic characteristic, histological examination and global transcriptome pattern of liver tissue specimens obtained from offspring of dams suffering from fatty liver, provided with proper choline intake during pregnancy and lactation (NN), fed a choline-deficient diet during both periods (DD), deprived of choline only during pregnancy (DN), or only during lactation (ND), was performed. The global gene expression profile was analyzed by using microarray approach (Affymetrix® Rat Gene 2.1 ST Array Strip). The relative expression of selected genes was validated by real-time polymerase chain reaction (qPCR).

The histological examination of rat liver sections indicated alternations typical for fatty liver in all analyzed groups with increased progression among groups deprived of choline. Choline deficiency in the maternal diet was associated with changes in body mass and composition but not with biochemical marker levels, except for the high density lipoprotein fraction of cholesterol (HDL). Enhanced expression of genes involved in oxidative stress, cell proliferation, activation of catabolic processes related to hepatocyte dysfunction and cell membrane composition were simultaneously observed in all choline-deficient groups.

An adequate amount of choline in the diet of a mother with fatty liver during pregnancy and/or lactation can regulate gene expression in the offspring's liver and contribute to a milder stage of the disease in the progeny. Moreover, proper choline supply during the postpartum period is as crucial as during the prenatal period.

Fatty liver hemorrhage syndrome (FLHS) has become one of the major factors leading to the death of laying hen in caged egg production. FLHS is commonly associated with lipid peroxidation, hepatocyte injury, decreased antioxidant capacity, and inflammation. However, there are limited evidences regarding the preventive effect of Lactiplantibacillus plantarum on FLHS in laying hens and its mechanisms. Our previous results showed that Lp. plantarum FRT4 alleviated FLHS by regulating lipid metabolism, but did not focus on its antioxidant and anti-inflammatory functions and mechanisms. Therefore, this study aimed to investigate the preventive mechanisms of Lp. plantarum FRT4 in alleviating FLHS, with a focus on its role in antioxidant activity and inflammation regulation.

Supplementation with Lp. plantarum FRT4 enhanced the levels of T-AOC, T-SOD, and GSH-Px, while reducing the levels of TNF-α, IL-1β, IL-8, and NLRP3 in the liver and ovary of laying hens. Additionally, Lp. plantarum FRT4 upregulated the mRNA expressions of SOD1, SOD2, CAT, and GPX1, downregulated the mRNA expressions of pro-inflammatory factors IL-1β, IL-6, and NLRP3, and upregulated the mRNA expressions of anti-inflammatory factors IL-4 and IL-10. Lp. plantarum FRT4 improved the structure and metabolic functions of gut microbiota, and regulated the relative abundances of dominant phyla (Bacteroidetes, Firmicute, and Proteobacteria) and genera (Prevotella and Alistipes). Additionally, it influenced key KEGG pathways, including tryptophan metabolism, amino sugar and nucleotide sugar metabolism, insulin signaling pathway, FoxO signaling pathway. Spearman analysis revealed that the abundance of microbiota at different taxonomic levels was closely related to antioxidant enzymes and inflammatory factors. Furthermore, Lp. plantarum FRT4 modulated the mRNA expressions of related factors in the FoxO/TLR-4/NF-κB signaling pathway by regulating gut microbiota. Moreover, the levels of E2, FSH, and VTG were significantly increased in the ovary after Lp. plantarum FRT4 intervention.

Lp. plantarum FRT4 effectively ameliorates FLHS in laying hens. This efficacy is attributed to its antioxidant and anti-inflammatory properties, which are mediated by modulating the structure and function of gut microbiota, and further intervening in the FoxO/TLR-4/NF-κB signaling pathway. These actions enhance hepatic and ovarian function and increase estrogen levels. Video Abstract.

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.

Background/Objectives: Sodium acetate (NaA) has demonstrated potential in improving non-alcoholic fatty liver disease (NAFLD) by targeting hepatocytes and Kupffer cells. However, its clinical application is hindered by low oral bioavailability and insufficient liver concentrations. Liposomes, with their capacity to encapsulate water-soluble drugs and be surface-modified, offer a promising solution for targeted oral drug delivery. Methods: We designed NaA-loaded liposomes modified with sodium cholate (SC) and mannose (MAN) (NaA@SC/MAN-LPs) to target hepatocytes and Kupffer cells. Results: The NaA@SC/MAN-LPs had a mean diameter of approximately 100 nm with a positive surface charge. Compared to free NaA, NaA@SC/MAN-LPs significantly extended the serum half-life from 2.85 h to 15.58 h, substantially improving in vivo bioavailability. In vivo distribution studies revealed that NaA@SC/MAN-LPs extended the acetate peak time in the liver from 15 min to 60 min and increased hepatic acetate accumulation to 3.75 times that of free NaA. In in vitro cell experiments, NaA@SC/MAN-LPs significantly reduced the lipid droplet, triglycerides (TG), and total cholesterol (TC) in a fatty acid-induced hepatocyte steatosis model and suppressed proinflammation in a lipopolysaccharide (LPS)-activated Kupffer cell inflammation model. Free NaA effectively improved hepatic lipid deposition in NAFLD mice. Furthermore, NaA@SC/MAN-LPs decreased hepatic TG, TC, and the relative area of lipid droplets by 30.44%, 15.26%, and 55.83%, compared to free NaA. Furthermore, the liposomes reduced macrophage infiltration and pro-inflammatory response. Conclusions: The NaA@SC/MAN-LPs demonstrated effective dual targeting effects on hepatocytes and Kupffer cells, significantly improving the pathogenesis of NAFLD, compared to free NaA. This study provides a new strategy for developing effective and safe oral drugs for NAFLD.

The gut microbiota actually shares the host's physical space and affects the host's physiological functions and health indicators through a complex network of interactions with the host. However, its role as a determinant of host health and disease is often underestimated. With the emergence of new technologies including next-generation sequencing (NGS) and advanced techniques such as microbial community sequencing, people have begun to explore the interaction mechanisms between microorganisms and hosts at various omics levels such as genomics, transcriptomics, metabolomics, and proteomics. With the enrichment of multi-omics integrated analysis methods based on the microbiome, an increasing number of complex statistical analysis methods have also been proposed. In this review, we summarized the multi-omics research analysis methods currently used to study the interaction between the microbiome and the host. We analyzed the advantages and limitations of various methods and briefly introduced their application progress.

The human gut microbiota (GM) is a community of microorganisms that resides in the gastrointestinal (GI) tract. Recognized as a critical element of human health, the functions of the GM extend beyond GI well-being to influence overall systemic health and susceptibility to disease. Among the other omic sciences, metaproteomics highlights additional facets that make it a highly valuable discipline in the study of GM. Indeed, it allows the protein inventory of complex microbial communities. Proteins with associated taxonomic membership and function are identified and quantified from their constituent peptides by liquid chromatography coupled to mass spectrometry analyses and by querying specific databases (DBs). The aim of this review was to compile comprehensive information on metaproteomic studies of the human GM, with a focus on the bacterial component, to assist newcomers in understanding the methods and types of research conducted in this field. The review outlines key steps in a metaproteomic-based study, such as protein extraction, DB selection, and bioinformatic workflow. The importance of standardization is emphasized. In addition, a list of previously published studies is provided as hints for researchers interested in investigating the role of GM in health and disease states.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a global health concern, affecting over 30 % of adults. It is a principal driver in the development of cirrhosis and hepatocellular carcinoma. The complex pathogenesis of MASLD involves an excessive accumulation of lipids, subsequently disrupting lipid metabolism and prompting inflammation within the liver. This review synthesizes the recent research progress in understanding the mechanisms contributing to MASLD progression, with particular emphasis on metabolic disorders and interorgan crosstalk. We highlight the molecular mechanisms linked to these factors and explore their potential as novel targets for pharmacological intervention. The insights gleaned from this article have important implications for both the prevention and therapeutic management of MASLD.

Probiotics are studied for their therapeutic potential in the treatment of several diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Part of the significant progress made in understanding the pathogenesis of steatosis has come from identifying the complex interplay between the gut microbiome and liver function. Recently, probiotics have shown beneficial effects for the treatment and prevention of steatosis and MASLD in rodent models and in clinical trials. Numerous studies have demonstrated the promising potential of lactic acid bacteria, especially the genus Lactobacillus. Lactobacillus is a prominent bile acid hydrolase bacterium that is involved in the biotransformation of bile acids. This genus' modulation of the gut microbiota also contributes to overall gut health; it controls gut microbial overgrowth, shapes the intestinal bile acid pool, and alleviates inflammation. This narrative review offers a comprehensive summary of the potential of Lactobacillus in the gut-liver axis to attenuate steatosis and MASLD. It also highlights the roles of Lactobacillus in hepatic lipid metabolism, insulin resistance, inflammation and fibrosis, and bile acid synthesis in attenuating MASLD.

Despite the increasing prevalence of nonalcoholic fatty liver disease (NAFLD), the pathophysiology is still not fully understood. Recent evidence suggests that the gut microbiota may play a role in the pathophysiology of NAFLD and may also offer new therapeutic options.

This prospective cross-sectional study included 100 consecutive newly diagnosed obese patients (BMI ≥ 95th percentile), aged 14-18 years with NAFLD (confirmed by ultrasound), persistently elevated levels of alanine aminotransferase (ALT) greater than 60 U/L for 1-6 months, and 100 healthy controls. We evaluated changes in the gut microbiota in NAFLD adolescents compared with healthy controls.

According to the multiple logistic regressions, the variables associated with NAFLD were the presence of Clostridium difficile, the presence of Salmonella spp., a greater abundance of Bifidobacterium and Prevotella, and a lower abundance of Lactobacillus.

Changes in the gut microbiota occur in adolescents with NAFLD compared with healthy individuals, which may be useful for identifying youths who are amenable to gut microbiota-based interventions.

Not applicable.

Evidence has indicated that Enterococcus plays a vital role in non-alcoholic fatty liver disease (NAFLD) development. However, the microbial genetic basis and metabolic potential in the disease are yet unknown. We previously isolated a bacteria Enterococcus faecium B6 (E. faecium B6) from children with NAFLD for the first time. Here, we aim to systematically investigate the potential of strain B6 in lipogenic effects. The lipogenic effects of strain B6 were explored in vitro and in vivo. The genomic and functional characterizations were investigated by whole-genome sequencing and comparative genomic analysis. Moreover, the metabolite profiles were unraveled by an untargeted metabolomic analysis. We demonstrated that strain B6 could effectively induce lipogenic effects in the liver of mice. Strain B6 contained a circular chromosome and two circular plasmids and posed various functions. Compared to the other two probiotic strains of E. faecium, strain B6 exhibited unique functions in pathways of ABC transporters, phosphotransferase system, and amino sugar and nucleotide sugar metabolism. Moreover, strain B6 produced several metabolites, mainly enriched in the protein digestion and absorption pathway. The unique potential of strain B6 in lipogenic effects was probably associated with glycolysis, fatty acid synthesis, and glutamine and choline transport. This study pioneeringly revealed the metabolic characteristics and specific detrimental traits of strain B6. The findings provided new insights into the underlying mechanisms of E. faecium in lipogenic effects, and laid essential foundations for further understanding of E. faecium-related disease.

Segatella is a prevalent genus within individuals' gut microbiomes worldwide, especially in non-Western populations. Although metagenomic assembly and genome isolation have shed light on its genetic diversity, the lack of available isolates from this genus has resulted in a limited understanding of how members' genetic diversity translates into phenotypic diversity. Within the confines of a single gut microbiome, we have isolated 63 strains from diverse lineages of Segatella. We performed comparative analyses that exposed differences in cellular morphologies, preferences in polysaccharide utilization, yield of short-chain fatty acids, and antibiotic resistance across isolates. We further show that exposure to Segatella isolates either evokes strong or muted transcriptional responses in human intestinal epithelial cells. Our study exposes large phenotypic differences within related Segatella isolates, extending this to host-microbe interactions.

Benzo[a]pyrene (BaP) is a ubiquitous environmental pollutant posing various toxicity effects on organisms. Previous studies demonstrated that BaP could induce hepatotoxicity, while the underlying mechanism remains incompletely elucidated. In this study, a comprehensive strategy including network toxicology, transcriptomics and gut microbiomics was applied to investigate the hepatotoxicity and the associated mechanism of BaP exposure in mice. The results showed that BaP induced liver damage, liver oxidative stress and hepatic lipid metabolism disorder. Mechanistically, BaP may disrupt hepatic lipid metabolism through increasing the uptake of free fatty acid (FFA), promoting the synthesis of FA and triglyceride (TG) in the liver and suppressing lipid synthesis in white adipose tissue. Moreover, integrated network toxicology and hepatic transcriptomics revealed that BaP induced hepatotoxicity by acting on several core targets, such as signal transducer and activator of transcription 1 (STAT1), C-X-C motif chemokine ligand 10 (CXCL10) and toll-like receptor 2 (TLR2). Further analysis suggested that BaP inhibited JAK2-STAT3 signaling pathway, as supported by molecular docking and western blot. The 16S rRNA sequencing showed that BaP changed the composition of gut microbiota which may link to the hepatotoxicity based on the correlation analysis. Taken together, this study demonstrated that BaP caused liver injury, hepatic lipid metabolism disorder and gut microbiota dysbiosis, providing novel insights into the hepatotoxic mechanism induced by BaP exposure.

The historical use of the term non-alcoholic fatty liver disease (NAFLD) in obese/overweight children has been controversial as to the appropriateness of this terminology in children, and lately, in adults too. Newer game-changer terminology, metabolic (dysfunction)-associated fatty liver disease (MAFLD), for this condition signifies a positive step forward that addresses the limitations of the previous definition for both adults and children. The prevalence of MAFLD has surged in tandem with the global rise in obesity rates, establishing itself as a predominant cause of chronic liver disease in both adult and pediatric populations. The adoption of the recently proposed nomenclature reflects a more encompassing comprehension of the disease and its etiology compared to its predecessor, NAFLD. Notably, the revised terminology facilitates the recognition of MAFLD as an autonomous condition while acknowledging the potential coexistence of other systemic fatty liver disorders. Particularly in children, this includes various paediatric-onset genetic and inherited metabolic disorders, necessitating thorough exclusion, especially in cases where weight loss interventions yield no improvement or in the absence of obesity. MAFLD presents as a multifaceted disorder; evidence suggests its origins lie in a complex interplay of nutritional, genetic, hormonal, and environmental factors. Despite advancements, current non-invasive diagnostic biomarkers exhibit limitations in accuracy, often necessitating imaging and histological evaluations for definitive diagnosis. While dietary and lifestyle modifications stand as cornerstone measures for MAFLD prevention and management, ongoing evaluation of therapeutic agents continues. This article provides an overview of the latest developments and emerging therapies in the realm of paediatric MAFLD.

In recent years, the prevalence of non-alcoholic fatty liver disease (NAFLD) has risen annually, yet due to the intricacies of its pathogenesis and therapeutic challenges, there remains no definitive medication for this condition. This review explores the intricate relationship between the intestinal microbiome and the pathogenesis of NAFLD, emphasizing the substantial roles played by Lactobacillus plantarum and Bifidobacterium bifidum. These probiotics manipulate lipid synthesis genes and phosphorylated proteins through pathways such as the AMPK/Nrf2, LPS-TLR4-NF-κB, AMPKα/PGC-1α, SREBP-1/FAS, and SREBP-1/ACC signaling pathways to reduce hepatic lipid accumulation and oxidative stress, key components of NAFLD progression. By modifying the intestinal microbial composition and abundance, they combat the overgrowth of harmful bacteria, alleviating the inflammatory response precipitated by dysbiosis and bolstering the intestinal mucosal barrier. Furthermore, they participate in cellular immune regulation, including CD4+ T cells and Treg cells, to suppress systemic inflammation. L. plantarum and B. bifidum also modulate lipid metabolism and immune reactions by adjusting gut metabolites, including propionic and butyric acids, which inhibit liver inflammation and fat deposition. The capacity of probiotics to modulate lipid metabolism, immune responses, and gut microbiota presents an innovative therapeutic strategy. With a global increase in NAFLD prevalence, these insights propose a promising natural method to decelerate disease progression, avert liver damage, and tackle associated metabolic issues, significantly advancing microbiome-focused treatments for NAFLD.

NAFLD/NASH has emerged as a global health concern with no FDA-approved treatment, necessitating the exploration of novel therapeutic elements for NASH. Probiotics are known as an important adjunct therapy in NASH. Zbiotics (ZB183) is the first commercially available genetically engineered probiotic. Herein, we aimed to evaluate the potential therapeutic effects of Zbiotics administration on NASH management by modulating the cGAS-STING-signaling pathway-related RNA network. In silico data analysis was performed and three DEGs (MAPK3/EDN1/TNF) were selected with their epigenetic modulators (miR-6888-5p miRNA, and lncRNA RABGAP1L-DT-206). The experimental design included NASH induction with an HSHF diet in Wistar rats and Zbiotics administration in NASH rats in comparison to statin treatment. Liver functions and lipid profile were assessed. Additionally, the expression levels of the constructed molecular network were assessed using RT-PCR. Moreover, the Zbiotics effects in NASH were further validated with histopathological examination of liver and colon samples. Also, immunohistochemistry staining of hepatic TNF-α and colonic occludin was assessed. Oral administration of Zbiotics for four weeks downregulated the expression of the cGAS-STING-related network (MAPK3/EDN1/TNF/miR-6888-5p miRNA/lncRNA RABGAP1L-DT-206) in NASH models. Zbiotics also ameliorated hepatic inflammation and steatosis, as evidenced by a notable improvement in NAS score and decreased hepatic TNF-α levels. Furthermore, Zbiotics exhibited favorable effects on colon health, including increased crypt length, reduced inflammatory cell infiltration, and restoration of colonic mucosa occludin expression. In conclusion, our findings suggest that Zbiotics has potential therapeutic effects on NASH via modulating the gut-liver axis and the cGAS-STING signaling pathway.

Metabolic syndrome (MetS) is a group of metabolic abnormalities that identifies people at risk for diabetes and cardiovascular disease. MetS is characterized by lipid disorders, and non-alcoholic fatty liver disease (NAFLD) and diabetic kidney disease (DKD) are thought to be the common hepatic and renal manifestations of MetS following abnormal lipid metabolism. This paper reviews the molecular mechanisms of lipid deposition in NAFLD and DKD, highlighting the commonalities and differences in lipid metabolic pathways in NAFLD and DKD. Hepatic and renal steatosis is the result of lipid acquisition exceeding lipid processing, i.e., fatty acid uptake and lipid regeneration exceed fatty acid oxidation and export. This process is directly regulated by the interactions of nuclear receptors, transporter proteins and transcription factors, whereas pathways such as oxidative stress, autophagy, cellular pyroptosis and gut flora are also key regulatory hubs for lipid metabolic homeostasis but act slightly differently in the liver and kidney. Such insights based on liver-kidney similarities and differences offer potential options for improved treatment.

Postbiotics could exert different metabolic activities in animal models of non-alcoholic fatty liver disease (NAFLD) and in humans affected by metabolic syndrome. This is a randomized, double-blind, placebo-controlled, parallel-group clinical trial that enrolled a sample of 50 Caucasian healthy individuals with NAFLD, defined as liver steatosis, and metabolic syndrome. After a 4-week run-in, the enrolled individuals were randomized to take a food for special medical purposes with functional release, one tablet a day, containing calcium butyrate (500 mg/tablet), zinc gluconate (zinc 5 mg/tablet), and vitamin D3 (500 IU/tablet), or an identical placebo for 3 months. Liver and metabolic parameters were measured at baseline and at the end of the study. No subject experienced any adverse events during the trial. In both groups, a significant decrease in total cholesterol (TC) and triglycerides (TG) plasma levels was observed at the randomization visit vs. pre-run-in visit (p < 0.05). Regarding liver parameters, after treatment, the fatty liver index (FLI) improved significantly vs. baseline values (p < 0.05) and vs. placebo group (p < 0.05) in the active treatment group, and the hepatic steatosis index (HSI) improved significantly vs. baseline values (p < 0.05). Moreover, after active treatment, TC, TG, and gamma-glutamyl transferase (gGT) improved significantly vs. baseline values (p < 0.05), and TC and TG improved vs. placebo group (p < 0.05), as well. In the placebo group, liver parameters remained unchanged after treatment; only TG improved significantly vs. baseline values (p < 0.05). In our study, we observed that the butyrate-based formula improved FLI and plasma lipid patterns in individuals affected by liver steatosis and metabolic syndrome.

Gut microbiota might affect the severity and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to characterize gut dysbiosis and clinical parameters regarding fibrosis stages assessed by magnetic resonance elastography. This study included 156 patients with MASLD, stratified into no/mild fibrosis (F0-F1) and moderate/severe fibrosis (F2-F4). Fecal specimens were sequenced targeting the V4 region of the 16S rRNA gene and analyzed using bioinformatics. The genotyping of PNPLA3, TM6SF2, and HSD17B13 was assessed by allelic discrimination assays. Our data showed that gut microbial profiles between groups significantly differed in beta-diversity but not in alpha-diversity indices. Enriched Fusobacterium and Escherichia_Shigella, and depleted Lachnospira were found in the F2-F4 group versus the F0-F1 group. Compared to F0-F1, the F2-F4 group had elevated plasma surrogate markers of gut epithelial permeability and bacterial translocation. The bacterial genera, PNPLA3 polymorphisms, old age, and diabetes were independently associated with advanced fibrosis in multivariable analyses. Using the Random Forest classifier, the gut microbial signature of three genera could differentiate the groups with high diagnostic accuracy (AUC of 0.93). These results indicated that the imbalance of enriched pathogenic genera and decreased beneficial bacteria, in association with several clinical and genetic factors, were potential contributors to the pathogenesis and progression of MASLD.

Clinical evidence for early identification and diagnosis of liver cirrhosis (LC) caused by different types of liver disease is limited. We investigated this topic through a meta-analysis of quantitative metabolomics.

Four databases were searched until October 31, 2022 for studies comparing metabolite levels between patients with different types of liver disease and control individuals. A random-effects model was applied for the meta-analysis.

This study included 55 studies with 8266 clinical participants, covering 348 metabolites. In LC related to drug-induced liver injury (DILI), hepatitis B virus (HBV) infection, and non-alcoholic fatty liver disease (NAFLD), the primary bile acid biosynthesis (taurocholic acid: SMD, 1.08[0.81, 1.35]; P < 0.00001; glycocholic acid: SMD, 1.35[1.07, 1.62]; P < 0.00001; taurochenodeoxycholic acid: SMD, 1.36[0.94, 1.78]; P < 0.00001; glycochenodeoxycholic acid: SMD, 1.49[0.93, 2.06]; P < 0.00001), proline and arginine (l-proline: SMD, 1.06[0.53, 1.58]; P < 0.0001; hydroxyproline: SMD, 0.81[0.30, 1.33]; P = 0.002), and fatty acid biosynthesis (palmitic acid: SMD, 0.44[0.21, 0.67]; P = 0.0002; oleic acid: SMD, 0.46[0.19, 0.73]; P = 0.0008; stearic acid: SMD, 0.37[0.07, 0.68]; P = 0.02) metabolic pathways were significantly altered.

We identified key biomarkers and metabolic characteristics for distinguishing and identifying LC related to different types of liver disease, providing a new perspective for early diagnosis, disease monitoring, and precise treatment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent type of liver disease worldwide. The exact pathophysiology behind MASLD remains unclear; however, it is thought that a combination of factors or "hits" act as precipitants for disease onset and progression. Abundant evidence supports the roles of diet, genes, metabolic dysregulation, and the intestinal microbiome in influencing the accumulation of lipids in hepatocytes and subsequent progression to inflammation and fibrosis. Currently, there is no cure for MASLD, but lifestyle changes have been the prevailing cornerstones of management. Research is now focusing on the intestinal microbiome as a potential therapeutic target for MASLD, with the spotlight shifting to probiotics, antibiotics, and fecal microbiota transplantation. In this review, we provide an overview of how intestinal microbiota interact with the immune system to contribute to the pathogenesis of MASLD and metabolic dysfunction-associated steatohepatitis (MASH). We also summarize key microbial taxa implicated in the disease and discuss evidence supporting microbial-targeted therapies in its management.

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders of varying severity, ultimately leading to fibrosis. This spectrum primarily consists of NAFL and non-alcoholic steatohepatitis. The pathogenesis of NAFLD is closely associated with disturbances in the gut microbiota and impairment of the intestinal barrier. Non-gut commensal flora, particularly bacteria, play a pivotal role in the progression of NAFLD. Notably, Porphyromonas gingivalis, a principal bacterium involved in periodontitis, is known to facilitate lipid accumulation, augment immune responses, and induce insulin resistance, thereby exacerbating fibrosis in cases of periodontitis-associated NAFLD. The influence of oral microbiota on NAFLD via the "oral-gut-liver" axis is gaining recognition, offering a novel perspective for NAFLD management through microbial imbalance correction. This review endeavors to encapsulate the intricate roles of oral bacteria in NAFLD and explore underlying mechanisms, emphasizing microbial control strategies as a viable therapeutic avenue for NAFLD.

Elevated fasting ethanol levels in peripheral blood frequently found in metabolic dysfunction-associated steatohepatitis (MASLD) patients even in the absence of alcohol consumption are discussed to contribute to disease development. To test the hypothesis that besides an enhanced gastrointestinal synthesis a diminished alcohol elimination through alcohol dehydrogenase (ADH) may also be critical herein, we determined fasting ethanol levels and ADH activity in livers and blood of MASLD patients and in wild-type ± anti-TNFα antibody (infliximab) treated and TNFα-/- mice fed a MASLD-inducing diet. Blood ethanol levels were significantly higher in patients and wild-type mice with MASLD while relative ADH activity in blood and liver tissue was significantly lower compared to controls. Both alterations were significantly attenuated in MASLD diet-fed TNFα-/- mice and wild-type mice treated with infliximab. Moreover, alcohol elimination was significantly impaired in mice with MASLD. In in vitro models, TNFα but not IL-1β or IL-6 significantly decreased ADH activity. Our data suggest that elevated ethanol levels in MASLD patients are related to TNFα-dependent impairments of ADH activity.

Non-alcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease and a progressive and chronic liver disorder with a significant risk for the development of liver-related morbidity and mortality. The complex and multifaceted pathophysiology of NASH makes its management challenging. Early identification of symptoms and management of patients through lifestyle modification is essential to prevent the development of advanced liver disease. Despite the increasing prevalence of NASH, there is no FDA-approved treatment for this disease. Currently, medications targeting metabolic disease risk factors and some antifibrotic medications are used for NASH patients but are not sufficiently effective. The beneficial effects of different drugs and phytochemicals represent new avenues for the development of safer and more effective treatments for NASH. In this review, different risk factors, clinical symptoms, diagnostic methods of NASH, and current treatment strategies for the management of patients with NASH are reviewed.

Altered gut microbiota and metabolites are important for non-alcoholic fatty liver disease (NAFLD) in children. We aimed to comprehensively examine the effects of gut metabolites on NAFLD progression. We performed integrative metabolomics (untargeted discovery and targeted validation) analysis of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and obesity in children. Fecal samples were collected from 75 subjects in the discovery cohort (25 NAFL, 25 NASH, and 25 obese control children) and 145 subjects in an independent validation cohort (53 NAFL, 39 NASH, and 53 obese control children). Among 2,491 metabolites, untargeted metabolomics revealed a complete NAFLD metabolic map containing 318 increased and 123 decreased metabolites. Then, machine learning selected 65 important metabolites that can distinguish the severity of the NAFLD. Furthermore, precision-targeted metabolomics selected 5 novel gut metabolites from 20 typical metabolites. The functionality of candidate metabolites was validated in hepatocyte cell lines. In the end, this study annotated two novel elevated pathogenic metabolites (dodecanoic acid and creatinine) and a relationship between depleted protective gut microbiota (Butyricicoccus and Alistipes), increased inflammation (IL-1β), lipid metabolism (TG), and liver function (ALT and AST). This study demonstrates the role of novel gut metabolites (dodecanoic acid and creatinine), as the fatty acid metabolism regulator contributing to NAFLD development through its influence on inflammation and liver function.

Altered gut microbiota and metabolites are a major cause of non-alcoholic fatty liver disease (NAFLD) in children. This study demonstrated a complete gut metabolic map of children with NAFLD, containing 318 increased and 123 decreased metabolites by untargeted metabolomic. Multiple validation approaches (machine learning and targeted metabolomic) selected five novel gut metabolites for targeted metabolomics, which can distinguish NAFLD status and severity. The gut microbiota (Butyricicoccus and Alistipes) and metabolites (creatinine and dodecanoic acid) were novel biomarkers associated with impaired liver function and inflammation and validated by experiments of hepatocyte cell lines. The data provide a better understanding of the importance of gut microbiota and metabolite alterations in NAFLD, which implies that the altered gut microbiota and metabolites may represent a potential target to prevent NAFLD development.

The systemic treatment of hepatocellular carcinoma (HCC) is changing rapidly. After a decade of tyrosine kinase inhibitors (TKIs), as the only therapeutic option for the treatment of advanced HCC, in the last few years several phase III trials demonstrated the efficacy of immune checkpoint inhibitors (ICIs). The combination of the anti-PD-L1 atezolizumab and the anti-vascular endothelial growth factor (VEGF) bevacizumab demonstrated the superiority over sorafenib and currently represents the standard of care treatment for advanced HCC. In addition, the combination of durvalumab (an anti-PD-L1) and tremelimumab (an anti-CTLA4) proved to be superior to sorafenib, and in the same trial durvalumab monotherapy showed non-inferiority compared to sorafenib. However, early reports suggest an influence of HCC etiology in modulating the response to these drugs. In particular, a lower effectiveness of ICIs has been suggested in patients with non-viral HCC (in particular non-alcoholic fatty liver disease). Nevertheless, randomized controlled trials available to date have not been stratified for etiology and data suggesting a possible impact of etiology in the outcome of patients managed with ICIs derive from subgroup not pre-specified analyses. In this review, we aim to examine the potential impact of HCC etiology on the response to immunotherapy regimens for HCC.

Metabolic dysfunction-associated steatotic liver disease (MASLD), a replacement of the nomenclature employed for NAFLD, is the most prevalent chronic liver disease worldwide. Despite its high global prevalence, NAFLD is often under-recognized due to the absence of reliable noninvasive biomarkers for diagnosis and staging. Growing evidence suggests that the gut microbiome plays a significant role in the occurrence and progression of NAFLD by causing immune dysregulation and metabolic alterations due to gut dysbiosis. The rapid advancement of sequencing tools and metabolomics has enabled the identification of alterations in microbiome signatures and gut microbiota-derived metabolite profiles in numerous clinical studies related to NAFLD. Overall, these studies have shown a decrease in α-diversity and changes in gut microbiota abundance, characterized by increased levels of Escherichia and Prevotella, and decreased levels of Akkermansia muciniphila and Faecalibacterium in patients with NAFLD. Furthermore, bile acids, short-chain fatty acids, trimethylamine N-oxide, and tryptophan metabolites are believed to be closely associated with the onset and progression of NAFLD. In this review, we provide novel insights into the vital role of gut microbiome in the pathogenesis of NAFLD. Specifically, we summarize the major classes of gut microbiota and metabolic biomarkers in NAFLD, thereby highlighting the links between specific bacterial species and certain gut microbiota-derived metabolites in patients with NAFLD.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are closely related liver conditions that have become more prevalent globally. This review examines the intricate interplay between microbiome dysbiosis and mitochondrial dysfunction in the development of NAFLD and NASH. The combination of these two factors creates a synergistic situation referred to as "double trouble", which promotes the accumulation of lipids in the liver and the subsequent progression from simple steatosis (NAFLD) to inflammation (NASH). Microbiome dysbiosis, characterized by changes in the composition of gut microbes and increased intestinal permeability, contributes to the movement of bacterial products into the liver. It triggers metabolic disturbances and has anti-inflammatory effects. Understanding the complex relationship between microbiome dysbiosis and mitochondrial dysfunction in the development of NAFLD and NASH is crucial for advancing innovative therapeutic approaches that target these underlying mechanisms.

Gut microbiota is known to have a significant impact on nonalcoholic fatty liver disease (NAFLD), particularly in children with obesity. However, the specific functions of microbiota at the strain level in this population have not been fully elucidated. In this study, we successfully isolated and identified several commensal gut bacterial strains that were dominant in children with obesity and NAFLD. Among these, four novel isolates were found to have significant lipogenic effects in vitro. These strains exhibited a potential link to hepatocyte steatosis by regulating the expression of genes involved in lipid metabolism and inflammation. Moreover, a larger cohort analysis confirmed that these identified bacterial strains were enriched in the NAFLD group. The integrated analysis of these strains effectively distinguished NASH from NAFL. These four strains might serve as potential biomarkers in children with NAFLD. These findings provided new insights into the exploration of therapeutic targets for NAFLD.

Non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) has recently risen to the top spot among chronic liver diseases in the world. However, there are no recognized treatments for it. Magnesium isoglycyrrhizate (MgIG) has potential as a NAFLD/NASH therapy.

To investigate the efficacy of MgIG in improving NAFLD/NASH and the possible pathways and mechanisms.

C57bl/6 mice were fed a high-fat diet (HFD) and 1 % dextran sulfate sodium (DSS) for 12 weeks to establish the NAFLD/NASH model. MgIG was administered by gavage during the last 7 weeks. First, the therapeutic effects of MgIG on hepatic steatosis and fibrosis, liver injury, and inflammation in the NAFLD/NASH mice were evaluated. Second, liver oxidative stress and hepatocyte apoptosis were detected. Finally, the effect of MgIG on intestinal permeability and short-chain fatty acid (SCFA) levels in mice's intestinal contents were examined.

MgIG administration attenuated HFD-induced hepatic steatosis and fibrosis, improved serum biochemical and NAFLD/NASH mice, reduced liver oxidative stress and hepatocyte apoptosis, improved intestinal permeability, and increased fecal SCFA levels in NAFLD/NASH mice.

MgIG protects against HFD-induced NAFLD/NASH through multiple pathways as well as mechanisms and holds promise as a potentially effective treatment for NAFLD/NASH.

Non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases worldwide. NAFLD is caused by numerous factors, including the genetic susceptibility, oxidative stress, unhealthy diet, and gut microbiota dysbiosis. Among these, gut microbiota is a key factor and plays an important role in the development of NAFLD. Therefore, modulating the composition and structure of gut microbiota might provide a new intervention strategy for NAFLD. Highland barley β-glucan (HBG) is a polysaccharide that can interact with gut microbiota after entering the lower gastrointestinal tract and subsequently improves NAFLD. Therefore, a Western diet was used to induce NAFLD in mouse models and the intervention effects and underlying molecular mechanisms of HBG on NAFLD mice based on gut microbiota were explored. The results indicated that HBG could regulate the composition of gut microbiota in NAFLD mice. In particular, HBG increased the abundance of short-chain fatty acids (SCFA)-producing bacteria (Prevotella-9, Bacteroides, and Roseburia) as well as SCFA contents. The increase in SCFA contents might activate the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, thereby improving the liver lipid metabolism disorder and reducing liver lipid deposition.

Gut microbiota plays an essential role in nonalcoholic fatty liver disease (NAFLD). However, the contribution of individual bacterial strains and their metabolites to childhood NAFLD pathogenesis remains poorly understood. Herein, the critical bacteria in children with obesity accompanied by NAFLD were identified by microbiome analysis. Bacteria abundant in the NAFLD group were systematically assessed for their lipogenic effects. The underlying mechanisms and microbial-derived metabolites in NAFLD pathogenesis were investigated using multi-omics and LC-MS/MS analysis. The roles of the crucial metabolite in NAFLD were validated in vitro and in vivo as well as in an additional cohort. The results showed that Enterococcus spp. was enriched in children with obesity and NAFLD. The patient-derived Enterococcus faecium B6 (E. faecium B6) significantly contributed to NAFLD symptoms in mice. E. faecium B6 produced a crucial bioactive metabolite, tyramine, which probably activated PPAR-γ, leading to lipid accumulation, inflammation, and fibrosis in the liver. Moreover, these findings were successfully validated in an additional cohort. This pioneering study elucidated the important functions of cultivated E. faecium B6 and its bioactive metabolite (tyramine) in exacerbating NAFLD. These findings advance the comprehensive understanding of NAFLD pathogenesis and provide new insights for the development of microbe/metabolite-based therapeutic strategies.

Limited studies have investigated the association between gut microbiota and metabolic dysfunction-associated fatty liver disease (MAFLD) in children and adolescents. We aimed to identify differences in gut microbiota composition and diversity between children with MAFLD and healthy counterparts.

Data were collected from a nested case-control study (October to December, 2021) of the "Huantai Childhood Cardiovascular Health Cohort Study" in Huantai County, Zibo City, China. The study included 52 children aged 5-11 years with new-onset MAFLD and 52 healthy children matched by age and sex. Stool samples were collected and analyzed using 16S rRNA gene sequencing. Shannon index and Chao index were used to assess the α diversity of gut microbiota and Principal coordinates analysis (PCoA) was performed to evaluate β diversity between the two groups. The differences in the relative abundance of gut microbiota between MAFLD group and control group were compared by the Wilcoxon rank-sum test after false discovery rate (FDR) correction. Additionally, the gut-microbial metabolic pathways were identified using the phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt).

We found that children with MAFLD had significant different gut microbiota composition and reduced α diversity compared with the control group. PCoA showed that the two groups can be significantly distinguished based on the unweighted unifrac distance algorithm. Gut microbiota at the phylum level such as Verrucomicrobia and Desulfobacterial, genus level such as Blautia, Lachnospiraceae_NK4A136_group, Coprococcus, Erysipelotrichaceae_UCG-003, UCG-002 and Akkermansia, and species level such as Bifidobacterium_longum abundances were significantly decreased in children with MAFLD compared with that in children without MAFLD. Notably, the abundance of these bacteria were found to be associated with HDL-C, SBP, DBP, WC, BMI, etc. In addition, our analysis of gut-microbial metabolic pathways identified differences in carbohydrate transport and metabolism, as well as amino acid transport and metabolism between the two groups.

Significant differences in gut microbiota composition are observed between children with and without MAFLD, which indicate that gut microbiota may be a potential contributor to the development of MAFLD in childhood.

The present systematic review and meta-analysis aimed to summarize the associations between gut microbiota composition and non-alcoholic fatty liver disease. To compare the differences between individuals with or without NAFLD, the standardized mean difference and 95% confidence interval were computed for each α-diversity index and relative abundance of gut microbes. The β-diversity indices were summarized in a qualitative manner. A total of 54 studies with 8894 participants were included. Overall, patients with NAFLD had moderate reduction in α-diversity indices including Shannon (SMD = -0.36, 95% CI = [-0.53, -0.19], p < 0.001) and Chao 1 (SMD = -0.42, 95% CI = [-0.68, -0.17], p = 0.001), but no significant differences were found for Simpson, observed species, phylogenetic diversity, richness, abundance-based coverage estimator, and evenness (p ranged from 0.081 to 0.953). Over 75% of the included studies reported significant differences in β-diversity. Although there was substantial interstudy heterogeneity, especially for analyses at the phylum, class, and family levels, the majority of the included studies showed alterations in the depletion of anti-inflammatory microbes (i.e., Ruminococcaceae and Coprococcus) and the enrichment of proinflammatory microbes (i.e., Fusobacterium and Escherichia) in patients with NAFLD. Perturbations in gut microbiota were associated with NAFLD, commonly reflected by a reduction in beneficial species and an increase in the pathogenic species.

Given the worldwide epidemic of overweight and obesity among children, evidence-based dietary recommendations are fundamentally important for obesity prevention. Although the significance of the human gut microbiome in shaping the physiological effects of diet and obesity has been widely recognized, nutritional therapeutics for the mitigation of pediatric obesity globally are only just starting to leverage advancements in the nutritional microbiology field. In this review, we extracted data from PubMed, EMBASE, Scopus, Web of Science, Google Scholar, CNKI, Cochrane Library and Wiley online library that focuses on the characterization of gut microbiota (including bacteria, fungi, viruses, and archaea) in children with obesity. We further review host-microbe interactions as mechanisms mediating the physiological effects of dietary fibers and how fibers alter the gut microbiota in children with obesity. Contemporary nutritional recommendations for the prevention of pediatric obesity are also discussed from a gut microbiological perspective. Finally, we propose an experimental framework for integrating gut microbiota into nutritional interventions for children with obesity and provide recommendations for the design of future studies on precision nutrition for pediatric obesity.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial complicated condition, reflected by the accumulation of extra fat in the liver. A detailed study of literature throws light on the fascinating connection between gut dysbiosis and NAFLD. The term 'gut dysbiosis' describes an imbalance in the harmony and operation of the gut microflora, which can upshoot a number of metabolic disorders. To recognize the underlying mechanisms and determine treatment options, it is essential to comprehend the connection between gut dysbiosis and NAFLD. This in-depth review discusses the normal gut microflora composition and its role in health, alterations in the gut microflora composition that leads to disease state focusing on NAFLD. The potential mechanisms influencing the advent and aggravation of NAFLD suggested disturbance of microbial metabolites, changes in gut barrier integrity, and imbalances in the composition of the gut microflora. Furthermore, it was discovered that gut dysbiosis affected immune responses, liver inflammation, and metabolic pathways, aggravating NAFLD.

Dysbiosis, generally defined as the disruption to gut microbiota composition or function, is observed in most diseases, including allergies, cancer, metabolic diseases, neurological disorders and diseases associated with autoimmunity. Dysbiosis is commonly associated with reduced levels of beneficial gut microbiota-derived metabolites such as short-chain fatty acids (SCFA) and indoles. Supplementation with these beneficial metabolites, or interventions to increase their microbial production, has been shown to ameliorate a variety of inflammatory diseases. Conversely, the production of gut 'dysbiotic' metabolites or by-products by the gut microbiota may contribute to disease development. This review summarizes the various 'dysbiotic' gut-derived products observed in cardiovascular diseases, cancer, inflammatory bowel disease, metabolic diseases including non-alcoholic steatohepatitis and autoimmune disorders such as multiple sclerosis. The increased production of dysbiotic gut microbial products, including trimethylamine, hydrogen sulphide, products of amino acid metabolism such as p-Cresyl sulphate and phenylacetic acid, and secondary bile acids such as deoxycholic acid, is commonly observed across multiple diseases. The simultaneous increased production of dysbiotic metabolites with the impaired production of beneficial metabolites, commonly associated with a modern lifestyle, may partially explain the high prevalence of inflammatory diseases in western countries.

Chronic inflammation and fibrosis are significant factors in the pathogenesis of metabolic-associated fatty liver disease (MAFLD). In this study, we conducted a bibliometric analysis of publications on inflammation and fibrogenesis in MAFLD, with a focus on reporting publication trends. Our findings indicate that the USA and China are the most productive countries in the field, with the University of California San Diego being the most productive institution. Over the past 23 years, Prof. Diehl AM has published 25 articles that significantly contributed to the research community. Notably, the research focus of the field has shifted from morbid obesity and adiponectin to metabolic syndrome, genetics, and microbiome. Our study provides a comprehensive and objective summary of the historical characteristics of research on inflammation and fibrogenesis in MAFLD, which will be of interest to scientific researchers in this field.

Liver disease is a major global health problem leading to approximately two million deaths a year. This is the consequence of a number of aetiologies, including alcohol-related, metabolic-related, viral infection, cholestatic and immune disease, leading to fibrosis and, eventually, cirrhosis. No specific registered antifibrotic therapies exist to reverse liver injury, so current treatment aims at managing the underlying factors to mitigate the development of liver disease. There are bidirectional feedback loops between the liver and the rest of the gastrointestinal tract via the portal venous and biliary systems, which are mediated by microbial metabolites, specifically short-chain fatty acids (SCFAs) and secondary bile acids. The interaction between the liver and the gastrointestinal microbiome has the potential to provide a novel therapeutic modality to mitigate the progression of liver disease and its complications. This review will outline our understanding of hepatic fibrosis, liver disease, and its connection to the microbiome, which may identify potential therapeutic targets or strategies to mitigate liver disease.

Human microbiome variation is linked to the incidence, prevalence, and mortality of many diseases and associates with race and ethnicity in the United States. However, the age at which microbiome variability emerges between these groups remains a central gap in knowledge. Here, we identify that gut microbiome variation associated with race and ethnicity arises after 3 months of age and persists through childhood. One-third of the bacterial taxa that vary across caregiver-identified racial categories in children are taxa reported to also vary between adults. Machine learning modeling of childhood microbiomes from 8 cohort studies (2,756 samples from 729 children) distinguishes racial and ethnic categories with 87% accuracy. Importantly, predictive genera are also among the top 30 most important taxa when childhood microbiomes are used to predict adult self-identified race and ethnicity. Our results highlight a critical developmental window at or shortly after 3 months of age when social and environmental factors drive race and ethnicity-associated microbiome variation and may contribute to adult health and health disparities.