Honokiol Ameliorates High-Fat-Diet-Induced Obesity of Different Sexes of Mice by Modulating the Composition of the Gut Microbiota

Background: Accumulating data support the fact that the gut microbiota plays an important role in the progression of obesity and its related metabolic disease. Sex-related differences are an important consideration in the study of gut microbiota. Polyphenols can regulate gut microbiota, thereby improving obesity and its associated complications. There have been no studies conducted on the ability of honokiol (HON, an extract from Chinese herbal medicine) to regulate gut microbiota. The aim of this study was to examine whether HON supplementation would improve obesity by regulating the gut microbiota and its related metabolite levels, and whether there were sex-based differences in high-fat diet-induced obese mice. Methods: C57BL/6 mice (n = 120) were fed a normal chow diet (ND group), high-fat diet (HFD group), or HFD plus HON at 200, 400, and 800 mg/kg BW for 8 weeks. Body weight, adipose tissue weight, adipocyte diameter, insulin resistance, blood lipid and serum inflammatory cytokines, gut microbiota, and its metabolite were examined at the end of the experiment. Results: The HON supplementation reduced body weight, adipose tissue weight, adipocyte diameter, insulin resistance, blood lipid, and serum inflammatory cytokine levels in HFD-fed mice, and this effect was significant in the high-dose group. In addition, HON not only reversed gut disorders in HFD-fed mice, such as by enhanced the abundance of Akkermansia and short-chain fatty acids (SCFAs) producing Bacteroides and reduced Oscillospira, but also improved the SCFAs and endotoxin (LPS) levels, although there were sex-based differences. The correlation between several specific genera and obesity-related indexes was revealed through Spearman's correlation analysis. Moreover, HON may have dose-dependent effects on regulating gut microbiota to alleviate obesity. Conclusions: These findings suggest that HON can prevent diet-induced obesity and its associated diseases by regulating the gut microbiota and improving microbial metabolite levels. Moreover, our findings indicate that sex may be an important factor affecting HON activity.

[1]  Xiaosong Hu,et al.  Resveratrol-induced gut microbiota reduces obesity in high-fat diet-fed mice , 2019, International Journal of Obesity.

[2]  B. Zhu,et al.  Sulfated Polysaccharide from Sea Cucumber and its Depolymerized Derivative Prevent Obesity in Association with Modification of Gut Microbiota in High‐Fat Diet‐Fed Mice , 2018, Molecular nutrition & food research.

[3]  C. Shively,et al.  Gut Microbiome Composition in Non-human Primates Consuming a Western or Mediterranean Diet , 2018, Front. Nutr..

[4]  F. Andreotti,et al.  Mechanisms, Pathophysiology, and Management of Obesity. , 2017, The New England journal of medicine.

[5]  S. Cocozza,et al.  Sex-related alterations of gut microbiota composition in the BTBR mouse model of autism spectrum disorder , 2017, Scientific Reports.

[6]  C. Pepine,et al.  Hypertension-Linked Pathophysiological Alterations in the Gut , 2017, Circulation research.

[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]  K. Qi,et al.  Short Chain Fatty Acids Prevent High-fat-diet-induced Obesity in Mice by Regulating G Protein-coupled Receptors and Gut Microbiota , 2016, Scientific Reports.

[9]  T. Shoji,et al.  Non-absorbable apple procyanidins prevent obesity associated with gut microbial and metabolomic changes , 2016, Scientific Reports.

[10]  T. Drake,et al.  Sex differences and hormonal effects on gut microbiota composition in mice , 2016, Gut microbes.

[11]  J. Clemente,et al.  Intestinal Microbiota Is Influenced by Gender and Body Mass Index , 2016, PloS one.

[12]  J. F. Stevens,et al.  The chemistry of gut microbial metabolism of polyphenols , 2016, Phytochemistry Reviews.

[13]  R. Gomis,et al.  Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice , 2015, Scientific Reports.

[14]  K. Chang,et al.  Honokiol activates the LKB1-AMPK signaling pathway and attenuates the lipid accumulation in hepatocytes. , 2015, Toxicology and applied pharmacology.

[15]  Young Woo Kim,et al.  Combination of honokiol and magnolol inhibits hepatic steatosis through AMPK-SREBP-1 c pathway , 2015, Experimental biology and medicine.

[16]  K. Svenson,et al.  Diet dominates host genotype in shaping the murine gut microbiota. , 2015, Cell host & microbe.

[17]  Angela C. Poole,et al.  Human Genetics Shape the Gut Microbiome , 2014, Cell.

[18]  Wen Jiang,et al.  Application of high-throughput sequencing in understanding human oral microbiome related with health and disease , 2014, Front. Microbiol..

[19]  R. Knight,et al.  Individual diet has sex-dependent effects on vertebrate gut microbiota , 2014, Nature Communications.

[20]  Patrice D Cani,et al.  Saccharomyces boulardii Administration Changes Gut Microbiota and Reduces Hepatic Steatosis, Low-Grade Inflammation, and Fat Mass in Obese and Type 2 Diabetic db/db Mice , 2014, mBio.

[21]  Jimmy D Bell,et al.  The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism , 2014, Nature Communications.

[22]  Y. Belkaid,et al.  Role of the Microbiota in Immunity and Inflammation , 2014, Cell.

[23]  E. El-Omar,et al.  Role of the gut microbiota in inflammatory bowel disease pathogenesis: what have we learnt in the past 10 years? , 2014, World journal of gastroenterology.

[24]  F. Bäckhed,et al.  Microbiota-Generated Metabolites Promote Metabolic Benefits via Gut-Brain Neural Circuits , 2014, Cell.

[25]  B. Cha,et al.  Long-term supplementation of honokiol and magnolol ameliorates body fat accumulation, insulin resistance, and adipose inflammation in high-fat fed mice. , 2013, Molecular nutrition & food research.

[26]  P. Bork,et al.  Richness of human gut microbiome correlates with metabolic markers , 2013, Nature.

[27]  Ling Wei,et al.  Neuro-Modulating Effects of Honokiol: A Review , 2013, Front. Neurol..

[28]  Myung-Shik Lee,et al.  An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice , 2013, Gut.

[29]  Lucie Geurts,et al.  Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity , 2013, Proceedings of the National Academy of Sciences.

[30]  Leah M. Feazel,et al.  Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity , 2013, Science.

[31]  Liping Zhao,et al.  The gut microbiota, obesity and insulin resistance. , 2013, Molecular aspects of medicine.

[32]  S. Tims,et al.  Microbiota conservation and BMI signatures in adult monozygotic twins , 2012, The ISME Journal.

[33]  Y. Sanz,et al.  Bacteroides uniformis CECT 7771 Ameliorates Metabolic and Immunological Dysfunction in Mice with High-Fat-Diet Induced Obesity , 2012, PloS one.

[34]  Katherine H. Huang,et al.  Structure, Function and Diversity of the Healthy Human Microbiome , 2012, Nature.

[35]  M. Rossmeisl,et al.  Sex differences during the course of diet-induced obesity in mice: adipose tissue expandability and glycemic control , 2012, International Journal of Obesity.

[36]  Zai-Qun Liu,et al.  Comparison of antioxidant abilities of magnolol and honokiol to scavenge radicals and to protect DNA. , 2011, Biochimie.

[37]  C. Ge,et al.  ANTIMICROBIAL ACTIVITY OF MAGNOLIA OFFICINALIS EXTRACTS IN VITRO AND ITS EFFECTS ON THE PRESERVATION OF CHILLED MUTTON , 2011 .

[38]  Youfang Cao,et al.  Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice , 2010, The ISME Journal.

[39]  Susan M. Huse,et al.  Defining the healthy "core microbiome" of oral microbial communities , 2009, BMC Microbiology.

[40]  C. Picó,et al.  Sex-associated differences in the leptin and ghrelin systems related with the induction of hyperphagia under high-fat diet exposure in rats , 2009, Hormones and Behavior.

[41]  R. Bibiloni,et al.  Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice , 2008, Diabetes.

[42]  L. Fulton,et al.  Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. , 2008, Cell host & microbe.

[43]  H. Hayashida,et al.  Comment on: Cani et al. (2007) Metabolic Endotoxemia Initiates Obesity and Insulin Resistance: Diabetes 56:1761–1772 , 2007, Diabetes.

[44]  A. Ramette Multivariate analyses in microbial ecology , 2007, FEMS microbiology ecology.

[45]  C. Knauf,et al.  Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia , 2007, Diabetologia.

[46]  Jeffrey I. Gordon,et al.  Mechanisms underlying the resistance to diet-induced obesity in germ-free mice , 2007, Proceedings of the National Academy of Sciences.

[47]  R. Knight,et al.  Quantitative and Qualitative β Diversity Measures Lead to Different Insights into Factors That Structure Microbial Communities , 2007, Applied and Environmental Microbiology.

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

[49]  P. B. Thompson,et al.  You Are What You Eat , 2006, Science.

[50]  F. Bäckhed,et al.  Obesity alters gut microbial ecology. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[51]  J. Doré,et al.  Colonic Microbiota Signatures across Five Northern European Countries , 2005, Applied and Environmental Microbiology.

[52]  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.

[53]  H. Nishino,et al.  Studies on inhibitors of skin tumor promotion, IX. Neolignans from Magnolia officinalis. , 1991, Journal of natural products.

[54]  David Brink,et al.  : A Review of the , 2018 .

[55]  Guoyun Li,et al.  Dietary fucoidan improves metabolic syndrome in association with increased Akkermansia population in the gut microbiota of high-fat diet-fed mice , 2017 .

[56]  Worldwide trends in children’s and adolescents’ body mass index, underweight, overweight and obesity, in comparison with adults, from 1975 to 2016: a pooled analysis of 2,416 population-based measurement studies with 128.9 million participants NCD Risk Factor Collaboration (NCD-RisC)* , 2017 .

[57]  Subrata Ghosh,et al.  Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. , 2012, Gastroenterology.

[58]  C. Knauf,et al.  Comment on: Cani et al. (2007) Metabolic Endotoxemia Initiates Obesity and Insulin Resistance: Diabetes , 2007 .