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Gut Microbiota-Derived Components and Metabolites in the Progression of Non-Alcoholic Fatty Liver Disease (NAFLD)

Yun Ji, Yue Yin, Ziru Li and 1 more

Nutrients · 2019 · Review · CC BY

doi:10.3390/nu11081712

Abstract

Human gut microbiota has been increasingly recognized as a pivotal determinant of non-alcoholic fatty liver disease (NAFLD). Apart from the changes in the composition of gut microbiota, the components and metabolites derived from intestinal microbiota have emerged as key factors in modulating the pathological process of NAFLD. Compelling evidences have revealed that gut microbiota generates a variety of bioactive substances that interact with the host liver cells through the portal vein. These substances include the components derived from bacteria such as lipopolysaccharides, peptidoglycan, DNA, and extracellular vesicles, as well as the metabolites ranging from short-chain fatty acids, indole and its derivatives, trimethylamine, secondary bile acids, to carotenoids and phenolic compounds. The mechanisms underlying the hepatic responses to the bioactive substances from gut bacteria have been associated with the regulation of glycolipid metabolism, immune signaling response, and redox homeostasis. Illuminating the interplay between the unique factors produced from gut microbiome and the liver will provide a novel therapeutical target for NAFLD. The current review highlights the recent advances on the mechanisms by which the key ingredients and metabolites from gut microbiota modulate the development and progression of NAFLD.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Non-alcoholic fatty liver disease (NAFLD), a spectrum of liver disease, includes simple steatosis (NAFL), non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. NAFLD has become the leading liver disease, with a prevalence of 22–29% in adults worldwide. NAFLD is associated with metabolic syndrome which is characterized by centripetal obesity, insulin resistance, hypertension, hyperlipidemia, and dyslipidemia. As of today, the intricate pathogenesis of NAFLD remains largely unknown. The “multiple hit” hypothesis has been proposed to supersede the outdated “two-hit” hypothesis as the major cause of the initiation and progression of NAFLD. The “multiple hit” hypothesis highlights the importance of gut microbiome, insulin resistance, and adipokines secreted from the adipose tissues, which consequently leads to lipotoxicity, oxidative stress, mitochondrial dysfunction, and inflammation in hepatic tissue.

It has been estimated that 10 times more microorganisms (above 1014) are present inside the gut than the number of human cells. These microorganisms are associated with the regulation of host metabolism, immunity, and diseases. Gut microbiome has drawn extensive attention as it plays a critical role in the development and progression of NAFLD via the gut-liver axis. Long term intake of unhealthy diet (e.g., rich in saturated fat or fructose) initiates dysbiosis of gut microbiota which in turn leads to disruption in barrier function and immune homeostasis. Gut microbiota or the components and metabolites derived from bacteria are carried to the liver through the portal vein. A variety of immune cells (e.g., Kupffer cells and hepatic stellate cells) resided in the liver copes with the gut-derived pro-inflammatory factors such as lipopolysaccharide, peptidoglycan, and lipoteichoic acid (LTA). The over-activated immune cells induced by the products generated from bacteria may result in more severe liver damage, inflammation, and fibrosis, thus accelerating the development of NAFLD. On the other hand, metabolites such as short-chain fatty acids (SCFAs), bile acids, tryptophan metabolites, carotenoids, and phenolic compounds from gut bacteria may ameliorate the inflammatory responses, oxidative damage, and lipogenesis in the liver tissue. Therefore, intestinal microbes are considered as the key element regulating the pathological process of NAFLD. Exploring the signaling pathways of the gut bacteria-derived factors on the liver tissue will provide novel therapeutic targets and strategy for NAFLD. The current article will summarize the functional mechanisms by which the gut microbial components and metabolites alter the progression of NAFLD.

2. Lipopolysaccharides

Lipopolysaccharides (LPS, also known as endotoxins), the major outer membrane component of gram-negative bacteria, has been well known to be implicated in the activation of the host innate immune system. The chronic low grade inflammation triggered by LPS is known as a pivotal factor for the progression of NAFLD. Previous study has demonstrated that treatment with antibiotics (e.g., polymyxin B) targeting gram-negative bacteria efficiently reduced tumor necrosis factor (TNF) production and plasma LPS levels, leading to the reversal of hepatic steatosis. Elevation of LPS levels in serum has been reported in both NAFLD patients and animals. Toll-like receptor 4 (TLR4), a pattern recognition receptor for LPS and multiple free fatty acids, is widely expressed in liver cell types including hepatocytes, Kupffer cells, and stellate cells. Activation of TLR4 induced by LPS results in the secretion of inflammatory cytokines (e.g., IL-6, IL-1β, and TNF-α) and chemokines from Kupffer cells, leading to hepatic damage and NASH. By contrast, mice carrying a TLR4 mutation exhibit resistance to LPS and high-fat diet-induced liver steatosis. In addition to TLR4, LPS binding protein (LBP) and cluster of differentiation 14 (CD14) are also involved in the recognition of LPS. LBP is a polypeptide of 50 kDa primarily synthesized by liver and exists in blood as a form of glycosylated protein. A clinical study has found an increase of LBP, a carrier of LPS, among patients with NAFL or NASH. Besides, LBP is correlated with insulin resistance and dyslipidaemia. Since free fatty acids are coupled with chronic low grade inflammation and steatohepatitis, loss of LBP may attenuate the progression of NAFLD. Indeed, it has been observed in HFD-induced NAFLD animal models that LBP knockout mice display improved lipid metabolism and alleviation of multiple pathologic features of NAFLD. This observation suggests that LBP is an indispensable factor for the development of NAFLD. In contrast, it has been noted that a high level of LBP appears to limit the inflammatory responses triggered by LPS, likely through delivering LPS to lipoproteins or promoting silent uptake of LPS. CD14 is a myeloid membrane glycoprotein that functions as a pattern recognition receptor for the complexes of LPS and LBP. CD14 exists in two forms: membrane CD14 (mCD14) and soluble CD14 (sCD14, also known as presepsin). LPS induces a cleavage of mCD14, leading to the subsequent release of presepsin into the circulation. Depletion of CD14 reduces lipid and macrophage content in liver tissues and attenuates liver steatosis in diet-induced obese mice. The clinical trial indicates that serum presepsin levels can be regarded as a biomarker for predicting the severity of NASH. The mechanism by which LPS produced by gut microbiota contributes to the occurrence and development of NAFLD involves the intestinal barrier dysfunction. Several lines of evidence have shown that increments of circulating LPS impairs intestinal barrier function and causes subsequent increases in intestinal permeability. This occurs through the TLR-4-dependent up-regulation of CD14 and MLCK (Myosin light chain kinase), and activation of IRAK-4 (IL-1R-associated kinase 4). More importantly, LPS that enters into the liver through the portal vein blood activates Kupffer cells and stellate cells via TLR4, which promote hepatic inflammation and fibrosis respectively. In addition, activation of NLRP3 inflammasome induced by LPS has recently been shown to be linked with the progression of NASH. The detail review can be found in the article by Wan et al..

3. Peptidoglycan

Peptidoglycan (PGN) is an inflexible envelope encompassing the cytoplasmic layer of most bacterial species. It is a unique and necessary bacterial component that provides the bacterial cell wall with stiffness and structure. Compared to the single thin layer surrounded by an outer membrane in Gram-negative bacteria, PGN is presented as a thick exposed layer in Gram-positive bacteria, in combination with lipoteichoic acid (LTA). It has long been known that PGN from bacteria promotes an inflammatory response. In mice with a high fat diet, the abundance of Firmicutes (the major gram-positive bacteria) increases. This alteration is associated with the increment of Toll-like receptor 2 (TLR2) ligands including PGN, lipoprotein, and LTA. The role of TLR2 in the pathophysiology of NASH has been controversial depending on the model of NASH. In high fat diet-induced obese mice, TLR2 deficiency has been shown to be resistant to insulin resistance, hepatic steatosis, and tissue inflammation. Conversely, in mice fed with a diet deficient in methionine and choline (MCDD), TLR2 knockout exacerbates MCDD-induced nonalcoholic steatohepatitis. In a human consuming a high fat diet, impaired TLR2 response observed is partly responsible for the increased risk of obesity. The sub-structures of PGN, such as meso-diaminopimelic acid PGN (meso-DAP PGN) and muramyl dipeptide PGN (MDP PGN), can mediate the generation of pro-inflammatory cytokines through nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) dependent activation of NOD1 (Nucleotide Binding Oligomerization Domain Containing 1) and NOD2 (Nucleotide Binding Oligomerization Domain Containing 2). It has been proposed that NOD1 senses excess nutrients by altering the intestinal microbiota and enhancing peptidoglycan translocation, since NOD1 can identify peptidoglycan from the intestinal microbiota. Supporting the function of the NOD1/2 signaling in the development of NAFLD, mice with a dual knockout of NOD1 and NOD2 are resistant to lipid accumulation and inflammation in the liver caused by a high fat diet. In short, PGN-mediated inflammatory lesions in the hepatic tissue are primarily associated with the signaling pathways of TLR2, NOD1, and NOD2. It should be noted that TLR2 is also known as a key ligand for other bacterial components such as LTA and lipoproteins. In rodents, gram-positive bacteria component LTA actuates hyperlipidemia which occurs as a consequence of increased lipolysis of excessive hepatic triglyceride.

4. Bacterial DNA

Bacterial DNAs play a vital role in the progression of NASH by the direct activation of immune cells including macrophages, NK cells, B cells, and dendritic cells. Bacterial DNA is trafficked into endolysosomal endosomes through endocytosis, in which it activates Toll-like receptor 9 (TLR9) to elicit inflammatory signaling in immune cells. The sensing of bacterial DNA by TLR9 in immune cells initiates the activation of NF-κB / MAPK, followed by the secretion of IL-12 and TNF-α. Alternatively, TLR9 results in the activation of IκB kinase α (IKKα) which interacts with microtubule-associated protein 1A/1B-light chain 3 (LC3) and the phosphorylation of IFN regulatory factor 7 (IRF7), leading to the release of type I interferon (IFN). TLR9 responses through species-specific CpG motif recognition to bacterial DNA. Recent evidence has shown that TLR9 is augmented in human and mouse NASH. This receptor is essential for the chemotaxis of M1-macrophages and neutrophils. Removal of TLR9 mitigates liver inflammation in experimental NASH mice. Consistently, a TLR9 antagonist treatment protects mice fed a high fat diet from NASH. Furthermore, it has been observed in choline-deficient amino acid-defined (CDAA) diet-triggered NASH model that the production of IL-1β in Kupffer cells induced by TLR9-MyD88 cascades accelerates the progress of NASH.

5. Extracellular Vesicles

A large variety of bacterial molecules, including nucleic acids, proteins, phospholipids, glycolipids, and polysaccharide, are present in microbiota-derived extracellular vesicles (EVs). EVs play important biological roles not only in the survival of bacteria through transferring virulence factors and the despoilment of nutrients, but also in the interaction between the host and the bacterial components or metabolites that regulate numerous signaling pathways in the host cells. Bacterial EVs that enter systemic circulation, as nanosize membrane particles, can trigger multiple metabolic cascades and immunological responses in various organs. For example, recent progress reported by Tulkens et al. has shown that patients with intestinal barrier dysfunction demonstrate increased systemic levels of LPS-positive bacterial extracellular vesicles. This observation suggests that the endotoxin is able to alter the biological function of the host via its presence on EVs. Emerging evidences have shown that host cells carry LPS from EVs into the cytosol by the signaling of TLR4-TRIF (TIR domain-containing adaptor-inducing interferon-β)-GBPs (guanylate-binding proteins). Other receptors mediating EVs-induced immune responses in host cells include TLR2, NOD1, and NOD2. As innate immune is a key mechanism mediating the inflammation and other pathological progress in NAFLD, EVs may regulate NAFLD through transferring the contents into Kupffer cells, stellate cells, and hepatocytes. Although the precise protein inside the EVs are largely unknown, the proteomics approach has revealed novel interaction pathways between bacterial effector protein and hepatic cells underlying the physiological and pathological functions of EVs. Short RNA (sRNA) in EVs can be released to alter biological functions of the host. Hence, EVs may have the potential to regulate NAFLD through sRNA-mediated epigenetic mechanism.

6. Short-Chain Fatty Acids

Short-chain fatty acids (SCFAs) are volatile fatty acids (acetate, propionate, and butyrate) mainly generated through the fermentation of soluble dietary fibers and nondigestible carbohydrates by gut microbes in the large bowel. The producers of acetic acid and propionate for the most part are the Bacteroidetes, whereas butyrate is principally delivered by the Firmicutes. Gut microbiota has been observed to be engaged with the modulation of NAFLD by means of their metabolites SCFAs. SCFAs regulate the metabolism and immune functions of liver tissue mainly through the inhibition of histone deacetylases or the activation of G-protein coupling receptors including GPR41, GPR43, GPR109a, and OLFR78. GPR41 is known to be expressed in adipose, intestinal, spleen, pancreas, peripheral blood, and nervous tissues, while GPR43 is present in the immune, liver, intestinal, and adipose tissues. All three SCFAs, especially acetate, can be recognized by GPR43. Mice exhibit increased GPR43 mRNA abundance in liver specific manner in response to a high fat diet feeding, suggesting a unique role of GPR43 in obesity-related liver diseases. Besides, propionate is a selective agonist for GPR41, while butyrate acts as an activator for GPR41 and GPR109a. Particularly, acetate and propionate serve as ligands for OLFR78 which is abundantly expressed in the colon and kidney. Depending on SCFA, both GPR41 and GPR43 participate in the regulation of energy homeostasis. A lack of GPR41 increases the body fat mass of mice, suggesting that SCFAs promote energy expenditure and prevent obesity via activation of GPR41. Deficiency of GPR43 renders mice resistant to the increase in liver weight and triglycerides content induced by HFD to at least in part through an increase in energy consumption. Inconsistently, results from Kimura et al. have found that mice lacking the GPR43 gene develop obesity even on a regular diet. The activation of GPR43 results in the suppression of insulin signaling and thus prevents the uptake and utilization of energy. A recent study by Rau et al. has found a higher level of SCFAs produced from gut bacteria in NAFLD patients. The increase of acetate and propionate maintains low degree inflammation through their impact on the circulating immune cellular system. However, the anti-inflammatory properties and the suppression role in hepatic lipogenesis and lipid accumulation of acetate and propionate have been observed in numerous previous studies. Importantly, compelling data from animal models has shown that butyrate attenuates steatohepatitis through the modulation of gut microbiota, intestinal barrier function, the up-regulation of glucagon-like peptide-1 receptor (GLP-1R) expression and down-regulation of inflammatory signaling as well as oxidative damage in the liver. It should be noted that histone acetylation regulates gene expression through the alteration in the structure of the nucleosomes or furnishing protein binding signaling. The addition of acetylate groups is catalyzed by histone acetyltransferases (HATs) while the elimination of acetylate groups is by histone deacetylases (HDACs). SCFAs from gut microbiota has been widely known as HDAC inhibitors to regulate immune homeostasis and hepatic lipid metabolism, suggesting an epigenetic mechanism by which SCFAs regulate host metabolism.

7. Indole and Its Derivatives

Tryptophan can be converted into several molecules, including indole and its derivatives, by both intestinal gram-positive and gram-negative bacteria present in the gut. Indole, which is produced through the catalysis of tryptophan by bacterial tryptophanase, has attracted much attention because of its beneficial effects on intestinal function of the host. Numerous bacterial species including the genera of Prevotella, Bacteroides, Fusobacterium, and Escherichia possess the capacity to degrade tryptophan into indole by tryptophanase. Indole functions to enhance tight junction of epithelial cells and mitigates inflammatory responses and injury in the gut. Additionally, indole modulates glucagon-like peptide-1 (GLP-1) secretion in colonic L cells via increasing calcium influx and reducing the decomposition rate of GLP-1. Recently, Beaumont et al. have demonstrated that mice receiving indole display resistance to liver inflammation and metabolic alternations of cholesterol induced by LPS. This observation suggests that indole may improve inflammatory disorder in the liver. Other indole derivatives that have received widespread attentions include indole-3-aldehyde (IAld), indole-3-acetic acid (IAA), and indole-3-propionic acid (IPA). These molecules exert vital biological functions through the action on the nuclear receptors in host cells. IAld is mainly synthesized from indole pyruvate under the catalysis of aromatic amino acid aminotransferase (ArAT). As a ligand of aryl hydrocarbon receptor (AhR), IAld induces the production of IL-22, thereby providing a protection against candidiasis and mucosal damage. Moreover, recent evidence from the human colon cell line has demonstrated that IAld induces the expression of IL-10R1, indicating an IL-10 signaling-dependent anti-inflammatory mechanism of IAld. Emerging researches have revealed a reduction in the level of IAA in individuals with metabolic syndrome. For instance, results from Natividad et al. have found that fecal samples of obese people demonstrate lower levels of IAA than those of non-obese people. Also, a reduction in the concentration of IAA in the colon content has been observed in mice fed with a high fat diet, which exhibits glucose intolerance and hepatic steatosis. Another study has reported a substantial deprivation of IAA in the liver and cecum (3 and 10-fold, respectively) of mice exposed to a high fat diet compared with those fed a normal diet. This study also demonstrates that IAA dose dependently reduces the induction of pro-inflammatory cytokines including TNF-α, MCP-1, and IL-1β by LPS, leading to a reduction in the synthesis of FFAs and palmitate in macrophage cell line. Besides, IAA alleviates the lipogenesis mediated by cytokine and free fatty acids via its direct action on hepatocytes in an AhR-dependent manner. The evidences above suggest a protective role of IAA against NAFLD through acting on both macrophages and hepatocytes. IPA, which serves as a ligand for pregnane X receptor (PXR), has also been shown to suppress intestinal pro-inflammatory cytokines and strengthen the barrier function. As a free radical scavenger, IPA is known to protect against oxidative stress-induced damage in brain, neuron, and hepatic microsomal membranes. Intriguingly, recent study uncovers that IPA improves glucose metabolism by reducing the levels of blood glucose and plasma insulin. Therefore, IPA may possess the therapeutic potential for metabolize dysfunction related to insulin resistance.

8. Bile Acids

Bile acids, which are synthesized from cholesterol in the liver and stored in the bile bladder, regulate multiple physiological and pathological processes. Bile acids not only facilitate the absorption of lipids in the intestine, but also function to modulate glucose and lipid metabolism. The therapeutic value of bile acids has been known in various diseases, including neurological disorders, fatty liver, liver inflammation, gallstones, primary biliary cirrhosis, pancreatitis, and inflammatory bowel disease. Gut microbiota converts the primary bile acids including cholic acid (CA) and chenodeoxycholic acid (CDCA) in the distal small intestine and colon of human beings into secondary bile acids such as deoxycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA). Compared with primary bile acids, secondary bile acids are more conducive to the selection of intestinal bacteria. In addition to their direct antimicrobial properties, bile acids indirectly involve in farnesoid X receptor (FXR)-mediated antimicrobial defense. FXR is a member of the nuclear hormonal receptor family that widely exists in ileum and the liver, and regulates gene expression in diverse metabolic pathways. Modulation of FXR signaling has emerged as a potential strategy for prevention and treatment of the fatty liver and relevant disturbance of metabolism. FXR has been reported to reduce fatty acid and triglyceride synthesis in the liver through down-regulating the expression of LXR and SREBP-1C. FXR-deficient mice exhibit a reduction in the tolerance for glucose and decrease in the sensitivity to insulin. In contrast, FXR activation by cholic acid (CA) reduces glucose levels by inhibiting expression of multiple genes related to gluconeogenesis in the liver. Reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression induced by small heterodimer partner (SHP) further suggests the crucial role of FXR in the regulation of glucose metabolism. Aside from FXR, Takeda-G-protein-receptor-5 (TGR5) is another classic receptor for bile acids. In hepatic tissue, TGR5 is expressed in Kupffer and endothelial cells and functions to modulate liver inflammation and glucose metabolism, and to improve insulin sensitivity. TGR5 mitigates inflammatory response through the inhibition of NF-κB signaling and cytokines generation in macrophages. In addition, TGR5 possesses a pivotal role in controlling the intestinal GLP-1 release from L cells and thus in maintaining the homeostasis of glucose. Interestingly, supplementation of bile acids to mice facilitates energy expenditure in brown adipose tissue in TGR5-dependent manner. These evidences suggest that TGR5 is functionally active in the regulation of inflammation, glucose metabolism and energy balance.

9. Trimethylamine

Trimethylamine (TMA) produced from the intestinal microbiota through the catabolism of dietary choline, phosphatidylcholine, betaine, and carnitine, enters into the liver via the portal vein. Trimethylamine-N-oxide (TMAO), an oxidative product of TMA catalyzed by flavin-containing monooxygenases (FMO) in the liver, has been considered as a novel biomarker for early metabolic syndrome. TMAO affects the development of NAFLD through multiple pathways. Firstly, the elevation of blood TMAO predicts an increase in TMA production, indirectly reflecting the changes in the metabolism of choline and phosphatidylcholine. In particular, deficiency of choline may hinder the synthesis and secretion of very low-density lipoprotein, thus leading to hepatic accumulation of triglycerides and fatty degeneration. Secondly, the expression of hepatic cytochrome P450 family 7 subfamily A member 1 (CYP7A1) gene, which encodes an endoplasmic reticulum membrane protein that catalyzes the conversion of cholesterol to bile acids, is positively associated with the serum level of TMAO in NAFLD patients. However, mice supplemented with TMAO in normal physiological conditions show a reduction in bile acid. This is attributed to the decrease in the expression of bile acid synthetic enzymes and transporters in the liver. Thus, TMAO may modulate NAFLD via the regulation of bile acid metabolism and transport. Finally, gut microbiota-mediated TMA/FMO3/TMAO pathway modulates insulin resistance, glycolipid metabolism, cholesterol homeostasis, and hepatic inflammation, thereby affecting hepatic triglyceride accumulation and liver steatosis.

10. Carotenoids and Phenolic Compounds

The importance of dietary phytonutrients including carotenoids and polyphenols in amelioration of NAFLD has been highlighted by numerous human and animal studies. Both carotenoids and polyphenols are discovered as secondary plant metabolites that possess potential anti-oxidant and anti-inflammatory properties. Carotenoids are a family of fat-soluble tetraterpenoids compounds that present as pigments in vegetables and fruits, while polyphenols are known as molecules that contain more than one hydroxyl group linked to benzene rings. Although the sources of carotenoids and polyphenols are mostly from plants, gut microbiota-derived contributions are of great concern. The bioaccessibility and bioavailability of dietary carotenoids and polyphenols, which have known to be improved by gut microbiota, may determine the extent of their benefits on human health. A growing appreciation has emerged for the role of gut microflora in facilitating the generation of carotenoids and phenols, through the degradation of intestinal content into simple molecules by microbial enzymes. Interestingly, comparative genomics have revealed four major phylogenetic lineages of microbiota with the capacity of carotenoid biosynthesis. In addition, an in vitro gut fermentation experiment uncovered the formation of phenolic metabolites of microbe in response to water-extractable dietary fiber. Hence, the microbiota present in the human gut brings about an increase in the concentrations of carotenoids and phenolic compounds in the circulatory system and thus the target tissues. The precise mechanisms of the protective roles of carotenoids and phenolic compounds in NAFLD are not fully elucidated, however, apart from the direct roles as free radical scavengers and anti-inflammatory molecules, carotenoids and phenolic compounds have been shown to function as agonists for AHR and PXR, thereby maintaining gut homeostasis, normal glucose metabolism, and resistance to inflammatory disorders. Further research is required to provide the mechanism underlying the defensive effects of carotenoids and phenolic compounds on NAFLD in specific receptor-dependent manner.

11. Conclusions

The gut microbiota is closely related to NAFLD and functions through delivering their own ingredients or metabolites. Bacterial endotoxin, peptidoglycan, DNA, and extracellular vesicles-induced inflammation may accelerate the development of NAFLD and the onset of NASH. Patients suffering from NAFLD appear intestinal dysbiosis and impaired intestinal barrier function, which in turn aggravates the uptake of bacterial component into the hepatic tissue and thus the immune responses. The key metabolites generated from gut microbiota, including short-chain fatty acids, secondary bile acids, indole and its derivatives, trimethylamine, carotenoids, and phenolic compounds, serve as regulators in host metabolism, immune cell systems, and redox homeostasis, thereby fundamentally altering the progression of NAFLD. Despite considerable progress being reported on the interaction between gut microbes and the liver diseases, the underlying mechanisms have not yet been fully elucidated. The mechanisms that clarify the association of the ingredients and metabolites derived from gut microbiome with NAFLD has been shown in Figure 1, according to the existing reports. The targeted application of microbial-derived factors requires a comprehensive description of their cellular receptors and potential signaling pathways on the host, which needs more extensive clinical and experimental research. Exploring the mechanisms whereby the components and metabolites generated from gut microbiota regulate host cells is in favor of the manipulation of susceptibility to liver diseases. Targeting gut microbiota-derived factors and the relevant host cell signaling will provide novel strategies for the intervention of NAFLD.

References 136

  1. 1.

    Younossi Z.M., Koenig A.B., Abdelatif D., Fazel Y., Henry L., Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73-84.

    Not in our library10.1002/hep.28431

  2. 2.

    Kim D., Touros A., Kim W.R. Nonalcoholic Fatty Liver Disease and Metabolic Syndrome. Clin. Liver Dis. 2018;22:133-140.

    Not in our library10.1016/j.cld.2017.08.010

  3. 3.

    Buzzetti E., Pinzani M., Tsochatzis E.A. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65:1038-1048.

    Not in our library10.1016/j.metabol.2015.12.012

  4. 4.
    Introduction to the human gut microbiota · 2017
    No notice
  5. 5.

    Zhu L., Baker R.D., Baker S.S. Gut microbiome and nonalcoholic fatty liver diseases. Pediatr. Res. 2015;77:245-251.

    Not in our library10.1038/pr.2014.157

  6. 6.

    Son G., Kremer M., Hines I.N. Contribution of gut bacteria to liver pathobiology. Gastroenterol. Res. Pract. 2010;2010.

    Not in our library10.1155/2010/453563

  7. 7.

    Pappo I., Bercovier H., Berry E.M., Haviv Y., Gallily R., Freund H.R. Polymyxin B reduces total parenteral nutrition-associated hepatic steatosis by its antibacterial activity and by blocking deleterious effects of lipopolysaccharide. JPEN J. Parenter Enteral. Nutr. 1992;16:529-532.

    Not in our library10.1177/0148607192016006529

  8. 8.
    Elevated endotoxin levels in non-alcoholic fatty liver disease · 2010
    No notice
  9. 9.
    High Fat Diet-Induced Gut Microbiota Exacerbates Inflammation and Obesity in Mice via the TLR4 Signaling Pathway · 2012
    No notice
  10. 10.

    Sharifnia T., Antoun J., Verriere T.G., Suarez G., Wattacheril J., Wilson K.T., Peek R.M., Abumrad N.N., Flynn C.R. Hepatic TLR4 signaling in obese NAFLD. Am. J. Physiol. Gastrointest. Liver Physiol. 2015;309:G270-G278.

    Not in our library10.1152/ajpgi.00304.2014

  11. 11.

    Fukunishi S., Sujishi T., Takeshita A., Ohama H., Tsuchimoto Y., Asai A., Tsuda Y., Higuchi K. Lipopolysaccharides accelerate hepatic steatosis in the development of nonalcoholic fatty liver disease in Zucker rats. J. Clin. Biochem. Nutr. 2014;54:39-44.

    Not in our library10.3164/jcbn.13-49

  12. 12.
    LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease · 2015
    No notice
  13. 13.

    Poggi M., Bastelica D., Gual P., Iglesias M.A., Gremeaux T., Knauf C., Peiretti F., Verdier M., Juhan-Vague I., Tanti J.F., et al. C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia. 2007;50:1267-1276.

    Not in our library10.1007/s00125-007-0654-8

  14. 14.

    Wan Y., Freeswick P.D., Khemlani L.S., Kispert P.H., Wang S.C., Su G.L., Billiar T.R. Role of lipopolysaccharide (LPS), interleukin-1, interleukin-6, tumor necrosis factor, and dexamethasone in regulation of LPS-binding protein expression in normal hepatocytes and hepatocytes from LPS-treated rats. Infect. Immun. 1995;63:2435-2442.

    Not in our library10.1128/iai.63.7.2435-2442.1995

  15. 15.

    Pang J., Xu W., Zhang X., Wong G.L., Chan A.W., Chan H.Y., Tse C.H., Shu S.S., Choi P.C., Chan H.L., et al. Significant positive association of endotoxemia with histological severity in 237 patients with non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 2017;46:175-182.

    Not in our library10.1111/apt.14119

  16. 16.

    Wong V.W., Wong G.L., Chan H.Y., Yeung D.K., Chan R.S., Chim A.M., Chan C.K., Tse Y.K., Woo J., Chu W.C., et al. Bacterial endotoxin and non-alcoholic fatty liver disease in the general population: A prospective cohort study. Aliment. Pharmacol. Ther. 2015;42:731-740.

    Not in our library10.1111/apt.13327

  17. 17.

    Jin C.J., Engstler A.J., Ziegenhardt D., Bischoff S.C., Trautwein C., Bergheim I. Loss of lipopolysaccharide-binding protein attenuates the development of diet-induced non-alcoholic fatty liver disease in mice. J. Gastroenterol. Hepatol. 2017;32:708-715.

    Not in our library10.1111/jgh.13488

  18. 18.

    Levels J.H., Marquart J.A., Abraham P.R., van den Ende A.E., Molhuizen H.O., van Deventer S.J., Meijers J.C. Lipopolysaccharide is transferred from high-density to low-density lipoproteins by lipopolysaccharide-binding protein and phospholipid transfer protein. Infect. Immun. 2005;73:2321-2326.

    Not in our library10.1128/iai.73.4.2321-2326.2005

  19. 19.

    Tsukamoto H., Takeuchi S., Kubota K., Kobayashi Y., Kozakai S., Ukai I., Shichiku A., Okubo M., Numasaki M., Kanemitsu Y., et al. Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1-IKK-IRF3 axis activation. J. Biol. Chem. 2018;293:10186-10201.

    Not in our library10.1074/jbc.m117.796631

  20. 20.

    Hamann L., Alexander C., Stamme C., Zahringer U., Schumann R.R. Acute-phase concentrations of lipopolysaccharide (LPS)-binding protein inhibit innate immune cell activation by different LPS chemotypes via different mechanisms. Infect. Immun. 2005;73:193-200.

    Not in our library10.1128/iai.73.1.193-200.2005

  21. 21.

    Chenevier-Gobeaux C., Borderie D., Weiss N., Mallet-Coste T., Claessens Y.E. Presepsin (sCD14-ST), an innate immune response marker in sepsis. Clin. Chim. Acta. 2015;450:97-103.

    Not in our library10.1016/j.cca.2015.06.026

  22. 22.

    Roncon-Albuquerque R., Moreira-Rodrigues M., Faria B., Ferreira A.P., Cerqueira C., Lourenco A.P., Pestana M., von Hafe P., Leite-Moreira A.F. Attenuation of the cardiovascular and metabolic complications of obesity in CD14 knockout mice. Life Sci. 2008;83:502-510.

    Not in our library10.1016/j.lfs.2008.07.021

  23. 23.

    Ogawa Y., Imajo K., Yoneda M., Kessoku T., Tomeno W., Shinohara Y., Kato S., Mawatari H., Nozaki Y., Fujita K., et al. Soluble CD14 levels reflect liver inflammation in patients with nonalcoholic steatohepatitis. PLoS ONE. 2013;8:e65211.

    Not in our library10.1371/journal.pone.0065211

  24. 24.

    Guo S., Al-Sadi R., Said H.M., Ma T.Y. Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14. Am. J. Pathol. 2013;182:375-387.

    Not in our library10.1016/j.ajpath.2012.10.014

  25. 25.

    Nighot M., Al-Sadi R., Guo S., Rawat M., Nighot P., Watterson M.D., Ma T.Y. Lipopolysaccharide-Induced Increase in Intestinal Epithelial Tight Permeability Is Mediated by Toll-Like Receptor 4/Myeloid Differentiation Primary Response 88 (MyD88) Activation of Myosin Light Chain Kinase Expression. Am. J. Pathol. 2017;187:2698-2710.

    Not in our library10.1016/j.ajpath.2017.08.005

  26. 26.

    Guo S., Nighot M., Al-Sadi R., Alhmoud T., Nighot P., Ma T.Y. Lipopolysaccharide Regulation of Intestinal Tight Junction Permeability Is Mediated by TLR4 Signal Transduction Pathway Activation of FAK and MyD88. J. Immunol. 2015;195:4999-5010.

    Not in our library10.4049/jimmunol.1402598

  27. 27.
    Role of NLRP3 Inflammasome in the Progression of NAFLD to NASH · 2016
    No notice
  28. 28.

    Humann J., Lenz L.L. Bacterial peptidoglycan degrading enzymes and their impact on host muropeptide detection. J. Innate. Immun. 2009;1:88-97.

    Not in our library10.1159/000181181

  29. 29.

    McDonald C., Inohara N., Nunez G. Peptidoglycan signaling in innate immunity and inflammatory disease. J. Biol. Chem. 2005;280:20177-20180.

    Not in our library10.1074/jbc.r500001200

  30. 30.

    Miura K., Ohnishi H. Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease. World J. Gastroenterol. 2014;20:7381-7391.

    Not in our library10.3748/wjg.v20.i23.7381

  31. 31.

    Cengiz M., Ozenirler S., Elbeg S. Role of serum toll-like receptors 2 and 4 in non-alcoholic steatohepatitis and liver fibrosis. J. Gastroenterol. Hepatol. 2015;30:1190-1196.

    Not in our library10.1111/jgh.12924

  32. 32.

    Ehses J.A., Meier D.T., Wueest S., Rytka J., Boller S., Wielinga P.Y., Schraenen A., Lemaire K., Debray S., Van Lommel L., et al. Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet. Diabetologia. 2010;53:1795-1806.

    Not in our library10.1007/s00125-010-1747-3

  33. 33.

    Himes R.W., Smith C.W. Tlr2 is critical for diet-induced metabolic syndrome in a murine model. FASEB J. 2010;24:731-739.

    Not in our library10.1096/fj.09-141929

  34. 34.

    Wan Z., Durrer C., Mah D., Simtchouk S., Little J.P. One-week high-fat diet leads to reduced toll-like receptor 2 expression and function in young healthy men. Nutr. Res. 2014;34:1045-1051.

    Not in our library10.1016/j.nutres.2014.08.012

  35. 35.

    Kawasaki A., Karasudani Y., Otsuka Y., Hasegawa M., Inohara N., Fujimoto Y., Fukase K. Synthesis of diaminopimelic acid containing peptidoglycan fragments and tracheal cytotoxin (TCT) and investigation of their biological functions. Chemistry. 2008;14:10318-10330.

    Not in our library10.1002/chem.200801121

  36. 36.

    Girardin S.E., Boneca I.G., Viala J., Chamaillard M., Labigne A., Thomas G., Philpott D.J., Sansonetti P.J. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J. Biol. Chem. 2003;278:8869-8872.

    Not in our library10.1074/jbc.c200651200

  37. 37.

    Martinic M.M., Caminschi I., O’Keeffe M., Thinnes T.C., Grumont R., Gerondakis S., McKay D.B., Nemazee D., Gavin A.L. The Bacterial Peptidoglycan-Sensing Molecules NOD1 and NOD2 Promote CD8(+) Thymocyte Selection. J. Immunol. 2017;198:2649-2660.

    Not in our library10.4049/jimmunol.1601462

  38. 38.

    Meli R., Mattace Raso G., Calignano A. Role of innate immune response in non-alcoholic Fatty liver disease: Metabolic complications and therapeutic tools. Front. Immunol. 2014;5:177.

    Not in our library10.3389/fimmu.2014.00177

  39. 39.

    Schertzer J.D., Tamrakar A.K., Magalhaes J.G., Pereira S., Bilan P.J., Fullerton M.D., Liu Z., Steinberg G.R., Giacca A., Philpott D.J., et al. NOD1 activators link innate immunity to insulin resistance. Diabetes. 2011;60:2206-2215.

    Not in our library10.2337/db11-0004

  40. 40.

    Nonogaki K., Moser A.H., Pan X.M., Staprans I., Grunfeld C., Feingold K.R. Lipoteichoic acid stimulates lipolysis and hepatic triglyceride secretion in rats in vivo. J. Lipid Res. 1995;36:1987-1995.

    Not in our library

  41. 41.

    Osawa Y., Iho S., Takauji R., Takatsuka H., Yamamoto S., Takahashi T., Horiguchi S., Urasaki Y., Matsuki T., Fujieda S. Collaborative action of NF-kappaB and p38 MAPK is involved in CpG DNA-induced IFN-alpha and chemokine production in human plasmacytoid dendritic cells. J. Immunol. 2006;177:4841-4852.

    Not in our library10.4049/jimmunol.177.7.4841

  42. 42.

    Gomes M.T., Campos P.C., Pereira Gde S., Bartholomeu D.C., Splitter G., Oliveira S.C. TLR9 is required for MAPK/NF-kappaB activation but does not cooperate with TLR2 or TLR6 to induce host resistance to Brucella abortus. J. Leukoc. Biol. 2016;99:771-780.

    Not in our library10.1189/jlb.4a0815-346r

  43. 43.

    Minton K. LC3 anchors TLR9 signalling. Nat. Rev. Immunol. 2018;18:418-419.

    Not in our library10.1038/s41577-018-0019-1

  44. 44.

    Hayashi K., Taura M., Iwasaki A. The interaction between IKKalpha and LC3 promotes type I interferon production through the TLR9-containing LAPosome. Sci. Signal. 2018;11.

    Not in our library10.1126/scisignal.aan4144

  45. 45.

    Bauer S., Kirschning C.J., Hacker H., Redecke V., Hausmann S., Akira S., Wagner H., Lipford G.B. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc. Natl. Acad. Sci. USA. 2001;98:9237-9242.

    Not in our library10.1073/pnas.161293498

  46. 46.

    Mridha A.R., Haczeyni F., Yeh M.M., Haigh W.G., Ioannou G.N., Barn V., Ajamieh H., Adams L., Hamdorf J.M., Teoh N.C., et al. TLR9 is up-regulated in human and murine NASH: Pivotal role in inflammatory recruitment and cell survival. Clin. Sci. 2017;131:2145-2159.

    Not in our library10.1042/cs20160838

  47. 47.

    Garcia-Martinez I., Santoro N., Chen Y., Hoque R., Ouyang X., Caprio S., Shlomchik M.J., Coffman R.L., Candia A., Mehal W.Z. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J. Clin. Investig. 2016;126:859-864.

    Not in our library10.1172/jci83885

  48. 48.

    Miura K., Kodama Y., Inokuchi S., Schnabl B., Aoyama T., Ohnishi H., Olefsky J.M., Brenner D.A., Seki E. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology. 2010;139:323-334.e7.

    Not in our library10.1053/j.gastro.2010.03.052

  49. 49.

    Yanez-Mo M., Siljander P.R., Andreu Z., Zavec A.B., Borras F.E., Buzas E.I., Buzas K., Casal E., Cappello F., Carvalho J., et al. Biological properties of extracellular vesicles and their physiological functions. J. Extracell. Vesicles. 2015;4:27066.

    Not in our library10.3402/jev.v4.27066

  50. 50.

    Anand D., Chaudhuri A. Bacterial outer membrane vesicles: New insights and applications. Mol. Membr. Biol. 2016;33:125-137.

    Not in our library10.1080/09687688.2017.1400602

  51. 51.

    Tulkens J., Vergauwen G., Van Deun J., Geeurickx E., Dhondt B., Lippens L., De Scheerder M.A., Miinalainen I., Rappu P., De Geest B.G., et al. Increased levels of systemic LPS-positive bacterial extracellular vesicles in patients with intestinal barrier dysfunction. Gut. 2018.

    Not in our library10.1136/gutjnl-2018-317726

  52. 52.

    Gu L., Meng R., Tang Y., Zhao K., Liang F., Zhang R., Xue Q., Chen F., Xiao X., Wang H., et al. Toll-Like Receptor 4 Signaling Licenses the Cytosolic Transport of Lipopolysaccharide From Bacterial Outer Membrane Vesicles. Shock. 2019;51:256-265.

    Not in our library10.1097/shk.0000000000001129

  53. 53.

    Bielig H., Rompikuntal P.K., Dongre M., Zurek B., Lindmark B., Ramstedt M., Wai S.N., Kufer T.A. NOD-like receptor activation by outer membrane vesicles from Vibrio cholerae non-O1 non-O139 strains is modulated by the quorum-sensing regulator HapR. Infect. Immun. 2011;79:1418-1427.

    Not in our library10.1128/iai.00754-10

  54. 54.

    Prados-Rosales R., Baena A., Martinez L.R., Luque-Garcia J., Kalscheuer R., Veeraraghavan U., Camara C., Nosanchuk J.D., Besra G.S., Chen B., et al. Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice. J. Clin. Investig. 2011;121:1471-1483.

    Not in our library10.1172/jci44261

  55. 55.

    Bai J., Kim S.I., Ryu S., Yoon H. Identification and characterization of outer membrane vesicle-associated proteins in Salmonella enterica serovar Typhimurium. Infect. Immun. 2014;82:4001-4010.

    Not in our library10.1128/iai.01416-13

  56. 56.

    Choi D.S., Kim D.K., Choi S.J., Lee J., Choi J.P., Rho S., Park S.H., Kim Y.K., Hwang D., Gho Y.S. Proteomic analysis of outer membrane vesicles derived from Pseudomonas aeruginosa. Proteomics. 2011;11:3424-3429.

    Not in our library10.1002/pmic.201000212

  57. 57.
    A Novel Mechanism of Host-Pathogen Interaction through sRNA in Bacterial Outer Membrane Vesicles · 2016
    No notice
  58. 58.
    The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism · 2013
    Not checked
  59. 59.

    Chakraborti C.K. New-found link between microbiota and obesity. World J. Gastrointest. Pathophysiol. 2015;6:110-119.

    Not in our library10.4291/wjgp.v6.i4.110

  60. 60.
    The SCFA Receptor GPR43 and Energy Metabolism · 2014
    No notice
  61. 61.

    Inoue D., Tsujimoto G., Kimura I. Regulation of Energy Homeostasis by GPR41. Front. Endocrinol. 2014;5:81.

    Not in our library10.3389/fendo.2014.00081

  62. 62.
    GPR41 and GPR43 in Obesity and Inflammation – Protective or Causative? · 2016
    No notice
  63. 63.

    Cornall L.M., Mathai M.L., Hryciw D.H., McAinch A.J. Diet-induced obesity up-regulates the abundance of GPR43 and GPR120 in a tissue specific manner. Cell Physiol. Biochem. 2011;28:949-958.

    Not in our library10.1159/000335820

  64. 64.

    Natarajan N., Pluznick J.L. Olfaction in the kidney: “Smelling” gut microbial metabolites. Exp. Physiol. 2016;101:478-481.

    Not in our library10.1113/ep085285

  65. 65.

    Fleischer J., Bumbalo R., Bautze V., Strotmann J., Breer H. Expression of odorant receptor Olfr78 in enteroendocrine cells of the colon. Cell Tissue Res. 2015;361:697-710.

    Not in our library10.1007/s00441-015-2165-0

  66. 66.

    Bellahcene M., O’Dowd J.F., Wargent E.T., Zaibi M.S., Hislop D.C., Ngala R.A., Smith D.M., Cawthorne M.A., Stocker C.J., Arch J.R. Male mice that lack the G-protein-coupled receptor GPR41 have low energy expenditure and increased body fat content. Br. J. Nutr. 2013;109:1755-1764.

    Not in our library10.1017/s0007114512003923

  67. 67.

    Bjursell M., Admyre T., Goransson M., Marley A.E., Smith D.M., Oscarsson J., Bohlooly Y.M. Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 2011;300:E211-E220.

    Not in our library10.1152/ajpendo.00229.2010

  68. 68.

    Kimura I., Ozawa K., Inoue D., Imamura T., Kimura K., Maeda T., Terasawa K., Kashihara D., Hirano K., Tani T., et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat. Commun. 2013;4:1829.

    Not in our library10.1038/ncomms2852

  69. 69.

    Rau M., Rehman A., Dittrich M., Groen A.K., Hermanns H.M., Seyfried F., Beyersdorf N., Dandekar T., Rosenstiel P., Geier A. Fecal SCFAs and SCFA-producing bacteria in gut microbiome of human NAFLD as a putative link to systemic T-cell activation and advanced disease. United Eur. Gastroenterol. J. 2018;6:1496-1507.

    Not in our library10.1177/2050640618804444

  70. 70.

    Nishina P.M., Freedland R.A. Effects of propionate on lipid biosynthesis in isolated rat hepatocytes. J. Nutr. 1990;120:668-673.

    Not in our library10.1093/jn/120.7.668

  71. 71.

    Tedelind S., Westberg F., Kjerrulf M., Vidal A. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: A study with relevance to inflammatory bowel disease. World J. Gastroenterol. 2007;13:2826-2832.

    Not in our library10.3748/wjg.v13.i20.2826

  72. 72.

    Sahuri-Arisoylu M., Brody L.P., Parkinson J.R., Parkes H., Navaratnam N., Miller A.D., Thomas E.L., Frost G., Bell J.D. Reprogramming of hepatic fat accumulation and ‘browning’ of adipose tissue by the short-chain fatty acid acetate. Int. J. Obes. 2016;40:955-963.

    Not in our library10.1038/ijo.2016.23

  73. 73.

    Zhou D., Pan Q., Xin F.Z., Zhang R.N., He C.X., Chen G.Y., Liu C., Chen Y.W., Fan J.G. Sodium butyrate attenuates high-fat diet-induced steatohepatitis in mice by improving gut microbiota and gastrointestinal barrier. World J. Gastroenterol. 2017;23:60-75.

    Not in our library10.3748/wjg.v23.i1.60

  74. 74.
    Sodium butyrate reduces high-fat diet-induced non-alcoholic steatohepatitis through upregulation of hepatic GLP-1R expression · 2018
    No notice
  75. 75.

    Jin C.J., Sellmann C., Engstler A.J., Ziegenhardt D., Bergheim I. Supplementation of sodium butyrate protects mice from the development of non-alcoholic steatohepatitis (NASH). Br. J. Nutr. 2015;114:1745-1755.

    Not in our library10.1017/s0007114515003621

  76. 76.
    Butyrate Protects Mice Against Methionine–Choline-Deficient Diet-Induced Non-alcoholic Steatohepatitis by Improving Gut Barrier Function, Attenuating Inflammation and Reducing Endotoxin Levels · 2018
    No notice
  77. 77.

    Verdone L., Caserta M., Di Mauro E. Role of histone acetylation in the control of gene expression. Biochem. Cell Biol. 2005;83:344-353.

    Not in our library10.1139/o05-041

  78. 78.

    Sasaki-Imamura T., Yoshida Y., Suwabe K., Yoshimura F., Kato H. Molecular basis of indole production catalyzed by tryptophanase in the genus Prevotella. FEMS Microbiol. Lett. 2011;322:51-59.

    Not in our library10.1111/j.1574-6968.2011.02329.x

  79. 79.

    Devlin A.S., Marcobal A., Dodd D., Nayfach S., Plummer N., Meyer T., Pollard K.S., Sonnenburg J.L., Fischbach M.A. Modulation of a Circulating Uremic Solute via Rational Genetic Manipulation of the Gut Microbiota. Cell Host Microbe. 2016;20:709-715.

    Not in our library10.1016/j.chom.2016.10.021

  80. 80.

    Sasaki-Imamura T., Yano A., Yoshida Y. Production of indole from L-tryptophan and effects of these compounds on biofilm formation by Fusobacterium nucleatum ATCC 25586. Appl. Environ. Microbiol. 2010;76:4260-4268.

    Not in our library10.1128/aem.00166-10

  81. 81.

    Chu W., Zere T.R., Weber M.M., Wood T.K., Whiteley M., Hidalgo-Romano B., Valenzuela E., McLean R.J. Indole production promotes Escherichia coli mixed-culture growth with Pseudomonas aeruginosa by inhibiting quorum signaling. Appl. Environ. Microbiol. 2012;78:411-419.

    Not in our library10.1128/aem.06396-11

  82. 82.

    Bansal T., Alaniz R.C., Wood T.K., Jayaraman A. The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators of inflammation. Proc. Natl. Acad. Sci. USA. 2010;107:228-233.

    Not in our library10.1073/pnas.0906112107

  83. 83.

    Whitfield-Cargile C.M., Cohen N.D., Chapkin R.S., Weeks B.R., Davidson L.A., Goldsby J.S., Hunt C.L., Steinmeyer S.H., Menon R., Suchodolski J.S., et al. The microbiota-derived metabolite indole decreases mucosal inflammation and injury in a murine model of NSAID enteropathy. Gut Microbes. 2016;7:246-261.

    Not in our library10.1080/19490976.2016.1156827

  84. 84.
    Bacterial Metabolite Indole Modulates Incretin Secretion from Intestinal Enteroendocrine L Cells · 2014
    No notice
  85. 85.

    Beaumont M., Neyrinck A.M., Olivares M., Rodriguez J., de Rocca Serra A., Roumain M., Bindels L.B., Cani P.D., Evenepoel P., Muccioli G.G., et al. The gut microbiota metabolite indole alleviates liver inflammation in mice. FASEB J. 2018.

    Not in our library10.1096/fj.201800544

  86. 86.

    Zelante T., Iannitti R.G., Cunha C., De Luca A., Giovannini G., Pieraccini G., Zecchi R., D’Angelo C., Massi-Benedetti C., Fallarino F., et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39:372-385.

    Not in our library10.1016/j.immuni.2013.08.003

  87. 87.

    Alexeev E.E., Lanis J.M., Kao D.J., Campbell E.L., Kelly C.J., Battista K.D., Gerich M.E., Jenkins B.R., Walk S.T., Kominsky D.J., et al. Microbiota-Derived Indole Metabolites Promote Human and Murine Intestinal Homeostasis through Regulation of Interleukin-10 Receptor. Am. J. Pathol. 2018;188:1183-1194.

    Not in our library10.1016/j.ajpath.2018.01.011

  88. 88.

    Natividad J.M., Agus A., Planchais J., Lamas B., Jarry A.C., Martin R., Michel M.L., Chong-Nguyen C., Roussel R., Straube M., et al. Impaired Aryl Hydrocarbon Receptor Ligand Production by the Gut Microbiota Is a Key Factor in Metabolic Syndrome. Cell Metab. 2018;28:737-749.

    Not in our library10.1016/j.cmet.2018.07.001

  89. 89.

    Krishnan S., Ding Y., Saedi N., Choi M., Sridharan G.V., Sherr D.H., Yarmush M.L., Alaniz R.C., Jayaraman A., Lee K. Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages. Cell Rep. 2018;23:1099-1111.

    Not in our library10.1016/j.celrep.2018.03.109

  90. 90.

    Venkatesh M., Mukherjee S., Wang H., Li H., Sun K., Benechet A.P., Qiu Z., Maher L., Redinbo M.R., Phillips R.S., et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity. 2014;41:296-310.

    Not in our library10.1016/j.immuni.2014.06.014

  91. 91.

    Poeggeler B., Pappolla M.A., Hardeland R., Rassoulpour A., Hodgkins P.S., Guidetti P., Schwarcz R. Indole-3-propionate: A potent hydroxyl radical scavenger in rat brain. Brain Res. 1999;815:382-388.

    Not in our library10.1016/s0006-8993(98)01027-0

  92. 92.

    Hwang I.K., Yoo K.Y., Li H., Park O.K., Lee C.H., Choi J.H., Jeong Y.G., Lee Y.L., Kim Y.M., Kwon Y.G., et al. Indole-3-propionic acid attenuates neuronal damage and oxidative stress in the ischemic hippocampus. J. Neurosci. Res. 2009;87:2126-2137.

    Not in our library10.1002/jnr.22030

  93. 93.

    Karbownik M., Reiter R.J., Garcia J.J., Cabrera J., Burkhardt S., Osuna C., Lewinski A. Indole-3-propionic acid, a melatonin-related molecule, protects hepatic microsomal membranes from iron-induced oxidative damage: Relevance to cancer reduction. J. Cell Biochem. 2001;81:507-513.

    Not in our library10.1002/1097-4644(20010601)81:3<507::aid-jcb1064>3.0.co;2-m

  94. 94.

    Abildgaard A., Elfving B., Hokland M., Wegener G., Lund S. The microbial metabolite indole-3-propionic acid improves glucose metabolism in rats, but does not affect behaviour. Arch. Physiol. Biochem. 2018;124:306-312.

    Not in our library10.1080/13813455.2017.1398262

  95. 95.

    Taoka H., Yokoyama Y., Morimoto K., Kitamura N., Tanigaki T., Takashina Y., Tsubota K., Watanabe M. Role of bile acids in the regulation of the metabolic pathways. World J. Diabetes. 2016;7:260-270.

    Not in our library10.4239/wjd.v7.i13.260

  96. 96.

    Chow M.D., Lee Y.H., Guo G.L. The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mol. Aspects Med. 2017;56:34-44.

    Not in our library10.1016/j.mam.2017.04.004

  97. 97.

    McMillin M., DeMorrow S. Effects of bile acids on neurological function and disease. FASEB J. 2016;30:3658-3668.

    Not in our library10.1096/fj.201600275r

  98. 98.

    Keren N., Konikoff F.M., Paitan Y., Gabay G., Reshef L., Naftali T., Gophna U. Interactions between the intestinal microbiota and bile acids in gallstones patients. Environ. Microbiol. Rep. 2015;7:874-880.

    Not in our library10.1111/1758-2229.12319

  99. 99.

    Yang H., Duan Z. Bile Acids and the Potential Role in Primary Biliary Cirrhosis. Digestion. 2016;94:145-153.

    Not in our library10.1159/000452300

  100. 100.

    Muili K.A., Wang D., Orabi A.I., Sarwar S., Luo Y., Javed T.A., Eisses J.F., Mahmood S.M., Jin S., Singh V.P., et al. Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin. J. Biol. Chem. 2013;288:570-580.

    Not in our library10.1074/jbc.m112.428896

  101. 101.

    Tiratterra E., Franco P., Porru E., Katsanos K.H., Christodoulou D.K., Roda G. Role of bile acids in inflammatory bowel disease. Ann. Gastroenterol. 2018;31:266-272.

    Not in our library10.20524/aog.2018.0239

  102. 102.

    Wahlstrom A., Sayin S.I., Marschall H.U., Backhed F. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. Cell Metab. 2016;24:41-50.

    Not in our library10.1016/j.cmet.2016.05.005

  103. 103.

    Tremblay S., Romain G., Roux M., Chen X.L., Brown K., Gibson D.L., Ramanathan S., Menendez A. Bile Acid Administration Elicits an Intestinal Antimicrobial Program and Reduces the Bacterial Burden in Two Mouse Models of Enteric Infection. Infect. Immun. 2017;85:e00942-16.

    Not in our library10.1128/iai.00942-16

  104. 104.

    Hofmann A.F., Eckmann L. How bile acids confer gut mucosal protection against bacteria. Proc. Natl. Acad. Sci. USA. 2006;103:4333-4334.

    Not in our library10.1073/pnas.0600780103

  105. 105.

    Zhang L., Xie C., Nichols R.G., Chan S.H., Jiang C., Hao R., Smith P.B., Cai J., Simons M.N., Hatzakis E., et al. Farnesoid X Receptor Signaling Shapes the Gut Microbiota and Controls Hepatic Lipid Metabolism. MSystems. 2016;1:e00070-16.

    Not in our library10.1128/msystems.00070-16

  106. 106.

    Yang Z.X., Shen W., Sun H. Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Hepatol. Int. 2010;4:741-748.

    Not in our library10.1007/s12072-010-9202-6

  107. 107.

    Ma K., Saha P.K., Chan L., Moore D.D. Farnesoid X receptor is essential for normal glucose homeostasis. J. Clin. Investig. 2006;116:1102-1109.

    Not in our library10.1172/jci25604

  108. 108.

    Cariou B., Duran-Sandoval D., Kuipers F., Staels B. Farnesoid X receptor: A new player in glucose metabolism? Endocrinology. 2005;146:981-983.

    Not in our library10.1210/en.2004-1595

  109. 109.

    Lou G., Ma X., Fu X., Meng Z., Zhang W., Wang Y.D., Van Ness C., Yu D., Xu R., Huang W. GPBAR1/TGR5 mediates bile acid-induced cytokine expression in murine Kupffer cells. PLoS ONE. 2014;9:e93567.

    Not in our library10.1371/journal.pone.0093567

  110. 110.

    Thomas C., Gioiello A., Noriega L., Strehle A., Oury J., Rizzo G., Macchiarulo A., Yamamoto H., Mataki C., Pruzanski M., et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009;10:167-177.

    Not in our library10.1016/j.cmet.2009.08.001

  111. 111.

    Watanabe M., Houten S.M., Mataki C., Christoffolete M.A., Kim B.W., Sato H., Messaddeq N., Harney J.W., Ezaki O., Kodama T., et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439:484-489.

    Not in our library10.1038/nature04330

  112. 112.

    Fennema D., Phillips I.R., Shephard E.A. Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease. Drug Metab. Dispos. 2016;44:1839-1850.

    Not in our library10.1124/dmd.116.070615

  113. 113.
    Trimethylamine-N-oxide (TMAO) as Novel Potential Biomarker of Early Predictors of Metabolic Syndrome · 2018
    No notice
  114. 114.
    Nonalcoholic Fatty Liver Disease: Focus on Lipoprotein and Lipid Deregulation · 2011
    No notice
  115. 115.

    Zhu H.-l., Tan X.-Y., Liu Y., Chen X.-L. Increased circulating trimethylamine N-oxide, a gut-flora-dependent metabolite of choline and betaine in nonalcoholic fatty liver disease is associated with high serum bile acids. FASEB J. 2016;30:272-2.

    Not in our library

  116. 116.

    Koeth R.A., Wang Z., Levison B.S., Buffa J.A., Org E., Sheehy B.T., Britt E.B., Fu X., Wu Y., Li L., et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 2013;19:576-585.

    Not in our library10.1038/nm.3145

  117. 117.

    Warrier M., Shih D.M., Burrows A.C., Ferguson D., Gromovsky A.D., Brown A.L., Marshall S., McDaniel A., Schugar R.C., Wang Z., et al. The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance. Cell Rep. 2015;10:326-338.

    Not in our library10.1016/j.celrep.2014.12.036

  118. 118.

    Shih D.M., Wang Z., Lee R., Meng Y., Che N., Charugundla S., Qi H., Wu J., Pan C., Brown J.M., et al. Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis. J. Lipid Res. 2015;56:22-37.

    Not in our library10.1194/jlr.m051680

  119. 119.

    Oellgaard J., Winther S.A., Hansen T.S., Rossing P., von Scholten B.J. Trimethylamine N-oxide (TMAO) as a New Potential Therapeutic Target for Insulin Resistance and Cancer. Curr. Pharm. Des. 2017;23:3699-3712.

    Not in our library10.2174/1381612823666170622095324

  120. 120.

    Christensen K., Lawler T., Mares J. Dietary Carotenoids and Non-Alcoholic Fatty Liver Disease among US Adults, NHANES 2003(-)2014. Nutrients. 2019;11:1101.

    Not in our library10.3390/nu11051101

  121. 121.

    Yilmaz B., Sahin K., Bilen H., Bahcecioglu I.H., Bilir B., Ashraf S., Halazun K.J., Kucuk O. Carotenoids and non-alcoholic fatty liver disease. Hepatobiliary Surg. Nutr. 2015;4:161-171.

    Not in our library10.3978/j.issn.2304-3881.2015.01.11

  122. 122.
    Astaxanthin prevents and reverses diet-induced insulin resistance and steatohepatitis in mice: A comparison with vitamin E · 2015
    No notice
  123. 123.

    Eo H., Jeon Y.J., Lee M., Lim Y. Brown Alga Ecklonia cava polyphenol extract ameliorates hepatic lipogenesis, oxidative stress, and inflammation by activation of AMPK and SIRT1 in high-fat diet-induced obese mice. J. Agric. Food Chem. 2015;63:349-359.

    Not in our library10.1021/jf502830b

  124. 124.

    Anhe F.F., Nachbar R.T., Varin T.V., Vilela V., Dudonne S., Pilon G., Fournier M., Lecours M.A., Desjardins Y., Roy D., et al. A polyphenol-rich cranberry extract reverses insulin resistance and hepatic steatosis independently of body weight loss. Mol. Metab. 2017;6:1563-1573.

    Not in our library10.1016/j.molmet.2017.10.003

  125. 125.

    Abenavoli L., Milic N., Luzza F., Boccuto L., De Lorenzo A. Polyphenols Treatment in Patients with Nonalcoholic Fatty Liver Disease. J. Transl. Int. Med. 2017;5:144-147.

    Not in our library10.1515/jtim-2017-0027

  126. 126.

    Mezzomo N., Ferreira S.R.S. Carotenoids Functionality, Sources, and Processing by Supercritical Technology: A Review. J. Chem.-Ny. 2016.

    Not in our library10.1155/2016/3164312

  127. 127.
    Plant Polyphenols as Dietary Antioxidants in Human Health and Disease · 2009
    No notice
  128. 128.
    The Role of Dietary Fiber in the Bioaccessibility and Bioavailability of Fruit and Vegetable Antioxidants · 2011
    No notice
  129. 129.

    Djuric Z., Bassis C., Ren J.W., Chan R., Kato I., Ruffin M.T., Sen A., Turgeon D.K. Predictors of Carotenoid Concentrations in Human Serum: Role of the Intestinal Microbiome. Faseb J. 2017;31:168-7.

    Not in our library

  130. 130.

    Klassen J.L. Phylogenetic and evolutionary patterns in microbial carotenoid biosynthesis are revealed by comparative genomics. PLoS ONE. 2010;5:e11257.

    Not in our library10.1371/journal.pone.0011257

  131. 131.

    Nordlund E., Aura A.M., Mattila I., Kosso T., Rouau X., Poutanen K. Formation of Phenolic Microbial Metabolites and Short-Chain Fatty Acids from Rye, Wheat, and Oat Bran and Their Fractions in the Metabolical in Vitro Colon Model. J. Agric. Food Chem. 2012;60:8134-8145.

    Not in our library10.1021/jf3008037

  132. 132.

    Amakura Y., Tsutsumi T., Sasaki K., Nakamura M., Yoshida T., Maitani T. Influence of food polyphenols on aryl hydrocarbon receptor-signaling pathway estimated by in vitro bioassay. Phytochemistry. 2008;69:3117-3130.

    Not in our library10.1016/j.phytochem.2007.07.022

  133. 133.

    Busbee P.B., Rouse M., Nagarkatti M., Nagarkatti P.S. Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders. Nutr. Rev. 2013;71:353-369.

    Not in our library10.1111/nure.12024

  134. 134.

    Murray I.A., Perdew G.H. Ligand activation of the Ah receptor contributes to gastrointestinal homeostasis. Curr. Opin. Toxicol. 2017;2:15-23.

    Not in our library10.1016/j.cotox.2017.01.003

  135. 135.

    Ruhl R. Induction of PXR-mediated metabolism by beta-carotene. Biochim. Biophys. Acta. 2005;1740:162-169.

    Not in our library10.1016/j.bbadis.2004.11.013

  136. 136.

    Li X., Li S., Chen M., Wang J., Xie B., Sun Z. (-)-Epigallocatechin-3-gallate (EGCG) inhibits starch digestion and improves glucose homeostasis through direct or indirect activation of PXR/CAR-mediated phase II metabolism in diabetic mice. Food Funct. 2018;9:4651-4663.

    Not in our library10.1039/c8fo01293h

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