Metabolic associated fatty liver disease (MAFLD) has become a prevalent chronic liver disease worldwide because of lifestyle and dietary changes. Gut microbiota and its metabolites have been shown to play a critical role in the pathogenesis of MAFLD. Understanding of the function of gut microbiota and its metabolites in MAFLD may help to elucidate pathological mechanisms, identify diagnostic markers, and develop drugs or probiotics for the treatment of MAFLD. Here we review the pathogenesis of MAFLD by gut microbiota and its metabolites and discuss the feasibility of treating MAFLD from the perspective of gut microbes.
Gastrointestinal Microbiome ; Fatty Liver/microbiology* ; Humans

Gastrointestinal Tract ; microbiology ; Humans ; Metagenome ; Microbiota ; Non-alcoholic Fatty Liver Disease ; microbiology

Advances in sequencing technology and the development of metagenomics have opened up new ways to investigate the microorganisms inhabiting the human gut. The intestinal microbiota confer protection against pathogens, contribute to the maturation of the immune system, and regulate host metabolism. The composition of gut microbiota in early life is influenced by mode of birth, diet, and antibiotics. Decreased biodiversity and alterations in the composition of the intestinal microbiota have been observed in many diseases including obesity, neonatal necrotizing enterocolitis, inflammatory bowel disease, and recurrent Clostridium difficile infection. Therapeutic options for the diseases linked to imbalance in the microbiota include modifying the gut microbiota through diet, probiotics, and fecal transplants.
Animals ; Anti-Bacterial Agents/therapeutic use ; Clostridium difficile/isolation & purification/pathogenicity ; Enterocolitis, Pseudomembranous/drug therapy/microbiology/pathology ; Fatty Liver/etiology/microbiology ; Humans ; Inflammatory Bowel Diseases/etiology/microbiology ; Intestines/*microbiology ; *Microbiota ; Obesity/etiology/microbiology

OBJECTIVETo study the effect of Jianpi Huoxue Recipe(JPHXR) on the gut flora in rats with alcoholic fatty liver (AFL) induced by Lieber-DeCarli liquid diet.

METHODSForty Sprague-Dawley rats were divided into 4 groups: A: normal rats, B: rats fed with non-alcoholic liquid diet, C: rats fed with ethanol liquid diet to make AFL model, and D: AFL model rats intervened by gastrogavage of JPHXR 1.0 mL/100 g per day for 8 successive weeks, 10 rats in each group. Except those in Group D (to them an equal volume normal saline was given for Successive instead), JPXHR was administered to rats in other three groups. At the end of experiment, rats were sacrificed, their blood and liver tissue samples were collected for determining serum activities of alanine transaminase (ALT) and aspartate aminotransferase (AST), endotoxin level in portal vein (expressed by lipopolysacchrides content, abbr. as LPS), and pathological examination of liver with HE staining and oil O red staining. Moreover, total DNA of gut flora were extracted from fresh rat fecal samples by Bead-beating method for determining the ERIC-PCR fingerprint, and a cluster analysis on the fingerprint was performed.

RESULTSCompared with the levels of ALT and AST in Group A (31.15 +/- 7.04 U/L, and 53.23 +/- 10.28 U/L respectively) and Group B (26.96 +/- 8.12 and 52.09 +/- 8.62), the corresponding levels in Group C (92.72 +/- 25.83 and 72.60 +/- 23.31) significantly increased (P < 0.01), while the increments in Group D (65.28 +/- 20.36 and 59.11 +/- 10.32) were decreased (P < 0.01, P < 0.05). Pathological examination showed marked fat deposition in Group C, but which was significantly reduced in Group D. Endotoxin level in the portal vein was (0.033 +/- 0.010, EU/mL) in Group A and 0.043 +/- 0.018 in Group B, which was increased significantly in Group C (0.541 +/- 0.085, P < 0.01) and Group D (0.349 +/- 0.098 EU/mL, P < 0.01), but the increase in Group C was more significant (P < 0.01). The cluster analysis of ERIC-PCR fingerprint showed significant changes in gut flora of Group C and D, which was in Group D partially recovered.

CONCLUSIONSJPHXR had good preventive effect against alcoholic fatty liver in rats, and could modify the structure of gut flora to some extent.

Animals ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Enterobacteriaceae ; physiology ; Fatty Liver, Alcoholic ; drug therapy ; microbiology ; Gastrointestinal Tract ; microbiology ; Male ; Phytotherapy ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the effect of intermittent fasting on metabolize and gut microbiota in obese presenium rats fed with high-fat-sugar-diet.

METHODSWe fed the Wistar rats with high-fat and high-sugar diet to induce adiposity, and the rats for intermittent fasting were selected base on their body weight. The rats were subjected to fasting for 72 h every 2 weeks for 18 weeks. OGTT test was performed and fasting blood samples and fecal samples were collected for measurement of TC, TG, HDL-C and LDL-C and sequence analysis of fecal 16S rRNA V4 tags using Illumina. Gut microbial community structure was analyzed with QIIME and LEfSe.

RESULTSAfter the intervention, the body weight of the fasting rats was significantly lower than that in high-fat diet group (P<0.01). OGTT results suggested impairment of sugar tolerance in the fasting group, which showed a significantly larger AUC than compared with the high-fat diet group (P<0.05). Intermittent fasting significantly reduced blood HDL-C and LDL-C levels (P<0.05) and partially restored liver steatosis, and improved the gut microbiota by increasing the abundance of YS2, RF32 and Helicobacteraceae and reducing Lactobacillus, Roseburia, Erysipelotrichaceae and Ralstonia. Bradyrhizobiaceae was found to be positively correlated with CHOL and HDL-C, and RF39 was inversely correlated with the weight of the rats.

CONCLUSIONIntermittent fasting can decrease the body weight and blood lipid levels and restore normal gut microbiota but can cause impairment of glucose metabolism in obese presenium rats.

Animals ; Body Weight ; Diet, High-Fat ; Fasting ; Fatty Liver ; microbiology ; physiopathology ; Gastrointestinal Microbiome ; Lipids ; blood ; Obesity ; microbiology ; physiopathology ; RNA, Ribosomal, 16S ; Rats ; Rats, Wistar

Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic diseases currently in the context of obesity worldwide, which contains a spectrum of chronic liver diseases, including hepatic steatosis, non-alcoholic steatohepatitis and hepatic carcinoma. In addition to the classical "Two-hit" theory, NAFLD has been recognized as a typical gut microbiota-related disease because of the intricate role of gut microbiota in maintaining human health and disease formation. Moreover, gut microbiota is even regarded as a "metabolic organ" that play complementary roles to that of liver in many aspects. The mechanisms underlying gut microbiota-mediated development of NAFLD include modulation of host energy metabolism, insulin sensitivity, and bile acid and choline metabolism. As a result, gut microbiota have been emerging as a novel therapeutic target for NAFLD by manipulating it in various ways, including probiotics, prebiotics, synbiotics, antibiotics, fecal microbiota transplantation, and herbal components. In this review, we summarized the most recent advances in gut microbiota-mediated mechanisms, as well as gut microbiota-targeted therapies on NAFLD.
Animals ; Bile Acids and Salts ; metabolism ; Choline ; metabolism ; Dietary Supplements ; Energy Metabolism ; Fecal Microbiota Transplantation ; Gastrointestinal Microbiome ; Humans ; Insulin Resistance ; Intestines ; microbiology ; Non-alcoholic Fatty Liver Disease ; microbiology ; therapy

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver dysfunction and a significant global health problem with substantial rise in prevalence over the last decades. It is becoming increasingly clear that NALFD is not only predominantly a hepatic manifestation of metabolic syndrome, but also involves extra-hepatic organs and regulatory pathways. Therapeutic options are limited for the treatment of NAFLD. Accordingly, a better understanding of the pathogenesis of NAFLD is critical for gaining new insight into the regulatory network of NAFLD and for identifying new targets for the prevention and treatment of NAFLD. In this review, we emphasize on the current understanding of the inter-organ crosstalk between the liver and peripheral organs that contributing to the pathogenesis of NAFLD.
Adipose Tissue ; pathology ; Animals ; Extracellular Vesicles ; metabolism ; Humans ; Hypothalamus ; metabolism ; Intestines ; microbiology ; pathology ; Non-alcoholic Fatty Liver Disease ; etiology ; metabolism ; microbiology ; pathology

OBJECTIVETo investigate the initial changes in the gut microenvironment that accompany intestinal endotoxemia related to alcoholic fatty liver disease (ALD) in order to explore the potential initiating factors and to observe the effect of probiotic therapy on these factors.

METHODSFifty Sprague-Dawley male rats were randomly divided into an ALD model group (alcoholic intragastric administration), an intervention group (ALD with probiotic intragastric administration), and a control group (physiological saline intragastric administration). Histological changes of the liver were evaluated using hematoxylin-eosin staining and light microscopy. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglycerides (TG), and plasma endotoxin and coli bacillus were determined. The structural integrity of intestinal mucosa and tight junctions were observed by transmission electron microscopy. Occludin protein expression in intestinal epithelial cells was detected by immunohistochemistry.

RESULTSAfter four weeks, the three groups showed significant differences in the plasma endotoxin levels [control: (0.67+/-0.14) pg/ml, model: (4.42+/-1.28) pg/ml, and intervention: (2.88+/-0.83) pg/ml; F = 27.288, P = 0.000] and numbers of Escherichia coli [control: (2.31+/-0.39) lg3/ml, model: (3.23+/-0.41) lg3/ml, and intervention: (2.24+/-0.44) lg3/ml; F = 10.692, P = 0.001]. The plasma endotoxin level and E. coli number were significantly higher in the model group than in the control group and the intervention group (all P less than 0.05). The three groups showed no significant differences in the levels of ALT, AST, and TG at four weeks. After eight weeks, however, all three serum markers were significantly different between the three groups [ALT: control: (62.33+/-7.12) U/L, model: (95.50+/-8.73) U/L, and intervention: (81.33+/-6.19) U/L; F = 18.051, P = 0.000]; [AST: control: (90.50+/-10.67) U/L, model: (130.00+/-14.91) U/L, and intervention: (110.33+/-7.26) U/L; F = 30.170, P = 0.000]; [TG: control: (0.84+/-0.84) mmol/L, model: (1.40+/-0.17) mmol/L, and intervention: (1.10+/-0.17) mmol/L; F = 10.592, P = 0.001]. In addition, the three groups showed significant differences in E. coli number [control: (2.23+/-0.46) lg3/ml, model: (4.81+/-0.29) lg3/ml, and intervention: (3.61+/-0.50) lg3/ml; F = 23.579, P = 0.000] and plasma endotoxin level [control: (0.52+/-0.21) pg/ml, model: (12.46+/-2.61) pg/ml, intervention: (6.83+/-1.74) pg/ml; F = 30.731, P = 0.000]. The levels of ALT, AST, TG and endotoxin, and the number of E. coli were all significantly higher in the model group than in the control group and the intervention group (all P less than 0.05). Small intestinal epithelial cell structural failure was more apparent and intercellular gaps more broad after eight weeks than after four weeks for all three groups. However, the intervention group showed clearer cell connection structures and less extensive cell gap broadening than the model group at eight weeks. After eight weeks, the occludin protein had become significantly down-regulated and distributed in a non-continuous pattern in the model group, as compared with the control group. However, the occludin protein expression was higher in intervention group than in the model group.

CONCLUSIONIntestinal endotoxemia related to perturbations in the microenvironment occurs in the early phase of ALD, and the increased intestinal permeability appears to be the initial factor of elevated plasma endotoxin, which may lead to liver damage. Probiotic therapy can reduced plasma endotoxin levels and postpone ALD progression by altering the composition of the gut microbiota and up-regulating expression of the occludin protein in intestinal epithelial cells.

Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Endotoxins ; blood ; Escherichia coli ; isolation & purification ; Fatty Liver, Alcoholic ; microbiology ; therapy ; Intestinal Mucosa ; metabolism ; microbiology ; Intestine, Small ; metabolism ; microbiology ; Male ; Occludin ; metabolism ; Probiotics ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Triglycerides ; blood

Metabolic syndrome characterized by obesity, hyperglycemia and liver steatosis is becoming prevalent all over the world. Herein, a water insoluble polysaccharide (WIP) was isolated and identified from the sclerotium of Poria cocos, a widely used Traditional Chinese Medicine. WIP was confirmed to be a (1-3)-β-D-glucan with an average Mw of 4.486 × 10 Da by NMR and SEC-RI-MALLS analyses. Furthermore, oral treatment with WIP from P. cocos significantly improved glucose and lipid metabolism and alleviated hepatic steatosis in ob/ob mice. 16S DNA sequencing analysis of cecum content from WIP-treated mice indicated the increase of butyrate-producing bacteria Lachnospiracea, Clostridium. It was also observed that WIP treatment elevated the level of butyrate in gut, improved the gut mucosal integrity and activated the intestinal PPAR-γ pathway. Fecal transplantation experiments definitely confirmed the causative role of gut microbiota in mediating the benefits of WIP. It is the first report that the water insoluble polysaccharide from the sclerotium of P. cocos modulates gut microbiota to improve hyperglycemia and hyperlipidemia. Thereby, WIP from P. cocos, as a prebiotic, has the potential for the prevention or cure of metabolic diseases and may elucidate new mechanism for the efficacies of this traditional herbal medicine on the regulation of lipid and glucose metabolism.
Animals ; Bacteria ; classification ; genetics ; isolation & purification ; metabolism ; Butyrates ; metabolism ; Fatty Liver ; drug therapy ; Fungal Polysaccharides ; chemistry ; pharmacology ; therapeutic use ; Gastrointestinal Microbiome ; drug effects ; genetics ; Hyperglycemia ; drug therapy ; Hyperlipidemias ; drug therapy ; Intestines ; drug effects ; microbiology ; Male ; Metabolic Syndrome ; drug therapy ; Mice ; Mice, Obese ; Prebiotics ; Wolfiporia ; chemistry