Myristica fragrans Extract Regulates Gut Microbes and Metabolites to Attenuate Hepatic Inflammation and Lipid Metabolism Disorders via the AhR–FAS and NF-κB Signaling Pathways in Mice with Non-Alcoholic Fatty Liver Disease

Recent studies have shown that non-alcoholic fatty liver disease (NAFLD) is closely related to the gut microbiome. Myristica fragrans is widely used as a traditional seasoning and has a therapeutic effect on gastrointestinal diseases. Although previous studies have shown that M. fragrans extracts have anti-obesity and anti-diabetes effects in mice fed a high-fat diet, few studies have determined the active components or the corresponding mechanism in vivo. In this study, for the first time, an M. fragrans extract (MFE) was shown to be a prebiotic that regulates gut microbes and metabolites in mice fed a high-fat diet. Bioinformatics, network pharmacology, microbiome, and metabolomics analyses were used to analyze the nutrient–target pathway interactions in mice with NAFLD. The National Center for Biotechnology Information Gene Expression Omnibus database was used to analyze NAFLD-related clinical data sets to predict potential targets. The drug database and disease database were then integrated to perform microbiome and metabolomics analyses to predict the target pathways. The concentrations of inflammatory factors in the serum and liver, such as interleukin-6 and tumor necrosis factor-α, were downregulated by MFE. We also found that the hepatic concentrations of low-density lipoprotein cholesterol, total cholesterol, and triglycerides were decreased after MFE treatment. Inhibition of the nuclear factor kappa B (NF-κB) pathway and downregulation of the fatty acid synthase (FAS)-sterol regulatory element-binding protein 1c pathway resulted in the regulation of inflammation and lipid metabolism by activating tryptophan metabolite–mediated aryl hydrocarbon receptors (AhR). In summary, MFE effectively attenuated inflammation and lipid metabolism disorders in mice with NAFLD through the NF-κB and AhR–FAS pathways.

[1]  Gut microbiota–derived metabolite 3-idoleacetic acid together with LPS induces IL-35+ B cell generation , 2022, Microbiome.

[2]  Yuting Lei,et al.  Berberine improves liver injury induced glucose and lipid metabolic disorders via alleviating ER stress of hepatocytes and modulating gut microbiota in mice. , 2021, Bioorganic & medicinal chemistry.

[3]  Do Yup Lee,et al.  Lactobacillus lactis and Pediococcus pentosaceus‐driven reprogramming of gut microbiome and metabolome ameliorates the progression of non‐alcoholic fatty liver disease , 2021, Clinical and translational medicine.

[4]  N. Everaert,et al.  Intestinal dysbiosis in nonalcoholic fatty liver disease (NAFLD): focusing on the gut–liver axis , 2021, Critical reviews in food science and nutrition.

[5]  Changtao Jiang,et al.  Intestinal hypoxia-inducible factor 2α regulates lactate levels to shape the gut microbiome and alter thermogenesis. , 2021, Cell metabolism.

[6]  N. Giribabu,et al.  Myristic acid defends against testicular oxidative stress, inflammation, apoptosis: Restoration of spermatogenesis, steroidogenesis in diabetic rats. , 2021, Life sciences.

[7]  Wei Chen,et al.  Daily intake of Lactobacillus alleviates autistic-like behaviors by ameliorating the 5-hydroxytryptamine metabolic disorder in VPA-treated rats during weaning and sexual maturation. , 2021, Food & function.

[8]  Wei Chen,et al.  Blautia—a new functional genus with potential probiotic properties? , 2021, Gut microbes.

[9]  Wei Chen,et al.  The Protective Effect of Myristica fragrans Houtt. Extracts Against Obesity and Inflammation by Regulating Free Fatty Acids Metabolism in Nonalcoholic Fatty Liver Disease , 2020, Nutrients.

[10]  P. Calder,et al.  Effect of Probiotic Use on Antibiotic Administration Among Care Home Residents: A Randomized Clinical Trial. , 2020, JAMA.

[11]  Y. Eguchi,et al.  The Signaling Molecule Indole Inhibits Induction of the AR2 Acid Resistance System in Escherichia coli , 2020, Frontiers in Microbiology.

[12]  Y. Sanz,et al.  Depletion of Blautia Species in the Microbiota of Obese Children Relates to Intestinal Inflammation and Metabolic Phenotype Worsening , 2020, mSystems.

[13]  E. Vittinghoff,et al.  Gut microbiome-targeted therapies in nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression. , 2019, The American journal of clinical nutrition.

[14]  J. Raes,et al.  Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study , 2019, Nature Medicine.

[15]  R. Rector,et al.  Prebiotic and probiotic treatment of nonalcoholic fatty liver disease: a systematic review and meta-analysis , 2018, Nutrition reviews.

[16]  Kyongbum Lee,et al.  Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages , 2018, Cell reports.

[17]  F. Gonzalez,et al.  PPARα Mediates the Hepatoprotective Effects of Nutmeg. , 2018, Journal of proteome research.

[18]  G. Mithieux Does Akkermansia muciniphila play a role in type 1 diabetes? , 2018, Gut.

[19]  Joseph L Evans,et al.  Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches , 2018, Redox biology.

[20]  D. Macêdo,et al.  IDO chronic immune activation and tryptophan metabolic pathway: A potential pathophysiological link between depression and obesity , 2018, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[21]  Kouichi Miura,et al.  The Roles of the Gut Microbiota and Toll-like Receptors in Obesity and Nonalcoholic Fatty Liver Disease , 2017, Journal of obesity & metabolic syndrome.

[22]  W. Pan,et al.  Berberine protects against diet-induced obesity through regulating metabolic endotoxemia and gut hormone levels , 2017, Molecular medicine reports.

[23]  K. Kang,et al.  Diarylbutane-type Lignans from Myristica fragrans (Nutmeg) show the Cytotoxicity against Breast Cancer Cells through Activation of AMP-activated Protein Kinase , 2017 .

[24]  Pierre Bedossa,et al.  Pathology of non‐alcoholic fatty liver disease , 2017, Liver international : official journal of the International Association for the Study of the Liver.

[25]  M. Fischbach,et al.  Modulation of a Circulating Uremic Solute via Rational Genetic Manipulation of the Gut Microbiota. , 2016, Cell host & microbe.

[26]  F. Anania,et al.  Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol. , 2016, Gastroenterology.

[27]  F. Bäckhed,et al.  Altered Microbiota Contributes to Reduced Diet-Induced Obesity upon Cold Exposure , 2016, Cell metabolism.

[28]  Gemma K. Alderton Tumour immunology: Intestinal bacteria are in command , 2015, Nature Reviews Immunology.

[29]  Gemma K. Alderton Tumour immunology: Intestinal bacteria are in command , 2015, Nature Reviews Cancer.

[30]  V. Wong,et al.  Nonalcoholic fatty liver disease , 2015, Nature Reviews Disease Primers.

[31]  Chih-Jung Chang,et al.  Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota , 2015, Nature Communications.

[32]  V. Tremaroli,et al.  Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life. , 2015, Cell host & microbe.

[33]  T. Dinan,et al.  Serotonin, tryptophan metabolism and the brain-gut-microbiome axis , 2015, Behavioural Brain Research.

[34]  Kouichi Miura,et al.  TOPIC HIGHLIGHT , 2014 .

[35]  J. Hoffman,et al.  Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets , 2013, Nature Reviews Gastroenterology &Hepatology.

[36]  J. Hoffman,et al.  Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets , 2013, Nature Reviews Gastroenterology &Hepatology.

[37]  A. Gupta,et al.  Chemistry, antioxidant and antimicrobial potential of nutmeg (Myristica fragrans Houtt) , 2013 .

[38]  V. Tremaroli,et al.  Functional interactions between the gut microbiota and host metabolism , 2012, Nature.

[39]  E. Hobeika,et al.  Natural Aryl Hydrocarbon Receptor Ligands Control Organogenesis of Intestinal Lymphoid Follicles , 2011, Science.

[40]  Jinjin Chen,et al.  Bifidobacterium adolescentis supplementation ameliorates visceral fat accumulation and insulin sensitivity in an experimental model of the metabolic syndrome , 2011, British Journal of Nutrition.

[41]  Hyoung‐Chun Kim,et al.  Methyleugenol reduces cerebral ischemic injury by suppression of oxidative injury and inflammation , 2010, Free radical research.

[42]  D. Seo,et al.  AMP-activated protein kinase (AMPK) activators from Myristica fragrans (nutmeg) and their anti-obesity effect. , 2010, Bioorganic & medicinal chemistry letters.

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

[44]  T. J. Zachariah,et al.  Fatty acids and leaf amino acids in Myristica fragrans Houtt. and related taxa , 2006 .

[45]  A. Akindahunsi,et al.  Antioxidant properties of Myristica fragrans (Houtt) and its effect on selected organs of albino rats , 2006 .

[46]  O. Hankinson The aryl hydrocarbon receptor complex. , 1995, Annual review of pharmacology and toxicology.

[47]  S. P. Pathak,et al.  The component glycerides of nutmeg butter (Myristica fragrans) , 1957 .