The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR), a lipid-related biomarker, remains underexplored in relation to the risk of advanced fibrosis and hepatic steatosis. The present study aimed to investigate the potential association between the NHHR and these hepatic conditions. A total of 6,907 individuals aged 20 years and older from the National Health and Nutrition Examination Survey 2017-2020 were included in the present study. Advanced fibrosis and hepatic steatosis were assessed using hepatic vibration-controlled transient elastography. Multivariate regression analysis and subgroup analysis were performed to explore the independent association between the NHHR and the presence of advanced fibrosis and hepatic steatosis. Among the 6,907 adults included in the present study (mean age, 50.56±17.21 years; 3,398 male patients and 3,509 female patients), 409 (5.92%) were diagnosed with advanced fibrosis and 3,034 (43.93%) were diagnosed with hepatic steatosis. Following multivariable adjustment (age, sex, ethnicity, education level, family income-to-poverty ratio, smoking status, alcohol use and vigorous physical activity), logistic regression analysis demonstrated that an elevated NHHR was positively associated with increased possibility for advanced fibrosis [odds ratio (OR), 1.10; 95% confidence interval (CI), 1.03-1.17; P=0.005]. The restricted cubic spline model indicated a linear dose-response association between the NHHR and advanced fibrosis. The NHHR also exhibited a significant association with a higher risk of hepatic steatosis after full adjustment for covariates (OR, 1.61; 95% CI, 1.53-1.68; P<0.001). Using a two-segment linear regression model, an S-shaped relationship was identified between the NHHR and hepatic steatosis, with an inflection point at 3.83. In conclusion, the present study established a robust association of the NHHR with advanced fibrosis and hepatic steatosis. The NHHR may serve as a straightforward anthropometric index for predicting these conditions.

Non-alcoholic fatty liver disease (NAFLD) has frequently been associated with obesity, type 2 diabetes (T2D), and dyslipidemia, all of which are shared by increased insulin resistance. It has become the most common liver disorder in Korea as well as in developed countries and is therefore associated with an increased health burden of morbidity and mortality. It has an association with T2D, and T2D increases the risk of cirrhosis and related complications. NAFLD encompasses a disease continuum from simple steatosis to non-alcoholic steatohepatitis which is characterized by faster fibrosis progression. Although its liver-related complication is estimated to be, at most, 10%, it will be a leading cause of cirrhosis and hepatocellular carcinoma soon in Korea. Although the main causes of death in people with NAFLD are cardiovascular disease and extra-hepatic malignancy, advanced liver fibrosis is a key prognostic marker for liver-related outcomes and can be assessed with combinations of non-invasive tests in the community. A number of components of metabolic syndrome involved could be another important prognostic information of NAFLD assessed easily in the routine care of the community. There is a few approved therapies for NAFLD, although several drugs, including antioxidants, attract practitioners' attention. Because of the modest effect of the present therapeutics, let alone complex pathophysiology and substantial heterogeneity of disease phenotypes, combination treatment is a viable option for many patients with NAFLD in the Korean community. Comprehensive approach taking healthy lifestyle and weight reduction into account remain a mainstay to the prevention and treatment of NAFLD.

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.

Non-alcoholic fatty liver disease (NAFLD) is a global cause of liver dysfunction. This spectrum of hepatic disorders can progress to severe conditions, such as non-alcoholic steatohepatitis (NASH) and cirrhosis, due to oxidative stress and sustained cellular injury. With limited pharmacological options, glutathione (GSH), a key antioxidant, has shown promising potential in reducing oxidative stress, maintaining redox balance, and improving liver function. This literature review examines studies from 2014-2024 exploring GSH therapy in NAFLD patients. Eligible studies assessed GSH as the primary intervention for NAFLD in human subjects, reporting outcomes such as liver function or oxidative stress markers. Randomized clinical trials (RCTs) were eligible, while combination therapy studies were included if GSH's effect could be isolated. Exclusions applied to non-NAFLD studies, animal/in vitro models, and non-GSH antioxidant interventions. Analysis of three studies (totaling 109 participants) demonstrated consistent improvements in alanine transaminase (ALT) levels and reductions in oxidative stress markers like 8-hydroxy-2-deoxyguanosine (8-OHdG). However, small sample sizes and inconsistent protocols limit generalizability. Further large-scale RCTs are required to confirm GSH's efficacy, determine optimal dosing, and assess long-term effects. This literature review highlights GSH's potential as a novel NAFLD therapeutic strategy while emphasizing the need for further studies to refine its clinical application.

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.

Background: Non-alcoholic fatty liver disease (NAFLD), more recently redefined as metabolic-associated fatty liver disease (MAFLD), is now recognized as the most prevalent cause of chronic liver disease. Its strong association with cardiovascular disease (CVD) underscores its emerging role in global morbidity and mortality. Objective: This review critically examines the pathophysiological mechanisms that link NAFLD/MAFLD with CVD. It focuses on shared metabolic disturbances, inflammatory pathways, and alterations in the gut microbiota that contribute to hepatic and cardiovascular pathology. Review and Gaps: Current evidence highlights insulin resistance, dyslipidemia, systemic inflammation, and gut dysbiosis as pivotal factors connecting NAFLD/MAFLD to CVD. Despite these insights, inconsistencies in diagnostic criteria and a lack of validated non-invasive biomarkers hinder a clear understanding of the causal relationship between liver and cardiovascular diseases. Conclusions: Addressing these knowledge gaps through standardized diagnostic protocols and large-scale longitudinal studies is essential. Improved biomarker validation and clearer delineation of the underlying mechanisms will improve cardiovascular risk stratification and enable more personalized therapeutic strategies for patients with NAFLD/MAFLD.

To investigate the features of gut microbiota in cirrhotic patients with myosteatosis and identify specific bacterial species that may be involved in the pathogenesis of myosteatosis.

80 patients with liver cirrhosis were categorized into the myosteatosis group (n = 44) and the non-myosteatosis group (n = 36). Metagenomic sequencing was used to analyze the differences in gut microbiota composition between the two groups. Subsequently, the value of meaningful gut microbiota in the diagnosis of myosteatosis in patients with liver cirrhosis was analyzed.

At the species level, however, 15 bacterial species exhibited significant differences in relative abundance between these two groups. The relative abundance of Roseburia hominis and Subdoligranulum unclassified was inversely associated with mean muscle attenuation density at the L3 level (p < 0.05). Assessement of the diagnostic potential of Roseburia hominis and Subdoligranulum unclassified for the development of myosteatosis showed that the areas under the ROC curves (AUCs) was 0.869 [95% confidence interval (CI): 0.709-1.029; p < 0.05] for Roseburia hominis and 0.828 (95% CI: 0.6472-1.009; p < 0.05) for Subdoligranulum unclassified.

Our study establishes compositional alterations of gut microbiota in patients with liver cirrhosis combined with myosteatosis and suggests the diagnostic potential for using gut microbiota as noninvasive biomarkers.

Summaries of the relationships between the microbiota and liver cirrhosis and their conclusions are not consistent. This study describes microbial differences in patients with liver cirrhosis by performing a meta-analysis.

We searched PubMed, Embase, Web of Science, and the Cochrane Library and collected related articles published before March 10, 2024. Ratio of autochthonous to non-autochthonous taxa was calculated as the cirrhosis dysbiosis ratio (CDR). Using a random-effects model, the standard mean deviation (SMD) and 95% confidence interval (CI) were calculated. We subsequently performed subgroup, sensitivity, and publication bias analyses. cirrhosis dysbiosis ratio.

A total of 53 eligible papers including 5076 participants were included. The pooled estimates revealed a moderately significant reduction in gut microbiome richness in patients with liver cirrhosis compared with controls, including the Shannon, Chao1, observed species, ACE, and PD indices, but no significant difference was observed for the Simpson index. Over 80% of the studies reported significant differences in β diversity. Families Enterobacteriaceae and Pasteurellaceae, belonging to the phylum Proteobacteria, along with the family Streptococcaceae and the genera Haemophilus, Streptococcus, and Veillonella, were significantly associated with liver cirrhosis compared to the control group. In contrast, the healthy group exhibited a higher abundance of the class Clostridia, particularly the families Lachnospiraceae and Ruminococcaceae, which are known for their diversity and role as common gut commensals. Furthermore, the class Bacilli, predominantly represented by the genus Streptococcus, was markedly enriched in the cirrhosis group.

The microbiota richness of liver cirrhosis patients was lower than that of healthy controls. Alterations in gut microbiota linked to liver cirrhosis were characterized by a decrease in Lachnospiraceae, Ruminococcaceae, and Clostridia and an enrichment of Enterobacteriaceae, Pasteurellaceae, Streptococcaceae, Bacilli, and Streptococcus.

The microbiome of the human intestine is a regulator of health that modulates immune response and plays an important role in metabolism. The diversity, and abundance of microbiota communities in the gut have been shown to change in cirrhosis and its complications. We aimed to review the current knowledge regarding microbiota alterations in cirrhosis, its potential differences according to etiology, and its role in the development of cirrhosis complications. A systematic search of the online bibliographic database up to July 2024 was performed. Randomized controlled trials and observational and cohort studies that included a total or at least a cohort of cirrhotic adult patients were enlisted for data extraction and analysis. A total of 73 publications were included for data extraction. Alpha diversity was found to decrease in cirrhotic patients in 30/38 (78%) of the studies, while beta diversity in 20/22 (90%) presented significant differences between healthy and cirrhotic groups. Proteobacteria significantly increased in 20/27 (74%) studies, followed by Actinobacteria and Fusobacteria, while 22/25 (88%) studies found either a reduction in cirrhotic patients or increased abundance in healthy controls for Firmicutes and Bacteroidetes. The most abundant genera in hepatic encephalopathy groups were pathobionts such as Enterococcus and Streptococcus, followed by Vellionella and Escherichia. Heterogeneity was found among studies regarding Alpha diversity in hepatocellular carcinoma (HCC) as it was decreased in three studies, indifferent in five, and increased in three studies in comparison to cirrhotic non-HCC patients. The dysbiosis of the gut microbiota is associated with cirrhosis and the development of complications such as hepatic encephalopathy and hepatocellular carcinoma.

Evidence suggests that the gastrointestinal microbiome plays a significant role in the biology of metabolic dysfunction-associated steatotic liver disease (MASLD). However, it remains unclear whether disparities in the gut microbiome across intestinal tissular compartments between the sexes lead to MASLD pathogenesis.

Sex-specific analyses of microbiome composition in two anatomically distinct regions of the gut, the small intestine and colon, were performed using an experimental model of MASLD. The study involved male and female spontaneously hypertensive rats and the Wistar-Kyoto control rat strain, which were fed either a standard chow diet or a high-fat diet for 12 weeks to induce MASLD (12 rats per group). High-throughput 16S sequencing was used for microbiome analysis.

There were significant differences in the overall microbiome composition of male and female rats with MASLD, including variations in topographical gut regions. The beta diversity of the jejunal and colon microbiomes was higher in female rats than in male rats (PERMANOVA p-value=0.001). Sex-specific analysis and discriminant features using LEfSe showed considerable variation in bacterial abundance, along with distinct functional properties, in the jejunum and colon of animals with MASLD. Significantly elevated levels of lipopolysaccharide and protein expression of Toll-like receptor 4 were observed in the livers of male rats with MASLD compared with their female counterparts.

This study uncovered sexual dimorphism in the gut microbiome of MASLD and identified microbial heterogeneity within intestinal compartments. Insights into sex-specific variations in gut microbiome composition could facilitate customised treatment strategies.

Gut microbiota regulates the immune system, the development and progression of autoimmune diseases (AIDs) and overall health. Recent studies have played a crucial part in understanding the specific role of different gut bacterial strains and their metabolites in different AIDs. Microbial signatures in AIDs are revealed by advanced sequencing and metabolomics studies. Microbes such as Faecalibacterium prausnitzii, Akkermansia muciniphila, Anaerostipes caccae, Bacteroides sp., Roseburia sp., Blautia sp., Blautia faecis, Clostridium lavalense, Christensenellaceae sp., Coprococcus sp., Firmicutes sp., Ruminococcaceae sp., Lachnospiraceae sp., Megamonas sp., Monoglobus sp., Streptococcus pneumoniae and Bifidobacterium sp. help maintain immune homeostasis; whereas, Prevotella copri, Ruminococcus gnavus, Lactobacillus salivarius, Enterococcus gallinarum, Elizabeth menigoseptica, Collinsella sp., Escherichia sp., Fusobacterium sp., Enterobacter ludwigii, Enterobacteriaceae sp., Proteobacteria, Porphyromonas gingivalis, Porphyromonas nigrescens, Dorea sp., and Clostridium sp. cause immuno-pathogenesis. A complex web of interactions is revealed by understanding the influence of gut microbiota on immune cells and various T cell subsets such as CD4+ T cells, CD8+ T cells, natural killer T cells, γδ T cells, etc. Certain AIDs, including rheumatoid arthritis, diabetes mellitus, atopic asthma, inflammatory bowel disease and non-alcoholic fatty liver disease exhibit a state of dysbiosis, characterized by alterations in microbial diversity and relative abundance of specific taxa. This review summarizes recent developments in understanding the role of certain microbiota composition in specific AIDs, and the factors affecting specific regulatory T cells through certain microbial metabolites and also focuses the potential application and therapeutic significance of gut microbiota-based interventions as novel adjunctive therapies for AIDs. Further research to determine the precise association of each gut bacterial strain in specific diseases is required.

Microbial signatures in the human microbiome are closely associated with various human diseases, driving the development of machine learning models for microbiome-based disease prediction. Despite progress, challenges remain in enhancing prediction accuracy, generalizability, and interpretability. Confounding factors, such as host's gender, age, and body mass index, significantly influence the human microbiome, complicating microbiome-based predictions.

To address these challenges, we developed MicroKPNN-MT, a unified model for predicting human phenotype based on microbiome data, as well as additional metadata like age and gender. This model builds on our earlier MicroKPNN framework, which incorporates prior knowledge of microbial species into neural networks to enhance prediction accuracy and interpretability. In MicroKPNN-MT, metadata, when available, serves as additional input features for prediction. Otherwise, the model predicts metadata from microbiome data using additional decoders. We applied MicroKPNN-MT to microbiome data collected in mBodyMap, covering healthy individuals and 25 different diseases, and demonstrated its potential as a predictive tool for multiple diseases, which at the same time provided predictions for the missing metadata. Our results showed that incorporating real or predicted metadata helped improve the accuracy of disease predictions, and more importantly, helped improve the generalizability of the predictive models.

https://github.com/mgtools/MicroKPNN-MT.

Gut microbiome dysbiosis is involved in non-alcoholic fatty liver disease (NAFLD) development. Hepatic transmembrane 4 L six family member 5 (TM4SF5) overexpression promotes NAFLD. However, how gut microbiota are associated with TM4SF5-mediated NAFLD remains unexplored. We analyzed the gut microbiome using feces from hepatocyte-specific TM4SF5-overexpressing transgenic (Alb-TGTm4sf5-Flag, TG) or Tm4sf5-/- knock-out (KO) mice fed a normal chow diet (NCD), high-fat diet (HFD) for 2 weeks (HFD2W), or methionine-choline-deficient diet (MCD) for 4 weeks to investigate associations among Tm4sf5 expression, diet, and the gut microbiome. TG-NCD mice showed a higher Firmicutes-to-Bacteroidetes (F/B) ratio, with less enrichment of Akkermansia muciniphila and Lactobacillus reuteri. NASH-related microbiomes in feces were more abundant in TG-HFD2w mice than in KO-HFD2w mice. Further, TG-MCD showed a higher F/B ratio than TG-NCD or KO mice, with decreases or increases in microbiomes beneficial or detrimental to the liver, respectively. Such effects in TG-MCD animals were correlated with functional pathways producing short-chain fatty acids (SCFAs). Furthermore, potential functional pathways of the gut microbiome were metabolically parallel to NAFLD features in TG-MCD mice. These results suggest that hepatocyte Tm4sf5 supports gut microbiome dysbiosis and metabolic activity, leading to SCFA production and hepatic inflammation during NAFLD development.

Background: The gut microbiota constitutes a complex microorganism community that harbors bacteria, viruses, fungi, protozoa, and archaea. The human gut bacterial microbiota has been extensively proven to participate in human metabolism, immunity, and nutrient absorption. Its imbalance, namely "dysbiosis", has been linked to disordered metabolism. Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the features of deranged human metabolism and is the leading cause of liver cirrhosis and hepatocellular carcinoma. Thus, there is a pathophysiological link between gut dysbiosis and MASLD. Aims and Methods: We aimed to review the literature data on the composition of the human bacterial gut microbiota and its dysbiosis in MASLD and describe the concept of the "gut-liver axis". Moreover, we reviewed the approaches for gut microbiota modulation in MASLD treatment. Results: There is consolidated evidence of particular gut dysbiosis associated with MASLD and its stages. The model explaining the relationship between gut microbiota and the liver has a bidirectional organization, explaining the physiopathology of MASLD. Oxidative stress is one of the keystones in the pathophysiology of MASLD and fibrosis generation. There is promising and consolidated evidence for the efficacy of pre- and probiotics in reversing gut dysbiosis in MASLD patients, with therapeutic effects. Few yet encouraging data on fecal microbiota transplantation (FMT) in MASLD are available in the literature. Conclusions: The gut dysbiosis characteristic of MASLD is a key target in its reversal and treatment via diet, pre/probiotics, and FMT treatment. Oxidative stress modulation remains a promising target for MASLD treatment, prevention, and reversal.

Non-communicable diseases (NCDs) are the leading cause of morbidity and mortality worldwide. These conditions have numerous health consequences and significantly impact patients' lifestyles. Effective long-term treatment is essential since NCDs are irreversible. Therefore, primary healthcare must be both exclusive and of the highest quality, ensuring comprehensive care. The primary goal should be to improve quality of life with a focus on patients, families, and communities, as most of these diseases can be prevented and controlled, although not cured. Several factors have been linked to individual health, including social, cultural, and economic aspects, lifestyle, and certain environmental factors, including work, that can have positive or negative effects. More of these variables may contribute to the onset of NCDs, which are defined by their chronic nature, propensity for prolongation, and generally slow rate of progression. Examples of NCDs include hypertension, type 2 diabetes (T2D), dyslipidemia, and fatty liver disease linked to metabolic dysfunction. The onset of these diseases has been associated with an imbalance in certain microbial niches, such as the gut, which hosts billions of microorganisms performing multiple metabolic functions, such as the production of metabolites like bile acids (BAs), short-chain fatty acids (SCFAs), and trimethylamine N-oxide (TMAO). Therefore, lifestyle changes and personal habits can significantly impact the gut microbiota (GM), potentially preventing chronic diseases associated with metabolism. NCDs are highly prevalent worldwide, prompting increased attention to strategies for modifying the intestinal microbiota (IM). Approaches such as probiotics, prebiotics, synbiotics, and fecal transplantation (FMT) have demonstrated improvements in the quality of life for individuals with these conditions. Additionally, lifestyle changes and the adoption of healthy habits can significantly impact IM and may help prevent chronic diseases related to metabolism. Therefore, the main aim of this review is to analyze and understand the importance of microbiota intervention in the prevention of non-communicable diseases. R3:A1.

Pediatric cases of metabolic dysfunction-associated fatty liver disease (MASLD, formerly termed non-alcoholic fatty liver disease (NAFLD) are a troubling new outcome of the pediatric obesity epidemic. Advising patients and families with this condition is challenging considering the nutrition needed to sustain developmentally appropriate growth in youth. Describing risk factors, comorbidities, management, and referrals for MASLD could improve surveillance and outcomes for this condition. MASLD is commonly seen with other comorbidities such as dyslipidemia, obstructive sleep apnea, type 2 diabetes, hypothyroidism, anxiety, and depression. Considerations of epigenetics, diabetes, and adverse childhood experiences will be explored as additional underlying contributors to MASLD. Screening patients for this condition in conjunction with other comorbidities is essential to preventing the progression to non-alcoholic steatohepatitis (NASH) and cirrhosis, as well as lowering the risk for hepatocellular carcinoma. This fraternal twin case report describes pertinent diagnostics, recommendations for referrals, follow-up consultations, and red flags for more advanced liver disease.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD)-previously described as nonalcoholic fatty liver disease-continues to rise globally. Despite this, therapeutic measures for MASLD remain limited. Recently, there has been a growing interest in the gut microbiome's role in the pathogenesis of MASLD. Understanding this relationship may allow for the administration of therapeutics that target the gut microbiome and/or its metabolic function to alleviate MASLD development or progression. This review will discuss the interplay between the gut microbiome's structure and function in relation to the development of MASLD, assess the diagnostic yield of gut microbiome-based signatures as a noninvasive tool to identify MASLD severity, and examine current and emerging therapies targeting the gut microbiome-liver axis.

Despite the slow, progressive nature of NAFLD, the number of patients with NAFLD-related cirrhosis has significantly increased. Although the management of patients with cirrhosis is constantly evolving, improving the prognosis of patients with NAFLD-related cirrhosis is a challenge because it is situated at the crossroads between the liver, the metabolic, and the cardiovascular diseases. Therefore, the therapeutic interventions should not only target the liver but also the associated cardiometabolic conditions and should be adapted accordingly. The objective of the current review is to critically discuss the particularities in the management of patients with NAFLD-related cirrhosis. We relied on the recommendations of scientific societies and discussed them in the specific context of NAFLD cirrhosis and the surrounding cardiometabolic milieu. Herein, we covered the following aspects: (1) the weight loss strategies through lifestyle interventions to avoid sarcopenia and improve portal hypertension; (2) the optimal control of metabolic comorbidities in particular type 2 diabetes aimed not only to improve cardiovascular morbidity/mortality but also to lower the incidence of cirrhosis-related complications (we discussed various aspects related to the safety of oral antidiabetic drugs in cirrhosis); (3) the challenges in performing bariatric surgery in patients with cirrhosis related to the portal hypertension and the risk of cirrhosis decompensation; (4) the particularities in the diagnosis and management of the portal hypertension and the difficulties in managing patients awaiting for liver transplantation; and (5) the difficulties in developing drugs and conducting clinical trials in patients with NAFLD-related cirrhosis. Moreover, we discussed the emerging options to overcome these obstacles.

Individual genes from microbiomes can drive host-level phenotypes. To help identify such candidate genes, several recent tools estimate microbial gene copy numbers directly from metagenomes. These tools rely on alignments to pangenomes, which in turn are derived from the set of all individual genomes from one species. While large-scale metagenomic assembly efforts have made pangenome estimates more complete, mixed communities can also introduce contamination into assemblies, and it is unknown how robust pangenome-based metagenomic analyses are to these errors. To gain insight into this problem, we re-analyzed a case-control study of the gut microbiome in cirrhosis, focusing on commensal Clostridia previously implicated in this disease. We tested for differentially prevalent genes in the Lachnospiraceae, then investigated which were likely to be contaminants using sequence similarity searches. Out of 86 differentially prevalent genes, we found that 33 (38%) were probably contaminants originating in taxa such as Veillonella and Haemophilus, unrelated genera that were independently correlated with disease status. Our results demonstrate that even small amounts of contamination in metagenome assemblies, below typical quality thresholds, can threaten to overwhelm gene-level metagenomic analyses. However, we also show that such contaminants can be accurately identified using a method based on gene-to-species correlation. After removing these contaminants, we observe that several flagellar motility gene clusters in the Lachnospira eligens pangenome are associated with cirrhosis status. We have integrated our analyses into an analysis and visualization pipeline, PanSweep, that can automatically identify cases where pangenome contamination may bias the results of gene-resolved analyses.

Metagenome-assembled genomes, or MAGs, can be constructed without pure cultures of microbes. Large scale efforts to build MAGs have yielded more complete pangenomes (i.e., sets of all genes found in one species). Pangenomes allow us to measure strain variation in gene content, which can strongly affect phenotype. However, because MAGs come from mixed communities, they can contaminate pangenomes with unrelated DNA, and how much this impacts downstream analyses has not been studied. Using a metagenomic study of gut microbes in cirrhosis as our test case, we investigate how contamination affects analyses of microbial gene content. Surprisingly, even small, typical amounts of MAG contamination (<5%) result in disproportionately high levels of false positive associations (38%). Fortunately, we show that most contaminants can be automatically flagged, and provide a simple method for doing so. Furthermore, applying this method reveals a new association between cirrhosis and gut microbial motility.

Hepatocellular carcinoma (HCC) related to metabolic dysfunction-associated steatotic liver disease (MASLD) is often diagnosed at a late stage, and its incidence is increasing. Predictive biomarkers are therefore needed to identify individuals at high risk of HCC. We aimed to characterize the gut microbiome and hepatic transcriptome associated with HCC development in female mice with hepatocyte-deletion of Pten (HepPten -). These mice present with large variations in HCC development, making them a powerful model for biomarker discovery.

Sequencing of stool 16S and hepatic RNA was performed on a first set of mice. Among all liver histology parameters measured, the strongest association with microbiome composition changes was with the number of tumors detected at necropsy, followed by inflammation. The gut microbiome of mice with more than 2 tumors was enriched with Lachnospiraceae UCG and depleted of Palleniella intestinalis and Odoribacter. In contrast, hepatic transcriptomic changes were most strongly associated with tumor burden, followed by liver fibrosis. The 840 differentially expressed genes correlating with tumor burden were enriched in leukocyte extravasation and interleukin 10 receptor A (IL10RA) pathways. In addition, the abundance of Spp1-high epithelial cells is correlated with tumor burden. Association between tumor number and depletion of Palleniella intestinalis, and between tumor burden and circulating levels of C-X-C motif chemokine ligand 13 (CXCL13) and stem cell factor (SCF), was further validated in an independent set of mice.

We identified microbiome components contributing to liver carcinogenesis by inducing inflammation, and changes in hepatic gene expression and hepatic cells distribution that contribute to tumor growth. Such information can be highly valuable for the development of new prevention strategies as well as of new biomarkers for risk modeling in HCC.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver ailment that can lead to serious conditions such as cirrhosis and hepatocellular carcinoma. Hepatic Nogo-B regulates glucose and lipid metabolism, and its inhibition has been shown to be protective against metabolic syndrome. Increasing evidence suggests that imbalances in the gut microbiota (GM) and lipid metabolism disorders are significant contributors to NAFLD progression. Nevertheless, it is not yet known whether Nogo-B can affect NAFLD by influencing the gut microbiota and metabolites. Hence, the aim of the present study was to characterize this process and explore its possible underlying mechanisms.

A NAFLD model was constructed by administering a high-fat diet (HFD) to Nogo-B-/- and WT mice from the same litter, and body weight was measured weekly in each group. The glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed to assess blood glucose levels. At the end of the 12-week period, samples of serum, liver, and intestinal contents were collected and used for serum biochemical marker and inflammatory factor detection; pathology evaluation; and gut microbiome and metabolomics analysis. Spearman's correlation analysis was performed to determine possible correlations between differential gut microbiota and differential serum metabolites between groups.

Nogo-B deficiency attenuated the effects of the HFD, including weight gain, liver weight gain, impaired glucose tolerance, hepatic steatosis, elevated serum lipid biochemicals levels, and liver function. Nogo-B deficiency suppressed M1 polarization and promoted M2 polarization, thus inhibiting inflammatory responses. Furthermore, Nogo-B-/--HFD-fed mice presented increased gut microbiota richness and diversity, decreased Firmicutes/Bacteroidota (F/B) ratios, and altered serum metabolites compared with those of WT-HFD-fed mice. During analysis, several differential gut microbiota, including Lachnoclostridium, Harryflintia, Odoribacter, UCG-009, and unclassified_f_Butyricoccaceae, were screened between groups. These microbiota were found to be positively correlated with upregulated purine metabolism and bile acid metabolites in Nogo-B deficiency, while they were negatively correlated with downregulated corticosterone and tricarboxylic acid cyclic metabolites in Nogo-B deficiency.

Nogo-B deficiency delayed NAFLD progression, as demonstrated by reduced hepatocellular lipid accumulation, attenuated inflammation and liver injury, and ameliorated gut microbiota dysbiosis and metabolic disorders. Importantly, Odoribacter was strongly positively correlated with ALB and taurodeoxycholic acid, suggesting that it played a considerable role in the influence of Nogo-B on the progression of NAFLD, a specific feature of NAFLD in Nogo-B-/- mice. The regulation of bile acid metabolism by the gut microbiota may be a potential target for Nogo-B deficiency to ameliorate NAFLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is constantly rising globally. There are barely any effective medications or supplements for the management of MASLD. We aim to systematically evaluate the most current evidence for gut microbiota-regulating supplements in patients with MASLD.

We searched multiple electronic data for randomized controlled trials (RCTs) published from January 1, 2012, to July 15, 2023. The intervention measures included probiotics, prebiotics, synbiotics, antibiotics, and fecal microbiota transplantation (FMT). The control group was treated with a placebo or usual care. The intervention duration was divided into two periods (>12 weeks and ≤12 weeks). Adequate evaluation data for antibiotics and FMT have not been obtained. Therefore, the other three microbiota regulators are the primary evaluation measures in this study.

We found that probiotics alone could not improve clinical indicators in MASLD patients. However, synbiotics exhibited an improvement in reducing liver steatosis, TNF-ɑ levels, and increasing HDL-c levels, and the inflammatory markers of liver cells (ALT and AST) were also improved. For the effective intervention duration, this systematic review suggested that around 12 weeks is an ideal intervention cycle for MASLD patients.

This meta-analysis supported the modulation of gut microbiota with synbiotics in the management of MASLD.

The new nomenclature of metabolic dysfunction-associated steatotic liver disease (MASLD) emphasizes a positive diagnosis based on cardiometabolic risk factors. This definition is not only less stigmatizing but also allows for subclassification and stratification, thereby addressing the heterogeneity of what was historically referred to as nonalcoholic fatty liver disease. The heterogeneity within this spectrum is influenced by several factors which include but are not limited to demographic/dietary factors, the amount of alcohol use and drinking patterns, metabolic status, gut microbiome, genetic predisposition together with epigenetic factors. The net effect of this dynamic and intricate system-level interaction is reflected in the phenotypic presentation of MASLD. Therefore, the application of precision medicine in this scenario aims at complex phenotyping with consequent individual risk prediction, development of individualized preventive strategies, and improvements in the clinical trial designs. In this review, we aim to highlight the importance of precision medicine approaches in MASLD, including the use of novel biomarkers of disease, and its subsequent utilization in future study designs.

The human microbiome has been increasingly recognized as having potential use for disease prediction. Predicting the risk, progression, and severity of diseases holds promise to transform clinical practice, empower patient decisions, and reduce the burden of various common diseases, as has been demonstrated for cardiovascular disease or breast cancer. Combining multiple modifiable and non-modifiable risk factors, including high-dimensional genomic data, has been traditionally favored, but few studies have incorporated the human microbiome into models for predicting the prospective risk of disease. Here, we review research into the use of the human microbiome for disease prediction with a particular focus on prospective studies as well as the modulation and engineering of the microbiome as a therapeutic strategy.

Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis, cirrhosis, and eventual hepatocellularcarcinoma (HCC). Notably, HBV infection stands as the primary etiologicalfactor driving the development of HCC. Given the significant contribution ofHBV infection to liver diseases, a comprehensive understanding of immunedynamics in the liver microenvironment, spanning chronic HBV infection,fibrosis, cirrhosis, and HCC, is essential. In this review, we focused on thefunctional alterations of CD8+ T cells within the pathogenic livermicroenvironment from HBV infection to HCC. We thoroughly reviewed the roles ofhypoxia, acidic pH, metabolic reprogramming, amino acid deficiency, inhibitory checkpointmolecules, immunosuppressive cytokines, and the gut-liver communication in shapingthe dysfunction of CD8+ T cells in the liver microenvironment. Thesefactors significantly impact the clinical prognosis. Furthermore, we comprehensivelyreviewed CD8+ T cell-based therapy strategies for liver diseases,encompassing HBV infection, fibrosis, cirrhosis, and HCC. Strategies includeimmune checkpoint blockades, metabolic T-cell targeting therapy, therapeuticT-cell vaccination, and adoptive transfer of genetically engineered CD8+ T cells, along with the combined usage of programmed cell death protein-1/programmeddeath ligand-1 (PD-1/PD-L1) inhibitors with mitochondria-targeted antioxidants.Given that targeting CD8+ T cells at various stages of hepatitis Bvirus-induced hepatocellular carcinoma (HBV + HCC) shows promise, we reviewedthe ongoing need for research to elucidate the complex interplay between CD8+ T cells and the liver microenvironment in the progression of HBV infection toHCC. We also discussed personalized treatment regimens, combining therapeuticstrategies and harnessing gut microbiota modulation, which holds potential forenhanced clinical benefits. In conclusion, this review delves into the immunedynamics of CD8+ T cells, microenvironment changes, and therapeuticstrategies within the liver during chronic HBV infection, HCC progression, andrelated liver diseases.

The gut ecosystem, termed microbiota, is composed of bacteria, archaea, viruses, protozoa, and fungi and is estimated to outnumber human cells. Microbiota can affect the host by multiple mechanisms, including the synthesis of metabolites and toxins, modulating inflammation and interaction with other organisms. Advances in understanding commensal organisms' effect on human conditions have also elucidated the importance of this community for cardiovascular disease (CVD). This effect is driven by both direct CV effects and conditions known to increase CV risk, such as obesity, diabetes mellitus (DM), hypertension, and renal and liver diseases. Cardioactive metabolites, such as trimethylamine N -oxide (TMAO), short-chain fatty acids (SCFA), lipopolysaccharides, bile acids, and uremic toxins, can affect atherosclerosis, platelet activation, and inflammation, resulting in increased CV incidence. Interestingly, this interaction is bidirectional with microbiota affected by multiple host conditions including diet, bile acid secretion, and multiple diseases affecting the gut barrier. This interdependence makes manipulating microbiota an attractive option to reduce CV risk. Indeed, evolving data suggest that the benefits observed from low red meat and Mediterranean diet consumption can be explained, at least partially, by the changes that these diets may have on the gut microbiota. In this article, we depict the current epidemiological and mechanistic understanding of the role of microbiota and CVD. Finally, we discuss the potential therapeutic approaches aimed at manipulating gut microbiota to improve CV outcomes. © 2024 American Physiological Society. Compr Physiol 14:5449-5490, 2024.

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.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease with increasing numbers worldwide. Adipokines like apelin (APLN) can act as key players in the complex pathophysiology of MASLD.

Investigating the role of APLN in MASLD.

Fecal and blood samples were collected in a MASLD cohort and healthy controls (HC). MASLD patients with liver fibrosis and MASLD-associated hepatocellular carcinoma (HCC) were included into the study. Systemic concentration of Apelin, Apelin receptor (APLNR) and circulating cytokines were measured in serum samples.

Apelin concentration correlated with the Fib-4 score and was elevated in MASLD patients (mild fibrosis, mF (Fib-4 <3.25) and severe fibrosis, sF (Fib-4 >3.25)) as well as in MASLD-associated HCC patients compared to HC. In accordance APLNR and circulating cytokines were also elevated in mF and sF. In contrast apelin levels were negatively associated with liver survival at three and five years. Changes in taxa composition at phylum level showed an increase of Enterobactericae, Prevotellaceae and Lactobacillaceae in patients with sF compared to mF. We could also observe an association between apelin concentrations and bacterial lineages (phyla).

Circulating apelin is associated with liver fibrosis and HCC. In addition, there might exist an interaction between systemic apelin and the gut microbiome.

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.

Non-alcoholic fatty liver disease (NAFLD) has become one of the most frequent chronic liver diseases worldwide in recent decades. Metabolic diseases like excessive blood glucose, central obesity, dyslipidemia, hypertension, and liver function abnormalities cause NAFLD. NAFLD significantly increases the likelihood of liver cancer, heart disease, and mortality, making it a leading cause of liver transplants. Non-alcoholic steatohepatitis (NASH) is a more advanced form of the disease that causes scarring and inflammation of the liver over time and can ultimately result in cirrhosis and hepatocellular carcinoma. In this review, we briefly discuss NAFLD's pathogenic mechanisms, their progression into NASH and afterward to NASH-related cirrhosis. It also covers disease epidemiology, metabolic mechanisms, glucose and lipid metabolism in the liver, macrophage dysfunction, bile acid toxicity, and liver stellate cell stimulation. Additionally, we consider the contribution of intestinal microbiota, genetics, epigenetics, and ecological factors to fibrosis progression and hepatocellular carcinoma risk in NAFLD and NASH patients.

Steatohepatitis is common in persons living with HIV and may be associated with gut microbial translocation (MT). However, few studies have evaluated the gut-liver axis in persons living with HIV. In the Women's Interagency HIV Study, we examined the associations of HIV and circulating biomarkers linked to MT and gut damage using the FibroScan-aspartate aminotransferase (FAST) score, a noninvasive surrogate for steatohepatitis with advanced fibrosis.

Among 883 women with HIV and 354 without HIV, we used multivariable regression to examine the associations of HIV and serum biomarkers linked to MT and gut damage (kynurenine and tryptophan ratio, intestinal fatty acid-binding protein, soluble CD14, and soluble CD163) with a log-transformed FAST score after adjusting for key covariates. We used a path analysis and mediation models to determine the mediating effect of each biomarker on the association of HIV with FAST.

HIV infection was associated with a 49% higher FAST score. MT biomarker levels were higher in women with HIV than women without HIV (P < .001 for each). MT biomarkers mediated 13% to 32% of the association of HIV and FAST score.

Biomarkers linked to MT and gut damage are associated with a higher FAST score and mediate the association of HIV with a higher FAST score. Our findings suggest that MT may be an important mechanism by which HIV increases the risk of steatohepatitis with advanced fibrosis.

Emerging evidence suggests that maternal obesity negatively impacts the health of offspring. Additionally, obesity is a risk factor for hepatocellular carcinoma (HCC). Our study aims to investigate the impact of maternal obesity on the risk for HCC development in offspring and elucidate the underlying transmission mechanisms.

Female mice were fed either a high-fat diet (HFD) or a normal diet (ND). All offspring received a ND after weaning. We studied liver histology and tumor load in a N-diethylnitrosamine (DEN)-induced HCC mouse model.

Maternal obesity induced a distinguishable shift in gut microbial composition. At 40 weeks, female offspring of HFD-fed mothers (HFD offspring) were more likely to develop steatosis (9.43% vs. 3.09%, p = 0.0023) and fibrosis (3.75% vs. 2.70%, p = 0.039), as well as exhibiting an increased number of inflammatory infiltrates (4.8 vs. 1.0, p = 0.018) and higher expression of genes involved in fibrosis and inflammation, compared to offspring of ND-fed mothers (ND offspring). A higher proportion of HFD offspring developed liver tumors after DEN induction (79.8% vs. 37.5%, p = 0.0084) with a higher mean tumor volume (234 vs. 3 μm3, p = 0.0041). HFD offspring had a significantly less diverse microbiota than ND offspring (Shannon index 2.56 vs. 2.92, p = 0.0089), which was rescued through co-housing. In the principal component analysis, the microbiota profile of co-housed animals clustered together, regardless of maternal diet. Co-housing of HFD offspring with ND offspring normalized their tumor load.

Maternal obesity increases female offspring's susceptibility to HCC. The transmission of an altered gut microbiome plays an important role in this predisposition.

The worldwide incidence of obesity is constantly rising, with more and more children born to obese mothers. In this study, we investigate the impact of maternal diet on gut microbiome composition and its role in liver cancer development in offspring. We found that mice born to mothers with a high-fat diet inherited a less diverse gut microbiome, presented chronic liver injury and an increased risk of developing liver cancer. Co-housing offspring from normal diet- and high-fat diet-fed mothers restored the gut microbiome and, remarkably, normalized the risk of developing liver cancer. The implementation of microbial screening and restoration of microbial diversity holds promise in helping to identify and treat individuals at risk to prevent harm for future generations.

The global prevalence of nonalcoholic fatty liver disease (NAFLD) is 25%. This study aimed to explore differences in the gut microbial community and blood lipids between normal livers and those affected by NAFLD using 16S ribosomal deoxyribonucleic acid sequencing.

Gut microbiome profiles of 40 NAFLD and 20 non-NAFLD controls were analyzed. Information about four blood lipids and 13 other clinical features was collected. Patients were divided into three groups by ultrasound and FibroScan, those with a normal liver, mild FL (FL1), and moderate-to-severe FL (FL2). FL1 and FL2 patients were divided into two groups, those with either hyperlipidemia or non-hyperlipidemia based on their blood lipids. Potential keystone species within the groups were identified using univariate analysis and a specificity-occupancy plot. Significant difference in biochemical parameters ion NAFLD patients and healthy individuals were identified by detrended correspondence analysis and canonical correspondence analysis.

Decreased gut bacterial diversity was found in patients with NAFLD. Firmicutes/Bacteroidetes decreased as NAFLD progressed. Faecalibacterium and Ruminococcus 2 were the most representative fatty-related bacteria. Glutamate pyruvic transaminase, aspartate aminotransferase, and white blood cell count were selected as the most significant biochemical indexes. Calculation of areas under the curve identified two microbiomes combined with the three biochemical indexes that identified normal liver and FL2 very well but performed poorly in diagnosing FL1.

Faecalibacterium and Ruminococcus 2, combined with glutamate pyruvic transaminase, aspartate aminotransferase, and white blood cell count distinguished NAFLD. We speculate that regulating the health of gut microbiota may release NAFLD, in addition to providing new targets for clinicians to treat NAFLD.

One of the key modes of microbial metabolism occurring in the gut microbiome is fermentation. This energy-yielding process transforms common macromolecules like polysaccharides and amino acids into a wide variety of chemicals, many of which are relevant to microbe-microbe and microbe-host interactions. Analogous transformations occur during the production of fermented foods, resulting in an abundance of bioactive metabolites. In foods, the products of fermentation can influence food safety and preservation, nutrient availability, and palatability and, once consumed, may impact immune and metabolic status, disease expression, and severity. Human signaling pathways perceive and respond to many of the currently known fermented food metabolites, though expansive chemical novelty remains to be defined. Here we discuss several aspects of fermented food-associated microbes and metabolites, including a condensed history, current understanding of their interactions with hosts and host-resident microbes, connections with commercial probiotics, and opportunities for future research on human health and disease and food sustainability.

Alterations in gut microbiota are associated with the pathogenesis of metabolic diseases, including metabolic-associated fatty liver disease (MAFLD). The aim of this study was to evaluate gut microbiota composition and functionality in patients with morbid obesity with different degrees of MAFLD, as assessed by biopsy.

110 patients with morbid obesity were evaluated by biopsy obtained during bariatric surgery for MAFLD. Stool samples were collected prior to surgery for microbiota analysis.

Gut microbiota from patients with steatosis and non-alcoholic steatohepatitis (NASH) were characterized by an enrichment in Enterobacteriaceae (an ethanol-producing bacteria), Acidaminococcus and Megasphaera and the depletion of Eggerthellaceae and Ruminococcaceae (SCFA-producing bacteria). MAFLD was also associated with enrichment of pathways related to proteinogenic amino acid degradation, succinate production, menaquinol-7 (K2-vitamin) biosynthesis, and saccharolytic and proteolytic fermentation. Basic histological hepatic alterations (steatosis, necroinflammatory activity, or fibrosis) were associated with specific changes in microbiota patterns. Overall, the core microbiome related to basic histological alterations in MAFLD showed an increase in Enterobacteriaceae and a decrease in Ruminococcaceae. Specifically, Escherichia coli was associated with steatosis and necroinflammatory activity, whilst Escherichia-shigella was associated with fibrosis and necroinflammatory activity.

We established a link between gut microbiota alterations and histological injury in liver diagnosis using biopsy. Harmful products such as ethanol or succinate may be involved in the pathogenesis and progression of MAFLD. Thus, these alterations in gut microbiota patterns and their possible metabolic pathways could add information to the classical predictors of MAFLD severity and suggest novel metabolic targets.

Hepatocellular carcinoma (HCC) is a common complication of chronic liver diseases and remains a relevant cause of cancer-related mortality worldwide. The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) as a risk factor for hepatocarcinogenesis is on the rise. Early detection of HCC has been crucial in improving the survival outcomes of patients with metabolic dysfunction-associated steatohepatitis (MASH), even in the absence of cirrhosis. Understanding how hepatocarcinogenesis develops in MASH is increasingly becoming a current research focus. Additive risk factors such as type 2 diabetes mellitus (T2DM), genetic polymorphisms, and intestinal microbiota may have specific impacts. Pathophysiological and epidemiological associations between MASH and HCC will be discussed in this review. We will additionally review the available tumor therapies concerning their efficacy in MASH-associated HCC treatment.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, resulting in a huge medical burden worldwide. Accumulating evidence suggests that the gut microbiome and bile acids play pivotal roles during the development of NAFLD. Patients with NAFLD exhibit unique signatures of the intestinal microbiome marked by the priority of Gram-negative bacteria, decreased ratio of Firmicutes/Bacteroidetes (F/B), and increased Prevotella and Lachnospiraceae. The intestinal microbiota is involved in the metabolism of bile acids. Ursodeoxycholic acid (UDCA) is a key determinant in maintaining the dynamic communication between the host and gut microbiota. It generally shows surprising therapeutic potential in NAFLD with several mechanisms, such as improving cellular autophagy, apoptosis, and mitochondrial functions. This action is based on its direct or indirect effect, targeting the farnesoid X receptor (FXR) and various other nuclear receptors. This review aims to discuss the current studies on the involvement of the microbiome-UDCA interface in NAFLD therapy and provide prospective insights into future preventative and therapeutic approaches for NAFLD.

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.

Cardiometabolic diseases are leading causes of mortality in Western countries. Well-established risk factors include host genetics, lifestyle, diet, and the gut microbiome. Moreover, gut bacterial communities and their activities can be altered by bacteriophages (also known simply as phages), bacteria-infecting viruses, making these biological entities key regulators of human cardiometabolic health. The manipulation of bacterial populations by phages enables the possibility of using phages in the treatment of cardiometabolic diseases through phage therapy and fecal viral transplants. First, however, a deeper understanding of the role of the phageome in cardiometabolic diseases is required. In this review, we first introduce the phageome as a component of the gut microbiome and discuss fecal viral transplants and phage therapy in relation to cardiometabolic diseases. We then summarize the current state of phageome research in cardiometabolic diseases and propose how the phageome might indirectly influence cardiometabolic health through gut bacteria and their metabolites.

Gastrointestinal (GI) cancers constitute more than 33% of new cancer cases worldwide and pose a considerable burden on public health. There exists a growing body of evidence that has systematically recorded an upward trajectory in GI malignancies within the last 5 to 10 years, thus presenting a formidable menace to the health of the human population. The perturbations in GI microbiota may have a noteworthy influence on the advancement of GI cancers; however, the precise mechanisms behind this association are still not comprehensively understood. Some bacteria have been observed to support cancer development, while others seem to provide a safeguard against it. Recent studies have indicated that alterations in the composition and abundance of microbiomes could be associated with the progression of various GI cancers, such as colorectal, gastric, hepatic, and esophageal cancers. Within this comprehensive analysis, we examine the significance of microbiomes, particularly those located in the intestines, in GI cancers. Furthermore, we explore the impact of microbiomes on various treatment modalities for GI cancer, including chemotherapy, immunotherapy, and radiotherapy. Additionally, we delve into the intricate mechanisms through which intestinal microbes influence the efficacy of GI cancer treatments.