Next Article in Journal
Prenatal Trimethyltin Exposure Induces Long-Term DNA Methylation Changes in the Male Mouse Hippocampus
Next Article in Special Issue
Establishment of an Adult Medaka Fatty Liver Model by Administration of a Gubra-Amylin-Nonalcoholic Steatohepatitis Diet Containing High Levels of Palmitic Acid and Fructose
Previous Article in Journal
Cell Signaling in Model Plants 2.0
Previous Article in Special Issue
Losartan Prevents Hepatic Steatosis and Macrophage Polarization by Inhibiting HIF-1α in a Murine Model of NAFLD
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 22
Issue 15
10.3390/ijms22158008
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Effect of Microbiome on Non-Alcoholic Fatty Liver Disease and the Role of Probiotics, Prebiotics, and Biogenics

by
Mayumi Nagashimada
and
Masao Honda
*
Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-0942, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(15), 8008; https://doi.org/10.3390/ijms22158008
Submission received: 2 June 2021 / Revised: 21 July 2021 / Accepted: 22 July 2021 / Published: 27 July 2021
(This article belongs to the Special Issue Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH) 2.0)
Browse Figures
Versions Notes

Abstract

:
Non-alcoholic fatty liver disease (NAFLD) is a leading cause of liver cirrhosis and hepatocellular carcinoma. NAFLD is associated with metabolic disorders such as obesity, insulin resistance, dyslipidemia, steatohepatitis, and liver fibrosis. Liver-resident (Kupffer cells) and recruited macrophages contribute to low-grade chronic inflammation in various tissues by modulating macrophage polarization, which is implicated in the pathogenesis of metabolic diseases. Abnormalities in the intestinal environment, such as the gut microbiota, metabolites, and immune system, are also involved in the pathogenesis and development of NAFLD. Hepatic macrophage activation is induced by the permeation of antigens, endotoxins, and other proinflammatory substances into the bloodstream as a result of increased intestinal permeability. Therefore, it is important to understand the role of the gut–liver axis in influencing macrophage activity, which is central to the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH). Not only probiotics but also biogenics (heat-killed lactic acid bacteria) are effective in ameliorating the progression of NASH. Here we review the effect of hepatic macrophages/Kupffer cells, other immune cells, intestinal permeability, and immunity on NAFLD and NASH and the impact of probiotics, prebiotics, and biogenesis on those diseases.

1. Introduction

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders worldwide and its prevalence is increasing [1,2]. NAFLD is characterized by hepatic damage caused by steatosis without secondary causes (e.g., medications, excessive alcohol consumption, or certain heritable conditions), which can progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma [3]. NASH has several histological features, such as steatosis, hepatocellular ballooning, lobular inflammation, and fibrosis [4,5].
Several cross-sectional clinical studies have focused on the pathogenesis of NASH. In addition, mouse models of NASH mimic the pathogenesis of diet-induced obesity and its resulting metabolic disturbances, including NAFLD and NASH [6,7,8,9,10]. The development and progression of NAFLD is closely related to metabolic syndrome, insulin resistance, and type 2 diabetes mellitus (T2DM) [11,12,13,14,15,16]. NAFLD is a genetic-environmental-metabolic stress-related disease of unclear pathogenesis. The two-hit hypothesis explains progression of NASH from NAFLD. The first hit is insulin resistance and excessive fatty acids, which induce simple hepatic steatosis. The second hit is oxidative stress, lipid peroxidation, reactive oxygen species (ROS), and mitochondrial dysfunction. Moreover, recent findings support the multiple-hit hypothesis of the pathogenesis of NAFLD, which implicates liver, intestinal tract, and adipose tissue changes [17,18,19] (Figure 1). It is important to assess the role of inflammatory immune cells and oxidative stress in inducing inflammation, or of overproduction of ROS in liver mitochondrial dysfunction, a major pathogenic factor in NASH [20,21]. Dysregulation and polarization of macrophages (inflammatory M1 macrophages and anti-inflammatory M2 macrophages) in the liver contribute to the development and progression of NAFLD and NASH [22,23,24]. Oxidative stress-induced endoplasmic reticulum (ER) stress leads to upregulated liver lipogenic sterols, resulting in hepatic steatosis. Moreover, the activation of redox-sensitive nuclear factor-κB (NF-κB) by oxidative stress causes an increase in the expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 [25]. The impaired mitochondrial respiratory chain caused by oxidative stress and peroxidation of cardiolipin (a dimeric phospholipid in the inner mitochondrial membrane) increases mitochondrial ROS production and promotes mitochondrial damage [26]. In addition, the intestinal barrier, immune cells, and microbiota composition are also involved in NAFLD and NASH development [27,28,29,30]. Herein we discuss the pathogenesis of NAFLD and NASH, and the potential of probiotics, prebiotics, biogenics for treatment.

2. Relationship between Hepatic Immune Cells and the Pathogenesis of NAFLD and NASH

Innate immune responses of NAFLD and NASH involve resident Kupffer cells, recruited macrophages derived from bone marrow cells, neutrophils, and natural killer T cells. These cells contribute to the progression of NASH by inducing inflammation, by promoting the production of cytokines, chemokines, eicosanoids, nitric oxide, and ROS. In addition, excessive free fatty acids (FFAs) and cholesterol cause hepatic lipotoxicity and stimulate macrophage activation, and production of proinflammatory cytokines [31]. Palmitate in serum FFAs showed elevation in patients with NASH [32]. Increased levels of palmitic acid and its metabolites, such as phospholipids, diacylglycerol and ceramides, activate LPS-mediated Toll-like receptor (TLR) 4, PKCs, and ER stress and increase ROS production by inducing mitochondrial dysfunction. ER stress and ROS activate the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome and NF-κB and increase production of proinflammatory cytokines and chemokines [33]. Moreover, C-C motif chemokine 2 (CCL2, also known as MCP-1), IL-1β, IL-18, and TNF-α recruit bone marrow-derived macrophages to activated hepatic stellate cells and cause damage to the liver. This section is focused on macrophage/Kupffer cells and chemokines, which play an important role in the progression from NAFLD to NASH.

2.1. Macrophages and Kupffer Cellsn

Liver macrophages comprise several populations and play a key role in liver immune homeostasis and the pathogenesis of liver disease [34]. Kupffer cells originate from the fetal yolk sack and form a self-renewing pool of organ-resident macrophages, independent of myeloid monocytic cells [35]. Macrophages recruited during inflammation are differentiated from circulating monocytes derived from bone marrow cells [36]. Although the populations of macrophages and their transcriptional controls are adequately characterized in mice, the distinction between macrophage subsets in humans is unclear [37,38,39,40].
Kupffer cells and recruited macrophages regulate liver immune homeostasis and the development of liver diseases. Kupffer cells recruit additional immune cells, including neutrophils and lymphocyte antigen 6C-high (Ly6Chi) inflammatory blood monocytes. The latter differentiate to CD11b+F4/80+ inflammatory macrophages (M1-type), which have phagocytic activity and secrete proinflammatory cytokines, such as TNF-α, IL-6, and IL-1β, and ROS [41,42]. Kupffer cell activation contributes to initial hepatic lipid deposition and liver injury [10]. M1/Kupffer cell-type macrophages secrete inflammatory mediators, such as TNF-α, interleukin (IL)-1β, and IL-6, leading to systemic insulin resistance and NASH [43]. M1 macrophages are stimulated by Toll-like receptor (TLR) ligands, such as lipopolysaccharide (LPS) and interferon-gamma (IFN-γ). By contrast, alternative activation of LY6ClowF4/80+ macrophages (M2-type) with an immunosuppressive, pro-fibrogenic phenotype is observed in the reparative phase of NAFLD and NASH. M2-type macrophages secrete high levels of IL-13 and transforming growth factor-β1 (TGFβ1), resulting in progressive fibrosis [44,45,46]. M2 macrophages ameliorate alcoholic fatty liver disease and NAFLD by inducing apoptosis of M1 macrophages [23]. Therefore, the pathology of NAFLD is associated with dynamic changes in macrophage polarization—M1 macrophages initiate and sustain inflammation and M2 macrophages attenuate chronic inflammation [23,24].

2.2. Chemokines and Monocytes

Chemokines recruit and activate monocytes and are important in the progression of chronic inflammation in obesity, which underlies adipose tissue inflammation, insulin resistance, and NAFLD [47]. Chemokines, such as C-C motif ligand (CCL) 2, are produced by KCs and recruited macrophages. CCL2 binds to C-chemokine receptor (CCR), and the resulting CCL2-CCR2 complex induces the recruitment of macrophages into adipose tissue and the liver, leading to hepatic steatosis and insulin resistance in obese patients [48,49]. However, CCL2 deficiency does not affect macrophage infiltration or insulin sensitivity, suggesting that CCL2-CCR2 signaling is not critical for obesity-induced macrophage recruitment or systemic insulin resistance [50,51]. Instead, other chemokines involved in obesity may contribute to macrophage recruitment and insulin resistance. CCR5 deficiency attenuates insulin resistance and hepatic fatty acid accumulation by modulating macrophage recruitment and M1/M2 polarization [52].
There are two major subsets of murine monocytes: differentiation into M1 or M2 macrophages, which is important in the pathogenesis of NAFLD and NASH. These subsets of monocytes are distinguished by expression of CCR2 and CX3C chemokine receptor 1 (CX3CR1) and include CCR2 + Ly6Chi and CX3CR1 + Ly6C- monocytes. Under inflammatory conditions, CCR2 + Ly6Chi monocytes transmigrate and differentiate into M1 macrophages. In steady state, CX3CR1 + Ly6C- monocytes differentiate into anti-inflammatory M2 macrophages and mediate tissue repair [53]. In high-fat (HF) diet-induced obese mice, which exhibit NAFLD features, adipose tissue shows significantly increased macrophage infiltration, inflammation, and tissue remodeling. Furthermore, CCR2 + Ly6Chigh monocytes are recruited to adipose tissue and differentiate into M1 macrophages. CX3CR1 + Ly6C- monocytes accumulate in adipose tissue and are classified as M2 macrophages [54]. DIO mice show increased M1 macrophages and decreased M2 macrophages compared with lean mice, leading to a shift to an M1 dominant macrophage phenotype and inducing inflammation and insulin resistance [52]. Indeed, CCR2 deficiency reduced liver steatosis in DIO mice by suppressing the recruitment of CCR2 + Ly6Chigh monocytes [48,49]. Moreover, loss of CX3CR1 in DIO mice exacerbated insulin resistance, inflammation, and steatohepatitis by inducing a shift to M1 macrophages in adipose tissue [55]. On the other hand, another study using a different strain of Cx3cr1 deficient mice found no changes in obesity-induced inflammation, insulin resistance, and adipose macrophage accumulation, as compared with control mice [56]. The relationship between CX3CR1 expression in immune cells and pathogenesis differs among organs [57,58]. In liver inflammation and fibrosis induced by carbon tetrachloride and bile duct ligation, CX3CR1-deficient mice showed increased accumulation of inflammatory Ly6C+ monocytes [59]. Furthermore, CX3CR1 contributes to hepatic macrophage polarization and ameliorates steatohepatitis by controlling intestinal barrier function and dysbiosis [60]. CX3CR1 and CCR2 may independently regulate monocyte phenotype and macrophage polarization, and contribute to adipose tissue inflammation and insulin resistance, and the progression of NAFLD.

3. The Gut–Liver Axis in NAFLD and NASH

The increased prevalence of NAFLD may be linked to increased energy intake caused by dietary changes, such as increased intake of carbohydrate (flour and cereal products), fat, and fructose. Moreover, increased use of corn syrup or fructose as sweeteners and sucralose as a non-caloric artificial sweetener may affect the development of NAFLD [61,62,63]. These changes in diet may alter the gut microbiota, intestinal immune system, and intestinal barrier function, promoting metabolic endotoxemia and low-grade hepatic inflammation, thereby contributing to the development of NAFLD and NASH. Hepatic inflammation due to altered food habits may be attributed to changes in the intestinal environment. Understanding the relationship between diet and the gut–liver axis is important for treating and preventing NAFLD and NASH [64].

3.1. Intestinal Permeability and the Microbiota

The liver and gut are impacted by nutrients and the microbiome via the biliary tract, portal vein, and systemic mediators. Liver damage caused by disruption of the gut microbiome, its derived metabolites, and the gut immune system is implicated in the pathogenesis of obesity-induced insulin resistance and NAFLD. The liver is exposed to portal system products, such as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and is strongly influenced by diet-induced dysbiosis. PAMPs and DAMPs induce an inflammatory response in hepatocytes, Kupffer cells, and hepatic stellate cells (HSCs) by a Toll-like receptor (TLR) cascade, enhancing release of cytokines and chemokines (such as TNFα, IL-1, IL-6, IL-8, and IFN-γ), resulting in liver damage. Mice fed a HF or choline-deficient diet and patients with NAFLD have increased intestinal permeability [30,65,66], triggering a proinflammatory cascade that worsens hepatic inflammation by facilitating portal influx of microbiome-derived metabolites to the liver [66,67] (Figure 2). Intestinal permeability is regulated by epithelial tight junctions, which consist of several integral membrane proteins, such as zonula occludens (ZO), occludin, junctional adhesion molecule-A (JAM-A), and claudins [68]. Mice fed a HF diet exhibit decreased tight junction proteins and low-grade gut inflammation as a result of microbiome abnormalities. That is, the intestinal barrier and gut vascular barrier are impaired by HF diet-induced microbiome changes, promoting the portal influx of bacterial products, thereby worsening non-hepatic inflammation and metabolic abnormalities (Figure 1). Moreover, the altered microbiota disrupts the intestinal epithelial and vascular barriers by acquiring the ability to cross the intestinal epithelial barrier in mice fed a HF diet [30]. Whether the ability to cross the damaged intestinal epithelium is an active mechanism or a result of increased intestinal permeability caused by decreased expression of tight junction proteins is unknown.
Several clinical studies have suggested a link between the gut microbiota (such as small intestinal bacterial overgrowth and microbial dysbiosis) and the pathogenesis of NAFLD, but causality has not been established [69]. Shotgun metagenomic sequencing indicated an association between a microbiome signature characterized by increased abundance of Escherichia coli and Bacteroides vulgatus and advanced fibrosis in patients with NAFLD [70]. Escherichia abundance was higher in obese children with NASH compared to those with only obesity [71]. Moreover, Bacteroides and Ruminococcus were significantly increased, and Prevotella decreased, in patients with NASH (stage ≥ 2 fibrosis) compared to those without NASH, shown by 16S amplicon sequencing [72]. This finding is consistent with evidence that Bacteroides and Prevotella are competitors in the gut microbiota, depending on dietary composition [73].

3.2. Intestinal Immune System

Intestinal immune cells contribute to the establishment of the intestinal mucosal barrier. These cells are classified as intraepithelial and lamina propria cells. Intraepithelial cells include intestinal intraepithelial lymphocytes (IELs), encompassing several T cell receptor (TCR)-positive and -negative subsets. TCR+ and TCR− IELs exhibit different subtypes depending on the developmental conditions: TCR+ IELs are induced after antigens are encountered, natural TCRαβ+ IELs undergo thymic agonist selection, TCRγδ+ IELs differentiate either intrathymically or extrathymically, and the development of TCR− IELs is similar to that of peripheral innate lymphocytes [74,75]. IELs produce proinflammatory type I cytokines (IL-1β, IL-1α, IL-12, TNF-α, and GFAP), are cytolytic, and release antimicrobial peptides upon activation by intestinal epithelial cell-released cytokines or engaging activating natural killer (NK) cell receptors [75]. IELs and intraepithelial mononuclear phagocytes fight infection and induce tolerance to food and microbial antigens. In the lamina propria (LP), immune cells act as a second line of defense and promote regeneration of damaged tissue. The immune cell population of the LP includes T lymphocytes (mostly CD4+), NK T lymphocytes, dendritic cells, macrophages, ILCs, IgA+ plasma cells, IgG+ and IgM+ plasma cells, and B lymphocytes [76,77]. CD4+ T cells in the LP comprised primarily T helper (Th) 17 cells and regulatory T (Treg) cells. Th17 cells release IL-17A, IL-17F, and IL-22, preventing bacterial dissemination by inducing the expression and secretion of antimicrobial peptides [78]. IL-17A maintained intestinal permeability by regulating the tight junction protein occludin in a dextran sulfate sodium injury model [79]. The reduced proportion of Th17 cells in the small intestine of obese mice induced weight gain and worsened glucose intolerance and insulin resistance [80]. By contrast, IL-17 promoted intestinal barrier dysfunction by disrupting tight junction structure and promoting bacterial dissemination in sepsis models [28]. Notably, the intestinal IL-17 level was elevated in mice with steatohepatitis, and the number of Th17 cells was increased among peripheral blood mononuclear cells in patients with NASH [29,81]. Intestinal Th17 cells migrate to the liver and secrete IL-17 to stimulate monocytes, Kupffer cells, biliary epithelial cells, and stellate cells, and to secrete proinflammatory cytokines and chemokines, triggering inflammation in the liver [82]. The effect of IL-17 in the intestinal tract may differ depending on the disease and is an important therapeutic target for NAFLD and NASH.

4. Treatment of NAFLD and NASH with Probiotics, Prebiotics, and Biogenics

Many pharmacotherapeutic strategies have been used for NASH, which can progress to cirrhosis. Insulin sensitizers, such as metformin or pioglitazone, have been studied for the treatment of NASH. In addition, vitamin E, a food ingredient with antioxidant properties, has also been studied for its therapeutic effect on NASH [83,84]. In the TONIC trial (metformin and vitamin E) and the PIVENS trial (pioglitazone and vitamin E), metformin, pioglitazone, and vitamin E improved steatosis and inflammation but not fibrosis. However, pioglitazone led to significant weight gain [85,86]. Clinical and animal studies have evaluated the therapeutic effects on NAFLD and NASH of probiotics, prebiotics and biogenics. These have been shown to ameliorate NAFLD and NASH, but there are issues in developing methods for evaluating clinical studies and appropriate biomarkers for prognosis and diagnosis.

4.1. Lactic Fermentation and Control of Gut Microbiome

Studies have investigated the ability of functional foods, such as lactic acid bacteria, to improve the gut microbiome in NASH and NAFLD. Functional foods are classified as probiotics, prebiotics, and biogenics based on their mechanisms of action [87]. Probiotics were defined as “live microorganisms, which when administered in adequate amounts, confer a health benefit on the host” by the 2001 World Health Organization/Food and Agriculture Organization (WHO/FAO) expert consultation. Probiotics positively alter the intestinal microbiota and immune system. Probiotics must promote survival and exert an immunomodulatory effect in the gastrointestinal tract, inhibit pathogenic bacteria, be safe, and not have antibiotic resistance genes [88]. Microorganisms used as probiotics include Lactobacillus, Streptococcus, Lactococcus, Enterococcus, Bifidobacterium, Bacillus, and Clostridium. These probiotics promote an anti-inflammatory environment and intestinal epithelial growth and survival and counteract pathogenic bacteria by modulating immunity. Prebiotics were defined by Gibson et al. in 1995 as, “A non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, and thus improves host health” [89].
Prebiotics include oligosaccharides and dietary fibers. Oligosaccharides encompass fructooligosaccharides and galactoses, such as lactulose, which have highly selective availability to bifidobacteria and promote their growth. The term “synbiotic” refers to a combination of probiotics and prebiotics, as defined by Gibson et al.
Biogenics was proposed by Mitsuoka et al., and applies to food ingredients that contain biologically active peptides and immunopotentiators (biological response modifiers) produced directly or indirectly by modulation of the intestinal microflora [90]. Biogenics encompass various biologically active peptides, plant polyphenols, docosahexaenoic acid, eicosapentaenoic acid, vitamins, and other food components related to biological regulation, biological defense, disease prevention, functional recovery, and aging control. Heat-inactivated probiotic bacteria are also considered biogenics. Probiotics or biogenics are taken up by M cells in Peyer’s patches and transferred to subepithelial dendritic cells, reducing the expression of proinflammatory cytokines in mice [91].

4.2. Therapeutic Effects of Probiotics, Prebiotics, and Biogenics on NAFLD and NASH

Several animal model studies and clinical trials have reported evidence of benefits. For example, VSL#3 and modified VSL#3 are a mixture of several probiotic bacteria of the genera Lactobacillus, Bifidobacterium, and Streptococcus, or Lactobacillus alone. VSL#3 protected against insulin resistance and NAFLD by inhibiting inflammatory signaling, such as c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) and restoring the reduced number of hepatic natural killer T cells caused by a HF diet [92,93]. By contrast, VSL#3 did not affect methionine-choline-supplemented (MCS) diet-induced hepatic steatosis or inflammation but ameliorated hepatic fibrosis by negatively regulating TGF-β signaling in mice [94]. Other animal model studies showed that probiotics improved the gut microbiota composition and maintained tight junctions, restoring the intestinal mucosal barrier and suppressing serum LPS levels. Liver inflammatory markers (e.g., ALT, AST, hepatic TG, and proinflammatory cytokines) were reduced by a decrease in serum LPS and liver TLR4 mRNA levels [95,96]. Lactobacillus plantarum NA136 isolated from fermented food suppressed the body weight gain and decreased the mass of fat tissues of HF diet and fructose-fed mice (NAFLD model).; lipids, AST, and ALT levels were also reduced L. plantarum NA136 decreased de novo lipogenesis and increased fatty acid oxidation by activating the AMPK pathway to phosphorylate ACC and suppress SREBP-1/FAS signaling in a NASH model. Furthermore, L. plantarum NA136 reduced oxidative stress in the liver by activating the AMPK/NF-E2-related factor 2 (Nrf2) pathway in a NAFLD model. These effects resulted in L. plantarum NA136 attenuating NAFLD [97]. Moreover, Lactobacillus paracasei decreased the expression of TLR-4, CCL2 and TNF-α and attenuated hepatic steatosis. L. paracasei decreased the proportion of M1 Kupffer cells and increased that of M2, leading to M2-dominant shift in the liver of a NASH animal model [98]. The effect of an aqueous probiotic suspension (SymproveTM, containing Lactobacillus acidophilus NCIMB 30175, Lactobacillus plantarum NCIMB 30173, Lactobacillus rhamnosus NCIMB 30174, and Enterococcus faecium NCIMB 30176) on the composition of human intestinal microbiota was studied using the M-SHIME® system on an in vitro human intestinal model. Three probiotics showed colonization and growth in the luminal and mucosal compartments of the proximal and distal colon, and growth in the luminal proximal colon. This increased the proximal and distal colonic lactate concentrations. Lactate stimulated growth of lactate-consuming bacteria, resulting in increased short-chain fatty acid (SCFA) production, especially butyrate. Additionally, the probiotics exerted immunomodulatory effects, such as increased production of anti-inflammatory cytokines (IL-10 and IL-6) and decreased production of proinflammatory chemokines (IL-8, CXCL 10 and MCP-1) [99]. A meta-analysis of the effects of probiotics on patients with NAFLD/NASH showed improved serum levels of liver aminotransferases, total cholesterol, and TNF-α, and amelioration of insulin resistance. However, the data are difficult to reconcile, given use of different probiotic strains and dosages, treatment durations, and outcome indices [100].
Prebiotics may have a beneficial effect on NAFLD and NASH. In animal models, prebiotics altered the gut microbiota composition and increased the plasma glucagon-like peptide-2 (GLP-2) level, improving gut barrier function. Moreover, prebiotics reduced liver inflammation and improved metabolic disorders in obesity and diabetes [101]. Furthermore, prebiotics including inulin and oligofructose controlled the growth of Faecalibacterium prausnitzii and Bifidobacterium and reduced the plasma endotoxin level by increasing GLP-1 secretion as well as the GLP-2 trophic effect on gut barrier integrity [102]. In humans, oligofructose supplementation improved glucose tolerance and promoted weight loss by regulating the expression of hormones involved in energy intake, such as ghrelin and peptide YY, in obesity [103]. Moreover, a meta-analysis of probiotic, prebiotic, and synbiotic therapies for NAFLD showed significantly reduced BMI, ALT, and AST. Synbiotics, but not prebiotics or probiotics, did not decrease serum lipids [104].
Heat-killed lactic acid bacteria in biogenics, which are easier to handle compared with live lactic acid bacteria, have been used in studies of NAFLD and NASH. Heat-killed Lactobacillus reuteri GMNL-263 (Lr263) reduced fibrosis in the liver and heart by TGF-β suppression in HF diet-fed mice [105]. Similarly, live Lr263 improved inflammation, insulin resistance and hepatic steatosis in high fructose-fed rats [106]. Moreover, heat-killed Lactobacillus plantarum L-137 (HK L-137), which is isolated from fermented fish and rice dishes, attenuated adipose tissue and hepatic inflammation in DahlS. Z-Leprfa/Leprfa rats as a model of metabolic syndrome [107]. Live and heat-killed Lactobacillus pentosus strain S-PT84, isolated from Kyoto pickles (shibazuke), reportedly enhances splenic natural killer activity and interferon-γ production in mice [108,109]. Heat-killed S-PT84 partially restored expression of ZO-1, occludin, and xlaudin-3 but did not restore the alteration the microbiota profile in a NASH model. Heat-killed S-PT84 suppressed metabolic endotoxemia by maintaining the gut barrier and intestinal permeability and suppressing IL-17-producing T (Th17) cell accumulation in the intestinal LP. By contrast, heat-killed S-PT84 had no effect on the abundance of NKT cells in the liver. However, heat-killed S-PT84 attenuated hepatic inflammation and fibrosis by decreasing the M1/M2 macrophage ratio in the liver. These results indicated that heat-killed S-PT84 attenuated lipotoxicity-induced hepatic insulin resistance and steatohepatitis in a NASH animal model [110]. By contrast, live Lactobacillus pentosaceus LP28 (LP28), isolated from longan fruit (Euphoria longana), showed reduced body weight gain, liver triglyceride and cholesterol in HF diet-fed mice. However, heat-killed LP28 did not prevent metabolic syndrome [111]. Heat-killed lactic acid bacteria as biogenics can also improve NAFLD and NASH, as do some live lactic acid bacteria. However, heat-killed lactic acid bacteria will continue to be investigated in clinical and animal studies because of their immunomodulatory effects, long shelf-life, and ease of storage and transportation.
Probiotic, prebiotic, and biogenic treatment of NAFLD and NASH is new and under development, and these agents regulate the gut microbiota and immunity. By contrast, probiotics do not regulate the intestinal environment or improve the symptoms of acute pancreatitis or Crohn’s disease. For instance, administration of Lactobacillus plantarum 299 v for at least 1 week preoperatively during the postoperative period in elective surgical patients did not influence bacterial translocation, gastric colonization, or the incidence of postoperative septic morbidity [112,113]. A meta-analysis of six randomized controlled trials involving 536 adults with severe acute pancreatitis showed that probiotics compared with the control did not significantly affect the pancreatic infection rate, total number of infections, operation rate, hospital length of stay, or mortality [114,115]. However, the probiotics did not exacerbate these diseases, and so safety concerns are unlikely. Probiotics, prebiotics and biogenics have been shown to be effective but not curative for NAFLD and NASH. Furthermore, the active components and molecular mechanisms of the therapeutic effects of probiotics, prebiotics and biogenics are unclear, and further studies are needed.

5. Conclusions

NAFLD is a common chronic liver disease worldwide, and its prevalence is increasing. Moreover, its association with obesity, type 2 diabetes mellitus, insulin resistance, metabolic syndrome, and progression to cirrhosis and hepatic carcinoma increase its clinical importance. The pathogenesis of NASH and NAFLD is complex, involving not only the hepatic immune system (monocyte or macrophage polarization) mechanisms but also adipokines produced by adipose tissue, and microbiome. Moreover, an altered gut microbiota composition and intestinal immunity are related to liver disease and are important in progression from NAFLD to NASH. In human and animal studies of NAFLD and NASH, probiotics, prebiotics and biogenics reduced serum levels of liver aminotransferases, inflammatory cytokines, and chemokines, and ameliorated insulin resistance and hepatic steatosis (Figure 3). Probiotics, prebiotics, and biogenics ameliorate NAFLD and NASH by regulating the intestinal environment and immunity; therefore, their efficiency is based on the gut–liver axis. Although probiotics, prebiotics, and biogenics are considered safe, their safety should continue to be evaluated. Additionally, future human studies of treatments for NAFLD and NASH should involve standardized probiotic strains and dosages, treatment durations, and outcome indications, as well as make use of advanced techniques, such as omics technologies. Further studies of the efficacy, safety, and molecular mechanisms of probiotics, prebiotics and biogenics in NAFLD and NASH are needed.

Author Contributions

M.N. wrote this manuscript. All authors contributed to the preparation of this review and approved the text. All authors have read and agreed to the published version of the manuscript.

Funding

This research was partially supported by the Japan Agency for Medical Research and Development under grant numbers JP20fk0210073, JP20fk0210049 and JSPS KAKENHI Grant Numbers 21H04823.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Tilg, H.; Moschen, A.R.; Roden, M. NAFLD and diabetes mellitus. Nat. Rev. Gastroenterol. Hepatol. 2017, 14, 32–42. [Google Scholar] [CrossRef]
  2. Italian Association for the Study of the Liver (AISF). AISF position paper on nonalcoholic fatty liver disease (NAFLD): Updates and future directions. Dig. Liver Dis. 2017, 49, 471–483. [Google Scholar] [CrossRef]
  3. Sheka, A.C.; Adeyi, O.; Thompson, J.; Hameed, B.; Crawford, P.A.; Ikramuddin, S. Nonalcoholic Steatohepatitis: A Review. JAMA 2020, 323, 1175–1183. [Google Scholar] [CrossRef]
  4. Benedict, M.; Zhang, X. Non-alcoholic fatty liver disease: An expanded review. World J. Hepatol. 2017, 9, 715–732. [Google Scholar] [CrossRef]
  5. Younossi, Z.M.; Loomba, R.; Anstee, Q.M.; Rinella, M.E.; Bugianesi, E.; Marchesini, G.; Neuschwander-Tetri, B.A.; Serfaty, L.; Negro, F.; Caldwell, S.H.; et al. Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis. Hepatology 2018, 68, 349–360. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Marchesini, G.; Brizi, M.; Bianchi, G.; Tomassetti, S.; Bugianesi, E.; Lenzi, M.; McCullough, A.J.; Natale, S.; Forlani, G.; Melchionda, N. Nonalcoholic fatty liver disease: A feature of the metabolic syndrome. Diabetes 2001, 50, 1844–1850. [Google Scholar] [CrossRef] [Green Version]
  7. Hebbard, L.; George, J. Animal models of nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 2011, 8, 35–44. [Google Scholar] [CrossRef]
  8. Matsumoto, M.; Hada, N.; Sakamaki, Y.; Uno, A.; Shiga, T.; Tanaka, C.; Ito, T.; Katsume, A.; Sudoh, M. An improved mouse model that rapidly develops fibrosis in non-alcoholic steatohepatitis. Int. J. Exp. Pathol. 2013, 94, 93–103. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Wada, T.; Kenmochi, H.; Miyashita, Y.; Sasaki, M.; Ojima, M.; Sasahara, M.; Koya, D.; Tsuneki, H.; Sasaoka, T. Spironolactone improves glucose and lipid metabolism by ameliorating hepatic steatosis and inflammation and suppressing enhanced gluconeogenesis induced by high-fat and high-fructose diet. Endocrinology 2010, 151, 2040–2049. [Google Scholar] [CrossRef] [Green Version]
  10. Matsuzawa, N.; Takamura, T.; Kurita, S.; Misu, H.; Ota, T.; Ando, H.; Yokoyama, M.; Honda, M.; Zen, Y.; Nakanuma, Y.; et al. Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology 2007, 46, 1392–1403. [Google Scholar] [CrossRef] [PubMed]
  11. Kwok, R.; Choi, K.C.; Wong, G.L.; Zhang, Y.; Chan, H.L.; Luk, A.O.; Shu, S.S.; Chan, A.W.; Yeung, M.W.; Chan, J.C.; et al. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: A prospective cohort study. Gut 2016, 65, 1359–1368. [Google Scholar] [CrossRef] [PubMed]
  12. 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. [Google Scholar] [CrossRef] [Green Version]
  13. Williams, C.D.; Stengel, J.; Asike, M.I.; Torres, D.M.; Shaw, J.; Contreras, M.; Landt, C.L.; Harrison, S.A. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: A prospective study. Gastroenterology 2011, 140, 124–131. [Google Scholar] [CrossRef]
  14. Loomba, R.; Abraham, M.; Unalp, A.; Wilson, L.; Lavine, J.; Doo, E.; Bass, N.M. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 2012, 56, 943–951. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Lonardo, A.; Nascimbeni, F.; Mantovani, A.; Targher, G. Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence? J. Hepatol. 2018, 68, 335–352. [Google Scholar] [CrossRef]
  16. Ota, T.; Takamura, T.; Kurita, S.; Matsuzawa, N.; Kita, Y.; Uno, M.; Akahori, H.; Misu, H.; Sakurai, M.; Zen, Y.; et al. Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. Gastroenterology 2007, 132, 282–293. [Google Scholar] [CrossRef]
  17. Takaki, A.; Kawai, D.; Yamamoto, K. Multiple hits, including oxidative stress, as pathogenesis and treatment target in non-alcoholic steatohepatitis (NASH). Int. J. Mol. Sci. 2013, 14, 20704–20728. [Google Scholar] [CrossRef] [Green Version]
  18. Konig, J.; Wells, J.; Cani, P.D.; Garcia-Rodenas, C.L.; MacDonald, T.; Mercenier, A.; Whyte, J.; Troost, F.; Brummer, R.J. Human Intestinal Barrier Function in Health and Disease. Clin. Transl. Gastroenterol. 2016, 7, e196. [Google Scholar] [CrossRef]
  19. Parthasarathy, G.; Revelo, X.; Malhi, H. Pathogenesis of Nonalcoholic Steatohepatitis: An Overview. Hepatol. Commun. 2020, 4, 478–492. [Google Scholar] [CrossRef] [Green Version]
  20. Wang, H.; Mehal, W.; Nagy, L.E.; Rotman, Y. Immunological mechanisms and therapeutic targets of fatty liver diseases. Cell. Mol. Immunol. 2021, 18, 73–91. [Google Scholar] [CrossRef]
  21. Ortiz, M.; Soto-Alarcon, S.A.; Orellana, P.; Espinosa, A.; Campos, C.; Lopez-Arana, S.; Rincon, M.A.; Illesca, P.; Valenzuela, R.; Videla, L.A. Suppression of high-fat diet-induced obesity-associated liver mitochondrial dysfunction by docosahexaenoic acid and hydroxytyrosol co-administration. Dig. Liver Dis. 2020, 52, 895–904. [Google Scholar] [CrossRef]
  22. Sica, A.; Mantovani, A. Macrophage plasticity and polarization: In vivo veritas. J. Clin. Investig. 2012, 122, 787–795. [Google Scholar] [CrossRef] [PubMed]
  23. Wan, J.; Benkdane, M.; Teixeira-Clerc, F.; Bonnafous, S.; Louvet, A.; Lafdil, F.; Pecker, F.; Tran, A.; Gual, P.; Mallat, A.; et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: A protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 2014, 59, 130–142. [Google Scholar] [CrossRef] [PubMed]
  24. Xue, J.; Sharma, V.; Hsieh, M.H.; Chawla, A.; Murali, R.; Pandol, S.J.; Habtezion, A. Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis. Nat. Commun. 2015, 6, 7158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Valenzuela, R.; Illesca, P.; Echeverria, F.; Espinosa, A.; Rincon-Cervera, M.A.; Ortiz, M.; Hernandez-Rodas, M.C.; Valenzuela, A.; Videla, L.A. Molecular adaptations underlying the beneficial effects of hydroxytyrosol in the pathogenic alterations induced by a high-fat diet in mouse liver: PPAR-alpha and Nrf2 activation, and NF-kappaB down-regulation. Food Funct. 2017, 8, 1526–1537. [Google Scholar] [CrossRef]
  26. Paradies, G.; Paradies, V.; Ruggiero, F.M.; Petrosillo, G. Oxidative stress, cardiolipin and mitochondrial dysfunction in nonalcoholic fatty liver disease. World J. Gastroenterol. WJG 2014, 20, 14205–14218. [Google Scholar] [CrossRef]
  27. Suzuki, T.; Hara, H. Dietary fat and bile juice, but not obesity, are responsible for the increase in small intestinal permeability induced through the suppression of tight junction protein expression in LETO and OLETF rats. Nutr. Metab. 2010, 7, 19. [Google Scholar] [CrossRef] [Green Version]
  28. Meng, J.; Banerjee, S.; Li, D.; Sindberg, G.M.; Wang, F.; Ma, J.; Roy, S. Opioid Exacerbation of Gram-positive sepsis, induced by Gut Microbial Modulation, is Rescued by IL-17A Neutralization. Sci. Rep. 2015, 5, 10918. [Google Scholar] [CrossRef] [Green Version]
  29. Zhou, D.; Pan, Q.; Liu, X.L.; Yang, R.X.; Chen, Y.W.; Liu, C.; Fan, J.G. Clostridium butyricum B1 alleviates high-fat diet-induced steatohepatitis in mice via enterohepatic immunoregulation. J. Gastroenterol. Hepatol. 2017, 32, 1640–1648. [Google Scholar] [CrossRef]
  30. Mouries, J.; Brescia, P.; Silvestri, A.; Spadoni, I.; Sorribas, M.; Wiest, R.; Mileti, E.; Galbiati, M.; Invernizzi, P.; Adorini, L.; et al. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. J. Hepatol. 2019, 71, 1216–1228. [Google Scholar] [CrossRef] [Green Version]
  31. Sutti, S.; Albano, E. Adaptive immunity: An emerging player in the progression of NAFLD. Nat. Rev. Gastroenterol. Hepatol. 2020, 17, 81–92. [Google Scholar] [CrossRef]
  32. Echeverria, F.; Valenzuela, R.; Espinosa, A.; Bustamante, A.; Alvarez, D.; Gonzalez-Manan, D.; Ortiz, M.; Soto-Alarcon, S.A.; Videla, L.A. Reduction of high-fat diet-induced liver proinflammatory state by eicosapentaenoic acid plus hydroxytyrosol supplementation: Involvement of resolvins RvE1/2 and RvD1/2. J. Nutr. Biochem. 2019, 63, 35–43. [Google Scholar] [CrossRef]
  33. Korbecki, J.; Bajdak-Rusinek, K. The effect of palmitic acid on inflammatory response in macrophages: An overview of molecular mechanisms. Inflamm. Res. Off. J. Eur. Histamine Res. Soc. 2019, 68, 915–932. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Kazankov, K.; Jorgensen, S.M.D.; Thomsen, K.L.; Moller, H.J.; Vilstrup, H.; George, J.; Schuppan, D.; Gronbaek, H. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 145–159. [Google Scholar] [CrossRef]
  35. Gomez Perdiguero, E.; Klapproth, K.; Schulz, C.; Busch, K.; Azzoni, E.; Crozet, L.; Garner, H.; Trouillet, C.; de Bruijn, M.F.; Geissmann, F.; et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 2015, 518, 547–551. [Google Scholar] [CrossRef]
  36. Krenkel, O.; Tacke, F. Liver macrophages in tissue homeostasis and disease. Nat. Rev. Immunol. 2017, 17, 306–321. [Google Scholar] [CrossRef]
  37. Mass, E.; Ballesteros, I.; Farlik, M.; Halbritter, F.; Gunther, P.; Crozet, L.; Jacome-Galarza, C.E.; Handler, K.; Klughammer, J.; Kobayashi, Y.; et al. Specification of tissue-resident macrophages during organogenesis. Science 2016, 353, aaf4238. [Google Scholar] [CrossRef] [Green Version]
  38. Scott, C.L.; Zheng, F.; De Baetselier, P.; Martens, L.; Saeys, Y.; De Prijck, S.; Lippens, S.; Abels, C.; Schoonooghe, S.; Raes, G.; et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 2016, 7, 10321. [Google Scholar] [CrossRef]
  39. Ni, Y.; Zhuge, F.; Nagashimada, M.; Ota, T. Novel Action of Carotenoids on Non-Alcoholic Fatty Liver Disease: Macrophage Polarization and Liver Homeostasis. Nutrients 2016, 8, 391. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  40. Heymann, F.; Tacke, F. Immunology in the liver--from homeostasis to disease. Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 88–110. [Google Scholar] [CrossRef] [PubMed]
  41. Ramachandran, P.; Pellicoro, A.; Vernon, M.A.; Boulter, L.; Aucott, R.L.; Ali, A.; Hartland, S.N.; Snowdon, V.K.; Cappon, A.; Gordon-Walker, T.T.; et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc. Natl. Acad. Sci. USA 2012, 109, E3186–E3195. [Google Scholar] [CrossRef] [Green Version]
  42. Jager, J.; Aparicio-Vergara, M.; Aouadi, M. Liver innate immune cells and insulin resistance: The multiple facets of Kupffer cells. J. Intern. Med. 2016, 280, 209–220. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Odegaard, J.I.; Ricardo-Gonzalez, R.R.; Red Eagle, A.; Vats, D.; Morel, C.R.; Goforth, M.H.; Subramanian, V.; Mukundan, L.; Ferrante, A.W.; Chawla, A. Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab. 2008, 7, 496–507. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Gordon, S.; Martinez, F.O. Alternative activation of macrophages: Mechanism and functions. Immunity 2010, 32, 593–604. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Murray, P.J.; Allen, J.E.; Biswas, S.K.; Fisher, E.A.; Gilroy, D.W.; Goerdt, S.; Gordon, S.; Hamilton, J.A.; Ivashkiv, L.B.; Lawrence, T.; et al. Macrophage activation and polarization: Nomenclature and experimental guidelines. Immunity 2014, 41, 14–20. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Martinez, F.O.; Gordon, S. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000prime Rep. 2014, 6, 13. [Google Scholar] [CrossRef] [Green Version]
  47. Sica, A.; Invernizzi, P.; Mantovani, A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology 2014, 59, 2034–2042. [Google Scholar] [CrossRef] [PubMed]
  48. Kanda, H.; Tateya, S.; Tamori, Y.; Kotani, K.; Hiasa, K.; Kitazawa, R.; Kitazawa, S.; Miyachi, H.; Maeda, S.; Egashira, K.; et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Investig. 2006, 116, 1494–1505. [Google Scholar] [CrossRef]
  49. Obstfeld, A.E.; Sugaru, E.; Thearle, M.; Francisco, A.M.; Gayet, C.; Ginsberg, H.N.; Ables, E.V.; Ferrante, A.W., Jr. C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis. Diabetes 2010, 59, 916–925. [Google Scholar] [CrossRef] [Green Version]
  50. Inouye, K.E.; Shi, H.; Howard, J.K.; Daly, C.H.; Lord, G.M.; Rollins, B.J.; Flier, J.S. Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes 2007, 56, 2242–2250. [Google Scholar] [CrossRef] [Green Version]
  51. Kirk, E.A.; Sagawa, Z.K.; McDonald, T.O.; O’Brien, K.D.; Heinecke, J.W. Monocyte chemoattractant protein deficiency fails to restrain macrophage infiltration into adipose tissue [corrected]. Diabetes 2008, 57, 1254–1261. [Google Scholar] [CrossRef] [Green Version]
  52. Kitade, H.; Sawamoto, K.; Nagashimada, M.; Inoue, H.; Yamamoto, Y.; Sai, Y.; Takamura, T.; Yamamoto, H.; Miyamoto, K.; Ginsberg, H.N.; et al. CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes 2012, 61, 1680–1690. [Google Scholar] [CrossRef] [Green Version]
  53. Yang, J.; Zhang, L.; Yu, C.; Yang, X.F.; Wang, H. Monocyte and macrophage differentiation: Circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark. Res. 2014, 2, 1. [Google Scholar] [CrossRef] [Green Version]
  54. Lumeng, C.N.; DelProposto, J.B.; Westcott, D.J.; Saltiel, A.R. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 2008, 57, 3239–3246. [Google Scholar] [CrossRef] [Green Version]
  55. Nagashimada, M.; Sawamoto, K.; Ni, Y.; Kitade, H.; Nagata, N.; Xu, L.; Kobori, M.; Mukaida, N.; Yamashita, T.; Kaneko, S.; et al. CX3CL1-CX3CR1 signalling deficiency exacerbates obesity-induced inflammation and insulin resistance in male mice. Endocrinology 2021, 162, bqab064. [Google Scholar] [CrossRef] [PubMed]
  56. Morris, D.L.; Oatmen, K.E.; Wang, T.; DelProposto, J.L.; Lumeng, C.N. CX3CR1 deficiency does not influence trafficking of adipose tissue macrophages in mice with diet-induced obesity. Obesity 2012, 20, 1189–1199. [Google Scholar] [CrossRef] [Green Version]
  57. Lee, M.; Lee, Y.; Song, J.; Lee, J.; Chang, S.Y. Tissue-specific Role of CX3CR1 Expressing Immune Cells and Their Relationships with Human Disease. Immune Netw. 2018, 18, e5. [Google Scholar] [CrossRef]
  58. Ni, Y.; Ni, L.; Zhuge, F.; Xu, L.; Fu, Z.; Ota, T. Adipose Tissue Macrophage Phenotypes and Characteristics: The Key to Insulin Resistance in Obesity and Metabolic Disorders. Obesity 2020, 28, 225–234. [Google Scholar] [CrossRef]
  59. Karlmark, K.R.; Zimmermann, H.W.; Roderburg, C.; Gassler, N.; Wasmuth, H.E.; Luedde, T.; Trautwein, C.; Tacke, F. The fractalkine receptor CX3CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. Hepatology 2010, 52, 1769–1782. [Google Scholar] [CrossRef]
  60. Schneider, K.M.; Bieghs, V.; Heymann, F.; Hu, W.; Dreymueller, D.; Liao, L.; Frissen, M.; Ludwig, A.; Gassler, N.; Pabst, O.; et al. CX3CR1 is a gatekeeper for intestinal barrier integrity in mice: Limiting steatohepatitis by maintaining intestinal homeostasis. Hepatology 2015, 62, 1405–1416. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  61. Tappy, L.; Le, K.A.; Tran, C.; Paquot, N. Fructose and metabolic diseases: New findings, new questions. Nutrition 2010, 26, 1044–1049. [Google Scholar] [CrossRef]
  62. Abid, A.; Taha, O.; Nseir, W.; Farah, R.; Grosovski, M.; Assy, N. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J. Hepatol. 2009, 51, 918–924. [Google Scholar] [CrossRef]
  63. Hernandez-Rodas, M.C.; Valenzuela, R.; Videla, L.A. Relevant Aspects of Nutritional and Dietary Interventions in Non-Alcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2015, 16, 25168–25198. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Kirpich, I.A.; Marsano, L.S.; McClain, C.J. Gut-liver axis, nutrition, and non-alcoholic fatty liver disease. Clin. Biochem. 2015, 48, 923–930. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Miele, L.; Valenza, V.; La Torre, G.; Montalto, M.; Cammarota, G.; Ricci, R.; Masciana, R.; Forgione, A.; Gabrieli, M.L.; Perotti, G.; et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009, 49, 1877–1887. [Google Scholar] [CrossRef] [PubMed]
  66. Albillos, A.; de Gottardi, A.; Rescigno, M. The gut-liver axis in liver disease: Pathophysiological basis for therapy. J. Hepatol. 2020, 72, 558–577. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Tilg, H.; Moschen, A.R.; Szabo, G. Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 2016, 64, 955–965. [Google Scholar] [CrossRef]
  68. Gonzalez-Mariscal, L.; Betanzos, A.; Nava, P.; Jaramillo, B.E. Tight junction proteins. Prog. Biophys. Mol. Biol. 2003, 81, 1–44. [Google Scholar] [CrossRef]
  69. Wieland, A.; Frank, D.N.; Harnke, B.; Bambha, K. Systematic review: Microbial dysbiosis and nonalcoholic fatty liver disease. Aliment. Pharmacol. Ther. 2015, 42, 1051–1063. [Google Scholar] [CrossRef]
  70. Loomba, R.; Seguritan, V.; Li, W.; Long, T.; Klitgord, N.; Bhatt, A.; Dulai, P.S.; Caussy, C.; Bettencourt, R.; Highlander, S.K.; et al. Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab. 2017, 25, 1054–1062.e5. [Google Scholar] [CrossRef] [PubMed]
  71. Zhu, L.; Baker, S.S.; Gill, C.; Liu, W.; Alkhouri, R.; Baker, R.D.; Gill, S.R. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: A connection between endogenous alcohol and NASH. Hepatology 2013, 57, 601–609. [Google Scholar] [CrossRef] [PubMed]
  72. Boursier, J.; Mueller, O.; Barret, M.; Machado, M.; Fizanne, L.; Araujo-Perez, F.; Guy, C.D.; Seed, P.C.; Rawls, J.F.; David, L.A.; 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, 764–775. [Google Scholar] [CrossRef] [Green Version]
  73. Gophna, U. Microbiology. The guts of dietary habits. Science 2011, 334, 45–46. [Google Scholar] [CrossRef]
  74. Olivares-Villagomez, D.; Van Kaer, L. Intestinal Intraepithelial Lymphocytes: Sentinels of the Mucosal Barrier. Trends Immunol. 2018, 39, 264–275. [Google Scholar] [CrossRef]
  75. McDonald, B.D.; Jabri, B.; Bendelac, A. Diverse developmental pathways of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 2018, 18, 514–525. [Google Scholar] [CrossRef]
  76. Middendorp, S.; Nieuwenhuis, E.E. NKT cells in mucosal immunity. Mucosal Immunol. 2009, 2, 393–402. [Google Scholar] [CrossRef] [Green Version]
  77. Wang, X.; Hao, G.L.; Wang, B.Y.; Gao, C.C.; Wang, Y.X.; Li, L.S.; Xu, J.D. Function and dysfunction of plasma cells in intestine. Cell Biosci. 2019, 9, 26. [Google Scholar] [CrossRef]
  78. Blaschitz, C.; Raffatellu, M. Th17 cytokines and the gut mucosal barrier. J. Clin. Immunol. 2010, 30, 196–203. [Google Scholar] [CrossRef] [Green Version]
  79. Lee, J.S.; Tato, C.M.; Joyce-Shaikh, B.; Gulen, M.F.; Cayatte, C.; Chen, Y.; Blumenschein, W.M.; Judo, M.; Ayanoglu, G.; McClanahan, T.K.; et al. Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability. Immunity 2015, 43, 727–738. [Google Scholar] [CrossRef] [Green Version]
  80. Hong, C.P.; Park, A.; Yang, B.G.; Yun, C.H.; Kwak, M.J.; Lee, G.W.; Kim, J.H.; Jang, M.S.; Lee, E.J.; Jeun, E.J.; et al. Gut-Specific Delivery of T-Helper 17 Cells Reduces Obesity and Insulin Resistance in Mice. Gastroenterology 2017, 152, 1998–2010. [Google Scholar] [CrossRef]
  81. Rau, M.; Schilling, A.K.; Meertens, J.; Hering, I.; Weiss, J.; Jurowich, C.; Kudlich, T.; Hermanns, H.M.; Bantel, H.; Beyersdorf, N.; et al. Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Is Marked by a Higher Frequency of Th17 Cells in the Liver and an Increased Th17/Resting Regulatory T Cell Ratio in Peripheral Blood and in the Liver. J. Immunol. 2016, 196, 97–105. [Google Scholar] [CrossRef]
  82. Saltzman, E.T.; Palacios, T.; Thomsen, M.; Vitetta, L. Intestinal Microbiome Shifts, Dysbiosis, Inflammation, and Non-alcoholic Fatty Liver Disease. Front. Microbiol. 2018, 9, 61. [Google Scholar] [CrossRef]
  83. Chen, G.; Ni, Y.; Nagata, N.; Xu, L.; Ota, T. Micronutrient Antioxidants and Nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2016, 17, 1379. [Google Scholar] [CrossRef] [Green Version]
  84. Nagashimada, M.; Ota, T. Role of vitamin E in nonalcoholic fatty liver disease. IUBMB Life 2019, 71, 516–522. [Google Scholar] [CrossRef]
  85. Sanyal, A.J.; Chalasani, N.; Kowdley, K.V.; McCullough, A.; Diehl, A.M.; Bass, N.M.; Neuschwander-Tetri, B.A.; Lavine, J.E.; Tonascia, J.; Unalp, A.; et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 2010, 362, 1675–1685. [Google Scholar] [CrossRef] [Green Version]
  86. Lavine, J.E.; Schwimmer, J.B.; Van Natta, M.L.; Molleston, J.P.; Murray, K.F.; Rosenthal, P.; Abrams, S.H.; Scheimann, A.O.; Sanyal, A.J.; Chalasani, N.; et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: The TONIC randomized controlled trial. JAMA 2011, 305, 1659–1668. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Mitsuoka, T. Development of functional foods. Biosci. Microbiota Food Health 2014, 33, 117–128. [Google Scholar] [CrossRef] [Green Version]
  88. Meroni, M.; Longo, M.; Dongiovanni, P. The Role of Probiotics in Nonalcoholic Fatty Liver Disease: A New Insight into Therapeutic Strategies. Nutrients 2019, 11, 2642. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Gibson, G.R.; Roberfroid, M.B. Dietary modulation of the human colonic microbiota: Introducing the concept of prebiotics. J. Nutr. 1995, 125, 1401–1412. [Google Scholar] [CrossRef] [PubMed]
  90. Mitsuoka, T. Significance of dietary modulation of intestinal flora and intestinal environment. Biosci. Microflora 2000, 19, 15–25. [Google Scholar] [CrossRef] [Green Version]
  91. Chiba, Y.; Shida, K.; Nagata, S.; Wada, M.; Bian, L.; Wang, C.; Shimizu, T.; Yamashiro, Y.; Kiyoshima-Shibata, J.; Nanno, M.; et al. Well-controlled proinflammatory cytokine responses of Peyer’s patch cells to probiotic Lactobacillus casei. Immunology 2010, 130, 352–362. [Google Scholar] [CrossRef] [PubMed]
  92. Ma, X.; Hua, J.; Li, Z. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J. Hepatol. 2008, 49, 821–830. [Google Scholar] [CrossRef] [Green Version]
  93. Li, Z.; Yang, S.; Lin, H.; Huang, J.; Watkins, P.A.; Moser, A.B.; Desimone, C.; Song, X.Y.; Diehl, A.M. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 2003, 37, 343–350. [Google Scholar] [CrossRef] [PubMed]
  94. Velayudham, A.; Dolganiuc, A.; Ellis, M.; Petrasek, J.; Kodys, K.; Mandrekar, P.; Szabo, G. VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice. Hepatology 2009, 49, 989–997. [Google Scholar]
  95. Xue, L.; He, J.; Gao, N.; Lu, X.; Li, M.; Wu, X.; Liu, Z.; Jin, Y.; Liu, J.; Xu, J.; et al. Probiotics may delay the progression of nonalcoholic fatty liver disease by restoring the gut microbiota structure and improving intestinal endotoxemia. Sci. Rep. 2017, 7, 45176. [Google Scholar] [CrossRef]
  96. Briskey, D.; Heritage, M.; Jaskowski, L.A.; Peake, J.; Gobe, G.; Subramaniam, V.N.; Crawford, D.; Campbell, C.; Vitetta, L. Probiotics modify tight-junction proteins in an animal model of nonalcoholic fatty liver disease. Ther. Adv. Gastroenterol. 2016, 9, 463–472. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Zhao, Z.; Wang, C.; Zhang, L.; Zhao, Y.; Duan, C.; Zhang, X.; Gao, L.; Li, S. Lactobacillus plantarum NA136 improves the non-alcoholic fatty liver disease by modulating the AMPK/Nrf2 pathway. Appl. Microbiol. Biotechnol. 2019, 103, 5843–5850. [Google Scholar] [CrossRef]
  98. Sohn, W.; Jun, D.W.; Lee, K.N.; Lee, H.L.; Lee, O.Y.; Choi, H.S.; Yoon, B.C. Lactobacillus paracasei Induces M2-Dominant Kupffer Cell Polarization in a Mouse Model of Nonalcoholic Steatohepatitis. Dig. Dis. Sci. 2015, 60, 3340–3350. [Google Scholar] [CrossRef]
  99. Moens, F.; Van den Abbeele, P.; Basit, A.W.; Dodoo, C.; Chatterjee, R.; Smith, B.; Gaisford, S. A four-strain probiotic exerts positive immunomodulatory effects by enhancing colonic butyrate production in vitro. Int. J. Pharm. 2019, 555, 1–10. [Google Scholar] [CrossRef]
  100. Ma, Y.Y.; Li, L.; Yu, C.H.; Shen, Z.; Chen, L.H.; Li, Y.M. Effects of probiotics on nonalcoholic fatty liver disease: A meta-analysis. World J. Gastroenterol. WJG 2013, 19, 6911–6918. [Google Scholar] [CrossRef]
  101. Cani, P.D.; Possemiers, S.; Van de Wiele, T.; Guiot, Y.; Everard, A.; Rottier, O.; Geurts, L.; Naslain, D.; Neyrinck, A.; Lambert, D.M.; 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, 1091–1103. [Google Scholar] [CrossRef] [Green Version]
  102. Parnell, J.A.; Reimer, R.A. Prebiotic fibres dose-dependently increase satiety hormones and alter Bacteroidetes and Firmicutes in lean and obese JCR:LA-cp rats. Br. J. Nutr. 2012, 107, 601–613. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Parnell, J.A.; Reimer, R.A. Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults. Am. J. Clin. Nutr. 2009, 89, 1751–1759. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Loman, B.R.; Hernandez-Saavedra, D.; An, R.; Rector, R.S. Prebiotic and probiotic treatment of nonalcoholic fatty liver disease: A systematic review and meta-analysis. Nutr. Rev. 2018, 76, 822–839. [Google Scholar] [CrossRef]
  105. Ting, W.J.; Kuo, W.W.; Hsieh, D.J.; Yeh, Y.L.; Day, C.H.; Chen, Y.H.; Chen, R.J.; Padma, V.V.; Huang, C.Y. Heat Killed Lactobacillus reuteri GMNL-263 Reduces Fibrosis Effects on the Liver and Heart in High Fat Diet-Hamsters via TGF-beta Suppression. Int. J. Mol. Sci. 2015, 16, 25881–25896. [Google Scholar] [CrossRef] [Green Version]
  106. Hsieh, F.C.; Lee, C.L.; Chai, C.Y.; Chen, W.T.; Lu, Y.C.; Wu, C.S. Oral administration of Lactobacillus reuteri GMNL-263 improves insulin resistance and ameliorates hepatic steatosis in high fructose-fed rats. Nutr. Metab. 2013, 10, 35. [Google Scholar] [CrossRef] [Green Version]
  107. Uchinaka, A.; Azuma, N.; Mizumoto, H.; Nakano, S.; Minamiya, M.; Yoneda, M.; Aoyama, K.; Komatsu, Y.; Yamada, Y.; Murohara, T.; et al. Anti-inflammatory effects of heat-killed Lactobacillus plantarum L-137 on cardiac and adipose tissue in rats with metabolic syndrome. Sci. Rep. 2018, 8, 8156. [Google Scholar] [CrossRef]
  108. Izumo, T.; Ida, M.; Maekawa, T.; Furukawa, Y.; Kitagawa, Y.; Kiso, Y. Comparison of the Immunomodulatory Effects of Live and Heat-killed Lactobacillus pentosus S-PT84. J. Health Sci. 2011, 57, 304–310. [Google Scholar] [CrossRef] [Green Version]
  109. Nonaka, Y.; Izumo, T.; Izumi, F.; Maekawa, T.; Shibata, H.; Nakano, A.; Kishi, A.; Akatani, K.; Kiso, Y. Antiallergic effects of Lactobacillus pentosus strain S-PT84 mediated by modulation of Th1/Th2 immunobalance and induction of IL-10 production. Int. Arch. Allergy Immunol. 2008, 145, 249–257. [Google Scholar] [CrossRef]
  110. Sakai, Y.; Arie, H.; Ni, Y.; Zhuge, F.; Xu, L.; Chen, G.; Nagata, N.; Suzuki, T.; Kaneko, S.; Ota, T.; et al. Lactobacillus pentosus strain S-PT84 improves steatohepatitis by maintaining gut permeability. J. Endocrinol. 2020, 247, 169–181. [Google Scholar] [CrossRef]
  111. Zhao, X.; Higashikawa, F.; Noda, M.; Kawamura, Y.; Matoba, Y.; Kumagai, T.; Sugiyama, M. The obesity and fatty liver are reduced by plant-derived Pediococcus pentosaceus LP28 in high fat diet-induced obese mice. PLoS ONE 2012, 7, e30696. [Google Scholar] [CrossRef] [Green Version]
  112. McNaught, C.E.; Woodcock, N.P.; MacFie, J.; Mitchell, C.J. A prospective randomised study of the probiotic Lactobacillus plantarum 299V on indices of gut barrier function in elective surgical patients. Gut 2002, 51, 827–831. [Google Scholar] [CrossRef] [PubMed]
  113. Khan, A.; Ding, Z.; Ishaq, M.; Bacha, A.S.; Khan, I.; Hanif, A.; Li, W.; Guo, X. Understanding the Effects of Gut Microbiota Dysbiosis on Nonalcoholic Fatty Liver Disease and the Possible Probiotics Role: Recent Updates. Int. J. Biol. Sci. 2021, 17, 818–833. [Google Scholar] [CrossRef]
  114. Gou, S.; Yang, Z.; Liu, T.; Wu, H.; Wang, C. Use of probiotics in the treatment of severe acute pancreatitis: A systematic review and meta-analysis of randomized controlled trials. Crit. Care 2014, 18, R57. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Wilkins, T.; Sequoia, J. Probiotics for Gastrointestinal Conditions: A Summary of the Evidence. Am. Fam. Phys. 2017, 96, 170–178. [Google Scholar]
Ijms 22 08008 g001 550
Figure 1. Multiple parallel-hit hypothesis of the progression of NAFLD/NASH. Overnutrition or inactivity caused by adipocyte hypertrophy and dysfunction. Obese adipose tissue shows chronic inflammation and insulin resistance as a result of infiltration of activated macrophages and T cells. Adipokines, such as interleukin-6 and tumor necrosis factor-α, and chemokines including CCL2 produced by adipocytes induce hepatocyte fat accumulation, hepatic inflammation, and insulin resistance. Overloading of triglycerides, free fatty acids, and free cholesterol induces endoplasmic reticulum stress and oxidative stress, leading to hepatic inflammation, mitochondrial dysfunction, fibrogenesis and, ultimately, hepatic steatosis. By contrast, microbial dysbiosis results in production of pathogen-associated molecular patterns and damage-associated molecular patterns, inducing an inflammatory response in hepatocytes, Kupffer cells, and hepatic stellate cells via a Toll-like receptor cascade, resulting in liver damage.
Figure 1. Multiple parallel-hit hypothesis of the progression of NAFLD/NASH. Overnutrition or inactivity caused by adipocyte hypertrophy and dysfunction. Obese adipose tissue shows chronic inflammation and insulin resistance as a result of infiltration of activated macrophages and T cells. Adipokines, such as interleukin-6 and tumor necrosis factor-α, and chemokines including CCL2 produced by adipocytes induce hepatocyte fat accumulation, hepatic inflammation, and insulin resistance. Overloading of triglycerides, free fatty acids, and free cholesterol induces endoplasmic reticulum stress and oxidative stress, leading to hepatic inflammation, mitochondrial dysfunction, fibrogenesis and, ultimately, hepatic steatosis. By contrast, microbial dysbiosis results in production of pathogen-associated molecular patterns and damage-associated molecular patterns, inducing an inflammatory response in hepatocytes, Kupffer cells, and hepatic stellate cells via a Toll-like receptor cascade, resulting in liver damage.
Ijms 22 08008 g001
Ijms 22 08008 g002 550
Figure 2. Interaction between dysbiosis-induced alteration of the intestinal mucosal barrier and progression of NASH. Tight junction dysfunction is induced by LPS, and proinflammatory cytokines are produced by intraepithelial lymphocytes (IELs) and the lamina propria (LP), enhancing intestinal epithelial permeability and inducing metabolic endotoxemia followed by hepatic inflammation, steatosis, and fibrosis. Intestinal IL-17 protects tight junctions in the gut, and the serum IL-17 level is increased in NASH patients. The secretion of IL-17 by Th17 cells stimulates monocytes, Kupffer cells, biliary epithelial cells, and stellate cells to secrete proinflammatory cytokines and chemokines, inducing inflammation in the liver.
Figure 2. Interaction between dysbiosis-induced alteration of the intestinal mucosal barrier and progression of NASH. Tight junction dysfunction is induced by LPS, and proinflammatory cytokines are produced by intraepithelial lymphocytes (IELs) and the lamina propria (LP), enhancing intestinal epithelial permeability and inducing metabolic endotoxemia followed by hepatic inflammation, steatosis, and fibrosis. Intestinal IL-17 protects tight junctions in the gut, and the serum IL-17 level is increased in NASH patients. The secretion of IL-17 by Th17 cells stimulates monocytes, Kupffer cells, biliary epithelial cells, and stellate cells to secrete proinflammatory cytokines and chemokines, inducing inflammation in the liver.
Ijms 22 08008 g002
Ijms 22 08008 g003 550
Figure 3. Schematic representation of the beneficial effects of probiotics, prebiotics (e.g., oligofructose), and biogenics (heat-killed lactic acid bacteria) on NAFLD and NASH progression by regulating the intestinal environment and reducing hepatic inflammation, lipid accumulation, and fibrosis. In NAFLD and NASH, probiotics, prebiotics, and biogenics suppress tight junction dysfunction and enhance intestinal epithelial permeability. Increased intestinal permeability or ‘leaky gut’ results in metabolic endotoxemia followed by low-grade inflammation in the liver. Probiotics, prebiotics, and biogenics ameliorate NAFLD and NASH by preventing leaky gut and metabolic endotoxemia due to tight junction dysfunction, and by depressing oxidative stress, inflammation, and fibrosis in the liver.
Figure 3. Schematic representation of the beneficial effects of probiotics, prebiotics (e.g., oligofructose), and biogenics (heat-killed lactic acid bacteria) on NAFLD and NASH progression by regulating the intestinal environment and reducing hepatic inflammation, lipid accumulation, and fibrosis. In NAFLD and NASH, probiotics, prebiotics, and biogenics suppress tight junction dysfunction and enhance intestinal epithelial permeability. Increased intestinal permeability or ‘leaky gut’ results in metabolic endotoxemia followed by low-grade inflammation in the liver. Probiotics, prebiotics, and biogenics ameliorate NAFLD and NASH by preventing leaky gut and metabolic endotoxemia due to tight junction dysfunction, and by depressing oxidative stress, inflammation, and fibrosis in the liver.
Ijms 22 08008 g003
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Nagashimada, M.; Honda, M. Effect of Microbiome on Non-Alcoholic Fatty Liver Disease and the Role of Probiotics, Prebiotics, and Biogenics. Int. J. Mol. Sci. 2021, 22, 8008. https://doi.org/10.3390/ijms22158008

AMA Style

Nagashimada M, Honda M. Effect of Microbiome on Non-Alcoholic Fatty Liver Disease and the Role of Probiotics, Prebiotics, and Biogenics. International Journal of Molecular Sciences. 2021; 22(15):8008. https://doi.org/10.3390/ijms22158008

Chicago/Turabian Style

Nagashimada, Mayumi, and Masao Honda. 2021. "Effect of Microbiome on Non-Alcoholic Fatty Liver Disease and the Role of Probiotics, Prebiotics, and Biogenics" International Journal of Molecular Sciences 22, no. 15: 8008. https://doi.org/10.3390/ijms22158008

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop