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Gut-liver interactions during NAFLD progression. Obesity is associated with intestinal dysbiosis and increased gut permeability.
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Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and covers a disease spectrum ranging from steatosis to inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The innate immune response in the liver plays an important role during NAFLD progression. In addition, changes in the intestina...
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... data demonstrate that PRR signaling and gut microbiota are closely associated with NAFLD progression. Changes in intestinal motility, the subsequent alteration of the microflora, decreased mucosal integrity and increased intestinal permeability are required for microbial products to translocate from the intestinal lumen to the liver, thereby contributing to inflammation and fibrogenesis via PRR signaling (Figure 1). For a better understanding of the impact of the microbiome on the inflammatory response during NAFLD, characterization of the (specific) bacterial communities and their metabolites should be investigated in large cohorts of patients and in more detail. ...
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Simple Summary
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Citations
... The guteliver axis is an essential link between gut microbiota and NAFLD development [8]. Dysbiosis, an imbalance in the gut microbiota, has been linked to the pathogenesis of NAFLD through increased intestinal permeability and translocation of bacterial products like lipopolysaccharides (LPS) into the liver, causing inflammation and oxidative stress [9,10]. This inflammatory response can accelerate the progression of NAFLD from simple steatosis to NASH and fibrosis [11,12]. ...
Background and aim: The impact of chronic low-grade inflammation in the development of non-alcoholic fatty liver disease (NAFLD) has been studied widely. Previous studies showed gut pathogens' effects on inflammation development in NAFLD patients; hence, hypothetically, gut microbial therapy by administration of probiotics, synbiotics, and prebiotics may alleviate inflammation in these individuals. Several studies were performed in this regard; however, conflicting results were obtained. In this study, we aimed to comprehensively evaluate the effects of gut microbial therapy on inflammatory markers in NAFLD patients in a meta-umbrella design. Methods: Two independent researchers investigated international databases, including PubMed, Web of Science, Scopus, and Cochrane Library, from inception until March 2023. Meta-analyses evaluating the impact of probiotics, synbiotics, or prebiotics on inflammatory markers of patients with NAFLD were eligible for our study. AMASTAR 2 checklist was used to evaluate the quality of included studies. Random effect model was performed for the analysis, and Egger's regression test was conducted to determine publication bias. Results: A total number of 12 studies were entered into our analysis. Our findings revealed that gut microbial therapy could significantly reduce serum C-reactive protein (CRP) levels among NAFLD patients (ES: −0.58; 95% CI: −0.73, −0.44, P < 0.001). In subgroup analysis, this reduction was observed with both probiotics (ES: −0.63; 95% CI: −0.81, −0.45, P < 0.001) and synbiotics (ES: −0.49; 95% CI: −0.74, −0.24, P < 0.001). In addition, gut microbial therapy could significantly decrease tumor necrosis factor-a (TNF-a) levels in NAFLD patients (ES: −0.48; 95% CI: −0.67 to −0.30, P < 0.001). In subgroup analysis, this decrease was observed with probiotics (ES: −0.32; 95% CI: −0.53, −0.11, P = 0.002) and synbiotics (ES: −0.96; 95% CI: −1.32, −0.60, P < 0.001). Not enough information was available for assessing prebiotics' impacts. Conclusion: The results of this umbrella review suggest that probiotics and synbiotics have promising effects on inflammatory markers, including TNF-a and CRP; however, more research is needed regarding the effects of prebiotics. PROSPERO registration code: CRD42022346998.
... TLRs are the best PRRs, with a family of cell surface and endocytic receptors found in most hepatic cells, including KCs, hepatic stellate cells, biliary epithelial cells, and sinusoidal endothelial cells [33][34][35]. The well-known hepatic TLRs are TLR2, TLR4, and TLR9 [34][35][36]. ...
Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition characterized by lipid accumulation in hepatocytes with low alcohol consumption. The development of sterile inflammation, which occurs in response to a range of cellular stressors or injuries, has been identified as a major contributor to the pathogenesis of NAFLD. Recent studies of the pathogenesis of NAFLD reported the newly developed roles of damage-associated molecular patterns (DAMPs). These molecules activate pattern recognition receptors (PRRs), which are placed in the infiltrated neutrophils, dendritic cells, monocytes, or Kupffer cells. DAMPs cause the activation of PRRs, which triggers a number of immunological responses, including the generation of cytokines that promote inflammation and the localization of immune cells to the site of the damage. This review provides a comprehensive overview of the impact of DAMPs and PRRs on the development of NAFLD.
... Furthermore, gut microbiota seems to be one of the key players of NAFLD development [3,4]. Markers and receptors of microbiota-related injury features have been described in this disorder such as TLRs, NLRs, and NLRP3 [5][6][7][8] as well as the activation of the innate and adaptive immune systems [9]. In early sets of experiments, we initially showed that hepatic steatosis in the obese diabetic mouse was due to an increased circulating concentration of lipopolysaccharides (LPS) i.e. metabolic endotoxemia [10]. ...
Background
Gut microbiota is involved in the development of liver diseases such as fibrosis. We and others identified that selected sets of gut bacterial DNA and bacteria translocate to tissues, notably the liver, to establish a non-infectious tissue microbiota composed of microbial DNA and a low frequency live bacteria. However, the precise set of bacterial DNA, and thereby the corresponding taxa associated with the early stages of fibrosis need to be identified. Furthermore, to overcome the impact of different group size and patient origins we adapted innovative statistical approaches. Liver samples with low liver fibrosis scores (F0, F1, F2), to study the early stages of the disease, were collected from Romania( n = 36), Austria( n = 10), Italy( n = 19), and Spain( n = 17). The 16S rRNA gene was sequenced. We considered the frequency, sparsity, unbalanced sample size between cohorts to identify taxonomic profiles and statistical differences.
Results
Multivariate analyses, including adapted spectral clustering with L1-penalty fair-discriminant strategies, and predicted metagenomics were used to identify that 50% of liver taxa associated with the early stage fibrosis were Enterobacteriaceae, Pseudomonadaceae, Xanthobacteriaceae and Burkholderiaceae. The Flavobacteriaceae and Xanthobacteriaceae discriminated between F0 and F1. Predicted metagenomics analysis identified that the preQ0 biosynthesis and the potential pathways involving glucoryranose and glycogen degradation were negatively associated with liver fibrosis F1-F2 vs F0.
Conclusions
Without demonstrating causality, our results suggest first a role of bacterial translocation to the liver in the progression of fibrosis, notably at the earliest stages. Second, our statistical approach can identify microbial signatures and overcome issues regarding sample size differences, the impact of environment, and sets of analyses.
Trial registration
TirguMECCH ROLIVER Prospective Cohort for the Identification of Liver Microbiota, registration 4065/2014. Registered 01 01 2014.
... A growing body of evidence reinforces the importance of TLRs in the pathogenesis of NAFLD [161]. TLR4 is of particular interest in connection with liver inflammation and fibrogenesis[158, 162,163]. TLR4 is a receptor that detects the LPS of Gram-negative bacteria and is widely known for its role in various diseases. ...
In recent years, there has been a steady growth of interest in non-alcoholic fatty liver disease (NAFLD), which is associated with negative epidemiological data on the prevalence of the disease and its clinical significance. NAFLD is closely related to the metabolic syndrome and these relationships are the subject of active research. A growing body of evidence shows cross-linkages between metabolic abnormalities and the innate immune system in the development and progression of NAFLD. These links are bidirectional and largely still unclear, but a better understanding of them will improve the quality of diagnosis and management of patients. In addition, lipid metabolic disorders and the innate immune system link NAFLD with other diseases, such as atherosclerosis, which is of great clinical importance.
... Elevated expression of Toll-like receptors (TLRs) has been remarked in NASH stage (19,20), which is accompanied by increased infiltration and activation of adaptive immune cells, such as CD8+ T cells and NKT cells (21). TLRs play a major role in activation and modulation of immune responses and their activity has been highlighted in the pathogenesis and progression of chronic liver diseases, including HBV and HCV infection, alcoholic liver disease, hepatic fibrosis, NAFLD/ NASH, cirrhosis and hepatocellular carcinoma (22-24). ...
Non-alcoholic fatty liver disease (NAFLD) and Hepatitis B virus infection (HBV) constitute common chronic liver diseases with worldwide distribution. NAFLD burden is expected to grow in the coming decade, especially in western countries, considering the increased incidence of diabetes and obesity. Despite the organized HBV vaccinations and use of anti-viral therapies globally, HBV infection remains endemic and challenging public health issue. As both NAFLD and HBV have been associated with the development of progressive fibrosis, cirrhosis and hepatocellular carcinoma (HCC), the co-occurrence of both diseases has gained great research and clinical interest. The causative relationship between NAFLD and HBV infection has not been elucidated so far. Dysregulated fatty acid metabolism and lipotoxicity in NAFLD disease seems to initiate activation of signaling pathways that enhance pro-inflammatory responses and disrupt hepatocyte cell homeostasis, promoting progression of NAFLD disease to NASH, fibrosis and HCC and can affect HBV replication and immune encountering of HBV virus, which may further have impact on liver disease progression. Chronic HBV infection is suggested to have an influence on metabolic changes, which could lead to NAFLD development and the HBV-induced inflammatory responses and molecular pathways may constitute an aggravating factor in hepatic steatosis development. The observed altered immune homeostasis in both HBV infection and NAFLD could be associated with progression to HCC development. Elucidation of the possible mechanisms beyond HBV chronic infection and NAFLD diseases, which could lead to advanced liver disease or increase the risk for severe complications, in the case of HBV-NAFLD co-existence is of high clinical significance in the context of designing effective therapeutic targets.
... The Toll-like receptor (TLR) family is one of major classes of the PRRs that play an essential role in the initiation of innate immune response. The roles of hepatic TLR2, TLR4 and TLR9 in NASH has been repeatedly reported (24)(25)(26). Activation of the TLR4 by LPS or TLR-9 by DNA derived from intestinal bacteria promotes steatohepatitis, while suppression of the TLR4 or TLR-9 attenuates liver steatosis, inflammation, and fibrosis in a few of mouse models of NASH (25,27). Altogether, these findings demonstrate that activation of the NLPR3 inflammasome and TLRs may contribute to the development and progression of NASH. ...
Liver fibrosis is a common pathological feature of end stage liver failure, a severe life-threatening disease worldwide. Nonalcoholic fatty liver disease (NAFLD), especially its more severe form with steatohepatitis (NASH), results from obesity, type 2 diabetes and metabolic syndrome and becomes a leading cause of liver fibrosis. Genetic factor, lipid overload/toxicity, oxidative stress and inflammation have all been implicated in the development and progression of NASH. Both innate immune response and adaptive immunity contribute to NASH-associated inflammation. Innate immunity may cause inflammation and subsequently fibrosis via danger-associated molecular patterns. Increasing evidence indicates that T cell-mediated adaptive immunity also provokes inflammation and fibrosis in NASH via cytotoxicity, cytokines and other proinflammatory and profibrotic mediators. Recently, the single-cell transcriptome profiling has revealed that the populations of CD4⁺ T cells, CD8⁺ T cells, γδ T cells, and TEMs are expanded in the liver with NASH. The activation of T cells requires antigen presentation from professional antigen-presenting cells (APCs), including macrophages, dendritic cells, and B-cells. However, since hepatocytes express MHCII molecules and costimulators, they may also act as an atypical APC to promote T cell activation. Additionally, the phenotypic switch of hepatocytes to proinflammatory cells in NASH contributes to the development of inflammation. In this review, we focus on T cells and in particular CD4⁺ T cells and discuss the role of different subsets of CD4⁺ T cells including Th1, Th2, Th17, Th22, and Treg in NASH-related liver inflammation and fibrosis.
... Furthermore, gut microbiota seems to be one of the key players of NAFLD development [3,4]. Markers and receptors of microbiota-related injury features have been described in this disorder such as TLRs, NLRs, and NLRP3 [5][6][7][8] as well as the activation of the innate and adaptive immune systems [9]. In early sets of experiments, we initially showed that hepatic steatosis in the obese diabetic mouse was due to an increased circulating concentration of lipopolysaccharides (LPS) i.e. metabolic endotoxemia [10]. ...
Background
Gut microbiota is involved in the development of liver diseases such as fibrosis. We and others identified that selected sets of gut bacterial DNA and bacteria translocate to tissues, notably the liver, to establish a non-infectious tissue microbiota composed of microbial DNA and a low frequency live bacteria. However, the precise set of bacterial DNA, and thereby the corresponding taxa associated with the early stages of fibrosis need to be identified. Furthermore, to overcome the impact of different group size and patient origins we adapted innovative statistical approaches. Liver samples with low liver fibrosis scores (F0, F1, F2) to study the early stages of the disease were collected from Romania(n = 36), Austria(n = 10), Italy(n = 19), and Spain(n = 17). The 16S rRNA gene was sequenced. We considered the frequency, sparsity, unbalanced sample size between cohorts to identify taxonomic profiles and statistical differences.ResultsMultivariate analyses, including adapted spectral clustering with L1-penalty fair-discriminant strategies, and predicted metagenomics were used to identify that 50% of liver taxa associated with the early stage fibrosis were Enterobacteriaceae and Pseudomonadaceae. The Caulobacteraceae, Flavobacteriaceae and Propionibacteriaceae discriminated between F0 and F1. Predicted metagenomics analysis identified the preQ0 biosynthesis and pathways involving glucoryranose and glycogen degradation were negatively associated with liver fibrosis F1-F2 vs F0.Conclusions
Without demonstrating causality, our results suggest first a role of bacterial translocation to the liver in the progression of fibrosis, notably at the earliest stages. Second, our statistical approach can identify microbial signatures and overcome issues regarding sample size differences, the impact of environment, and sets of analyses. TirguMECCH ROLIVER Prospective Cohort for the Identification of Liver Microbiota, registration 4065/2014 . Registered 01 01 2014
... TLR4 is one of the most important and key TLRs that contains a well-known Toll/IL-1 receptor domain in its cytoplasmic region, which binds to the carboxyl end of the intracytoplasmic adaptor protein MYD88 to form a complex; then, this complex binds to IL-1 receptor-related kinase and phosphorylates itself. After binding to tumor necrosis factor receptor-related factor 6, IκB kinase is activated, causing ubiquitination and degradation of IKB to activate NF-κB, which is translocated from cytoplasm to the nucleus to either initiates or enhances the transcription several genes [76,77]. ...
Nucleoredoxin (NXN), an oxidoreductase enzyme, contributes to cellular redox homeostasis by regulating different signaling pathways in a redox-dependent manner. By interacting with seven proteins so far, namely disheveled (DVL), protein phosphatase 2A (PP2A), phosphofructokinase-1 (PFK1), translocation protein SEC63 homolog (SEC63), myeloid differentiation primary response gene-88 (MYD88), flightless-I (FLII), and calcium/calmodulin-dependent protein kinase II type alpha (CAMK2A), NXN is involved in the regulation of several key cellular processes, including proliferation, organogenesis, cell cycle progression, glycolysis, innate immunity and inflammation, motility, contraction, protein transport into the endoplasmic reticulum, neuronal plasticity, among others; as a result, NXN has been implicated in different pathologies, such as cancer, alcoholic and polycystic liver disease, liver fibrogenesis, obesity, Robinow syndrome, diabetes mellitus, Alzheimer’s disease, and retinitis pigmentosa. Together, this evidence places NXN as a strong candidate to be a master redox regulator of cell physiology and as the hub of different redox-sensitive signaling pathways and associated pathologies. This review summarizes and discusses the current insights on NXN-dependent redox regulation and its implication in different pathologies.
... TLR4 was a subtype of TLRs and could identify pathogenic bacteria in the innate immune system. It could activate IκB kinase (IKKs), cause the ubiquitination and degradation of IκB, activate NF-κB, and increase TNF-α expressions, thereby mediating hepatic inflammation, lung injury, and heart injury (Bieghs and Trautwein, 2014;Yin et al., 2018;Shen et al., 2019;Chang et al., 2021). HMGB1 was typically found in the nucleus of a variety of cells (immune, endothelial, epithelial cells, etc.). ...
Sepsis is a systemic inflammatory reaction caused by various infectious or noninfectious factors, which can lead to shock, multiple organ dysfunction syndrome, and death. It is one of the common complications and a main cause of death in critically ill patients. At present, the treatments of sepsis are mainly focused on the controlling of inflammatory response and reduction of various organ function damage, including anti-infection, hormones, mechanical ventilation, nutritional support, and traditional Chinese medicine (TCM). Among them, Xuebijing injection (XBJI) is an important derivative of TCM, which is widely used in clinical research. However, the molecular mechanism of XBJI on sepsis is still not clear. The mechanism of treatment of “bacteria, poison and inflammation” and the effects of multi-ingredient, multi-target, and multi-pathway have still not been clarified. For solving this issue, we designed a new systems pharmacology strategy which combines target genes of XBJI and the pathogenetic genes of sepsis to construct functional response space (FRS). The key response proteins in the FRS were determined by using a novel node importance calculation method and were condensed by a dynamic programming strategy to conduct the critical functional ingredients group (CFIG). The results showed that enriched pathways of key response proteins selected from FRS could cover 95.83% of the enriched pathways of reference targets, which were defined as the intersections of ingredient targets and pathogenetic genes. The targets of the optimized CFIG with 60 ingredients could be enriched into 182 pathways which covered 81.58% of 152 pathways of 1,606 pathogenetic genes. The prediction of CFIG targets showed that the CFIG of XBJI could affect sepsis synergistically through genes such as TAK1, TNF-α, IL-1β, and MEK1 in the pathways of MAPK, NF-κB, PI3K-AKT, Toll-like receptor, and tumor necrosis factor signaling. Finally, the effects of apigenin, baicalein, and luteolin were evaluated by in vitro experiments and were proved to be effective in reducing the production of intracellular reactive oxygen species in lipopolysaccharide-stimulated RAW264.7 cells, significantly. These results indicate that the novel integrative model can promote reliability and accuracy on depicting the CFIGs in XBJI and figure out a methodological coordinate for simplicity, mechanism analysis, and secondary development of formulas in TCM.
... In addition, the metabolite lipopolysaccharide is released into the blood and liver through the portal system, promoting the release of inflammatory factors and resulting in NAFLD [69]. Studies have found that the application of intestinal microbiota regulator probiotics or synbiotics can reduce hepatic steatosis and inflammation in NAFLD [70], which may be related to the improvement of intestinal permeability and regulation of intestinal microecological balance [71]. ...
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with a pathogenesis that has not been fully elucidated. With the development of the theory of the gut-liver axis and the deepening of related research, the role of the intestinal tract in the pathogenesis of NAFLD has been investigated more. Intestinal microbiota, intestinal metabolites, and intestinal epithelial and immune-based barriers constitute the intestinal environment, which uses crosstalk to maintain the homeostasis of the intestinal environment. This paper reviews the progress in the study of intestinal microbiota, intestinal environment, and NAFLD and suggests that repair of intestinal functional balance may be a new idea for early prevention and intervention of NAFLD.
