Fluoride Exposure Induced Bloom of Erysipelatoclostridium Ramosum Mediates the Exacerbation of Obesity in High-fat-diet Fed Mice

Background: Fluoride, a necessary mineral element for our health, is widely presented in drinking water and foods. The intake of excessive fluoride showed potential risk to human health. A strong relation between fluoride exposure and obesity has been reported. However, the knowledge on the potential mechanisms on fluoride-induced obesity is still limited.Results: In this work, we showed here that fluoride alone did not induce obesity in normal diet fed mice, whereas, it could trigger exacerbation of obesity in high-fat diet (HFD) fed mice. Fluoride impaired intestinal barrier and activated Toll-like receptor 4 (TLR4) signaling to induce obesity, which was further verified in TLR4-/- mice. Furthermore, fluoride could deteriorate the gut microbiota in HFD mice. The fecal microbiota transplantation from fluoride-induced mice was sufficient to induce obesity, while the exacerbation of obesity by fluoride was blocked upon gut microbiota depletion. The fluoride-induced bloom of Erysipelatoclostridium ramosum belonged to Erysipelotrichaceae was responsible for the exacerbation of obesity. In addition, a potential strategy for prevention of fluoride-induced obesity was proposed by intervention with polysaccharides from Fuzhuan brick tea.Conclusions: Overall, these results provide the first evidence of a comprehensive cross-talk mechanism between fluoride and obesity in HFD fed mice, which is mediated by gut microbiota and intestinal barrier. E. ramosum was identified as a crucial mediator of fluoride-induced obesity, which could be explored as potential target for prevention and treatment of obesity with exciting translational value.

[1]  G. Seddaiu,et al.  Impacts of soil and water fluoride contamination on the safety and productivity of food and feed crops: A systematic review , 2021 .

[2]  A. Awasthi,et al.  High-salt diet mediates interplay between NK cells and gut microbiota to induce potent tumor immunity , 2021, Science advances.

[3]  K. Mehmood,et al.  Exposure to Fluoride induces apoptosis in liver of ducks by regulating Cyt-C/Caspase 3/9 signaling pathway. , 2021, Ecotoxicology and environmental safety.

[4]  Bian-hua Zhou,et al.  Estrogen Deficiency Aggravates Fluoride-Induced Liver Damage and Lipid Metabolism Disorder in Rats , 2021, Biological Trace Element Research.

[5]  F. Bäckhed,et al.  Feeding diversified protein sources exacerbates hepatic insulin resistance via increased gut microbial branched-chain fatty acids and mTORC1 signaling in obese mice , 2021, Nature Communications.

[6]  A. Pan,et al.  Epidemiology and determinants of obesity in China. , 2021, The lancet. Diabetes & endocrinology.

[7]  Yuan Liu,et al.  Gut microbiome alterations in high-fat-diet-fed mice are associated with antibiotic tolerance , 2021, Nature Microbiology.

[8]  J. Faith,et al.  Food colorants metabolized by commensal bacteria promote colitis in mice with dysregulated expression of interleukin-23. , 2021, Cell metabolism.

[9]  R. Niu,et al.  Co-exposure to inorganic arsenic and fluoride prominently disrupts gut microbiota equilibrium and induces adverse cardiovascular effects in offspring rats. , 2021, The Science of the total environment.

[10]  Patrice D Cani,et al.  Multi‐compartment metabolomics and metagenomics reveal major hepatic and intestinal disturbances in cancer cachectic mice , 2021, Journal of cachexia, sarcopenia and muscle.

[11]  D. Guyonnet,et al.  Shaping the Future of Probiotics and Prebiotics. , 2021, Trends in microbiology.

[12]  A. Dzutsev,et al.  Transkingdom interactions between Lactobacilli and hepatic mitochondria attenuate western diet-induced diabetes , 2021, Nature Communications.

[13]  G. Liebisch,et al.  Bacteroides uniformis combined with fiber amplifies metabolic and immune benefits in obese mice , 2021, Gut microbes.

[14]  L. Niu,et al.  Dietary betaine prevents obesity through gut microbiota-drived microRNA-378a family , 2021, Gut microbes.

[15]  Pengcheng Hu,et al.  The beneficial or detrimental fluoride to gut microbiota depends on its dosages. , 2020, Ecotoxicology and environmental safety.

[16]  Jing Xie,et al.  Correlations between α-Linolenic Acid-Improved Multitissue Homeostasis and Gut Microbiota in Mice Fed a High-Fat Diet , 2020, mSystems.

[17]  Huiping Yuan,et al.  Gut bacteria Akkermansia is associated with reduced risk of obesity: evidence from the American Gut Project , 2020, Nutrition & Metabolism.

[18]  A. Masclee,et al.  Intestinal permeability in human nonalcoholic fatty liver disease: A systematic review and meta‐analysis , 2020, Liver international : official journal of the International Association for the Study of the Liver.

[19]  Patrice D Cani,et al.  Mucus barrier, mucins and gut microbiota: the expected slimy partners? , 2020, Gut.

[20]  O. Pedersen,et al.  Gut microbiota in human metabolic health and disease , 2020, Nature Reviews Microbiology.

[21]  Yi-Xiang J. Wang,et al.  Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites , 2020, Gut.

[22]  A. Grakoui,et al.  Contribution of the Intestinal Microbiome and Gut Barrier to Hepatic Disorders. , 2020, Gastroenterology.

[23]  Hang Xiao,et al.  Foodborne Titanium Dioxide Nanoparticles Induce Stronger Adverse Effects in Obese Mice than Non-Obese Mice: Gut Microbiota Dysbiosis, Colonic Inflammation, and Proteome Alterations. , 2020, Small.

[24]  A. Gupta,et al.  Fluoride and human health: Systematic appraisal of sources, exposures, metabolism, and toxicity , 2020, Critical Reviews in Environmental Science and Technology.

[25]  S. Ng,et al.  Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization , 2020, Gastroenterology.

[26]  Yang Bai,et al.  A practical guide to amplicon and metagenomic analysis of microbiome data , 2020, Protein & Cell.

[27]  M. Nitsche,et al.  Toxicity of fluoride: critical evaluation of evidence for human developmental neurotoxicity in epidemiological studies, animal experiments and in vitro analyses , 2020, Archives of Toxicology.

[28]  X. Ren,et al.  Gut microbiota perturbations and neurodevelopmental impacts in offspring rats concurrently exposure to inorganic arsenic and fluoride. , 2020, Environment international.

[29]  J. Kang,et al.  Modulation of the Gut Microbiota during High-Dose Glycerol Monolaurate-Mediated Amelioration of Obesity in Mice Fed a High-Fat Diet , 2020, mBio.

[30]  R. Seeley,et al.  Leveraging the Gut to Treat Metabolic Disease. , 2020, Cell metabolism.

[31]  S. Strobel,et al.  Principles of fluoride toxicity and the cellular response: a review , 2020, Archives of Toxicology.

[32]  C. Xie,et al.  Alterations in cecal microbiota and intestinal barrier function of laying hens fed on fluoride supplemented diets. , 2020, Ecotoxicology and Environmental Safety.

[33]  Yan Ling,et al.  Hepatocyte-Derived Extracellular Vesicles Promote Endothelial Inflammation and Atherogenesis via microRNA-1. , 2020, Journal of hepatology.

[34]  K. Ishii,et al.  Antigen-specific Mucosal Immunity Regulates Development of Intestinal Bacteria-mediated Diseases. , 2019, Gastroenterology.

[35]  Wence Wang,et al.  Ochratoxin A induces liver inflammation: involvement of intestinal microbiota , 2019, Microbiome.

[36]  K. Kristiansen,et al.  Lysates of Methylococcus capsulatus Bath induce a lean-like microbiota, intestinal FoxP3+RORγt+IL-17+ Tregs and improve metabolism , 2019, Nature Communications.

[37]  Lijun Yao,et al.  γ-Mangostin ameliorates free fatty acid-induced lipid accumulation via the SIRT1/LKB1/AMPK pathway in HepG2 and L02 cells. , 2019, Journal of agricultural and food chemistry.

[38]  Li Liu,et al.  Low-to-moderate fluoride exposure in relation to overweight and obesity among school-age children in China. , 2019, Ecotoxicology and environmental safety.

[39]  Gemma L D'Adamo,et al.  The future of faecal transplants , 2019, Nature Reviews Microbiology.

[40]  G. Reid,et al.  Probiotics and prebiotics in intestinal health and disease: from biology to the clinic , 2019, Nature Reviews Gastroenterology & Hepatology.

[41]  Liang Zhang,et al.  Flavor augmentations affect fluoride bioavailability from brewed dark tea , 2019, LWT.

[42]  Bin Gao,et al.  Fructose Promotes Leaky Gut, Endotoxemia, and Liver Fibrosis Through Ethanol‐Inducible Cytochrome P450‐2E1–Mediated Oxidative and Nitrative Stress , 2019, Hepatology.

[43]  Xiaoxiong Zeng,et al.  Gut microbiota modulation and anti‐inflammatory properties of anthocyanins from the fruits of Lycium ruthenicum Murray in dextran sodium sulfate‐induced colitis in mice , 2019, Free radical biology & medicine.

[44]  M. Camilleri.  Leaky gut: mechanisms, measurement and clinical implications in humans , 2019, Gut.

[45]  K. Venema,et al.  Gut microbial metabolites in obesity, NAFLD and T2DM , 2019, Nature Reviews Endocrinology.

[46]  J. Schrenzel,et al.  Functional Gut Microbiota Remodeling Contributes to the Caloric Restriction-Induced Metabolic Improvements , 2018, Cell metabolism.

[47]  M. Buzalaf,et al.  Effect of Duration of Exposure to Fluoride and Type of Diet on Lipid Parameters and De Novo Lipogenesis , 2018, Biological Trace Element Research.

[48]  D. Ojcius,et al.  Gut commensal Parabacteroides goldsteinii plays a predominant role in the anti-obesity effects of polysaccharides isolated from Hirsutella sinensis , 2018, Gut.

[49]  E. Le Chatelier,et al.  Major microbiota dysbiosis in severe obesity: fate after bariatric surgery , 2018, Gut.

[50]  Kassem M. Makki,et al.  The Impact of Dietary Fiber on Gut Microbiota in Host Health and Disease. , 2018, Cell host & microbe.

[51]  Bradley W. Bolling,et al.  A common antimicrobial additive increases colonic inflammation and colitis-associated colon tumorigenesis in mice , 2018, Science Translational Medicine.

[52]  Chenhong Zhang,et al.  Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes , 2018, Science.

[53]  Rob Knight,et al.  American Gut: an Open Platform for Citizen Science Microbiome Research , 2018, mSystems.

[54]  Xiaoxiong Zeng,et al.  Kudingcha and Fuzhuan Brick Tea Prevent Obesity and Modulate Gut Microbiota in High‐Fat Diet Fed Mice , 2018, Molecular nutrition & food research.

[55]  J. Edwardson,et al.  The effect of fluoride on the structure, function, and proteome of intestinal epithelia , 2018, Environmental toxicology.

[56]  R. L. Nielsen,et al.  Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: a randomised cross-over trial , 2017, Gut.

[57]  C. Huttenhower,et al.  Fluoride Depletes Acidogenic Taxa in Oral but Not Gut Microbial Communities in Mice , 2017, mSystems.

[58]  T. R. Licht,et al.  High-fat feeding rather than obesity drives taxonomical and functional changes in the gut microbiota in mice , 2017, Microbiome.

[59]  M. Buzalaf,et al.  Fluoride Intensifies Hypercaloric Diet-Induced ER Oxidative Stress and Alters Lipid Metabolism , 2016, PloS one.

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

[61]  J. Delcour,et al.  A Critical Look at Prebiotics Within the Dietary Fiber Concept. , 2016, Annual review of food science and technology.

[62]  N. Kaakoush.  Insights into the Role of Erysipelotrichaceae in the Human Host , 2015, Front. Cell. Infect. Microbiol..

[63]  R. Knight,et al.  The gut microbiota in human energy homeostasis and obesity , 2015, Trends in Endocrinology & Metabolism.

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

[65]  A. Rigalli,et al.  Low-Level Fluoride Exposure Increases Insulin Sensitivity in Experimental Diabetes , 2015, Journal of dental research.

[66]  N. Sravanthi,et al.  Rutin potentially attenuates fluoride-induced oxidative stress-mediated cardiotoxicity, blood toxicity and dyslipidemia in rats , 2015, Toxicology mechanisms and methods.

[67]  M. Blaut,et al.  Clostridium ramosum Promotes High-Fat Diet-Induced Obesity in Gnotobiotic Mouse Models , 2014, mBio.

[68]  E. Segal,et al.  Artificial sweeteners induce glucose intolerance by altering the gut microbiota , 2014, Nature.

[69]  Michael Y. Galperin,et al.  A genomic update on clostridial phylogeny: Gram-negative spore formers and other misplaced clostridia. , 2013, Environmental microbiology.

[70]  K. Eskridge,et al.  Diet-Induced Alterations of Host Cholesterol Metabolism Are Likely To Affect the Gut Microbiota Composition in Hamsters , 2012, Applied and Environmental Microbiology.

[71]  S. Rayalu,et al.  Fluoride in drinking water and defluoridation of water. , 2012, Chemical reviews.

[72]  L. D. Del Razo,et al.  Fluoride exposure impairs glucose tolerance via decreased insulin expression and oxidative stress. , 2009, Toxicology.

[73]  S. Ayoob,et al.  Fluoride in Drinking Water: A Review on the Status and Stress Effects , 2006 .

[74]  Da-xiang Li,et al.  Analysis of Naturally Occurring Fluoride in Commercial Teas and Estimation of Its Daily Intake through Tea Consumption. , 2016, Journal of food science.

[75]  Zhonghua Liu,et al.  Bioactive Constituents , Metabolites , and Functions Fuzhuan brick tea polysaccharides attenuate metabolic syndrome in high-fat diet induced mice in association with modulation in the gut microbiota , 2022 .