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Non-alcoholic steatohepatitis (NASH) is an epidemic metabolic disease with limited therapeutic strategies. Cumulative data support the pivotal role of gut microbiota in NASH. Here, we investigated the hypothesis regarding whether fecal microbiota transplantation (FMT) is effective in attenuating high-fat diet (HFD)-induced steatohepatitis in mice. Mice were randomized into control, HFD and HFD + FMT groups. After an 8-week HFD, FMT treatment was initiated and carried out for 8 weeks. The gut microbiota structure, butyrate concentrations of the cecal content, liver pathology and intrahepatic lipid and cytokines were examined. Our results showed that after FMT, the gut microbiota disturbance was corrected in HFD-fed mice with elevated abundances of the beneficial bacteria Christensenellaceae and Lactobacillus . FMT also increased butyrate concentrations of the cecal content and the intestinal tight junction protein ZO-1, resulting in relief of endotoxima in HFD-fed mice. Steatohepatitis was alleviated after FMT, as indicated by a significant decrease in intrahepatic lipid accumulation (reduced Oli-red staining, decreased intrahepatic triglyceride and cholesterol), intrahepatic pro-inflammatory cytokines, and the NAS score. Accordingly, intrahepatic IFN-γ and IL-17 were decreased, but Foxp3, IL-4 and IL-22 were increased after FMT intervention. These data indicate that FMT attenuated HFD-induced steatohepatitis in mice via a beneficial effect on the gut microbiota.

Microbial metabolites have emerged as critical components that mediate the metabolic effects of the gut microbiota. Here, we show that indole-3-propionic acid (IPA), a tryptophan metabolite produced by gut bacteria, is a potent anti-non-alcoholic steatohepatitis (NASH) microbial metabolite. Here, we demonstrate that administration of IPA modulates the microbiota composition in the gut and inhibits microbial dysbiosis in rats fed a high-fat diet. IPA induces the expression of tight junction proteins, such as ZO-1 and Occludin, and maintains intestinal epithelium homeostasis, leading to a reduction in plasma endotoxin levels. Interestingly, IPA inhibits NF-κB signaling and reduces the levels of proinflammatory cytokines, such as TNFα, IL-1β, and IL-6, in response to endotoxin in macrophages to repress hepatic inflammation and liver injury. Moreover, IPA is sufficient to inhibit the expression of fibrogenic and collagen genes and attenuate diet-induced NASH phenotypes. The beneficial effects of IPA on the liver are likely mediated through inhibiting the production of endotoxin in the gut. These findings suggest a protective role of IPA in the control of metabolism and uncover the gut microbiome and liver cross-talk in regulating the intestinal microenvironment and liver pathology via a novel dietary nutrient metabolite. IPA may provide a new therapeutic strategy for treating NASH. Fatty liver disease: Bacterial metabolite protects liver by maintaining gut integrity A molecule made by beneficial microbes in the gut helps protect against a severe form of fatty liver disease by preventing bacterial toxins from leaking out of the intestines into the bloodstream. A research team in China led by Yu Li from the Shanghai Institute of Nutrition and Health (CAS) and Jian-Gao Fan from Xinhua Hospital (SJTU) showed in a rat model of non-alcoholic steatohepatitis that indole-3-propionic acid (IPA), a metabolite produced by gut bacteria, helps maintain the integrity of the intestinal inner lining. The more robust intestinal barrier ensures that bacterial toxins do not enter the bloodstream and eventually reach the liver, where they can trigger injury-inducing inflammation. The findings reveal an interaction between the gut microbiome and the liver, and suggest a role for IPA in the treatment of fatty liver disease.

Background Recent studies found associations between non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS), but the causal nature of this association is still uncertain. Methods We performed a bidirectional two-sample Mendelian randomization (MR) analysis to test for the causal association between NAFLD and PCOS using data from a large-scale biopsy-confirmed NAFLD genome-wide association study (GWAS) (1483 cases and 17,781 controls) and PCOS GWAS (10,074 cases and 103,164 controls) in European ancestries. Data from glycemic-related traits GWAS (in up to 200,622 individuals) and sex hormones GWAS (in 189,473 women) in the UK Biobank (UKB) were used in the MR mediation analysis to assess potential mediating roles of these molecules in the causal pathway between NAFLD and PCOS. Replication analysis was conducted using two independent datasets from NAFLD and PCOS GWASs in the UKB and a meta-analysis of data from FinnGen and the Estonian Biobank, respectively. A linkage disequilibrium score regression was conducted to assess genetic correlations between NAFLD, PCOS, glycemic-related traits, and sex hormones using full summary statistics. Results Individuals with higher genetic liability to NAFLD were more likely to develop PCOS (OR per one-unit log odds increase in NAFLD: 1.10, 95% CI: 1.02–1.18; P = 0.013). Indirect causal effects of NAFLD on PCOS via fasting insulin only (OR: 1.02, 95% CI: 1.01–1.03; P = 0.004) and further a suggestive indirect causal effect via fasting insulin in concert with androgen levels were revealed in MR mediation analyses. However, the conditional F statistics of NAFLD and fasting insulin were less than 10, suggesting likely weak instrument bias in the MVMR and MR mediation analyses. Conclusions Our study suggests that genetically predicted NAFLD was associated with a higher risk of developing PCOS but less evidence for vice versa. Fasting insulin and sex hormones might mediate the link between NAFLD and PCOS.

Insulin-induced gene (Insig) negatively regulates SREBP-mediated de novo fatty acid synthesis in the liver. However, the upstream regulation of Insig is incompletely understood. Here we report that AMPK interacts with and mediates phosphorylation of Insig. Thr222 phosphorylation following AMPK activation is required for protein stabilization of Insig-1, inhibition of cleavage and processing of SREBP-1, and lipogenic gene expression in response to metformin or A769662. AMPK-dependent phosphorylation ablates Insig’s interaction with E3 ubiquitin ligase gp78 and represses its ubiquitination and degradation, whereas AMPK deficiency shows opposite effects. Interestingly, activation of AMPK by metformin causes an augmentation of Insig stability and reduction of lipogenic gene expression, and leads to the attenuation of hepatic steatosis in HFHS diet-fed mice. Moreover, hepatic overexpression of Insig-1 rescues hepatic steatosis in liver-specific AMPKα2 knockout mice fed with HFHS diet. These findings uncover a novel effector of AMPK. Targeting Insig may have the therapeutic potential for treating fatty liver disease and related disorders. Insulin-related gene (Insig) negatively regulates hepatic fatty acid synthesis, a process involved in development of non-alcoholic fatty liver disease (NAFLD). Here, the authors show that AMPK activation by metformin promotes Insig phosphorylation, stabilizing it and inhibiting lipogenic gene expression. This is protective against steatosis in diabetic mice.

Glucagon-like peptide-1 (GLP-1) has a broad spectrum of biological activity by regulating metabolic processes via both the direct activation of the class B family of G protein-coupled receptors and indirect nonreceptor-mediated pathways. GLP-1 receptor (GLP-1R) agonists have significant therapeutic effects on non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in animal models. However, clinical studies indicated that GLP-1 treatment had little effect on hepatic steatosis in some NAFLD patients, suggesting that GLP-1 resistance may occur in these patients. It is well-known that the gut metabolite sodium butyrate (NaB) could promote GLP-1 secretion from intestinal L cells. However, it is unclear whether NaB improves hepatic GLP-1 responsiveness in NAFLD. In the current study, we showed that the serum GLP-1 levels of NAFLD patients were similar to those of normal controls, but hepatic GLP-1R expression was significantly downregulated in NAFLD patients. Similarly, in the NAFLD mouse model, mice fed with a high-fat diet showed reduced hepatic GLP-1R expression, which was reversed by NaB treatment and accompanied by markedly alleviated liver steatosis. In addition, NaB treatment also upregulated the hepatic p-AMPK/p-ACC and insulin receptor/insulin receptor substrate-1 expression levels. Furthermore, NaB-enhanced GLP-1R expression in HepG2 cells by inhibiting histone deacetylase-2 independent of GPR43/GPR109a. These results indicate that NaB is able to prevent the progression of NAFL to NASH via promoting hepatic GLP-1R expression. NaB is a GLP-1 sensitizer and represents a potential therapeutic adjuvant to prevent NAFL progression to NASH. Fatty liver disease: A gutsy way to prevent disease progression A treatment for non-alcoholic fatty liver disease that incorporates a metabolite found in the gut could prevent progression to a more serious liver condition. Drugs that enhance the activity of glucagon-like peptide-1 (GLP-1), a protein involved in regulating metabolic processes, have shown promise in targeting non-alcoholic fatty liver disease and the more serious condition, steatohepatitis. However, some patients appear resistant to treatment. Jian-Gao Fan at Shanghai Jiao Tong University in China, Huiping Zhou at McGuire VA Medical Center in Richmond, USA, and co-workers demonstrated that a gut metabolite called sodium butyrate may help encourage responsiveness to GLP-1 treatment. The team found that liver GLP-1R expression was considerably reduced in patients with liver disease compared with healthy controls. Experiments on mouse models showed that treatment incorporating sodium butyrate improved GLP-1R levels and reduced fatty liver deposits.

Background Emerging metabolomics-based studies suggested links between amino acid metabolism and metabolic dysfunction-associated fatty liver disease (MAFLD) risk; however, whether there exists an aetiological role of amino acid metabolism in MAFLD development remains unknown. The aim of the present study was to assess the causal relationship between circulating levels of amino acids and MAFLD risk. Methods We conducted a two-sample Mendelian randomization (MR) analysis using summary-level data from genome-wide association studies (GWAS) to evaluate the causal relationship between genetically predicted circulating levels of amino acids and the risk of MAFLD. In the discovery MR analysis, we used data from the largest MAFLD GWAS (8434 cases and 770,180 controls), while in the replication MR analysis, we used data from a GWAS on MAFLD (1483 cases and 17,781 controls) where MAFLD cases were diagnosed using liver biopsy. We used Wald ratios or inverse variance-weighted (IVW) methods in the MR main analysis and weighted median and MR-Egger regression analyses in sensitivity analyses. Furthermore, we performed a conservative MR analysis by restricting genetic instruments to those directly involved in amino acid metabolism pathways. Results We found that genetically predicted higher alanine (OR = 1.43, 95% CI 1.13–1.81) and lower glutamine (OR = 0.83, 95% CI 0.73–0.96) levels were associated with a higher risk of developing MAFLD based on the results from the MR main and conservative analysis. The results from MR sensitivity analyses and complementary analysis using liver proton density fat fraction as a continuous outcome proxying for MAFLD supported the main findings. Conclusions Novel causal metabolites related to MAFLD development were uncovered through MR analysis, suggesting future potential for evaluating these metabolites as targets for MAFLD prevention or treatment.

The human gut microbiome (bacteria, fungi, viruses, and archaea) is a complex and diverse ecosystem. It plays an important role in human health, but is involved in several intestinal and extraintestinal diseases. Most research to date has focused on the role of bacteria, while studies focusing on fungi (also referred to as “mycobiome” or “fungome”) are still in its infancy. In this review, we focus on the existing literature available about the gut mycobiome with an emphasis on compositional mycobiome changes associated with liver diseases, the impact on pathogenesis of disease, and its potential use as therapeutic targets. We also provide insights into current methodologies of studying mycobiome, and we highlight the interkingdom interactions in the context of disease and how they affect health of the host. Herein, by focusing on the gut mycobiome, this review provides novel insights and directions for liver research.

The incidence and prevalence of non‐alcoholic fatty liver disease (NAFLD) have been steadily increasing worldwide, with a huge societal and economic burden. Recently, NAFLD and non‐alcoholic steatohepatitis have been renamed and redefined as metabolic dysfunction associated steatotic liver disease (MASLD) and steatohepatitis (Metabolic Dysfunction Associated Steatohepatitis (MASH)), which result from an imbalance between metabolic and inflammatory stress (mainly as a consequence of adipose tissue dysfunction and insulin resistance) and the defence and repair mechanisms of the steatotic liver. Once MASLD progresses to end‐stage of liver disease, treatment efficacy becomes limited and may require liver transplantation. Early detection and intervention are crucial. Lifestyle modification is consequently the cornerstone of its management. Timely consideration of bariatric surgeries should be given to patients meeting specific criteria. A multidisciplinary approach is warranted, starting from the concept that MASLD/MASH is at the centre of the cardiovascular‐liver‐metabolic syndrome. In some cases, pharmacological treatment can complement lifestyle modification. Several drugs used to treat the cardiometabolic co‐morbidities have some potential efficacy in slowing Down disease progression, and some have demonstrated efficacy on histological endpoints that are likely to translate into long‐term clinical benefits. Optimising the use of these drugs within their licenced indications is thus paramount for patients with MASLD. Several MASH‐specific drugs are on the horizon and are likely to enrich our therapeutic armamentarium in the near future, particularly in non‐cirrhotic stages of the disease. Much work still needs to be done to understand the specific features of MASH cirrhosis and develop efficacious treatments for this disease stage.

For patients with metabolic dysfunction-associated fatty liver disease (MAFLD), weight loss is advised but challenging in practice. In China, there is a pronounced shortage of tailored digital lifestyle interventions for this population. This study aimed to assess the effects of a WeChat mini-program-delivered lifestyle intervention on weight loss and hepatic steatosis among individuals with MAFLD who were overweight or obese. Adults who are overweight or obese and have clinically diagnosed MAFLD with transient elastography examination were enrolled in this prospective randomized controlled trial. Patients were randomly assigned to receive either WeChat mini-program management (intervention group) or standard care (control group) at a 1:1 ratio. The intervention was structured around the development and implementation of personalized diet and exercise plans, supplemented by guided exercise video courses and reinforced through continuous monitoring and informational support. Body weight and clinical parameters were assessed at baseline and then at 6 months. A total of 89 patients met the inclusion criteria and were randomly assigned to the intervention group (n=45) or control group (n=44). Among the 89 patients with MAFLD, 60% (27/45) of them achieved a weight loss of ≥5%, and 24.4% (11/45) of them had a weight loss of ≥10% in the intervention group, which was greater than those in the control group (27/45 vs 7/44; relative risk [RR] 3.771, 95% CI 1.836-7.748; P<.001; 11/45 vs 3/44, RR 3.585, 95% CI 1.072-11.988; P=.02). Importantly, patients receiving the intervention were significantly more likely to achieve a ≥10% reduction or normalization of controlled attenuation parameter (CAP) than those in the control group (26/45 vs 14/44; RR 1.816, 95% CI 1.102-2.992; P=.01). After adjusting for key baseline covariates, multivariate analysis confirmed the intervention's positive effect on achieving a weight loss of ≥5% (OR [odds ratio] 8.380, 95% CI 2.886-24.331; P<.001) of ≥10% (OR 4.612, 95% CI 1.138-18.686; P=.03), as well as on CAP reduction of ≥10 % or normalization (OR 2.853, 95% CI 1.092-7.456; P=.03). In parallel, the intervention group presented greater reductions in liver enzymes (alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase) and metabolic parameters (fasting insulin, hemoglobin A1c, and triglyceride) than the control group (all P<.05). According to the fibrosis assessment, only the FibroScan-aspartate aminotransferase score decreased more in the intervention group than in the control group (median difference -0.06, 95% CI -0.13 to -0.01; P=.02), as compared to other non-invasive indicators. Readily scalable in primary care and varied-resource settings, our WeChat mini-program-based intervention extends beyond weight loss to reduce hepatic steatosis and improve metabolic parameters, thereby addressing the critical gap in targeted MAFLD management in China with a low-cost model for high-burden populations. Nevertheless, larger future studies are needed to confirm these findings with greater precision and assess long-term sustainability.