Modulation of the Gut Microbiota in Rats by Hugan Qingzhi Tablets during the Treatment of High-Fat-Diet-Induced Nonalcoholic Fatty Liver Disease

Background Accumulative evidence showed that gut microbiota was important in regulating the development of nonalcoholic fatty liver disease (NAFLD). Hugan Qingzhi tablet (HQT), a lipid-lowering and anti-inflammatory medicinal formula, has been used to prevent and treat NAFLD. However, its mechanism of action is unknown. The aim of this study was to confirm whether HQT reversed the gut microbiota dysbiosis in NAFLD rats. Methods We established an NAFLD model of rats fed with a high-fat diet (HFD), which was given different interventions, and measured the level of liver biochemical indices and inflammatory factors. Liver tissues were stained with hematoxylin-eosin and oil red O. Changes in the gut microbiota composition were analyzed using 16S rRNA sequencing. Results The hepatic histology and biochemical data displayed that HQT exhibited protective effects on HFD-induced rats. Moreover, HQT also reduced the abundance of the Firmicutes/Bacteroidetes ratio in HFD-fed rats and modified the gut microbial species at the genus level, increasing the abundances of gut microbiota which were reported to have an effect on relieving NAFLD, such as Ruminococcaceae, Bacteroidales_S24-7_group, Bifidobacteria, Alistipes, and Anaeroplasma, and significantly inhibiting the relative abundance of Enterobacteriaceae, Streptococcus, Holdemanella, Allobaculum, and Blautia, which were reported to be potentially related to NAFLD. Spearman's correlation analysis found that [Ruminococcus]_gauvreauii_group, Lachnoclostridium, Blautia, Allobaculum, and Holdemanella exhibited significant (p < 0.001) positive correlations with triglyceride, cholesterol, low-density lipoprotein cholesterol, interleukin-6, interleukin-1β, tumor necrosis factor-α, and body weight and negative correlations with high-density lipoprotein cholesterol (p < 0.001). The norank_f__Bacteroidales_S24-7_group and Alistipes showed an opposite trend. Moreover, the HQT could promote flavonoid biosynthesis compared with the HFD group. Conclusion In summary, the HQT has potential applications in the prevention and treatment of NAFLD, which may be closely related to its modulatory effect on the gut microbiota.

[1]  X. Yao,et al.  Isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics for the investigation of the effect of Hugan Qingzhi on non-alcoholic fatty liver disease in rats. , 2018, Journal of ethnopharmacology.

[2]  L. Drago,et al.  Bifidobacteria and lactobacilli in the gut microbiome of children with non-alcoholic fatty liver disease: which strains act as health players? , 2016, Archives of medical science : AMS.

[3]  Jun Xu,et al.  Understanding the Molecular Mechanisms of the Interplay Between Herbal Medicines and Gut Microbiota , 2017, Medicinal research reviews.

[4]  Q. Pan,et al.  Sodium butyrate attenuates high-fat diet-induced steatohepatitis in mice by improving gut microbiota and gastrointestinal barrier. , 2017, World journal of gastroenterology.

[5]  N. LeBrasseur,et al.  High fat diet and exercise lead to a disrupted and pathogenic DNA methylome in mouse liver , 2017, Epigenetics.

[6]  Ying Zhu,et al.  Response of gut microbiota and inflammatory status to bitter melon (Momordica charantia L.) in high fat diet induced obese rats. , 2016, Journal of ethnopharmacology.

[7]  Zhibin Liu,et al.  The modulatory effect of infusions of green tea, oolong tea, and black tea on gut microbiota in high-fat-induced obese mice. , 2016, Food & function.

[8]  J. Graf,et al.  Role of Gut Microbiota and Short Chain Fatty Acids in Modulating Energy Harvest and Fat Partitioning in Youth. , 2016, The Journal of clinical endocrinology and metabolism.

[9]  E. Elinav,et al.  Non-alcoholic fatty liver and the gut microbiota , 2016, Molecular metabolism.

[10]  Hongyuan Wang,et al.  Effect of biochar additions to soil on nitrogen leaching, microbial biomass and bacterial community structure , 2016 .

[11]  Jun Xu,et al.  Gut microbiota-involved mechanisms in enhancing systemic exposure of ginsenosides by coexisting polysaccharides in ginseng decoction , 2016, Scientific Reports.

[12]  R. Liu,et al.  Phenolic contents and cellular antioxidant activity of Chinese hawthorn "Crataegus pinnatifida". , 2015, Food chemistry.

[13]  Liping Zhao,et al.  Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats , 2015, Scientific Reports.

[14]  X. Yao,et al.  Hugan Qingzhi Exerts Anti-Inflammatory Effects in a Rat Model of Nonalcoholic Fatty Liver Disease , 2015, Evidence-based complementary and alternative medicine : eCAM.

[15]  E. Le Chatelier,et al.  Specific gut microbiota features and metabolic markers in postmenopausal women with obesity , 2015, Nutrition & Diabetes.

[16]  M. Cowie National Institute for Health and Care Excellence. , 2015, European heart journal.

[17]  M. Blaser,et al.  Altering the Intestinal Microbiota during a Critical Developmental Window Has Lasting Metabolic Consequences , 2014, Cell.

[18]  Houliang Deng,et al.  Hugan Qingzhi medication ameliorates hepatic steatosis by activating AMPK and PPARα pathways in L02 cells and HepG2 cells. , 2014, Journal of ethnopharmacology.

[19]  Jesse R. Zaneveld,et al.  Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences , 2013, Nature Biotechnology.

[20]  N. Hall,et al.  Colonic mucosa-associated diffusely adherent afaC+ Escherichia coli expressing lpfA and pks are increased in inflammatory bowel disease and colon cancer , 2013, Gut.

[21]  E. Murphy,et al.  Targeting the Microbiota to Address Diet-Induced Obesity: A Time Dependent Challenge , 2013, PloS one.

[22]  Tetsu Watanabe,et al.  Butyrate-Producing Probiotics Reduce Nonalcoholic Fatty Liver Disease Progression in Rats: New Insight into the Probiotics for the Gut-Liver Axis , 2013, PloS one.

[23]  N. Tam,et al.  Illumina Sequencing of 16S rRNA Tag Revealed Spatial Variations of Bacterial Communities in a Mangrove Wetland , 2013, Microbial Ecology.

[24]  H. Nittono,et al.  Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. , 2013, Journal of Hepatology.

[25]  J. Turnay,et al.  Bile acids in the colon, from healthy to cytotoxic molecules. , 2013, Toxicology in vitro : an international journal published in association with BIBRA.

[26]  J. Lobaccaro,et al.  Bile acids: from digestion to cancers. , 2013, Biochimie.

[27]  E. Comelli,et al.  Intestinal microbiota in patients with nonalcoholic fatty liver disease , 2013, Hepatology.

[28]  Lixin Zhu,et al.  Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: A connection between endogenous alcohol and NASH , 2013, Hepatology.

[29]  L. Kucharski,et al.  The activity of mate saponins (Ilex paraguariensis) in intra-abdominal and epididymal fat, and glucose oxidation in male Wistar rats. , 2012, Journal of ethnopharmacology.

[30]  Yu Yan,et al.  [The quality standard study on Hugan qingzhi tablets]. , 2012, Zhong yao cai = Zhongyaocai = Journal of Chinese medicinal materials.

[31]  Patrick D. Schloss,et al.  Reducing the Effects of PCR Amplification and Sequencing Artifacts on 16S rRNA-Based Studies , 2011, PloS one.

[32]  Tetsuya Hayashi,et al.  Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. , 2011, Gastroenterology.

[33]  A. Moschetta,et al.  Bile acids and colon cancer: Solving the puzzle with nuclear receptors. , 2011, Trends in molecular medicine.

[34]  J. Duan,et al.  Simultaneous determination of eleven major flavonoids in the pollen of Typha angustifolia by HPLC-PDA-MS. , 2011, Phytochemical analysis : PCA.

[35]  C. Huttenhower,et al.  Metagenomic biomarker discovery and explanation , 2011, Genome Biology.

[36]  J. Gordon,et al.  Human nutrition, the gut microbiome and the immune system , 2011, Nature.

[37]  Robert G. Beiko,et al.  Identifying biologically relevant differences between metagenomic communities , 2010, Bioinform..

[38]  K. Al-Jashamy,et al.  Prevalence of colorectal cancer associated with Streptococcus bovis among inflammatory bowel and chronic gastrointestinal tract disease patients. , 2010, Asian Pacific journal of cancer prevention : APJCP.

[39]  R. Knight,et al.  The Effect of Diet on the Human Gut Microbiome: A Metagenomic Analysis in Humanized Gnotobiotic Mice , 2009, Science Translational Medicine.

[40]  Rob Knight,et al.  High-fat diet determines the composition of the murine gut microbiome independently of obesity. , 2009, Gastroenterology.

[41]  G. La Torre,et al.  Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease , 2009, Hepatology.

[42]  J. Ferrières,et al.  Metabolic Endotoxemia Initiates Obesity and Insulin Resistance , 2007, Diabetes.

[43]  H. Flint,et al.  Understanding the effects of diet on bacterial metabolism in the large intestine , 2007, Journal of applied microbiology.

[44]  E. Mardis,et al.  An obesity-associated gut microbiome with increased capacity for energy harvest , 2006, Nature.

[45]  Shuzhong Guo,et al.  The role of bifidobacteria in gut barrier function after thermal injury in rats. , 2006, The Journal of trauma.

[46]  G. Gibson,et al.  In vitro fermentation of sugar beet arabinan and arabino‐oligosaccharides by the human gut microflora , 2006, Journal of applied microbiology.

[47]  G. Wolf Gut microbiota: a factor in energy regulation. , 2006, Nutrition reviews.

[48]  O. Cummings,et al.  Design and validation of a histological scoring system for nonalcoholic fatty liver disease , 2005, Hepatology.

[49]  Ting Wang,et al.  The gut microbiota as an environmental factor that regulates fat storage. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Dong-Hyun Kim,et al.  Antiallergic Activity of Hesperidin Is Activated by Intestinal Microflora , 2004, Pharmacology.

[51]  L. Duffy,et al.  In Vivo Effects of Bifidobacteria and Lactoferrin on Gut Endotoxin Concentration and Mucosal Immunity in Balb/c Mice , 2004, Digestive Diseases and Sciences.

[52]  B. Beutler,et al.  Innate immune sensing and its roots: the story of endotoxin , 2003, Nature Reviews Immunology.

[53]  I. Roberts-Thomson,et al.  The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor α in the pathogenesis of non-alcoholic steatohepatitis , 2001, Gut.

[54]  M. Blaut,et al.  Anaerobic degradation of flavonoids by Eubacterium ramulus , 2000, Archives of Microbiology.

[55]  P. Hollman,et al.  The sugar moiety is a major determinant of the absorption of dietary flavonoid glycosides in man. , 1999, Free radical research.

[56]  J. Lehmann,et al.  Bile acids: natural ligands for an orphan nuclear receptor. , 1999, Science.

[57]  J. Marshall The gut as a potential trigger of exercise-induced inflammatory responses. , 1998, Canadian journal of physiology and pharmacology.

[58]  A. Weintraub,et al.  Structure-activity relationships in lipopolysaccharides of Bacteroides fragilis. , 1990, Reviews of infectious diseases.