Akebia Saponin D Regulates the Metabolome and Intestinal Microbiota in High Fat Diet-Induced Hyperlipidemic Rats

Hyperlipidemia is a major component of metabolic syndrome, and regarded as one of the main risk factors causing metabolic diseases. We have developed a therapeutic drug, akebia saponin D (ASD), and determined its anti-hyperlipidemia activity and the potential mechanism(s) of action by analyzing the metabolome and intestinal microbiota. Male Sprague-Dawley rats were fed a high fat diet to induce hyperlipidemia, and then given ASD orally for 8 weeks. Lipid levels in serum were determined biochemically. Metabolites in serum, urine and feces were analyzed by UPLC-Q/TOF-MS, and the structure of the intestinal microbiota was determined by 16S rRNA sequencing. The ASD treatment significantly decreased the levels of TC, TG and LDL-c and increased the serum level of HDL-c. Metabolomics analysis indicated that the ASD treatment mainly impacted seven differential metabolites in the serum, sixteen differential metabolites in the urine and four differential metabolites in feces compared to the model group. The ASD treatment significantly changed eight bacteria at the genus level compared to the model group. In conclusion, ASD treatment can significantly alleviate HFD-induced hyperlipidemia and the hypolipidemic effect of ASD treatment is certainly associated with a systematic change in the metabolism, as well as dynamic changes in the structure of the intestinal microbiota.

[1]  R. Linhardt,et al.  Akebia saponin D reverses corticosterone hypersecretion in an Alzheimer's disease rat model. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[2]  R. Linhardt,et al.  Mechanism of enhanced oral absorption of akebia saponin D by a self-nanoemulsifying drug delivery system loaded with phospholipid complex , 2018, Drug development and industrial pharmacy.

[3]  I. Hwang,et al.  Metabolomics Analysis of the Lipid-Regulating Effect of Allium hookeri in a Hamster Model of High-Fat Diet-Induced Hyperlipidemia by UPLC/ESI-Q-TOF Mass Spectrometry , 2018, Evidence-based complementary and alternative medicine : eCAM.

[4]  F. Bäckhed,et al.  Abundance of gut Prevotella at baseline and metabolic response to barley prebiotics , 2018, European Journal of Nutrition.

[5]  F. Wang,et al.  Comprehensive Metabolomics Analysis of Xueshuan Xinmaining Tablet in Blood Stasis Model Rats Using UPLC-Q/TOF-MS , 2018, Molecules.

[6]  Z. Xiu,et al.  Anti-diabetic effect of baicalein is associated with the modulation of gut microbiota in streptozotocin and high-fat-diet induced diabetic rats , 2018, Journal of Functional Foods.

[7]  Yongzhong Zhao,et al.  Gut microbiota derived metabolites in cardiovascular health and disease , 2018, Protein & Cell.

[8]  M. Qu,et al.  Metabolomics analysis of alloxan-induced diabetes in mice using UPLC-Q-TOF-MS after Crassostrea gigas polysaccharide treatment. , 2018, International journal of biological macromolecules.

[9]  L. Fan,et al.  Polysaccharide from Plantago asiatica L. attenuates hyperglycemia, hyperlipidemia and affects colon microbiota in type 2 diabetic rats , 2017, Food Hydrocolloids.

[10]  Yali Lv,et al.  Akebia saponin D alleviates hepatic steatosis through BNip3 induced mitophagy. , 2017, Journal of pharmacological sciences.

[11]  W. Tang,et al.  Gut Microbiota and Atherosclerosis , 2017, Current Atherosclerosis Reports.

[12]  Jian-Dong Jiang,et al.  Gut Microbiota-Mediated Personalized Treatment of Hyperlipidemia Using Berberine , 2017, Theranostics.

[13]  Yali Lv,et al.  Akebia Saponin D Decreases Hepatic Steatosis through Autophagy Modulation , 2016, The Journal of Pharmacology and Experimental Therapeutics.

[14]  K. Ke,et al.  Asperosaponin VI promotes bone marrow stromal cell osteogenic differentiation through the PI3K/AKT signaling pathway in an osteoporosis model , 2016, Scientific Reports.

[15]  Y. Wang,et al.  Preparation and evaluation of a self-nanoemulsifying drug delivery system loaded with Akebia saponin D–phospholipid complex , 2016, International journal of nanomedicine.

[16]  Matej Oresic,et al.  Metabolomics enables precision medicine: “A White Paper, Community Perspective” , 2016, Metabolomics.

[17]  Yubo Xiao,et al.  Rhizoma Coptidis alkaloids alleviate hyperlipidemia in B6 mice by modulating gut microbiota and bile acid pathways. , 2016, Biochimica et biophysica acta.

[18]  Meng Li,et al.  Integrative analysis of metabolome and gut microbiota in diet-induced hyperlipidemic rats treated with berberine compounds , 2016, Journal of Translational Medicine.

[19]  Y. Wang,et al.  Enhancement of oral bioavailability of akebia saponin D by destroying self-micelles and inhibiting multidrug resistance-associated protein mediated efflux , 2016 .

[20]  R. Hu,et al.  Treatment with Akebia Saponin D Ameliorates Aβ1–42-Induced Memory Impairment and Neurotoxicity in Rats , 2016, Molecules.

[21]  Huiru Tang,et al.  Correlations of Fecal Metabonomic and Microbiomic Changes Induced by High-fat Diet in the Pre-Obesity State , 2016, Scientific Reports.

[22]  Lian‐Wen Qi,et al.  Human plasma metabolomics for identifying differential metabolites and predicting molecular subtypes of breast cancer , 2016, Oncotarget.

[23]  F. Bäckhed,et al.  Dietary Fiber-Induced Improvement in Glucose Metabolism Is Associated with Increased Abundance of Prevotella. , 2015, Cell metabolism.

[24]  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.

[25]  James B. Mitchell,et al.  The nitroxide radical TEMPOL prevents obesity, hyperlipidaemia, elevation of inflammatory cytokines, and modulates atherosclerotic plaque composition in apoE-/- mice. , 2015, Atherosclerosis.

[26]  Mei J. Zhu,et al.  Maternal obesity alters gut microbial ecology in offspring of NOD mice , 2015 .

[27]  W. Ng,et al.  A brief review on possible approaches towards controlling sulfate-reducing bacteria (SRB) in wastewater treatment systems , 2015 .

[28]  N. Abraham,et al.  Heme oxygenase‐2 deletion impairs macrophage function: implication in wound healing , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[29]  Lanjuan Li,et al.  Impacts of infection with different toxigenic Clostridium difficile strains on faecal microbiota in children , 2014, Scientific Reports.

[30]  J. Youngren,et al.  Insulin Resistance Induced by Hyperinsulinemia Coincides with a Persistent Alteration at the Insulin Receptor Tyrosine Kinase Domain , 2014, PloS one.

[31]  M. Davidson,et al.  Overcoming toxicity and side-effects of lipid-lowering therapies. , 2014, Best practice & research. Clinical endocrinology & metabolism.

[32]  Wen-ting Zhou,et al.  Effect of Cydonia oblonga Mill. leaf extract on serum lipids and liver function in a rat model of hyperlipidaemia. , 2014, Journal of ethnopharmacology.

[33]  T. Yeh,et al.  Effect of propolis on TGF-beta 1-induced epithelial-mesenchymal transition in human alveolar epithelial cells via PPAR gamma activation , 2013 .

[34]  Lin-na Wang,et al.  Akebia Saponin D attenuates amyloid β-induced cognitive deficits and inflammatory response in rats: Involvement of Akt/NF-κB pathway , 2012, Behavioural Brain Research.

[35]  M. Li,et al.  Structural Changes of Gut Microbiota during Berberine-Mediated Prevention of Obesity and Insulin Resistance in High-Fat Diet-Fed Rats , 2012, PloS one.

[36]  Antje Bruckbauer,et al.  Effects of a Leucine and Pyridoxine-Containing Nutraceutical on Fat Oxidation, and Oxidative and Inflammatory Stress in Overweight and Obese Subjects , 2012, Nutrients.

[37]  Haibo Zhu,et al.  Long-term oral Asperosaponin VI attenuates cardiac dysfunction, myocardial fibrosis in a rat model of chronic myocardial infarction. , 2012, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[38]  Lin-na Wang,et al.  Akebia saponin D attenuates ibotenic acid-induced cognitive deficits and pro-apoptotic response in rats: Involvement of MAPK signal pathway , 2012, Pharmacology Biochemistry and Behavior.

[39]  Hui Sun,et al.  Pattern recognition approaches and computational systems tools for ultra performance liquid chromatography-mass spectrometry-based comprehensive metabolomic profiling and pathways analysis of biological data sets. , 2012, Analytical chemistry.

[40]  Q. Mei,et al.  Asperosaponin VI, A Saponin Component from Dipsacus asper Wall, induces Osteoblast Differentiation through Bone Morphogenetic Protein‐2/p38 and Extracellular Signal‐regulated Kinase 1/2 Pathway , 2011, Phytotherapy research : PTR.

[41]  F. Bushman,et al.  Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes , 2011, Science.

[42]  Haibo Zhu,et al.  Asperosaponin VI protects cardiac myocytes from hypoxia-induced apoptosis via activation of the PI3K/Akt and CREB pathways. , 2010, European journal of pharmacology.

[43]  J. Chen,et al.  Effect of traditional Chinese medicine berberine on type 2 diabetes based on comprehensive metabonomics. , 2010, Talanta.

[44]  Jingwei Tian,et al.  Protective roles of Asperosaponin VI, a triterpene saponin isolated from Dipsacus asper Wall on acute myocardial infarction in rats. , 2010, European journal of pharmacology.

[45]  B. Ma,et al.  Application of GC/MS-based metabonomic profiling in studying the lipid-regulating effects of Ginkgo biloba extract on diet-induced hyperlipidemia in rats , 2009, Acta Pharmacologica Sinica.

[46]  Ping Li,et al.  Akebia saponin D, a saponin component from Dipsacus asper Wall, protects PC 12 cells against amyloid‐β induced cytotoxicity , 2009, Cell biology international.

[47]  E. Fleck,et al.  Statin-associated focal myositis. , 2009, International journal of cardiology.

[48]  R. Reimer,et al.  Dairy protein and leucine alter GLP-1 release and mRNA of genes involved in intestinal lipid metabolism in vitro. , 2009, Nutrition.

[49]  H. Vogel,et al.  Metabolomic profiling of dietary‐induced insulin resistance in the high fat–fed C57BL/6J mouse , 2008, Diabetes, obesity & metabolism.

[50]  M. Zemel,et al.  Leucine and Calcium Regulate Fat Metabolism and Energy Partitioning in Murine Adipocytes and Muscle Cells , 2007, Lipids.

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

[52]  W. Insull Clinical Utility of Bile Acid Sequestrants in the Treatment of Dyslipidemia: A Scientific Review , 2006, Southern medical journal.

[53]  P. G. Boelens,et al.  Glutamine: recent developments in research on the clinical significance of glutamine , 2004, Current opinion in clinical nutrition and metabolic care.

[54]  M. Langman,et al.  Sulphide‐induced energy deficiency in colonic cells is prevented by glucose but not by butyrate , 2002, Alimentary pharmacology & therapeutics.

[55]  K. Kakehi,et al.  Chromatographic and capillary electrophoretic methods for the analysis of nicotinic acid and its metabolites. , 2000, Journal of chromatography. B, Biomedical sciences and applications.

[56]  Hong-Wei Liu,et al.  An insoluble polysaccharide from the sclerotium of Poria cocos improves hyperglycemia, hyperlipidemia and hepatic steatosis in ob/ob mice via modulation of gut microbiota. , 2019, Chinese journal of natural medicines.

[57]  Ying-Yong Zhao,et al.  Metabolomics in dyslipidemia. , 2014, Advances in clinical chemistry.

[58]  A. Neish,et al.  REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY Microbes in Gastrointestinal Health and Disease , 2009 .