v
Search
Advanced Search

Publications > Journals > Journal of Clinical and Translational Hepatology > Article Full Text

  • Review Article
  • OPEN ACCESS

The Gut Microbiome and Ferroptosis in MAFLD

  • Jie Ji1,2,
  • Liwei Wu1,2,
  • Jue Wei3,
  • Jianye Wu1,* and
  • Chuanyong Guo1,2,* 
 Author information
Journal of Clinical and Translational Hepatology   2023;11(1):174-187

doi: 10.14218/JCTH.2022.00136

Abstract

Metabolic-associated fatty liver disease (MAFLD) is a new disease definition, and is proposed to replace the previous name, nonalcoholic fatty liver disease (NAFLD). Globally, MAFLD/NAFLD is the most common liver disease, with an incidence rate ranging from 6% to 35% in adult populations. The pathogenesis of MAFLD/NAFLD is closely related to insulin resistance (IR), and the genetic susceptibility to acquired metabolic stress-associated liver injury. Similarly, the gut microbiota in MAFLD/NAFLD is being revaluated by scientists, as the gut and liver influence each other via the gut-liver axis. Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation. Emerging evidence suggests that ferroptosis has a key role in the pathological progression of MAFLD/NAFLD, and inhibition of ferroptosis may become a novel therapeutic strategy for the treatment of NAFLD. This review focuses on the main mechanisms behind the promotion of MAFLD/NAFLD occurrence and development by the intestinal microbiota and ferroptosis. It outlines new strategies to target the intestinal microbiota and ferroptosis to facilitate future MAFLD/NAFLD therapies.

Graphical Abstract

Keywords

Gut microbiota, Ferroptosis, Nonalcoholic fatty liver disease, Gut-liver axis

Introduction

Because of its close association with metabolic diseases and the many challenges faced by previous diagnostic strategies of exclusion, a new disease nomenclature, metabolic-associated fatty liver disease (MAFLD), has been proposed to replace the previous name, nonalcoholic fatty liver disease (NAFLD).1 Globally, MAFLD/NAFLD is the most common liver disease, with an incidence rate between 6% and 35% in adult populations.2 Studies have shown that the long-term existence of NAFL and NASH are important causes of liver cirrhosis and hepatocellular carcinoma (HCC).3 Indeed, the predominant HCC etiology in the USA is MAFLD/NAFLD. NASH is the second most frequent reason for liver transplantation in the USA, and is likely to supersede hepatitis C as the most common cause of transplantation in the future.4 Although MAFLD/NAFLD is not inherently serious, its complications are, and include liver cirrhosis and HCC which seriously affect quality of life or even endanger patient lives. MAFLD/NAFLD occurrence is an extremely complex pathological process that involves a variety of hepatic cells and multiple extrahepatic signals.5 In recent years, immunoinflammatory responses, genetic metabolism, insulin resistance (IR), ferroptosis, and the gut microbiome have been closely associated with MAFLD/NAFLD.2,5

Bacteria, viruses, fungi, and archaea collectively colonize the human intestines, and are known as the gut microbiome. More than 1×1014 microorganisms are found in healthy individuals and comprise more than nine million genes, which is approximately 150 times larger than the human genome.6 Although the human gut microbiome is closely related to host physiological activities, its importance to human health and disease has long been neglected because of inadequate research methods. However, in recent years, technical advances in DNA/RNA sequencing, bioinformatics data analysis, and culture-based microbiology have increased our understanding of microbes in health and disease.7,8 Simultaneously, the increased gut microbiome literature has been instrumental in delineating metabolic diseases, including NAFLD, obesity, cardiovascular disease, carcinoma, and type 2 diabetes mellitus.9,10 Thus, rather than existing as individual pathogens, microbes exist as complex consortia with myriad interactions with their hosts.

The liver and intestinal tract are anatomically and functionally related, having both developed from the same germ layer in the embryo.11 Since the gut-liver axis was first proposed by Marshall in 1998, it has attracted much interest in the relationships between liver disease and the intestinal tract.12 The portal vein connects the gut to the liver and provides 70% of its blood supply. The unique anatomical structure of the liver increases its susceptibility to gut bacteria, bacterial products, endotoxins, and microbiome inflammatory molecules.13 Under normal physiological conditions, the intestinal mucosal barrier is the first bodily defense against external pathogen invasion.14 The liver also produces specific antibodies and inflammatory factors that monitor the intestinal mucosa.15 However, under some pathological conditions, these defense mechanisms become disrupted, thereby facilitating bacterial migration outside the gut. In patients with NAFLD, intestinal bacteria migrate through the portal vein into the liver and cause abnormal activation of the immune system, leading to inflammation responses and injury.16 In addition, interactions between the intestine and liver are bidirectional, and hepatogenic inflammatory cytokines thus impair intestinal mucosal barrier function, disrupting tight junctions of the intestinal epithelium, and forming a malignant liver-gut cycle during NAFLD.17,18

Ferroptosis is a novel form of cell death characterized by iron overload and reactive oxygen species (ROS)-dependent accumulation of lipid peroxides. Ferroptosis, morphologically manifests as mitochondrial shrinkage, reduction or disappearance of mitochondrial cristae, and increased mitochondrial membrane density. Like other cell death modes, ferroptosis is tightly regulated by a variety of intracellular metabolic processes, including glutathione (GSH) synthesis, lipid peroxidation, cysteine transport, iron homeostasis, and NADPH.19 In recent years, many studies have found that ferroptosis is involved in the progression of NAFLD, and preliminarily confirmed that ferroptosis of hepatocytes and intrahepatic macrophages can trigger NASH.20 Inhibition of ferroptosis may become a new therapeutic strategy for NAFLD in the future. In this review, we focus on how the gut microbiota and ferroptosis promote NAFLD development via the gut-liver axis and explore gut microbiome potential as a novel diagnostic biomarker and therapeutic strategy for NAFLD.

Interaction between the Gut-Liver axis and the gut microbiome

The liver and intestinal tract are physiologically bidirectional organs. In one direction, the liver excretes bile and other bioactive mediators into the intestinal cavity via the bile duct, while in the other direction, metabolic nutrients are transported into the liver via the portal vein after reabsorption from the small intestine.11 Simultaneously, intestinal bacteria and their products, e.g., vitamins, short-chain fatty acids (SCFAs), lipopolysaccharide (LPS), endogenous ethanol, and other metabolites are transported through the portal vein, exposing the liver to intestinal microenvironments and pathological changes.17,21

Bile acids (BAs) and enterohepatic circulation

BAs are small molecules synthesized from cholesterol via cholesterol 7a-hydroxylase (CYP7A1) catalysis by liver cells.22 They not only participate in lipid digestion and absorption, but are also important signal regulators that affect energy metabolism, inflammation, and development of liver disease.23 Recent studies have reported that interactions between BAs and intestinal microbiota are closely related to NAFLD.24 BA synthesis is highly complex and includes multistep reactions involving at least 17 different catalytic enzymes (Fig. 1).25 Synthesis occurs in the liver and is accomplished via two different steps. Under normal physiological conditions, at least 75% of BA is synthesized by the classical pathway, which is initiated by cholesterol 7a-hydroxylation catalyzed by CYP7A1.26 CYP7A1 is the rate-limiting enzyme in the process and determines total BAs production.27 The selective pathway is initiated by sterol-27-hydroxylase (CYP27A1) and is further hydroxylated by hydroxysterol 7a-hydroxylase (CYP7B1).28 Studies have shown that the gut microbiota regulates the expression of key enzymes in BA synthesis, including CYP7A1, CYP7B1, and CYP27A1.29 Sayin et al.30 confirmed that liver-based CYP7A1 was regulated by gut microbiota via farnesoid X receptor (FXR)-dependent mechanisms throughout the enterohepatic system in germ-free and conventionally raised mice.30 Moreover, recent research confirmed that inhibiting the intestinal microbiota of hamsters up-regulated CYP7B1 in the alternative BAs synthesis pathway, increased BAs hydrophilicity, and increased tauro-β-muricholic acid (TβMCA).31

Bile acid metabolism in the liver and intestine.
Fig. 1  Bile acid metabolism in the liver and intestine.

CYP7A1, cholesterol 7a-hydroxylase; CYP27A1, sterol-27-hydroxylase; CYP7B1, hydroxysterol 7a-hydroxylase; AKR1D1, aldo-keto reductase family 1, member D1; HSD3B7, hydroxy-δ-5-steroid dehydrogenase, 3β- and steroid δ-isomerase 7; CA, cholic acid; CDCA, chenodeoxycholic acid, DCA, deoxycholic acid; LCA, lithocholic acid; UDCA, ursodeoxycholic acid.

Intestinal barriers and permeability

The intestinal barrier is an important bodily defense mechanism and is composed of mechanical, chemical, biological, and immune barriers.14 Under normal physiological conditions, large numbers of anaerobic bacteria grow in the intestinal lumen or intestinal mucosa surfaces and include Bifidobacterium that adhere closely to the intestinal epithelium to form a membrane barrier that resists and repels invasion by foreign pathogens.32 Studies have shown that the intestinal microbiota maintain intestinal barrier stability by producing a series of metabolites and instigating signal pathways. Ijssennagger et al.33 reported that sulfide produced by sulfate-reducing bacteria dissolved the mucin polymer network, thinned the mucus layer, and changed the mechanical barrier of the intestinal mucosa. In addition, the Bacteriodes fragilis toxin had proteolytic enzyme-like activity that degraded mucin and destroyed mucus layer structures.34 Furthermore, SCFAs like acetic, propionic, and butyric acids, which are the main metabolites of colonic bacteria required for carbohydrate fermentation, protect the chemical barrier of the intestinal mucosa. Researchers transplanted the butyric acid-producing bacteria, Butyrivibrio fibrisolvens into sterile mice and observed that bacteria restored energy metabolism to colonic epithelial cells and restored cell oxidative phosphorylation and ATP levels, maintained energy homeostasis, inhibited autophagy, and protected colonic epithelial cell integrity.35 More important, the intestinal microbiota are important elements of the intestinal biological barrier; their mechanism of action toward intestinal barrier function is to primarily secrete bacteriocins to kill pathogenic bacteria,36 antagonize pathogen colonization,37 and compete for oxygen and nutrients.38

Destruction of one or more of the barriers affects intestinal barrier integrity. The main driving factors for increased permeability are intestinal inflammation and dysbiosis,39 which are related to long-term antibiotic use,40 chronic alcohol intake,41 continuous high-fat diets,42 and immune-mediated inflammatory disease.43Akkermansia muciniphila is a Gram-negative anaerobic bacterium that colonizes intestinal mucus layers and is an important link between the intestinal microbiota, inflammation, and intestinal barrier integrity.44 Decreased abundance of A. muciniphila is related to thinning of the mucus layer and increased inflammation, which promotes alcoholic and nonalcoholic liver damage.45 When intestinal permeability increases, microorganisms and microorganism-derived molecules are transferred to the liver through the gut-liver axis causing inflammation and liver damage.46 Some translocated intestinal metabolites may directly interact with host factors, leading to liver disease.18,47 The next section discusses the influence of the gut microbiota on NAFLD and underlying mechanisms.

Gut microbiota in NAFLD

During embryological development, the gut and liver are intrinsically connected, with the liver budding directly from the foregut during this period. Increasing evidence shows that the intestine and liver have multiple interdependence levels and that dysbiosis and metabolic changes in intestinal microbiota are closely associated with NAFLD (Table 1).45,48–53 This includes observations that patients with NAFLD experience increased intestinal permeability when compared with non-NAFLD patients,54 exhibit correlations between liver disease and microbiota changes,55 and the impact of flora manipulation on liver injury.16

Table 1

Changes in the gut microbiota in fatty liver disease

DiseaseSpeciesIncreased gut microbiotaDecreased gut microbiotaReference
ALDMouseCandida sppIntestinal fungi51
HumanBifidobacteria, Lactobacilli, Proteobacteria, FusobacteriaFaecalibacterium, prausnitzii, Coprococcus, Roseburia spp52,53
NASH/NAFLDMouseBacteroides and FirmicutesA. muciniphila45,48
HumanProteobacteria, Enterobacteriaceae, Escherichia, Bacteroides, RuminococcusRuminococcaceae, Anaerospacter, Coprococcus, Eubacterium, Faecalibacterium, Prevotella49,50,51

ALD, alcohol-related liver disease; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.

Dysbiosis

Dysbiosis refers to the destruction of the normal intestinal microbiota, including the loss of beneficial bacteria, changes in bacterial abundance, and increased pathogen levels.6 The condition is induced by factors that include drastic environmental changes, immune or host factors, changes in bile composition, gastric pH, and intestinal motility disorders.6,56 In recent years, studies linking dysbiosis with NAFLD pathogenesis have rapidly increased, focusing on the metabolism of intestinal microbes and their metabolites. However, the exact mechanism by which the gut microbiota promotes the progression of NAFLD needs additional study, and it is also necessary to discover more effective new treatments for gut microbes in NAFLD. A 2001 study by Wigg et al.57 was the first to describe the link between gut dysbiosis and liver disease. Using a 14C-D-xylose-lactulose breath test, the study showed that small intestinal bacterial overgrowth (SIBO) was present in 50% of patients with nonalcoholic steatosis, but in only 22% of control subjects (p=0.048). However, low participant numbers and excluded diseases potentially affected SIBO, such as diabetes and anemia, were major study limitations. In addition, subsequent studies showed that SIBO was related to low intestinal motility and other factors such as the inhibition of gastric acid secretion, decreased secretion of intestinal enzymes, and decreased bile flow, which is a causative factor in NAFLD.58,59 Furthermore, patients with SIBO experienced increased intestinal permeability with more severe portal endotoxemia that may have exacerbated NAFLD progression.48

Animal studies where the microbiome is manipulated provide powerful evidence of dysbiosis in NAFLD. Turnbaugh et al.60 reported that obesity was related to changes in the relative abundance of two main bacteria, Bacteroides and Firmicutes by comparing the gut microbiota of genetically ob/ob mice with lean littermates. They also showed that the ability that the obese microbiota to obtain energy from the diet was partially transmissible, for a significant increase in total body fat after colonizing obese flora in sterile mice compared with the lean flora group. Furthermore, transgenic mouse models have been used to study NAFLD-related intestinal dysbiosis to unravel mechanisms underpinning liver disease progression. Rahman et al.61 used F11r (−/−) mice encoding junctional adhesion molecule A (JAM-A) found that JAM-A deficiency led to more severe NASH. Associated inflammation was reduced by antibiotics, which emphasized the contribution of microbial dysbiosis to NASH development.

Although some animal studies have emphasized the role of gut microbiota in NAFLD, the literature on intestinal dysbiosis in human NAFLD is scarce, especially on the full spectrum of NAFLD lesions. An obesity study reported that an increased abundance of Bacteroides was related to percentage weight loss but not to changes in dietary calorie levels. The study was performed by sequencing 16S ribosomal RNA genes from stool samples, suggesting obesity displayed correlations with gut microbiota changes.49 Another study using 16S ribosomal RNA gene sequencing in 57 patients with biopsy-proven NAFLD, revealed that Bacteroides and Ruminococcus were significantly increased, whereas Prevotella abundance was decreased in those with NASH compared with those without the condition.50 Indeed, studies of fecal microbiota transplantation have provided direct evidence. In one study, obese patients with metabolic syndrome received small intestinal infusions of allogenic microbiota from a thin male donor with a body mass index (BMI) <23 kg/m2 or autologous microbiota. Six weeks after infusion, recipient insulin sensitivity and intestinal butyrate-producing microbiota levels were both significantly increased.62 The findings suggest that gut microbiota changes may be used to improve human insulin sensitivity, indicating the potential benefit for NAFLD treatment.

Leaky gut

As the hepatic portal vein collects blood supplies from the intestine, the liver is often exposed to potentially harmful intestinal metabolites, including translocated bacteria, LPS, endotoxins, and secreted cytokines.63 Therefore, leaky gut, previously associated with liver disease, has attracted considerable attention in recent decades, and has been widely associated with complementary/alternative medicine approaches.64 Leaky gut is typically caused by several pathogenic factors, including high-fat diet, gut microbiota dysbiosis, and reduced BAs secretion. The conditions change the intestinal mucosal barrier, which increases intestinal mucosa permeability, causing leakage of bacteria, toxic digestive metabolites, and bacterial toxins into the blood, inducing liver immune responses.6,63,65 Dysbiosis changes tight junction proteins in the intestinal mucosa, increases mucosa permeability, and exposes intestinal mucosal cells and the liver to potentially pro-inflammatory bacterial products. Cani et al.66 reported that gut dysbiosis induced by obesity increased lower plasma LPS and cytokine levels and increased the expression of inflammatory and oxidative stress markers associated with higher intestinal permeability and tight junction integrity changes. Meanwhile, gut microbiota are reported to have positive effects on intestinal barriers and permeability. For example, Bifidobacteria was shown to enhance barrier function in experimental necrotizing enterocolitis in mice and the yeast Saccharomyces boulardii had beneficial effects on altered intestinal microbiota and epithelial barrier defects in different pathologies.67

Products from translocated microorganisms may participate in NAFLD pathogenesis through a variety of mechanisms. LPS is the central component of the outer membrane of Gram-negative bacteria and is an endotoxin related to NAFLD pathogenesis. Studies have shown that plasma LPS-binding proteins in patients with NAFLD are significantly increased.68 LPS binds to LPS-binding proteins than then bind to toll-like receptor 4 (TLR4), triggering IR and inflammation.69 During NAFLD occurrence and development, gut dysbiosis leads to increased LPS secretion. SIBO, changed intestinal barrier, and increased permeability promotes circulating LPS level, which then elevated portal levels of gut-derived TLR ligands. Activated TLR4 on hepatic Kupffer cells and stellate cells further stimulated pro-inflammatory and profibrotic pathways via a range of cytokines, including interleukin-1 (IL1), IL6, and tumor necrosis factor (TNF).56,70,71 TLR signal proteins have complex and cooperative interactions with inflammasomes in metabolic diseases.72 Henao-Mejia et al.72 reported that inflammasome-deficient mice had an increased expression of TLR4 and TLR9 agonists and more severe liver steatosis, which were closely related to an imbalance of intestinal microbiota. In fact, TLR signaling enhanced NASH progression by increasing the expression of pro-inflammatory cytokines, such as TNF-α. Specifically, TNF-α regulates liver cell death and prevents insulin signal transduction by inhibiting the insulin receptor and insulin receptor substrate-1, leading to IR.73 Inflammasomes have also been shown to activate several liver processes, including cleavage of pro-caspase 1 to active caspase 1 leading to cell apoptosis.74 Another downstream effect mediated by inflammasomes is the release of IL1β, which promotes NAFLD progression. IL1β regulates lipid metabolism by inhibiting peroxisome proliferator-activated receptor alpha (PPARα) and downstream molecules, leading to accumulation of triglycerides in the liver and promoting steatosis.73

Microbiota metabolism

Studies that evaluated the metabolic characteristics associated with NAFLD or NAFLD-fibrosis and are summarized elsewhere.75 Changes in metabolites, including molecules produced by intestinal microorganisms, e.g., ethanol,76 SCFAs such as butyric, propionic, and acetic acid,56 and BA metabolites that target FXR in the liver or intestine,17,77,78 all have important roles in liver injury pathophysiology. Here, we discuss the role of intestinal microbial metabolic substrates and circulating intestinal microbial-derived metabolites in promoting NAFLD progression.

BAs

BAs are synthesized by hepatocytes and are discharged into the intestinal tract via the large papilla of the duodenum. Their physiological functions include promoting fat digestion, increasing pancreatic lipase and lipoprotein esterase activity, and regulating the intestinal microbiota.79 BA metabolism (enterohepatic circulation) and associated interactions with gut microbes are extremely complex and have been discussed earlier. In recent decades, BA functions in the pathogenesis and treatment of the fatty liver have received considerable attention and are discussed in several reviews.29,80,81 As a signal regulator molecules, BAs regulate bodily immune homeostasis and inflammatory responses via the FXR (also known as NR1H4) and the G protein-coupled BA receptor, Gpbar1 (TGR-5; also known as GPR131, GPBAR1, M-BAR, and BG37), and further affect the physiological processes of liver cell fatty degeneration, cell damage, and apoptosis.82 FXR is a nuclear receptor believed to be the master regulator of BA metabolism. It is involved in all phases of the biosynthetic pathway and is expressed in a variety of tissues and organs, with the highest expression in liver and ileum cells.83 In addition, the FXR is activated by BAs to inhibit NLRP3 inflammasome activation by interacting with caspase-1, and to reduce release of IL-1B and other inflammatory factors to relieve NAFLD.84 A recent study reported that FXR knockout mice had an increased proportion of secondary BAs and infiltration of lymphocytes and neutrophils, whereas FXR overexpression alleviated liver damage caused by inflammation and infection.85 Indeed, FXR signaling is modulated by the gut microbiota. Li et al.86 used the antioxidant, Tempol, to alter the microbiota and BA distribution, resulting in increased TβMCA levels and suppressed FXR signaling.

TGR-5 is another BA response receptor involved in host metabolism. Functioning as a plasma membrane-bound G protein-coupled receptor (GPCR), the protein is generally highly expressed in the gallbladder, placenta, lung, spleen, intestine, liver, brown and white adipose tissue, skeletal muscle, and bone marrow.87 Recently, TGR-5 was shown to have a key role in anti-inflammatory effects,88 reinforcing barrier functions,89 and regulating BA metabolism in participation with intestinal microbiota.23,90 TGR-5 knockout mice had conventional phenotypes and reproductive abilities, but their BA pool was significantly reduced, suggesting that the TGR-5 receptor had important roles in maintaining BA homeostasis.91 In addition, it was demonstrated that treating obese db/db mice with INT-767, a TGR-5 agonist, reduced liver steatosis and inhibited the expression of pro-inflammatory cytokines, indicating the TGR-5 signaling pathway had the potential to treat NAFLD.77

SCFAs

SCFAs are organic fatty acids with 1–6 carbon atoms that are produced by microbial carbohydrate fermentation in the intestinal tract. The most common SCFAs are acetic acid, produced by both the host and bacteria; propionic acid, butyric acid, produced by bacterial fermentation; isovaleric acid, and valeric acid. Acetic, propionic, and butyric acid account for more than 95% of the entire SCFA complement.92 Butyrate is an energy source for intestinal cells and helps maintain the intestinal barrier.6 Recently, it was shown that SCFAs inhibited cell proliferation,93 induced cell differentiation and apoptosis,94 and is closely associated with inflammatory bowel disease (IBD),95 irritable bowel syndrome (IBS),96 colon cancer,97 NAFLD,56,98 and other digestive diseases. SCFA types and levels in the intestine vary with carbohydrate consumption and gut dysbiosis, but they promote NAFLD progression via several mechanisms such as binding to GPCRs. Using isotope-labeled SCFA enemas in rats, Besten et al.99 found that acetic acid, propionic acid, and butyric acid were involved in the expression of fat metabolism-related genes. SCFAs protected the liver by reducing intestinal mucosa permeability through the gut-liver axis and inhibiting endotoxin translocation.99 A recent study by Mollica et al.100 reported that butyric acid and its synthetic derivative, N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA), regulated mitochondrial function, efficiency, and kinetics, and proposed it as a new therapeutic strategy to combat obesity and IR. Specifically, butyric acid and FBA improved respiratory capacity and fatty acid oxidation, activated the AMPK acetyl-CoA carboxylase pathway, and promoted inefficient metabolism, thereby reducing intracellular lipid accumulation and oxidative stress.100 Moreover, in another study, acetic acid inhibited liver fat accumulation without changing food consumption or skeletal muscle weight, and was also associated with the PPARα and AMPK pathways.101 Notably, an NAFLD study demonstrated statistically significant differences in Clostridium and Bacteroidetes percentages compared with normal groups. Indeed, the changes between Clostridium and Bacteroidetes may adjust the proportion of SCFAs that affect the energy supply and demand in the liver, altering the progress of NAFLD.102

The GPCRs, GPR41 and GPR43 are the main targets of SCFAs acting on intestinal endocrine cells, and produce a variety of effects that may lead to NAFLD. The exact mechanisms are related to the slowing of gastric emptying and intestinal transit and improved nutrient absorption,103 inhibiting lipolysis and promoting fat cell differentiation,16,104 and increasing intestinal inflammation and permeability to participate in NASH pathogenesis.105

Bacterially-derived ethanol

Endogenous alcohol refers to ethanol produced by dietary sugar fermentation, with intestinal microbiota being the main source of this alcohol. Under normal physiological conditions, the body’s metabolism will continuously produce ethanol.106 After eating nonalcoholic food, the blood ethanol concentration also increases. Bacterially-derived ethanol is quickly and completely eliminated in the portal vein by liver alcohol dehydrogenase (ADH), catalase, and the microsomal ethanol oxidizing system. When ADH is inhibited, blood ethanol concentrations increase. The fact that the human liver and digestive tract both have the highest ADH activities proves that the intestinal tract produces alcohol.107

NAFLD and alcoholic fatty liver disease are pathologically similar and may have common pathogenic mechanisms. Studies have confirmed that blood ethanol concentrations are higher in obese patients or obese mice than in lean individuals, suggesting intestinal alcohol may be related to the occurrence of NASH.108 In addition, excess growth of small intestinal bacteria and gut dysbiosis (e.g., increased Escherichia coli) may lead to increased levels of endogenous alcohol. Zhu et al.109 reported significantly increased E. coli levels in patients with NASH compared with obese patients. As E. coli is the main alcohol-producing bacteria, differences in blood ethanol concentrations were observed, suggesting a role for alcohol-producing microbiota in this condition. Moreover, recent studies reported the increased expression of alcohol-metabolizing enzymes (i.e. ADH) in patients with NASH. Specifically, increased ADH activity increased acetaldehyde levels, which further increased small intestine mucosa permeability. The absorption of intestinal microbiota metabolites increased, which augmented acetaldehyde levels and promoted NASH.110

Ferroptosis in NAFLD

Iron overload is prevalent in NAFLD patients, and it is widely accepted that iron-induced lipid peroxidation is one of the major triggers of NAFLD.111 In addition, iron imbalance is associated with obesity and IR, both of which are typical features of patients with NAFLD.112 In general, people tend to speculate that ferroptosis may be involved in the pathogenesis of NAFLD, which has been confirmed by numerous studies.113 Fortunately, some drugs that act on ferroptosis targets (e.g., sorafenib, sulfasalazine, and artesunate) have been widely reported, making it possible that ferroptosis could be a key target for the treatment of NAFLD (Table 2).114–126

Table 2

Drugs targeting ferroptosis in liver disease

DrugTargetMechanismReference
Ferroptosis promotersErastin, glutamate, ulfasalazine, sorafenibSystem Xc−Inhibits system Xc−, resulting in GSH depletion177,116
FIN56GPX4Depletes CoQ10, resulting in lipid peroxidation117
FINO2GPX4inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation118
StatinHMG-CoA reductaseInhibits CoQ10, resulting in lipid peroxidation119
ArtesunateFerritinophagyActivates ferritinophagy120
Ferroptosis inhibitorsFerrostatins, liproxstatins-1, vitamin EPUFAs, GPX4Inhibits lipid peroxidation121–123
Ginkgolide BNrf2Activates Nrf2, leading to reducing lipid peroxidation114
Deferoxamine (DFO), deferiproneIronChelate iron ions124,125
Dihydrobiopterin (BH2), tetrahydrobiopterin (BHA)Lipid RemodelingSelectively preventing depletion of phospholipids with two polyunsaturated fatty acyl tails126

CoQ10, coenzyme Q10; GPX4, glutathione peroxidase 4; GSH, glutathione; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; Nrf2, nuclear factor erythroid 2-related factor 2; PUFAs, polyunsaturated fatty acids.

Dietary Fe3+ is absorbed by duodenal intestinal epithelial cells and reduced to Fe2+ by divalent metal-ion transporter-1 (DMT1). Fe2+ absorbed into the blood is oxidized to Fe3+ by ceruloplasmin, bound by transferrin, and then transported to tissues. However, because of the first-pass effect of the hepatic portal circulation, iron exposure of the liver is much greater than that of other tissues, resulting in liver damage and various complications.127 Serum ferritin is a clinical biomarker for detecting iron homeostasis in the body. When the serum ferritin content is abnormal, the overload operation of the liver as an organ responsible for removing serum ferritin further aggravates liver damage. The expression of ferritin is influenced by iron stores and inflammation, and elevated ferritin levels are common in NAFLD.128 In a study of 628 adult patients with biopsy-proven NAFLD, a serum ferritin (SF) 1.5 times the upper limit of normal has been associated with a diagnosis of NASH, higher steatosis grade, and lobular inflammation. Elevated SF was also found to be an independent predictor of advanced hepatic fibrosis in patients with NAFLD.129 Also, a study of 25,597 participants in Korean National Health and Nutritional Examination Surveys between 2007 and 2012 and confirmed that people with higher SF levels were more likely to have NAFLD. An increase in SF of 10 ng/mL increased the likelihood of NAFLD by 3–10%.130 Therefore, many researchers have proposed that in equivocal circumstances, SF measurement can be used to assess the risk of NAFLD.131 However more long-term studies are needed to assess the relationship between SF levels and complications of liver disease (e.g., HCC) and liver-related mortality.

Iron overload is prevalent in NAFLD patients.132 In a retrospective study, patients with biopsy-proven NAFLD and iron overload had poor long-term outcomes133 that may have been the result of increased IR, excess hepatic lipid peroxidation, and accelerated liver fibrosis progression caused by iron overload.134 Loguercio et al.135 found that more than 90% of NAFLD patients had increased levels of lipid peroxidation markers, including malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), which were significantly higher in NASH patients than in steatosis patients. Qi et al.113 studies the impact of ferroptosis on the progression of NASH induced by a methionine/choline-deficient diet (MCD) for 10 days. RSL3, a ferroptosis activator, aggravated symptoms, including serum biochemical index levels, liver steatosis, and inflammation) in mice with NASH induced by the MCD diet. Sodium selenite, a GPx4 activator, rescued RSL3-induced lipid peroxidation and cell death. Similarly, Li et al.20 used RNA-seq analysis to show that arachidonic acid metabolism promote ferroptosis in the MCD diet-induced NASH mouse model, suggesting that ferroptosis may be a therapeutic target for NASH treatment. Consistently, other studies found that some drugs like Ginkgolide B and dehydroabietic acid alleviated NASH severity by inhibiting ferroptosis. In that context, Nrf2 and GPx4 stand out as major protective mechanisms.114,136 Overall, the results imply that the regulation of ferroptosis in the context of NAFLD is an intriguing notion that deserves further investigation.

Targeting the gut microbiota to prevent NAFLD

As discussed, gut dysbiosis and associated metabolites such as BAs, SCFAs, and endogenous ethanol, and inflammatory responses and damage of the intestinal barrier are important factors during NAFLD occurrence and development. If those conditions are corrected, NAFLD progression can be slowed and possibly reversed. This section focuses on gut microbiota regulation as a therapeutic target for NAFLD prevention, including lifestyle and diet therapies, antibiotics, probiotics, and prebiotics, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RA), and sodium/glucose cotransporter-2 inhibitors (SGLT2i; Table 3).[137,–146]

Table 3

Gut microbiota-targeted therapies of NAFLD

InterventionsMain effectsExperimental modelClinicaltrials.gov IDReference
Lifestyle and diet therapyKeeping circadian rhythmCircadian rhythm disorders increase intestinal permeability, promoting hepatic steatosisHigh-fat diet (45% fat)–137
Weight loss/exerciseIncreasing gut microbe diversity, improving metabolic capacity, and reducing Bacteroides to Firmicutes ratioMice with HFD (45% kcal from fat) for 12 weeks–138
AntibioticRifaximin (1,200 mg/daily)Reduction in serum AST, ALT, and endotoxinBiopsy-proven NAFLD, n=42NCT02009592139
CidomycinLowering serum levels of ALT, AST and alleviating the severity of NASHRats with NASH–143
ProbioticsLactobacillus (LcS)Suppressing NASH developmentMCD diet-induced NASH in mice–144
Bifidobacterium (Bif)Ameliorating visceral fat accumulation and insulin sensitivityHFD-fed rats–145
VSL#3Improving the degree of liver disease in children44 obese children with NAFLDNCT01650025146
PrebioticFructo-oligosaccharides (FOS)Restoring normal gastrointestinal microflora and decreasing steatohepatitisMCD diet-induced NASH in mice–140
LactuloseAmeliorating the hepatic inflammation and decreasing serum levels of ALT and ASTHFD-induced NASH in rats–141
GLP-1 RAliraglutidedecreasing Proteobacteria and increasing Akkermansia muciniphilaHFD mice–142

NASH, nonalcoholic steatohepatitis; NAFLD, nonalcoholic fatty liver disease; HFD, high-fat diet; MCD, methionine-choline-deficient; GLP-1 RA, glucagon-like peptide-1 (GLP-1) receptor agonists.

Lifestyle and diet therapy

NAFLD is closely related to obesity.147 Studies have shown that eating foods rich in fat and fructose alters the intestinal microbiota, changes intestinal barrier function, and causes endotoxemia and inflammatory reactions, all of which promote obesity and NAFLD.148 Therefore, the most important treatment goal for patients with NAFLD is weight reduction and maintenance of a healthy lifestyle to reduce liver fat deposition and inflammatory responses. In addition, a balanced diet, adequate sleep, and appropriate exercise are essential to maintain intestinal microbiota stability and health, and to reduce the risk of other diseases. Dietary interventions are effective in the treatment of NAFLD patients. Even a modest 3–5 kg weight gain predicts the development of NAFLD independent of baseline BMI. In addition, patients with NAFLD were found to experience a 75% remission rate with a weight loss of 5% or more from baseline.149 Much evidence suggests that the Mediterranean diet can reduce liver fat, even without weight loss. It is the most recommended diet for NAFLD.150 The Mediterranean diet includes nuts, fruits, legumes, olive oil, vegetables, and fish, in which consumption of sugar and refined carbohydrates is decreased and consumption of monounsaturated fatty acids and omega-3 fatty acids is increased. Dietary micronutrients also greatly influence the progression of NAFLD. Studies have shown that the intake of micronutrients such as vitamin C, vitamin D, and choline is significantly negatively correlated with the prevalence of NAFLD, which may be related to their antioxidant and antifibrotic activity.151 However, randomized controlled trials have not resulted in clear evidence that high-dose vitamin D supplementation is beneficial for hepatic steatosis or IR in NAFLD.152 Although the Mediterranean diet advocates moderate alcohol consumption, whether or not alcohol should be allowed in NAFLD patients remains controversial. Regular alcohol consumption increases the risk of developing HCC in NASH patients with cirrhosis, so alcohol should be avoided in such patients.153 However, in patients without cirrhosis, uncertainty about the impact of moderate drinking (e.g., 12 ounces of beer, 4 ounces of wine, or 1 ounce of liquor) is not clear, so prudent drinking is advised.

Sleep is an essential physiological process required for normal function, and adequate sleep patterns help maintain normal homeostasis. In recent decades, studies have shown that sleep-related factors, especially sleep time, influence the risk of obesity.154 A prospective study by Nielsen et al.155 reported that patients with obesity slept for significantly shorter periods than nonobese individuals. Also, Gildner et al.156 observed that in middle-aged individuals, short sleep duration was significantly correlated with elevated BMI and waist circumference. However, obesity-associated mechanisms caused by shortened sleep times remain unclear. A recent study showed that a chronic lack of sleep decreased leptin and increased ghrelin levels, resulting in a “hyperappetite.”157 Increased eating rate caused by prolonged wakefulness was also a cause of obesity.158 People with short sleep times are prone to fatigue that leads to reduced exercise, increased weight gain, or obesity. In addition to sleep time, changes in circadian rhythm influence development of obesity and NAFLD progression.137 Voigt et al.159 reported that reversing circadian rhythms in mice changed the Firmicutes and Bacteroidetes composition in those fed a high-sugar diet, but the microbiome in mice fed normal diets did not change. Summa et al.160 also found that circadian rhythm disorders increased intestinal permeability in mice, promoting alcohol-induced steatohepatitis.160

Weight loss is recognized as a basic and key measure for NAFLD management, and exercise is an effective and safe way to lose weight. For patients with NAFLD, exercise not only directly reduced liver fat content, but also reduced fatty acid absorption, improved insulin sensitivity,161 reduced liver transaminase indicators, and improved other metabolic indicators.162 In 2009, George et al.162 compared the low intensity exercise, medium intensity exercise, and control groups. After a 3-month intervention, patients who maintained more than 150 min/week had decreased serum transaminase levels, independent of changes in body mass, effectively illustrating physiological exercise advantages for these patients. Previous studies have also shown that exercising changes the composition of intestinal microbes and affects NAFLD progression.163 Munukka et al.164 recruited 17 overweight adult women for a 6-week bicycle endurance training study and found that exercises decreased Proteobacteria, but significantly increased Akkermansia levels. Animal studies have also confirmed the effect of exercises on gut microbiota. Petriz et al.165 reported that treadmill exercises changed the composition and abundance of microorganisms, and training increased lactobacilli, (beneficial bacteria) numbers in obese rats. Denou et al.138 conducted a 6-week high-intensity exercise regime in rats fed a high-fat diet, and found that the exercise intervention increased gut microbe diversity, improved metabolic capacity, and reduced the Bacteroides to Firmicutes ratio.

Antibiotics

Therapeutic antibiotics inhibit excessive proliferation of intestinal microbes and bacterial translocation. They alter disease-related microbial communities to ensure healthy homeostasis. Antibiotics eliminate harmful microbiota, and are effective in several digestive-system models, including hepatic encephalopathy,166 IBS,[1167] IBD,168 and NAFLD.47,169 The therapeutic effects of antibiotics in NAFLD are attributed to (1) improving leaky gut by reducing pathogens and potential pathogens and suppressing liver inflammation and (2) reducing harmful bacterial metabolites which promote NAFLD. In an observational study, Gangarapu et al.139 reported that after 28 days of with rifaximin treatment of NASH patients, circulating endotoxin levels were significantly reduced. Short-term rifaximin treatment acted on intestinal bacteria to achieve the desired therapeutic effectiveness. However, more clinical trials are required to confirm effective rifaximin treatment cycles for patients with NAFLD.

Animal studies have reported that antibiotics quickly and significantly altered the intestinal microbiota. Broad-spectrum antibiotics, such as ampicillin, neomycin, metronidazole, and vancomycin reduced hepatitis by regulating free secondary BA levels and improving liver steatosis by inhibiting the FXR pathway to downregulate liver SREBP1C expression.85,170 However, another study found that penicillin G and erythromycin aggravated liver lipid metabolism and inflammatory reactions.171 Antibiotics also promoted liver lipid accumulation, inflammatory responses, and liver fibrosis by increasing liver immune damage.172 At the same time, we cannot ignore the impact of antibiotics on the beneficial intestinal microbiota, therefore correct use of effective antibiotic treatment requires more comprehensive research.

Probiotics and prebiotics

Probiotics are living microorganisms that benefit host health.6 Studies show that they regulate the intestinal microbiota,173 enhance intestinal barrier function,174 reduce intestinal permeability,175 alleviate immune and metabolic damage,176 up-regulate fatty acid oxidation,177 and reduce liver steatosis and inflammatory-response damage.178 A recent meta-analysis confirmed that Lactobacillus, Bifidobacterium, Streptococcus probiotics, when used for 8–24 weeks were beneficial for the recovery of liver enzymes and IR in patients with NAFLD.179 A clinical study reported that after a 6 month intervention with the probiotic, Lepicol in 10 patients with NASH, intrahepatic triacylglycerol levels were reduced by more than 30% compared with baseline levels and serum AST levels were significantly reduced.180 A randomized controlled trial of 42 patients with NAFLD found that fasting blood glucose, insulin, IR, TNF-a, and IL6 were significantly reduced after 8 weeks of probiotic treatment (two capsules/day).181 Other studies have reported an association of probiotics on liver fibrosis or death in NAFLD patients, therefore results are inconsistent. A liver biopsy clinical study reported that Bifidobacterium longum supplementation significantly improved liver steatosis, but not liver fibrosis.182 In a long-term survey of 39 biopsy-confirmed patients with NAFLD, the continuous use of the probiotic, VSL#3 for 1 year significantly improved NAFLD activity scores, hepatocyte swelling, and liver fibrosis. Prebiotics are dietary supplements that benefit the host by selectively stimulating the growth and/or activity of one or several bacterial colonies.183 Matsumoto et al.140 studied the effects of fructo-oligosaccharides (FOSs) on intestinal barrier function and steatohepatitis in mice with methionine-choline deficiency. Liver inflammation and hepatocyte steatosis in FOS-treated mice were significantly reduced (p<0.01), suggesting that 3 weeks of treatment improved NAFLD and restored barrier functions in the intestinal tract.140 The probiotic lactulose promoted Bifidobacteria and lactic acid bacteria growth. Fan et al.141 used it to treat mice with NAFLD induced by a high-fat diet, and showed that liver inflammation indicators such as AST and ALT in the lactulose treatment group (0.9 mL/kg/day for 8 weeks) were significantly reduced, but hepatocyte steatosis was not significantly improved, suggesting that lactulose reduced liver inflammation but did not improve fat degeneration in liver cells.141

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) and sodium/glucose cotransporter-2 inhibitors (SGLT2is)

GLP-1 is an incretin secreted by L cells in the distal small intestine and colonic mucosa after meal stimulation in a glucose concentration-dependent manner. It promotes insulin secretion and participates in the regulation of blood glucose homeostasis. GLP-1 has a very short half-life in vivo, and is degraded by dipeptidyl peptidase-4 (DPP-4), so it cannot be used for disease treatment.184 GLP-1 RA belongs is an incretin drug with pleiotropic effects such as lowering blood glucose and blood lipids and reducing body weight.185 Recent studies have found that GLP-1 RA improved IR in NAFLD, reduced liver steatosis, and improved liver fibrosis. It is of great significance for the treatment of NAFLD, especially NAFLD complicated with T2DM.186 A randomized, multicenter, double-blind, placebo-controlled phase 2 trial in the UK that evaluated the safety and efficacy of subcutaneous liraglutide, an acylated GLP-1 RA, 1.8 mg daily compared with placebo in patients with biopsy-confirmed NASH. Liraglutide significantly improved hepatic steatosis by 83% in the liraglutide group and 45% in the placebo group, and hepatocyte swelling by 61% in the liraglutide group and 32% in the placebo group. which indicated that the patient’s NASH was in remission. The histological effects of liraglutide on NASH were not entirely mediated by its action on the improvement of glycemic control.187 A study by Moreira et al.142 showed that liraglutide not only reduced hepatic fat accumulation by 78% in ob/ob mice and reversed steatosis in HFD mice, but also altered the overall gut microbial composition. Proteobacteria decreased and Akkermansia muciniphila increased in the mice fed the HFD. The studies suggest that GLP-1 RA contributed to the improvement of NAFLD by the regulation of gut microbiota, which offers a new perspective for us to find gut microbiota-targeted therapies of NAFLD.

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a class of hypoglycemic drugs that is commonly used in clinical practice to reduce the reabsorption of glucose by the kidneys, intestines, and heart. Several studies showed that SGLT-2i was associated with improvement of hepatic steatosis.143 In an open-label, randomized, active-controlled trial, Ito et al.189 of 66 patients with type 2 diabetes and NAFLD found that ipragliflozin 50 mg significantly reduced body weight and visceral fat area. A similar study by Nasiri-Ansari et al.190 in mice fed an HFD found that empagliflozin reduced fasting glucose, total cholesterol, and serum triglyceride levels; and decreased the NAFLD activity score, expression of lipogenic enzymes, and inflammatory molecules. However, side effects associated with SGLT-2 inhibitors, such as increased risk of urinary and genital infections cannot be ignored. The increased risk may be explained by the fact that persistent diabetes may promote the growth of pathogenic microorganisms. A meta-analysis showed that gliflozins were associated with an increase in genitourinary infections,191 and they have also been reported to increase the risk of malignancy, particularly of the breast or bladder, but no studies have confirmed that possibility.192

Conclusions

Evidence that the gut microbiota has important mechanistic roles in NAFLD occurrence and progression is increasing. Gut microbiota dysbiosis usually reduces beneficial bacteria and SIBO, changes small intestine mucosal barriers, and increases intestinal permeability and microbial metabolites (e.g., LPS and SCFAs). That increases endotoxins and inflammatory factors that enter the liver via the gut-liver axis, inducing immune and inflammatory reactions, and culminating in NAFLD (Fig. 2).

Promotion of gut microbiota in NAFLD.
Fig. 2  Promotion of gut microbiota in NAFLD.

Gut microbiota dysbiosis includes the reduction of beneficial bacteria and SIBO, change of the small intestine mucosal barrier, increase of intestinal permeability and microbial metabolites including LPS and SCFAs, leads to an increase in endotoxins and inflammatory factors that enter the liver through the gut-liver axis that induces immune and inflammatory reactions, leading to the progression of NAFLD NASH, nonalcoholic steatohepatitis; NAFLD, nonalcoholic fatty liver disease; BAs, bile acids; SCFAs, short-chain fatty acids; LPS, lipopolysaccharide; VLDL, very low-density lipoprotein; IL-1, interleukin-1; TNF-α, tumor necrosis factor-α.

No drugs are currently licensed for NAFLD therapy, but diet and exercise have proven to be effective treatments. Because of the relationship between NAFLD and T2DM, many diabetes drugs have achieved positive results in relieving NASH. In addition, experimental drugs targeting intermediate metabolism in NAFLD have also been shown to be beneficial, but adverse effects may limit their use. This review focuses of the gut microbiota and ferroptosis treatments for NAFLD, as well as proposing new treatment strategies. Lifestyle and diet, antibiotics, regulation of ferroptosis, probiotics, and prebiotics, GLP-1 RA, and SGLT2i may become effective and safe treatments to alleviate NAFLD. However, to effectively transform and apply animal model findings to humans, well-designed large clinical trials, spanning multiple disease etiologies and patient characteristics, are required.

Abbreviations

BAs: 

bile acids

FXR: 

farnesoid X receptor

FOS: 

fructo-oligosaccharide

GLP-1 RA: 

glucagon-like peptide-1 receptor agonists

HFD: 

high fat diet

IR: 

insulin resistance

LPS: 

lipopolysaccharide

MAFLD: 

metabolic-associated fatty liver disease

NAFLD: 

nonalcoholic fatty liver disease

NASH: 

non-alcoholic steatohepatitis

ROS: 

reactive oxygen species

SCFAs: 

short-chain fatty acids

SIBO: 

small intestinal bacterial overgrowth

SGLT2i: 

sodium/glucose cotransporter-2 inhibitors

TLR4: 

toll-like receptor 4

TNF: 

tumor necrosis factor

Declarations

Acknowledgement

We thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.

Funding

This study was supported by: (1) the National Natural Science Foundation of China (grant number: 82002539); (2) the Natural Science Foundation of Shanghai (grant number: 19ZR1447700); (3) the Health System Innovation Project of Shanghai Putuo Science and Technology Commission (grant numbers: PTKWWS201903); (4) The Yangfan Plan of Shanghai Science and Technology Commission (grant no. 21YF1435400); (5) Shanghai Municipal Health Commission, China (grant no. 201840233).

Conflict of interest

The authors have no conflicts of interest related to this publication.

Authors’ contributions

Study concept and design (JJ, LW), drafting of the manuscript (JJ, LW), critical revision of the manuscript for important intellectual content (JJ, JW), administrative support (GC, JW), and study supervision (CG). All authors have made a significant contribution to this study and have approved the final manuscript.

References

  1. Younossi ZM, Rinella ME, Sanyal AJ, Harrison SA, Brunt EM, Goodman Z, et al. From NAFLD to MAFLD: Implications of a Premature Change in Terminology. Hepatology 2021;73(3):1194-1198 View Article PubMed/NCBI
  2. Bessone F, Razori MV, Roma MG. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci 2019;76(1):99-128 View Article PubMed/NCBI
  3. Paul S, Davis AM. Diagnosis and Management of Nonalcoholic Fatty Liver Disease. JAMA 2018;320(23):2474-2475 View Article PubMed/NCBI
  4. Bertot LC, Adams LA. Trends in hepatocellular carcinoma due to non-alcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2019;13(2):179-187 View Article PubMed/NCBI
  5. Haas JT, Francque S, Staels B. Pathophysiology and Mechanisms of Nonalcoholic Fatty Liver Disease. Annu Rev Physiol 2016;78:181-205 View Article PubMed/NCBI
  6. Yu Q, Wu L, Ji J, Feng J, Dai W, Li J, et al. Gut Microbiota, Peroxisome Proliferator-Activated Receptors, and Hepatocellular Carcinoma. J Hepatocell Carcinoma 2020;7:271-288 View Article PubMed/NCBI
  7. Seo DO, Holtzman DM. Gut Microbiota: From the Forgotten Organ to a Potential Key Player in the Pathology of Alzheimer’s Disease. J Gerontol A Biol Sci Med Sci 2020;75(7):1232-1241 View Article PubMed/NCBI
  8. Young VB. The role of the microbiome in human health and disease: an introduction for clinicians. BMJ 2017;356:j831 View Article PubMed/NCBI
  9. Wu J, Wang K, Wang X, Pang Y, Jiang C. The role of the gut microbiome and its metabolites in metabolic diseases. Protein Cell 2021;12(5):360-373 View Article PubMed/NCBI
  10. Ren Z, Li A, Jiang J, Zhou L, Yu Z, Lu H, et al. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma. Gut 2019;68(6):1014-1023 View Article PubMed/NCBI
  11. Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, et al. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 2018;15(7):397-411 View Article PubMed/NCBI
  12. Marshall JC. The gut as a potential trigger of exercise-induced inflammatory responses. Can J Physiol Pharmacol 1998;76(5):479-484 View Article PubMed/NCBI
  13. Thompson MR, Kaminski JJ, Kurt-Jones EA, Fitzgerald KA. Pattern recognition receptors and the innate immune response to viral infection. Viruses 2011;3(6):920-940 View Article PubMed/NCBI
  14. Ren Z, Guo C, Yu S, Zhu L, Wang Y, Hu H, et al. Progress in Mycotoxins Affecting Intestinal Mucosal Barrier Function. Int J Mol Sci 2019;20(11):E2777 View Article PubMed/NCBI
  15. Perez-Lopez A, Behnsen J, Nuccio SP, Raffatellu M. Mucosal immunity to pathogenic intestinal bacteria. Nat Rev Immunol 2016;16(3):135-148 View Article PubMed/NCBI
  16. Safari Z, Gérard P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD). Cell Mol Life Sci 2019;76(8):1541-1558 View Article PubMed/NCBI
  17. Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: Pathophysiological basis for therapy. J Hepatol 2020;72(3):558-577 View Article PubMed/NCBI
  18. Milosevic I, Vujovic A, Barac A, Djelic M, Korac M, Radovanovic Spurnic A, et al. Gut-Liver Axis, Gut Microbiota, and Its Modulation in the Management of Liver Diseases: A Review of the Literature. Int J Mol Sci 2019;20(2):E395 View Article PubMed/NCBI
  19. Zheng J, Conrad M. The Metabolic Underpinnings of Ferroptosis. Cell Metab 2020;32(6):920-937 View Article PubMed/NCBI
  20. Li X, Wang TX, Huang X, Li Y, Sun T, Zang S, et al. Targeting ferroptosis alleviates methionine-choline deficient (MCD)-diet induced NASH by suppressing liver lipotoxicity. Liver Int 2020;40(6):1378-1394 View Article PubMed/NCBI
  21. Schwabe RF, Greten TF. Gut microbiome in HCC - Mechanisms, diagnosis and therapy. J Hepatol 2020;72(2):230-238 View Article PubMed/NCBI
  22. Santamaría E, Rodríguez-Ortigosa CM, Uriarte I, Latasa MU, Urtasun R, Alvarez-Sola G, et al. The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis. Hepatology 2019;69(4):1632-1647 View Article PubMed/NCBI
  23. Funabashi M, Grove TL, Wang M, Varma Y, McFadden ME, Brown LC, et al. A metabolic pathway for bile acid dehydroxylation by the gut microbiome. Nature 2020;582(7813):566-570 View Article PubMed/NCBI
  24. Lee G, You HJ, Bajaj JS, Joo SK, Yu J, Park S, et al. Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD. Nat Commun 2020;11(1):4982 View Article PubMed/NCBI
  25. de Aguiar Vallim TQ, Tarling EJ, Edwards PA. Pleiotropic roles of bile acids in metabolism. Cell Metab 2013;17(5):657-669 View Article PubMed/NCBI
  26. Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 2008;7(8):678-693 View Article PubMed/NCBI
  27. Wahlström A, Sayin SI, Marschall HU, Bäckhed F. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. Cell Metab 2016;24(1):41-50 View Article PubMed/NCBI
  28. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 2003;72:137-174 View Article PubMed/NCBI
  29. Jiao N, Baker SS, Chapa-Rodriguez A, Liu W, Nugent CA, Tsompana M, et al. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD. Gut 2018;67(10):1881-1891 View Article PubMed/NCBI
  30. Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013;17(2):225-235 View Article PubMed/NCBI
  31. Sun L, Pang Y, Wang X, Wu Q, Liu H, Liu B, et al. Ablation of gut microbiota alleviates obesity-induced hepatic steatosis and glucose intolerance by modulating bile acid metabolism in hamsters. Acta Pharm Sin B 2019;9(4):702-710 View Article PubMed/NCBI
  32. Hegyi P, Maléth J, Walters JR, Hofmann AF, Keely SJ. Guts and Gall: Bile Acids in Regulation of Intestinal Epithelial Function in Health and Disease. Physiol Rev 2018;98(4):1983-2023 View Article PubMed/NCBI
  33. Ijssennagger N, Belzer C, Hooiveld GJ, Dekker J, van Mil SW, Müller M, et al. Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon. Proc Natl Acad Sci U S A 2015;112(32):10038-10043 View Article PubMed/NCBI
  34. Rhee KJ, Wu S, Wu X, Huso DL, Karim B, Franco AA, et al. Induction of persistent colitis by a human commensal, enterotoxigenic Bacteroides fragilis, in wild-type C57BL/6 mice. Infect Immun 2009;77(4):1708-1718 View Article PubMed/NCBI
  35. Donohoe DR, Garge N, Zhang X, Sun W, O’Connell TM, Bunger MK, et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab 2011;13(5):517-526 View Article PubMed/NCBI
  36. Spinler JK, Taweechotipatr M, Rognerud CL, Ou CN, Tumwasorn S, Versalovic J. Human-derived probiotic Lactobacillus reuteri demonstrate antimicrobial activities targeting diverse enteric bacterial pathogens. Anaerobe 2008;14(3):166-171 View Article PubMed/NCBI
  37. Candela M, Perna F, Carnevali P, Vitali B, Ciati R, Gionchetti P, et al. Interaction of probiotic Lactobacillus and Bifidobacterium strains with human intestinal epithelial cells: adhesion properties, competition against enteropathogens and modulation of IL-8 production. Int J Food Microbiol 2008;125(3):286-292 View Article PubMed/NCBI
  38. Hooper LV. Do symbiotic bacteria subvert host immunity?. Nat Rev Microbiol 2009;7(5):367-374 View Article PubMed/NCBI
  39. Sánchez de Medina F, Romero-Calvo I, Mascaraque C, Martínez-Augustin O. Intestinal inflammation and mucosal barrier function. Inflamm Bowel Dis 2014;20(12):2394-2404 View Article PubMed/NCBI
  40. Wang Y, Tong J, Chang B, Wang B, Zhang D, Wang B. Effects of alcohol on intestinal epithelial barrier permeability and expression of tight junction-associated proteins. Mol Med Rep 2014;9(6):2352-2356 View Article PubMed/NCBI
  41. Fukui H, Brauner B, Bode JC, Bode C. Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay. J Hepatol 1991;12(2):162-169 View Article PubMed/NCBI
  42. Martinez-Medina M, Denizot J, Dreux N, Robin F, Billard E, Bonnet R, et al. Western diet induces dysbiosis with increased E coli in CEABAC10 mice, alters host barrier function favouring AIEC colonisation. Gut 2014;63(1):116-124 View Article PubMed/NCBI
  43. Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 2009;9(5):313-323 View Article PubMed/NCBI
  44. Grander C, Adolph TE, Wieser V, Lowe P, Wrzosek L, Gyongyosi B, et al. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut 2018;67(5):891-901 View Article PubMed/NCBI
  45. Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A 2013;110(22):9066-9071 View Article PubMed/NCBI
  46. Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol 2012;590(3):447-458 View Article PubMed/NCBI
  47. Hu H, Lin A, Kong M, Yao X, Yin M, Xia H, et al. Intestinal microbiome and NAFLD: molecular insights and therapeutic perspectives. J Gastroenterol 2020;55(2):142-158 View Article PubMed/NCBI
  48. Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009;49(6):1877-1887 View Article PubMed/NCBI
  49. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 2006;444(7122):1022-1023 View Article PubMed/NCBI
  50. Boursier J, Mueller O, Barret M, Machado M, Fizanne L, Araujo-Perez F, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 2016;63(3):764-775 View Article PubMed/NCBI
  51. Lang S, Schnabl B. Microbiota and Fatty Liver Disease-the Known, the Unknown, and the Future. Cell Host Microbe 2020;28(2):233-244 View Article PubMed/NCBI
  52. Dubinkina VB, Tyakht AV, Odintsova VY, Yarygin KS, Kovarsky BA, Pavlenko AV, et al. Links of gut microbiota composition with alcohol dependence syndrome and alcoholic liver disease. Microbiome 2017;5(1):141 View Article PubMed/NCBI
  53. Chu H, Duan Y, Lang S, Jiang L, Wang Y, Llorente C, et al. The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease. J Hepatol 2020;72(3):391-400 View Article PubMed/NCBI
  54. Volynets V, Küper MA, Strahl S, Maier IB, Spruss A, Wagnerberger S, et al. Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD). Dig Dis Sci 2012;57(7):1932-1941 View Article PubMed/NCBI
  55. Tarantino G, Savastano S, Colao A. Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance. World J Gastroenterol 2010;16(38):4773-4783 View Article PubMed/NCBI
  56. Leung C, Rivera L, Furness JB, Angus PW. The role of the gut microbiota in NAFLD. Nat Rev Gastroenterol Hepatol 2016;13(7):412-425 View Article PubMed/NCBI
  57. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001;48(2):206-211 View Article PubMed/NCBI
  58. Quigley EM, Marsh MN, Shaffer JL, Markin RS. Hepatobiliary complications of total parenteral nutrition. Gastroenterology 1993;104(1):286-301 View Article PubMed/NCBI
  59. Carter BA, Karpen SJ. Intestinal failure-associated liver disease: management and treatment strategies past, present, and future. Semin Liver Dis 2007;27(3):251-258 View Article PubMed/NCBI
  60. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444(7122):1027-1031 View Article PubMed/NCBI
  61. Rahman K, Desai C, Iyer SS, Thorn NE, Kumar P, Liu Y, et al. Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol. Gastroenterology 2016;151(4):733-746.e12 View Article PubMed/NCBI
  62. Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte RS, Bartelsman JF, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012;143(4):913-6.e7 View Article PubMed/NCBI
  63. Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut 2019;68(8):1516-1526 View Article PubMed/NCBI
  64. Cho YE, Kim DK, Seo W, Gao B, Yoo SH, Song BJ. Fructose Promotes Leaky Gut, Endotoxemia, and Liver Fibrosis Through Ethanol-Inducible Cytochrome P450-2E1-Mediated Oxidative and Nitrative Stress. Hepatology 2021;73(6):2180-2195 View Article PubMed/NCBI
  65. Abdelhamid L, Luo XM. Retinoic Acid, Leaky Gut, and Autoimmune Diseases. Nutrients 2018;10(8):E1016 View Article PubMed/NCBI
  66. Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009;58(8):1091-1103 View Article PubMed/NCBI
  67. Terciolo C, Dapoigny M, Andre F. Beneficial effects of Saccharomyces boulardii CNCM I-745 on clinical disorders associated with intestinal barrier disruption. Clin Exp Gastroenterol 2019;12:67-82 View Article PubMed/NCBI
  68. Ruiz AG, Casafont F, Crespo J, Cayón A, Mayorga M, Estebanez A, et al. Lipopolysaccharide-binding protein plasma levels and liver TNF-alpha gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis. Obes Surg 2007;17(10):1374-1380 View Article PubMed/NCBI
  69. Caesar R, Reigstad CS, Bäckhed HK, Reinhardt C, Ketonen M, Lundén GÖ, et al. Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice. Gut 2012;61(12):1701-1707 View Article PubMed/NCBI
  70. Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012;21(4):504-516 View Article PubMed/NCBI
  71. Krawczyk M, Maciejewska D, Ryterska K, Czerwińka-Rogowska M, Jamioł-Milc D, Skonieczna-Żydecka K, et al. Gut Permeability Might be Improved by Dietary Fiber in Individuals with Nonalcoholic Fatty Liver Disease (NAFLD) Undergoing Weight Reduction. Nutrients 2018;10(11):E1793 View Article PubMed/NCBI
  72. Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012;482(7384):179-185 View Article PubMed/NCBI
  73. Stienstra R, Saudale F, Duval C, Keshtkar S, Groener JE, van Rooijen N, et al. Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity. Hepatology 2010;51(2):511-522 View Article PubMed/NCBI
  74. Dixon LJ, Flask CA, Papouchado BG, Feldstein AE, Nagy LE. Caspase-1 as a central regulator of high fat diet-induced non-alcoholic steatohepatitis. PLoS One 2013;8(2):e56100 View Article PubMed/NCBI
  75. Sharpton SR, Ajmera V, Loomba R. Emerging Role of the Gut Microbiome in Nonalcoholic Fatty Liver Disease: From Composition to Function. Clin Gastroenterol Hepatol 2019;17(2):296-306 View Article PubMed/NCBI
  76. Cope K, Risby T, Diehl AM. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology 2000;119(5):1340-1347 View Article PubMed/NCBI
  77. Arab JP, Karpen SJ, Dawson PA, Arrese M, Trauner M. Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives. Hepatology 2017;65(1):350-362 View Article PubMed/NCBI
  78. Compare D, Coccoli P, Rocco A, Nardone OM, De Maria S, Cartenì M, et al. Gut—liver axis: the impact of gut microbiota on non alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2012;22(6):471-476 View Article PubMed/NCBI
  79. Malhi H, Camilleri M. Modulating bile acid pathways and TGR5 receptors for treating liver and GI diseases. Curr Opin Pharmacol 2017;37:80-86 View Article PubMed/NCBI
  80. Gottlieb A, Canbay A. Why Bile Acids Are So Important in Non-Alcoholic Fatty Liver Disease (NAFLD) Progression. Cells 2019;8(11):E1358 View Article PubMed/NCBI
  81. Chávez-Talavera O, Tailleux A, Lefebvre P, Staels B. Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease. Gastroenterology 2017;152(7):1679-1694.e3 View Article PubMed/NCBI
  82. Schneider KM, Albers S, Trautwein C. Role of bile acids in the gut-liver axis. J Hepatol 2018;68(5):1083-1085 View Article PubMed/NCBI
  83. Teodoro JS, Rolo AP, Palmeira CM. Hepatic FXR: key regulator of whole-body energy metabolism. Trends Endocrinol Metab 2011;22(11):458-466 View Article PubMed/NCBI
  84. Hao H, Cao L, Jiang C, Che Y, Zhang S, Takahashi S, et al. Farnesoid X Receptor Regulation of the NLRP3 Inflammasome Underlies Cholestasis-Associated Sepsis. Cell Metab 2017;25(4):856-867.e5 View Article PubMed/NCBI
  85. Jena PK, Sheng L, Liu HX, Kalanetra KM, Mirsoian A, Murphy WJ, et al. Western Diet-Induced Dysbiosis in Farnesoid X Receptor Knockout Mice Causes Persistent Hepatic Inflammation after Antibiotic Treatment. Am J Pathol 2017;187(8):1800-1813 View Article PubMed/NCBI
  86. Li F, Jiang C, Krausz KW, Li Y, Albert I, Hao H, et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 2013;4:2384 View Article PubMed/NCBI
  87. Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem 2003;278(11):9435-9440 View Article PubMed/NCBI
  88. Guo C, Xie S, Chi Z, Zhang J, Liu Y, Zhang L, et al. Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome. Immunity 2016;45(4):802-816 View Article PubMed/NCBI
  89. Cipriani S, Mencarelli A, Chini MG, Distrutti E, Renga B, Bifulco G, et al. The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLoS One 2011;6(10):e25637 View Article PubMed/NCBI
  90. Jia W, Xie G, Jia W. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol 2018;15(2):111-128 View Article PubMed/NCBI
  91. Schubert K, Olde Damink SWM, von Bergen M, Schaap FG. Interactions between bile salts, gut microbiota, and hepatic innate immunity. Immunol Rev 2017;279(1):23-35 View Article PubMed/NCBI
  92. Ganapathy V, Thangaraju M, Prasad PD, Martin PM, Singh N. Transporters and receptors for short-chain fatty acids as the molecular link between colonic bacteria and the host. Curr Opin Pharmacol 2013;13(6):869-874 View Article PubMed/NCBI
  93. Yang LL, Millischer V, Rodin S, MacFabe DF, Villaescusa JC, Lavebratt C. Enteric short-chain fatty acids promote proliferation of human neural progenitor cells. J Neurochem 2020;154(6):635-646 View Article PubMed/NCBI
  94. Tsugawa H, Kabe Y, Kanai A, Sugiura Y, Hida S, Taniguchi S, et al. Short-chain fatty acids bind to apoptosis-associated speck-like protein to activate inflammasome complex to prevent Salmonella infection. PLoS Biol 2020;18(9):e3000813 View Article PubMed/NCBI
  95. Lavelle A, Sokol H. Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2020;17(4):223-237 View Article PubMed/NCBI
  96. Gargari G, Taverniti V, Gardana C, Cremon C, Canducci F, Pagano I, et al. Fecal Clostridiales distribution and short-chain fatty acids reflect bowel habits in irritable bowel syndrome. Environ Microbiol 2018;20(9):3201-3213 View Article PubMed/NCBI
  97. Gomes SD, Oliveira CS, Azevedo-Silva J, Casanova MR, Barreto J, Pereira H, et al. The Role of Diet Related Short-Chain Fatty Acids in Colorectal Cancer Metabolism and Survival: Prevention and Therapeutic Implications. Curr Med Chem 2020;27(24):4087-4108 View Article PubMed/NCBI
  98. Ding Y, Yanagi K, Cheng C, Alaniz RC, Lee K, Jayaraman A. Interactions between gut microbiota and non-alcoholic liver disease: The role of microbiota-derived metabolites. Pharmacol Res 2019;141:521-529 View Article PubMed/NCBI
  99. den Besten G, Lange K, Havinga R, van Dijk TH, Gerding A, van Eunen K, et al. Gut-derived short-chain fatty acids are vividly assimilated into host carbohydrates and lipids. Am J Physiol Gastrointest Liver Physiol 2013;305(12):G900-G910 View Article PubMed/NCBI
  100. Mollica MP, Mattace Raso G, Cavaliere G, Trinchese G, De Filippo C, Aceto S, et al. Butyrate Regulates Liver Mitochondrial Function, Efficiency, and Dynamics in Insulin-Resistant Obese Mice. Diabetes 2017;66(5):1405-1418 View Article PubMed/NCBI
  101. Kondo T, Kishi M, Fushimi T, Kaga T. Acetic acid upregulates the expression of genes for fatty acid oxidation enzymes in liver to suppress body fat accumulation. J Agric Food Chem 2009;57(13):5982-5986 View Article PubMed/NCBI
  102. Mouzaki M, Comelli EM, Arendt BM, Bonengel J, Fung SK, Fischer SE, et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013;58(1):120-127 View Article PubMed/NCBI
  103. Musso G, Gambino R, Cassader M. Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded?. Diabetes Care 2010;33(10):2277-2284 View Article PubMed/NCBI
  104. Anania C, Perla FM, Olivero F, Pacifico L, Chiesa C. Mediterranean diet and nonalcoholic fatty liver disease. World J Gastroenterol 2018;24(19):2083-2094 View Article PubMed/NCBI
  105. Moniri NH, Farah Q. Short-chain free-fatty acid G protein-coupled receptors in colon cancer. Biochem Pharmacol 2021;186:114483 View Article PubMed/NCBI
  106. Sarkola T, Eriksson CJ. Effect of 4-methylpyrazole on endogenous plasma ethanol and methanol levels in humans. Alcohol Clin Exp Res 2001;25(4):513-516 PubMed/NCBI
  107. Engeland K, Maret W. Extrahepatic, differential expression of four classes of human alcohol dehydrogenase. Biochem Biophys Res Commun 1993;193(1):47-53 View Article PubMed/NCBI
  108. Chen J, Vitetta L. Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications. Int J Mol Sci 2020;21(15):E5214 View Article PubMed/NCBI
  109. Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, Baker RD, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 2013;57(2):601-609 View Article PubMed/NCBI
  110. Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, et al. Alcoholic liver disease. Nat Rev Dis Primers 2018;4(1):16 View Article PubMed/NCBI
  111. Wu J, Wang Y, Jiang R, Xue R, Yin X, Wu M, et al. Ferroptosis in liver disease: new insights into disease mechanisms. Cell Death Discov 2021;7(1):276 View Article PubMed/NCBI
  112. Folgueras AR, Freitas-Rodríguez S, Ramsay AJ, Garabaya C, Rodríguez F, Velasco G, et al. Matriptase-2 deficiency protects from obesity by modulating iron homeostasis. Nat Commun 2018;9(1):1350 View Article PubMed/NCBI
  113. Qi J, Kim JW, Zhou Z, Lim CW, Kim B. Ferroptosis Affects the Progression of Nonalcoholic Steatohepatitis via the Modulation of Lipid Peroxidation-Mediated Cell Death in Mice. Am J Pathol 2020;190(1):68-81 View Article PubMed/NCBI
  114. Yang Y, Chen J, Gao Q, Shan X, Wang J, Lv Z. Study on the attenuated effect of Ginkgolide B on ferroptosis in high fat diet induced nonalcoholic fatty liver disease. Toxicology 2020;445:152599 View Article PubMed/NCBI
  115. Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell 2021;12(8):599-620 View Article PubMed/NCBI
  116. Wang L, Liu Y, Du T, Yang H, Lei L, Guo M, et al. ATF3 promotes erastin-induced ferroptosis by suppressing system Xc. Cell Death Differ 2020;27(2):662-675 View Article PubMed/NCBI
  117. Sun Y, Berleth N, Wu W, Schlütermann D, Deitersen J, Stuhldreier F, et al. Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells. Cell Death Dis 2021;12(11):1028 View Article PubMed/NCBI
  118. Gaschler MM, Andia AA, Liu H, Csuka JM, Hurlocker B, Vaiana CA, et al. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol 2018;14(5):507-515 View Article PubMed/NCBI
  119. Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 2019;575(7784):693-698 View Article PubMed/NCBI
  120. Su Y, Zhao B, Zhou L, Zhang Z, Shen Y, Lv H, et al. Ferroptosis, a novel pharmacological mechanism of anti-cancer drugs. Cancer Lett 2020;483:127-136 View Article PubMed/NCBI
  121. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012;149(5):1060-1072 View Article PubMed/NCBI
  122. Zilka O, Shah R, Li B, Friedmann Angeli JP, Griesser M, Conrad M, et al. On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death. ACS Cent Sci 2017;3(3):232-243 View Article PubMed/NCBI
  123. Hu Q, Zhang Y, Lou H, Ou Z, Liu J, Duan W, et al. GPX4 and vitamin E cooperatively protect hematopoietic stem and progenitor cells from lipid peroxidation and ferroptosis. Cell Death Dis 2021;12(7):706 View Article PubMed/NCBI
  124. Yao X, Zhang Y, Hao J, Duan HQ, Zhao CX, Sun C, et al. Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis. Neural Regen Res 2019;14(3):532-541 View Article PubMed/NCBI
  125. Masaldan S, Clatworthy SAS, Gamell C, Meggyesy PM, Rigopoulos AT, Haupt S, et al. Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis. Redox Biol 2018;14:100-115 View Article PubMed/NCBI
  126. Kraft VAN, Bezjian CT, Pfeiffer S, Ringelstetter L, Müller C, Zandkarimi F, et al. GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling. ACS Cent Sci 2020;6(1):41-53 View Article PubMed/NCBI
  127. Salgia RJ, Brown K. Diagnosis and management of hereditary hemochromatosis. Clin Liver Dis 2015;19(1):187-198 View Article PubMed/NCBI
  128. Lombardi R, Pisano G, Fargion S. Role of Serum Uric Acid and Ferritin in the Development and Progression of NAFLD. Int J Mol Sci 2016;17(4):548 View Article PubMed/NCBI
  129. Kowdley KV, Belt P, Wilson LA, Yeh MM, Neuschwander-Tetri BA, Chalasani N, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2012;55(1):77-85 View Article PubMed/NCBI
  130. Jung JY, Shim JJ, Park SK, Ryoo JH, Choi JM, Oh IH, et al. Serum ferritin level is associated with liver steatosis and fibrosis in Korean general population. Hepatol Int 2019;13(2):222-233 View Article PubMed/NCBI
  131. Shah RA, Kowdley KV. Serum ferritin as a biomarker for NAFLD: ready for prime time?. Hepatol Int 2019;13(2):110-112 View Article PubMed/NCBI
  132. Fujita N, Takei Y. Iron overload in nonalcoholic steatohepatitis. Adv Clin Chem 2011;55:105-132 View Article PubMed/NCBI
  133. Eder SK, Feldman A, Strebinger G, Kemnitz J, Zandanell S, Niederseer D, et al. Mesenchymal iron deposition is associated with adverse long-term outcome in non-alcoholic fatty liver disease. Liver Int 2020;40(8):1872-1882 View Article PubMed/NCBI
  134. Mayneris-Perxachs J, Cardellini M, Hoyles L, Latorre J, Davato F, Moreno-Navarrete JM, et al. Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome. Microbiome 2021;9(1):104 View Article PubMed/NCBI
  135. Loguercio C, De Girolamo V, de Sio I, Tuccillo C, Ascione A, Baldi F, et al. Non-alcoholic fatty liver disease in an area of southern Italy: main clinical, histological, and pathophysiological aspects. J Hepatol 2001;35(5):568-574 View Article PubMed/NCBI
  136. Zhang H, Zhang E, Hu H. Role of Ferroptosis in Non-Alcoholic Fatty Liver Disease and Its Implications for Therapeutic Strategies. Biomedicines 2021;9(11):1660 View Article PubMed/NCBI
  137. Saran AR, Dave S, Zarrinpar A. Circadian Rhythms in the Pathogenesis and Treatment of Fatty Liver Disease. Gastroenterology 2020;158(7):1948-1966.e1 View Article PubMed/NCBI
  138. Denou E, Marcinko K, Surette MG, Steinberg GR, Schertzer JD. High-intensity exercise training increases the diversity and metabolic capacity of the mouse distal gut microbiota during diet-induced obesity. Am J Physiol Endocrinol Metab 2016;310(11):E982-E993 View Article PubMed/NCBI
  139. Gangarapu V, Ince AT, Baysal B, Kayar Y, Kılıç U, Gök Ö, et al. Efficacy of rifaximin on circulating endotoxins and cytokines in patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2015;27(7):840-845 View Article PubMed/NCBI
  140. Matsumoto K, Ichimura M, Tsuneyama K, Moritoki Y, Tsunashima H, Omagari K, et al. Fructo-oligosaccharides and intestinal barrier function in a methionine-choline-deficient mouse model of nonalcoholic steatohepatitis. PLoS One 2017;12(6):e0175406 View Article PubMed/NCBI
  141. Fan JG, Xu ZJ, Wang GL. Effect of lactulose on establishment of a rat non-alcoholic steatohepatitis model. World J Gastroenterol 2005;11(32):5053-5056 View Article PubMed/NCBI
  142. Moreira GV, Azevedo FF, Ribeiro LM, Santos A, Guadagnini D, Gama P, et al. Liraglutide modulates gut microbiota and reduces NAFLD in obese mice. J Nutr Biochem 2018;62:143-154 View Article PubMed/NCBI
  143. Wu WC, Zhao W, Li S. Small intestinal bacteria overgrowth decreases small intestinal motility in the NASH rats. World J Gastroenterol 2008;14(2):313-317 View Article PubMed/NCBI
  144. Okubo H, Sakoda H, Kushiyama A, Fujishiro M, Nakatsu Y, Fukushima T, et al. Lactobacillus casei strain Shirota protects against nonalcoholic steatohepatitis development in a rodent model. Am J Physiol Gastrointest Liver Physiol 2013;305(12):G911-G918 View Article PubMed/NCBI
  145. Chen J, Wang R, Li XF, Wang RL. Bifidobacterium adolescentis supplementation ameliorates visceral fat accumulation and insulin sensitivity in an experimental model of the metabolic syndrome. Br J Nutr 2012;107(10):1429-1434 View Article PubMed/NCBI
  146. Alisi A, Bedogni G, Baviera G, Giorgio V, Porro E, Paris C, et al. Randomised clinical trial: The beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2014;39(11):1276-1285 View Article PubMed/NCBI
  147. Polyzos SA, Kountouras J, Mantzoros CS. Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics. Metabolism 2019;92:82-97 View Article PubMed/NCBI
  148. Wu L, Mo W, Feng J, Li J, Yu Q, Li S, et al. Astaxanthin attenuates hepatic damage and mitochondrial dysfunction in non-alcoholic fatty liver disease by up-regulating the FGF21/PGC-1α pathway. Br J Pharmacol 2020;177(16):3760-3777 View Article PubMed/NCBI
  149. Zelber-Sagi S, Lotan R, Shlomai A, Webb M, Harrari G, Buch A, et al. Predictors for incidence and remission of NAFLD in the general population during a seven-year prospective follow-up. J Hepatol 2012;56(5):1145-1151 View Article PubMed/NCBI
  150. Trovato FM, Catalano D, Martines GF, Pace P, Trovato GM. Mediterranean diet and non-alcoholic fatty liver disease: the need of extended and comprehensive interventions. Clin Nutr 2015;34(1):86-88 View Article PubMed/NCBI
  151. Da Silva HE, Arendt BM, Noureldin SA, Therapondos G, Guindi M, Allard JP. A cross-sectional study assessing dietary intake and physical activity in Canadian patients with nonalcoholic fatty liver disease vs healthy controls. J Acad Nutr Diet 2014;114(8):1181-1194 View Article PubMed/NCBI
  152. Kitson MT, Pham A, Gordon A, Kemp W, Roberts SK. High-dose vitamin D supplementation and liver histology in NASH. Gut 2016;65(4):717-718 View Article PubMed/NCBI
  153. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010;51(6):1972-1978 View Article PubMed/NCBI
  154. Reutrakul S, Van Cauter E. Sleep influences on obesity, insulin resistance, and risk of type 2 diabetes. Metabolism 2018;84:56-66 View Article PubMed/NCBI
  155. Nielsen LS, Danielsen KV, Sørensen TI. Short sleep duration as a possible cause of obesity: critical analysis of the epidemiological evidence. Obes Rev 2011;12(2):78-92 View Article PubMed/NCBI
  156. Gildner TE, Liebert MA, Kowal P, Chatterji S, Josh Snodgrass J. Sleep duration, sleep quality, and obesity risk among older adults from six middle-income countries: findings from the study on global AGEing and adult health (SAGE). Am J Hum Biol 2014;26(6):803-812 View Article PubMed/NCBI
  157. Brondel L, Romer MA, Nougues PM, Touyarou P, Davenne D. Acute partial sleep deprivation increases food intake in healthy men. Am J Clin Nutr 2010;91(6):1550-1559 View Article PubMed/NCBI
  158. Knutson KL. Does inadequate sleep play a role in vulnerability to obesity?. Am J Hum Biol 2012;24(3):361-371 View Article PubMed/NCBI
  159. Voigt RM, Forsyth CB, Green SJ, Mutlu E, Engen P, Vitaterna MH, et al. Circadian disorganization alters intestinal microbiota. PLoS One 2014;9(5):e97500 View Article PubMed/NCBI
  160. Summa KC, Voigt RM, Forsyth CB, Shaikh M, Cavanaugh K, Tang Y, et al. Disruption of the Circadian Clock in Mice Increases Intestinal Permeability and Promotes Alcohol-Induced Hepatic Pathology and Inflammation. PLoS One 2013;8(6):e67102 View Article PubMed/NCBI
  161. Cox KL, Burke V, Morton AR, Beilin LJ, Puddey IB. Independent and additive effects of energy restriction and exercise on glucose and insulin concentrations in sedentary overweight men. Am J Clin Nutr 2004;80(2):308-316 View Article PubMed/NCBI
  162. St George A, Bauman A, Johnston A, Farrell G, Chey T, George J. Independent effects of physical activity in patients with nonalcoholic fatty liver disease. Hepatology 2009;50(1):68-76 View Article PubMed/NCBI
  163. Hashida R, Kawaguchi T, Bekki M, Omoto M, Matsuse H, Nago T, et al. Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: A systematic review. J Hepatol 2017;66(1):142-152 View Article PubMed/NCBI
  164. Munukka E, Ahtiainen JP, Puigbó P, Jalkanen S, Pahkala K, Keskitalo A, et al. Six-Week Endurance Exercise Alters Gut Metagenome That Is not Reflected in Systemic Metabolism in Over-weight Women. Front Microbiol 2018;9:2323 View Article PubMed/NCBI
  165. Petriz BA, Castro AP, Almeida JA, Gomes CP, Fernandes GR, Kruger RH, et al. Exercise induction of gut microbiota modifications in obese, non-obese and hypertensive rats. BMC Genomics 2014;15:511 View Article PubMed/NCBI
  166. Bajaj JS. Review article: potential mechanisms of action of rifaximin in the management of hepatic encephalopathy and other complications of cirrhosis. Aliment Pharmacol Ther 2016;43(Suppl 1):11-26 View Article PubMed/NCBI
  167. Ford AC, Sperber AD, Corsetti M, Camilleri M. Irritable bowel syndrome. Lancet 2020;396(10263):1675-1688 View Article PubMed/NCBI
  168. Glassner KL, Abraham BP, Quigley EMM. The microbiome and inflammatory bowel disease. J Allergy Clin Immunol 2020;145(1):16-27 View Article PubMed/NCBI
  169. Ma J, Zhou Q, Li H. Gut Microbiota and Nonalcoholic Fatty Liver Disease: Insights on Mechanisms and Therapy. Nutrients 2017;9(10):E1124 View Article PubMed/NCBI
  170. Jiang C, Xie C, Li F, Zhang L, Nichols RG, Krausz KW, et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 2015;125(1):386-402 View Article PubMed/NCBI
  171. Jin Y, Wu Y, Zeng Z, Jin C, Wu S, Wang Y, et al. From the Cover: Exposure to Oral Antibiotics Induces Gut Microbiota Dysbiosis Associated with Lipid Metabolism Dysfunction and Low-Grade Inflammation in Mice. Toxicol Sci 2016;154(1):140-152 View Article PubMed/NCBI
  172. Schneider KM, Mohs A, Kilic K, Candels LS, Elfers C, Bennek E, et al. Intestinal Microbiota Protects against MCD Diet-Induced Steatohepatitis. Int J Mol Sci 2019;20(2):E308 View Article PubMed/NCBI
  173. Sanders ME, Merenstein DJ, Reid G, Gibson GR, Rastall RA. Probiotics and prebiotics in intestinal health and disease: from biology to the clinic. Nat Rev Gastroenterol Hepatol 2019;16(10):605-616 View Article PubMed/NCBI
  174. Liu Q, Yu Z, Tian F, Zhao J, Zhang H, Zhai Q, et al. Surface components and metabolites of probiotics for regulation of intestinal epithelial barrier. Microb Cell Fact 2020;19(1):23 View Article PubMed/NCBI
  175. Kim B, Kwon J, Kim MS, Park H, Ji Y, Holzapfel W, et al. Protective effects of Bacillus probiotics against high-fat diet-induced metabolic disorders in mice. PLoS One 2018;13(12):e0210120 View Article PubMed/NCBI
  176. Frei R, Akdis M, O’Mahony L. Prebiotics, probiotics, synbiotics, and the immune system: experimental data and clinical evidence. Curr Opin Gastroenterol 2015;31(2):153-158 View Article PubMed/NCBI
  177. Kim DH, Kim H, Jeong D, Kang IB, Chon JW, Kim HS, et al. Kefir alleviates obesity and hepatic steatosis in high-fat diet-fed mice by modulation of gut microbiota and mycobiota: targeted and untargeted community analysis with correlation of biomarkers. J Nutr Biochem 2017;44:35-43 View Article PubMed/NCBI
  178. Kim DH, Jeong D, Kang IB, Kim H, Song KY, Seo KH. Dual function of Lactobacillus kefiri DH5 in preventing high-fat-diet-induced obesity: direct reduction of cholesterol and upregulation of PPAR-α in adipose tissue. Mol Nutr Food Res 2017;61(11):1700252 View Article PubMed/NCBI
  179. Tang Y, Huang J, Zhang WY, Qin S, Yang YX, Ren H, et al. Effects of probiotics on nonalcoholic fatty liver disease: a systematic review and meta-analysis. Therap Adv Gastroenterol 2019;12:1756284819878046 View Article PubMed/NCBI
  180. Wong VW, Won GL, Chim AM, Chu WC, Yeung DK, Li KC, et al. Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study. Ann Hepatol 2013;12(2):256-262 PubMed/NCBI
  181. Sepideh A, Karim P, Hossein A, Leila R, Hamdollah M, Mohammad G, et al. Effects of Multistrain Probiotic Supplementation on Glycemic and Inflammatory Indices in Patients with Nonalcoholic Fatty Liver Disease: A Double-Blind Randomized Clinical Trial. J Am Coll Nutr 2016;35(6):500-505 View Article PubMed/NCBI
  182. Malaguarnera M, Vacante M, Antic T, Giordano M, Chisari G, Acquaviva R, et al. Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Dig Dis Sci 2012;57(2):545-553 View Article PubMed/NCBI
  183. Holscher HD. Dietary fiber and prebiotics and the gastrointestinal microbiota. Gut Microbes 2017;8(2):172-184 View Article PubMed/NCBI
  184. Ghazanfar H, Kandhi SD, Nawaz I, Javed N, Abraham MC, Farag M, et al. Role of Glucagon-Like Peptide-1 Receptor Agonists in the Management of Non-Alcoholic Steatohepatitis: A Clinical Review Article. Cureus 2021;13(5):e15141 View Article PubMed/NCBI
  185. Cuthbertson DJ, Irwin A, Gardner CJ, Daousi C, Purewal T, Furlong N, et al. Improved glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists. PLoS One 2012;7(12):e50117 View Article PubMed/NCBI
  186. Ghosal S, Datta D, Sinha B. A meta-analysis of the effects of glucagon-like-peptide 1 receptor agonist (GLP1-RA) in nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes (T2D). Sci Rep 2021;11(1):22063 View Article PubMed/NCBI
  187. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387(10019):679-690 View Article PubMed/NCBI
  188. Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, et al. Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial). Diabetes Care 2018;41(8):1801-1808 View Article PubMed/NCBI
  189. Ito D, Shimizu S, Inoue K, Saito D, Yanagisawa M, Inukai K, et al. Comparison of Ipragliflozin and Pioglitazone Effects on Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Randomized, 24-Week, Open-Label, Active-Controlled Trial. Diabetes Care 2017;40(10):1364-1372 View Article PubMed/NCBI
  190. Nasiri-Ansari N, Nikolopoulou C, Papoutsi K, Kyrou I, Mantzoros CS, Kyriakopoulos G, et al. Empagliflozin Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in High Fat Diet Fed ApoE(-/-) Mice by Activating Autophagy and Reducing ER Stress and Apoptosis. Int J Mol Sci 2021;22(2):E818 View Article PubMed/NCBI
  191. Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013;159(4):262-274 View Article PubMed/NCBI
  192. Faillie JL. Pharmacological aspects of the safety of gliflozins. Pharmacol Res 2017;118:71-81 View Article PubMed/NCBI
Copyright © 2023 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

Article Options

Metrics

Cite this Article

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 1989299
  • Visits today : 2932
Back to Top

The Gut Microbiome and Ferroptosis in MAFLD

Jie Ji, Liwei Wu, Jue Wei, Jianye Wu, Chuanyong Guo
  • Reset Zoom
  • Download TIFF