Alleviation of adverse effects associated with α-glucosidase inhibitors by Ocimum basilicum L., Matricaria chamomilla L., and Salvia officinalis L. reveals novel selective inhibition of Bacillus α-glucosidase by acarbose.

NAFLD vs. MAFLD – It is not the name but the disease that decides the outcome in fatty liver

The increasing burden of non-alcoholic fatty liver disease: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world. NAFLD encompasses a spectrum of liver disease, ranging from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). With the pandemic of obesity and type 2 diabetes mellitus (T2DM), there has been an exponential growth in the prevalence of NAFLD over the past two decades. The prevalence of NAFLD in most Asian countries, including China, is above 25% in the general adult population.[1] Furthermore, there is a developing childhood obesity pandemic, and a meta-analysis of 20,595 children in Asia generated a pooled NAFLD prevalence of 5.53%, which had increased by approximately 1.6-fold since 2010. The pooled prevalence of NAFLD in Asian children increased from those with normal weight (1.5%) to those who were overweight (16.7%) or obese (50.1%).[2] A recent study suggested that NAFLD is not uncommon in lean Chinese adults with a normal waist circumstance. Metabolic risk factors, rather than genetic factors, may play an important role in the development of lean NAFLD,[3] and the hepatic and extra-hepatic complications can also develop in lean patients, which reinforces the importance of considering metabolic phenotype in the assessment of NAFLD, rather than using body mass index-based approaches.[4] Renaming of NAFLD to MAFLD: A diagnosis of NAFLD is made on the basis of histological or imaging-derived evidence of steatosis, in the absence of a known etiology of fatty liver. With advances in knowledge of the pathogenesis of the condition, the "exclusive" term NAFLD no longer serves to precisely describe a highly heterogeneous disease. In 2020, the novel term of metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed in an attempt to create an "inclusive" diagnosis.[5] Zeng et al[6] performed a cross-sectional study of Chinese adults which showed that the prevalence of MAFLD is higher than that of NAFLD, and therefore the newly-defined label of MAFLD may better reflect the metabolic pathogenesis. Furthermore, a pathologic analysis of patients with MAFLD showed that a single metabolic defect can have a significant role in the development of fibrosis and that insulin resistance plays a key role in the progression of steatohepatitis and the development of significant fibrosis.[7] As Zheng et al discussed, by using the new terminology, "cryptogenic cirrhosis" and MAFLD can now be diagnosed in lean individuals using metabolic criteria, rather than being viewed as completely separate entities. The renaming of NAFLD to MAFLD may result in significant improvements in awareness, advocacy, research, and the clinical management of the condition.[8] Update on the pathogenesis of MAFLD: The pathogenesis of NAFLD/MAFLD is a multifactorial process, involving interactions among nutrition, metabolism, genetic predisposition, the gut microbiota, and environmental factors. Although a great deal of progress has been made in recent decades, the pathogenic mechanism of NAFLD/MAFLD has yet to be fully elucidated. In this issue of the Chinese Medical Journal (CMJ), Pan et al[9] give an overview of the role of hepatocyte nuclear factor 4α (HNF4α) in the pathogenesis of NAFLD. HNF4α has been shown to regulate bile acid, lipid, and glucose metabolism; and hepatic HNF4α expression is much lower in patients with NAFLD and mouse models of NASH. Furthermore, there is evidence that hepatic HNF4α plays a key role in the initiation and progression of NAFLD and may represent a therapeutic target for NAFLD.[9] Huang et al[10] presented a systematic review regarding the role of retinol-binding protein 4 (RBP4) in the development of NAFLD and its potential therapeutic application. RBP4 induces hepatic de novo lipogenesis, impairs fatty acid oxidation, increases insulin resistance, and promotes hepatic inflammation. Furthermore, a high plasma RBP4 concentration is associated with a high risk of NAFLD; and agents that reduce the circulating RBP4 concentration and/or hepatic RBP4 expression have a protective effect against NAFLD. These findings suggest that RBP4 could be targeted as a novel diagnostic marker or therapeutic target for NAFLD.[10] Jackson et al[11] summarized the essential physiology of bile acid and sphingolipid metabolism, because the dysregulation of both are potential contributors to NAFLD. Specifically, the dysregulation of bile acid and sphingolipid metabolism has been linked to hepatic steatosis, inflammation, and fibrosis, and the further exploration of the pathologic effects mediated by bile acids and sphingolipids may also lead to new diagnostic and therapeutic strategies for NAFLD. Hepatitis B and concurrent MAFLD: Concomitant NAFLD/MAFLD in patients with chronic hepatitis B (CHB) has become highly prevalent over the past two decades. However, the risks associated with the dual etiologies, outcomes, and mechanisms involved in the interaction between CHB and NAFLD have not been fully characterized. Tong et al[12] summarize the findings of recent clinical and basic research studies related to the potential interactions between CHB and NAFLD. The prevalence of hepatic steatosis in CHB has been reported to be 32.8% (95% CI, 28.9%–37.0%); and it is higher in men and patients with obesity. The presence of hepatic steatosis in patients with CHB is related to metabolic, rather than viral factors. Patients with both CHB and NAFLD are more likely to experience liver-related outcomes or death than those with CHB alone. Many studies have shown that steatosis is positively associated with the clearance of hepatitis B virus (HBV) surface antigen and a reduction in HBV DNA, and the prevalence and incidence of NAFLD in patients with CHB may be lower than in those without. In Chang and colleagues' multi-center, prospective study of 1000 treatment-naïve patients with biopsy-confirmed CHB, NASH was found in 182 patients (18.2%), 46% of these achieved resolution of NASH, and only 4% of the patients developed new-onset NASH after 72 weeks of entecavir treatment. Body mass at baseline and a slight weight change during follow-up were associated with the prevalence, incidence, and remission of NASH in patients with CHB.[13] Finally, steatosis is more prevalent in patients with CHB and is a common reason for abnormal circulating liver enzyme activities in infected patients with a low HBV-DNA load or a good response to infection. From MAFLD to HCC: Although viral hepatitis remains the most common etiology of liver cancer-related deaths, NAFLD is the most rapidly growing contributor to mortality and morbidity related to liver disease in the world. The global burden of HCC is increasing alongside the NAFLD pandemic. A recently published review in CMJ summarizes the characteristics of NAFLD-related HCC.[14] The incidence of NAFLD-related HCC is much higher in patients with severe steatohepatitis, advanced fibrosis, and cirrhosis than in individuals with NAFLD in general, and it is most likely to occur in older men with metabolic syndrome. The incidence of HCC in patients with NAFLD-related cirrhosis is lower than that in those with hepatitis C virus- or HBV-related cirrhosis. Compared with HCCs of other etiologies, NAFLD-related HCCs are generally large, well-differentiated, solitary lesions with a higher level of inflammatory infiltration, and they are less likely to metastasize extra-hepatically. Moreover, NAFLD-related HCC is more likely to develop in the absence of cirrhosis.[14] In a recent issue of CMJ, Rios et al reviewed the progression of MAFLD to HCC and stated that lipotoxicity, insulin resistance, oxidative stress, chronic inflammation, multiple gene mutations, and alterations to the fecal microbial composition are the most important factors determining hepatic carcinogenesis, whereas steatohepatitis and fibrosis are not essential for the development of HCC in obesity-related fatty liver disease.[15] Non-invasive diagnosis of MAFLD: Accumulating evidence suggests that non-invasive tests can be used to diagnose NAFLD, assess its severity, and predict its prognosis. In a recent issue of CMJ, Li et al review new developments in non-invasive testing for NAFLD, with respect to steatosis, steatohepatitis, and fibrosis.[16] For the identification of steatosis, ultrasonography remains the most common method, because of its wide availability and low cost, but magnetic resonance imaging-proton density fat fraction is currently the most accurate means of identifying hepatic steatosis, and transient elastography (TE) represents a promising technique for the evaluation of hepatic steatosis and fibrosis. Except for the widely used controlled attenuation parameter, ultrasonographic attenuation has been reported to have a low failure rate and shows moderate-to-high performance for the discrimination of degrees of steatosis in patients with chronic liver disease.[17] Various non-invasive algorithms, such as the fatty liver index (FLI) and hepatic steatosis index (HSI), have been used as screening tests for steatosis in epidemiologic studies. In Chen et al's study, both FLI and HSI were shown to be useful screening tools for NAFLD in adults with obstructive sleep apnea/hypopnea syndrome.[18] In patients with steatohepatitis, some circulating biomarkers correlate with the severity of NASH but show modest predictive accuracy. Regarding liver fibrosis, liver stiffness measurement (LSM) using TE is highly accurate and is widely used worldwide. Magnetic resonance elastography is marginally better than TE, but it is limited by its cost and availability. In contrast, simple fibrosis scores, such as the fibrosis-4 (FIB-4) index and the NAFLD fibrosis score, can be easily calculated and are recommended for use in primary care. These scores and LSM have sufficiently high negative predictive values to exclude advanced fibrosis. Recently, Shi et al found that the combination of the presence of a metabolic disorder and the FIB-4 index provides for a more accurate diagnosis of advanced fibrosis in patients with NAFLD.[19] Thus, as part of the redefinition of MAFLD, metabolic risk factors should be taken into account during diagnosis and management. Therapeutic approaches to MAFLD: In a recent issue of CMJ, Shi et al[20] discuss recent advances and provide a perspective regarding the treatment of MAFLD. Weight management through an appropriate diet and physical activity remains the most important component of the treatment of MAFLD. Weight loss through bariatric surgery may be an effective means of achieving significant improvements in patients with morbid obesity and MAFLD. Although numerous agents, including novel modulators of glucolipid metabolism, are being assessed in clinical trials, there is still no approved drug for the treatment of MAFLD. The nomenclature of MAFLD emphasizes the existence of concomitant metabolic disorders and obesity, and patients with MAFLD are therefore subject to both hepatic and other metabolic risks. Thus, drugs targeting underlying cardiometabolic risk factors are essential to improve the outcomes of patients with MAFLD. The screening of patients who are at a high risk of MAFLD and the provision of a comprehensive individual therapeutic program are critical. For example, patients with MAFLD and T2DM would benefit from the use of antidiabetic agents, patients with overweight or obesity would gain greater benefit from weight management, and those with metabolic syndrome require comprehensive individualized management. These therapeutic approaches might help identify the patients with MAFLD who are at the greatest risk of disease progression and facilitate more precise and appropriate management. Summary and prospects: The growing burden of NAFLD parallels the increasing prevalences of obesity and metabolic syndrome worldwide. Cardiometabolic risk factors have a bidirectional relationship with NAFLD. The majority of patients with NAFLD meet the diagnostic criteria for MAFLD, and this represents a more appropriate term. Further clinical studies of the changes created by the redefinition of NAFLD/MAFLD, including the epidemiologic character, prognosis, diagnosis, prevention, and treatment of the condition, are required. Currently, MAFLD and CHB are increasingly being diagnosed in the same individuals, and the pathophysiological interaction between MAFLD and HBV infection in patients is worthy of further exploration. The long-term outcomes of MAFLD are related to the severity of metabolic dysfunction and liver fibrosis, rather than obesity. Metabolic syndrome and T2DM are the most important risk factors for MAFLD-related cirrhosis and HCC. A lack of awareness regarding the factors underlying MAFLD-related HCC may lead to delay in its diagnosis. The further development and validation of non-invasive diagnostic techniques and clinical pathways will help clinicians assess the severity of MAFLD, categorize patients, and identify those requiring specific treatments. There is still no effective approved drug for MAFLD, but the in-depth study of pathologic mechanisms may provide new therapeutic targets. Measures to increase awareness and treat or prevent the associated cardiometabolic diseases are necessary to reduce the growing burden of MAFLD. Funding This study was supported by grants from the National Key Research and Development Program of China (No. 2021YFC2700802), the National Natural Science Foundation of China (Nos. 81900507 and 82170593). Conflicts of interest None.

Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is characterized by hepatic fat accumulation by metabolic dysfunction. The rising prevalence of MAFLD, especially among Asians, may be associated with changes in gut microbiota. We investigated gut microbiota characteristics and potential mechanisms leading to MAFLD development according to enterotypes. Case-control studies examining the gut microbiota composition between MAFLD and non-MAFLD participants were searched in public databases until July 2023. Gut microbiota was categorized into two enterotypes by principal component analysis. According to the enterotypes, LEfSe, ALDEx2, XGBoost, and DCiPatho were utilized to identify differential abundances and pathogenic microbes in the gut between the MAFLD and non-MAFLD groups. We analyzed microbial community networks with the SprCC module and predicted microbial functions. In the Prevotella enterotype (ET-P), 98.6% of Asians and 65.1% of Caucasians were associated with MAFLD (p = 0.049). MAFLD incidence was correlated with enterotype, age, obesity, and ethnicity (p < 0.05). Asian MAFLD patients exhibited decreased Firmicutes and Akkermansia muciniphila and increased Bacteroidetes and P. copri. The pathogenicity scores were 0.006 for A. muciniphila and 0.868 for P. copri. The Asian MAFLD group showed decreased stability and complexity in the gut microbiota network. Metagenome function analysis revealed higher fructose metabolism and lipopolysaccharide (LPS) biosynthesis and lower animal proteins and α-linolenic acid metabolism in Asians with MAFLD compared with the non-MAFLD group. LPS biosynthesis was positively correlated with P. copri (p < 0.05). In conclusion, P. copri emerged as a potential microbial biomarker for MAFLD. These findings enhance our understanding of the pathological mechanisms of MAFLD mediated through the gut microbiota, providing insights for future interventions.

Altered gut microbiome associated with metabolic-associated fatty liver disease in Chinese children

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disease. MAFLD is a major risk factor for end-stage liver disease including cirrhosis and primary liver cancer. The pathogenesis of MAFLD is complex and has not yet been clarified. To the best of our knowledge, few studies have conducted quantitative bibliometric analysis to evaluate published MAFLD research. In this study, we conducted a comprehensive analysis of MAFLD publications over the past decade to summarize the current research hotspots and predict future research directions in this field. Articles into MAFLD published from 2012 to 2021 were identified from the Science Citation Index-Expanded of Web of Science Core Collection. CiteSpace software, VOSviewer, the "bibliometrix" R package, and the Online Analysis Platform of Literature Metrology were used to analyze the current publication trends and hotspots. We retrieved 13959 English articles about MAFLD published from 2012 to 2021. Primary sites of publication were dominated by the United States until 2014, when China became the source of most published MAFLD-related research papers. The United States was found to be the most engaged country in international cooperative efforts. Shanghai Jiao Tong University was the most productive institution. Loomba R was the most productive author with 123 articles. The co-cited keyword cluster tag showed ten main clusters: #0 liver fibrosis, #1 hemoglobin, #2 metabolic associated fatty liver disease, #3 egcg, #4 myocardial infarction, #5 heart disease, #6 pnpla3, #7 hepatocellular carcinoma, #8 noninvasive marker, and #9 children. Keyword burst analysis showed that gut microbiota was the highest-intensity research hotspot. In the past decade, the number of publications on MAFLD increased dramatically, especially in the last three years. Gut microbiota became an important research direction for etiological and therapeutic investigations into MAFLD. Insulin resistance was also a key factor in studying the development of MAFLD in recent years. Liver fibrosis was an important focus of disease development. This study provides systematic information, helps guide future research, and helps to identify mechanisms and new treatment methods for MAFLD.

Expanding the liver exposome: Should hepatologists care about air pollution?

Gut microbiota-based metabolism contributes to the protection of pseudolaric acid B against MAFLD.

ObjectiveWe evaluated the clinical characteristics of metabolic dysfunction-associated fatty liver disease (MAFLD) to evaluate the usefulness of the MAFLD diagnostic criteria in a resident health survey.MethodsIn 1056 participants of a health survey, we compared obesity, diabetes, metabolic dysregulation, FibroScan-aspartate aminotransferase (FAST) score, dietary habits, and gut microbiota between healthy individuals and participants with MAFLD and Nonalcoholic fatty liver disease (NAFLD).ResultsThe proportion of participants with MAFLD in the fatty liver was higher than that with NAFLD (88.1% vs. 75.5%, respectively). Of 36 participants with a FAST score > 0.35, 29 (80.6%) participants had MAFLD and 23 (63.9%) participants had NAFLD. Of 29 patients with liver fibrosis, 26 (89.7%) participants had obesity and metabolic dysregulation. In the evaluation of diet, the total energy, protein, dietary fiber, and salt intake were significantly higher in participants with MAFLD than those in participants without fatty liver. In the microbiota analysis, the results of the linear discriminant analysis effect size analysis revealed nine bacterial genera that were significantly different in participants with MAFLD in comparison with participants without fatty liver. Of these genera, the relative abundance of Blautia was especially low in participants with MAFLD.ConclusionIn a resident health survey, participants with MAFLD had a higher proportion of fatty liver than those with NAFLD. MAFLD criteria could help in improved screening of participants with liver fibrosis. Therefore, the MAFLD criteria could be a useful diagnostic tool for aggressively identifying participants with a high risk of fatty liver. Additionally, Blautia might be involved in the development of MAFLD.

Gut microbiota regulation is a key strategy for treating metabolic dysfunction-associated fatty liver disease (MAFLD). Arbutin (ARB) is a natural hydroquinone active agent with anti-inflammatory and antioxidant effects, as well as regulatory effects on the gut microbiota. However, its therapeutic effect on MAFLD and the responsible mechanisms remain unclear. This study explored the therapeutic effect and mechanisms of ARB in MAFLD treatment. High-fat diet (HFD)-fed mice served as the in vivo MAFLD model, and ARB treatment was given simultaneously. The extent of liver injury was assessed through histopathological staining. AML12 cells treated with free fatty acids served as the in vitro model. The effects of ARB were evaluated via oil red O staining and biochemical assays. Subsequently, we utilized bioinformatics techniques to predict the potential mechanisms and targets of ARB. The expression of liver apoptosis-related genes was detected using molecular biology techniques. Alterations in the gut microbiota were analyzed by 16S rRNA sequencing. Ultrahigh-performance liquid chromatography–high-resolution mass spectrometry was used to analyze the changes in fecal metabolite levels. ARB treatment effectively improved liver injury in mice with MAFLD. Its mechanism was associated with anti-apoptotic effects mediated by signal transducer and activator of transcription 3. Meanwhile, ARB effectively reversed gut microbiota imbalance in mice with MAFLD and altered the composition of gut microbes and fecal metabolites. ARB displayed potential effects in alleviating the pathology of MAFLD, exerting anti-apoptotic actions, and restoring the gut microbiota balance.

Multi-target regulation by artemether in MAFLD through EGFR/HSP90 pathways.

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

Steatosis drives monocyte-derived macrophage accumulation in human metabolic dysfunction-associated fatty liver disease

Is the increased risk for MAFLD patients to develop severe COVID-19 linked to perturbation of the gut-liver axis?

Gut microbiota plays a critical role in developing and progressing metabolic dysfunction-associated steatotic liver disease (MASLD). Studies show reduced microbial diversity and specific shifts in bacterial populations in MASLD patients, with harmful species increasing and beneficial ones decreasing. These changes contribute to liver fat accumulation by impairing fiber fermentation, disrupting bile acid metabolism, increasing intestinal permeability, and promoting inflammation. The progression of MASLD is linked to evolving microbiota changes, and probiotics like Lactobacillus plantarum show potential in mitigating disease by restoring gut balance. Thus, gut microbiota serves as both a key factor and therapeutic target in MASLD. Interventions on microbiota are possible targets in treating MASLD or preventing progression toward advanced stages. At the same time, prebiotics and probiotics have shown results in ameliorating MASLD, post-biotic therapy, immuno-nutrition, bacteria engineering, or phages, which have been applied only in experimental studies.

The global threat of metabolic dysfunction-associated fatty liver disease (MAFLD) is significant, but effective measures are still lacking. To explore the potential impact of hydroxytyrosol (HT), a plant polyphenol, in the metabolic outcomes of MAFLD and the mediating role of the gut microbiota, we performed an 8-week randomized placebo-controlled clinical trial in MAFLD patients and collected fecal bacteria for metagenomics analysis and targeted metabolomics. In this population-based trial, we have revealed that HT mitigates liver injury and steatosis in patients with MAFLD, as well as systemic glucolipid metabolism disorder. Through analysis of the differences in bacterial taxon and functional profiles, as well as correlation analysis between species and metabolic indicators, it was found that Fusicatenibacter saccharivorans (F. saccharivorans), the microbial species with the greatest difference after HT intervention, was also the most significantly correlated with metabolic parameters of MAFLD and showed a significant positive correlation with the content of fecal butanoic acid. Butanoic acid was further associated with MAFLD-related metabolic indexes. To confirm the potential causal relationship between alterations in gut microbiota induced by HT intervention and improved MAFLD metabolic phenotypes, fecal microbiota transplantation (FMT) was conducted using a model of pseudogerm-free mice. We have further demonstrated that the fecal microbiota from donors of MAFLD patients receiving HT supplementation can ameliorate liver and systemic phenotypes in western-diet-induced MAFLD mice, interpreting the robust action of gut microbiota remodeled by HT in improving MAFLD. Consequently, HT supplementation may represent a tactic for improving MAFLD by modulating the composition and functionality of the gut microbiota.