Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Gut Microbiota, Obesity and Bariatric Surgery: Current Knowledge and Future Perspectives

Author(s): Adriana Florinela Cӑtoi, Dan Cristian Vodnar, Andreea Corina, Dragana Nikolic*, Roberto Citarrella, Pablo Pérez-Martínez and Manfredi Rizzo

Volume 25, Issue 18, 2019

Page: [2038 - 2050] Pages: 13

DOI: 10.2174/1381612825666190708190437

Price: $65

Abstract

Background: There is an urgent need for a better understanding and management of obesity and obesity- associated diseases. It is known that obesity is associated with structural and functional changes in the microbiome.

Methods: The purpose of this review is to present current evidence from animal and human studies, demonstrating the effects and the potential efficacy of microbiota modulation in improving obesity and associated metabolic dysfunctions.

Results: This review discusses possible mechanisms linking gut microbiota dysbiosis and obesity, since there is a dual interaction between the two of them. Furthermore, comments on bariatric surgery, as a favourable model to understand the underlying metabolic and inflammatory effects, as well as its association with changes in the composition of the gut microbiota, are included. Also, a possible impact of anti-obesity drugs and the novel antidiabetic drugs on the gut microbiota has been briefly discussed.

Conclusion: More research is needed to better understand here discussed the association between microbiota modulation and obesity. It is expected that research in this field, in the following years, will lead to a personalized therapeutic approach considering the patient’s microbiome, and also give rise to the discovery of new drugs and/or the combination therapies for the management of obesity and obesity-related co-morbidities.

Keywords: Adiposity, bariatric surgery, inflammation, microbiota, obesity, obesity-associated diseases.

[1]
Nikolic D, Katsiki N, Montalto G, Isenovic ER, Mikhailidis DP, Rizzo M. Lipoprotein subfractions in metabolic syndrome and obesity: Clinical significance and therapeutic approaches. Nutrients 2013; 5(3): 928-48. [http://dx.doi.org/10.3390/nu5030928]. [PMID: 23507795].
[2]
Papanas N, Katsiki N, Putz Z, Mikhailidis DP. Diabetes, obesity and vascular disease--an update. Curr Pharm Des 2013; 19(27): 4900-3. [http://dx.doi.org/10.2174/1381612811319270013]. [PMID: 23278495].
[3]
Katsiki N, Perez-Martinez P, Anagnostis P, Mikhailidis DP, Karagiannis A. Is nonalcoholic fatty liver disease indeed the hepatic manifestation of metabolic syndrome? Curr Vasc Pharmacol 2018; 16(3): 219-27. [http://dx.doi.org/10.2174/1570161115666170621075619]. [PMID: 28669328].
[4]
Cani PD. Gut Microbiome and Obesity: lessons from the microbiom. Brief Funct Genomics 2013; 12(4): 381-7. [http://dx.doi.org/10.1201/b16473-19].
[5]
Castaner O, Goday A, Park YM, et al. The gut microbiome profile in obesity: A systematic review. Int J Endocrinol 2018; 2018: 4095789. [http://dx.doi.org/10.1155/2018/4095789]. [PMID: 29849617].
[6]
Martinez KB, Pierre JF, Chang EB. The gut microbiota: The gateway to improved metabolism. Gastroenterol Clin North Am 2016; 45(4): 601-14. [http://dx.doi.org/10.1016/j.gtc.2016.07.001]. [PMID: 27837775].
[7]
Maruvada P, Leone V, Kaplan LM, Chang EB. The human microbiome and obesity: Moving beyond associations. Cell Host Microbe 2017; 22(5): 589-99. [http://dx.doi.org/10.1016/j.chom.2017.10.005]. [PMID: 29120742].
[8]
Duranti S, Ferrario C, van Sinderen D, Ventura M, Turroni F. Obesity and microbiota: An example of an intricate relationship. Genes Nutr 2017; 12: 18. [http://dx.doi.org/10.1186/s12263-017-0566-2]. [PMID: 28638490].
[9]
Stefan N, Häring HU, Schulze MB. Metabolically healthy obesity: The low-hanging fruit in obesity treatment? Lancet Diabetes Endocrinol 2018; 6(3): 249-58. [http://dx.doi.org/10.1016/S2213-8587(17)30292-9]. [PMID: 28919065].
[10]
Tuccinardi D, Farr OM, Upadhyay J, et al. Lorcaserin treatment decreases body weight and reduces cardiometabolic risk factors in obese adults: A six-month, randomized, placebo-controlled, double-blind clinical trial. Diabetes Obes Metab 2019; 21(6): 1487-92. [http://dx.doi.org/10.1111/dom.13655]. [PMID: 30724455].
[11]
Katsiki N, Hatzitolios AI, Mikhailidis DP. Naltrexone sustained-release (SR) + bupropion SR combination therapy for the treatment of obesity: ‘A new kid on the block’? Ann Med 2011; 43(4): 249-58. [http://dx.doi.org/10.3109/07853890.2010.541490]. [PMID: 21254901].
[13]
Miras AD, le Roux CW. Can medical therapy mimic the clinical efficacy or physiological effects of bariatric surgery? Int J Obes 2014; 38(3): 325-33. [http://dx.doi.org/10.1038/ijo.2013.205]. [PMID: 24213310].
[14]
Anhê FF, Roy D, Pilon G, et al. A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut 2015; 64(6): 872-83. [http://dx.doi.org/10.1136/gutjnl-2014-307142]. [PMID: 25080446].
[15]
Cardinelli CS, Sala PC, Alves CC, Torrinhas RS, Waitzberg DL. Influence of intestinal microbiota on body weight gain: A narrative review of the literature. Obes Surg 2015; 25(2): 346-53. [http://dx.doi.org/10.1007/s11695-014-1525-2]. [PMID: 25511750].
[16]
Villanueva-Millán MJ, Pérez-Matute P, Oteo JA. Gut microbiota: A key player in health and disease. A review focused on obesity. J Physiol Biochem 2015; 71(3): 509-25. [http://dx.doi.org/10.1007/s13105-015-0390-3]. [PMID: 25749935].
[17]
Guarner F, Malagelada JR. Gut flora in health and disease. Lancet 2003; 361(9356): 512-9. [http://dx.doi.org/10.1016/S0140-6736(03)12489-0]. [PMID: 12583961].
[18]
Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 2016; 14(8): e1002533. [http://dx.doi.org/10.1371/journal.pbio.1002533]. [PMID: 27541692].
[19]
Sender R, Fuchs S, Milo R. Are We Really Vastly Outnumbered? Revisiting the Ratio of Bacterial to Host Cells in Humans. Cell 2016; 164(3): 337-40. [http://dx.doi.org/10.1016/j.cell.2016.01.013]. [PMID: 26824647].
[20]
Andersson AF, Lindberg M, Jakobsson H, Bäckhed F, Nyrén P, Engstrand L. Comparative analysis of human gut microbiota by barcoded pyrosequencing. PLoS One 2008; 3(7): e2836. [http://dx.doi.org/10.1371/journal.pone.0002836]. [PMID: 18665274].
[21]
Angelakis E, Armougom F, Million M, Raoult D. The relationship between gut microbiota and weight gain in humans. Future Microbiol 2012; 7(1): 91-109. [http://dx.doi.org/10.2217/fmb.11.142]. [PMID: 22191449].
[22]
O’Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep 2006; 7(7): 688-93. [http://dx.doi.org/10.1038/sj.embor.7400731]. [PMID: 16819463].
[23]
Compare D, Rocco A, Sanduzzi Zamparelli M, Nardone G. The Gut Bacteria-Driven Obesity Development. Dig Dis 2016; 34(3): 221-9. [http://dx.doi.org/10.1159/000443356]. [PMID: 27028448].
[24]
Zhernakova A, Kurilshikov A, Bonder MJ, et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 2016; 352(6285): 565-9. [http://dx.doi.org/10.1126/science.aad3369]. [PMID: 27126040].
[25]
Mohajeri MH, Brummer RJM, Rastall RA, et al. The role of the microbiome for human health: From basic science to clinical applications. Eur J Nutr 2018; 57(Suppl. 1): 1-14. [http://dx.doi.org/10.1007/s00394-018-1703-4]. [PMID: 29748817].
[26]
Fu J, Bonder MJ, Cenit MC, et al. The gut microbiome contributes to a substantial proportion of the variation in blood lipids. Circ Res 2015; 117(9): 817-24. [http://dx.doi.org/10.1161/CIRCRESAHA.115.306807]. [PMID: 26358192].
[27]
Tamboli CP, Neut C, Desreumaux P, Colombel JF. Dysbiosis in inflammatory bowel disease. Gut 2004; 53(1): 1-4. [http://dx.doi.org/10.1136/gut.53.1.1]. [PMID: 14684564].
[28]
Nyangale EP, Mottram DS, Gibson GR. Gut microbial activity, implications for health and disease: The potential role of metabolite analysis. J Proteome Res 2012; 11(12): 5573-85. [http://dx.doi.org/10.1021/pr300637d]. [PMID: 23116228].
[29]
DuPont AW, DuPont HL. The intestinal microbiota and chronic disorders of the gut. Nat Rev Gastroenterol Hepatol 2011; 8(9): 523-31. [http://dx.doi.org/10.1038/nrgastro.2011.133]. [PMID: 21844910].
[30]
Omer E, Atassi H. The microbiome that shapes us: Can it cause obesity? Curr Gastroenterol Rep 2017; 19(12): 59. [http://dx.doi.org/10.1007/s11894-017-0600-y]. [PMID: 29080046].
[31]
Seganfredo FB, Blume CA, Moehlecke M, et al. Weight-loss interventions and gut microbiota changes in overweight and obese patients: A systematic review. Obes Rev 2017; 18(8): 832-51. [http://dx.doi.org/10.1111/obr.12541]. [PMID: 28524627].
[32]
Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 2004; 101(44): 15718-23. [http://dx.doi.org/10.1073/pnas.0407076101]. [PMID: 15505215].
[33]
Ley RE, Bäckhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci USA 2005; 102(31): 11070-5. [http://dx.doi.org/10.1073/pnas.0504978102]. [PMID: 16033867].
[34]
Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444(7122): 1027-31. [http://dx.doi.org/10.1038/nature05414]. [PMID: 17183312].
[35]
Turnbaugh PJ, Bäckhed F, Fulton L, Gordon JI. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 2008; 3(4): 213-23. [http://dx.doi.org/10.1016/j.chom.2008.02.015]. [PMID: 18407065].
[36]
Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: Human gut microbes associated with obesity. Nature 2006; 444(7122): 1022-3. [http://dx.doi.org/10.1038/4441022a]. [PMID: 17183309].
[37]
Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature 2009; 457(7228): 480-4. [http://dx.doi.org/10.1038/nature07540]. [PMID: 19043404].
[38]
Rahat-Rozenbloom S, Fernandes J, Gloor GB, Wolever TM. Evidence for greater production of colonic short-chain fatty acids in overweight than lean humans. Int J Obes 2014; 38(12): 1525-31. [http://dx.doi.org/10.1038/ijo.2014.46]. [PMID: 24642959].
[39]
Aron-Wisnewsky J, Prifti E, Belda E, et al. Major microbiota dysbiosis in severe obesity: Fate after bariatric surgery. Gut 2019; 68(1): 70-82. [http://dx.doi.org/10.1136/gutjnl-2018-316103]. [PMID: 29899081].
[40]
Kasai C, Sugimoto K, Moritani I, et al. Comparison of the gut microbiota composition between obese and non-obese individuals in a Japanese population, as analyzed by terminal restriction fragment length polymorphism and next-generation sequencing. BMC Gastroenterol 2015; 15: 100. [http://dx.doi.org/10.1186/s12876-015-0330-2]. [PMID: 26261039].
[41]
Abdallah Ismail N, Ragab SH, Abd Elbaky A, Shoeib AR, Alhosary Y, Fekry D. Frequency of Firmicutes and Bacteroidetes in gut microbiota in obese and normal weight Egyptian children and adults. Arch Med Sci 2011; 7(3): 501-7. [http://dx.doi.org/10.5114/aoms.2011.23418]. [PMID: 22295035].
[42]
Duncan SH, Lobley GE, Holtrop G, et al. Human colonic microbiota associated with diet, obesity and weight loss. Int J Obes 2008; 32(11): 1720-4. [http://dx.doi.org/10.1038/ijo.2008.155]. [PMID: 18779823].
[43]
Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature 2011; 473(7346): 174-80. [http://dx.doi.org/10.1038/nature09944]. [PMID: 21508958].
[44]
Finucane MM, Sharpton TJ, Laurent TJ, Pollard KS. A taxonomic signature of obesity in the microbiome? Getting to the guts of the matter. PLoS One 2014; 9(1): e84689. [http://dx.doi.org/10.1371/journal.pone.0084689]. [PMID: 24416266].
[45]
Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI. The effect of diet on the human gut microbiome: A metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 2009; 1(6): 6ra14. [http://dx.doi.org/10.1126/scitranslmed.3000322]. [PMID: 20368178].
[46]
Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA 2007; 104(3): 979-84. [http://dx.doi.org/10.1073/pnas.0605374104]. [PMID: 17210919].
[47]
Fleissner CK, Huebel N, Abd El-Bary MM, Loh G, Klaus S, Blaut M. Absence of intestinal microbiota does not protect mice from diet-induced obesity. Br J Nutr 2010; 104(6): 919-29. [http://dx.doi.org/10.1017/S0007114510001303]. [PMID: 20441670].
[48]
Sonnenburg ED, Smits SA, Tikhonov M, Higginbottom SK, Wingreen NS, Sonnenburg JL. Diet-induced extinctions in the gut microbiota compound over generations. Nature 2016; 529(7585): 212-5. [http://dx.doi.org/10.1038/nature16504]. [PMID: 26762459].
[49]
Carmody RN, Gerber GK, Luevano JM Jr, et al. Diet dominates host genotype in shaping the murine gut microbiota. Cell Host Microbe 2015; 17(1): 72-84. [http://dx.doi.org/10.1016/j.chom.2014.11.010]. [PMID: 25532804].
[50]
Murphy EF, Cotter PD, Healy S, et al. Composition and energy harvesting capacity of the gut microbiota: Relationship to diet, obesity and time in mouse models. Gut 2010; 59(12): 1635-42. [http://dx.doi.org/10.1136/gut.2010.215665]. [PMID: 20926643].
[51]
Ridaura VK, Faith JJ, Rey FE, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 2013; 341(6150): 1241214. [http://dx.doi.org/10.1126/science.1241214]. [PMID: 24009397].
[52]
Zhang C, Zhang M, Wang S, et al. Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice. ISME J 2010; 4(2): 232-41. [http://dx.doi.org/10.1038/ismej.2009.112]. [PMID: 19865183].
[53]
David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014; 505(7484): 559-63. [http://dx.doi.org/10.1038/nature12820]. [PMID: 24336217].
[54]
Caricilli AM, Saad MJ. Gut microbiota composition and its effects on obesity and insulin resistance. Curr Opin Clin Nutr Metab Care 2014; 17(4): 312-8. [http://dx.doi.org/10.1097/MCO.0000000000000067]. [PMID: 24848531].
[55]
Shen J, Obin MS, Zhao L. The gut microbiota, obesity and insulin resistance. Mol Aspects Med 2013; 34(1): 39-58. [http://dx.doi.org/10.1016/j.mam.2012.11.001]. [PMID: 23159341].
[56]
Larsson E, Tremaroli V, Lee YS, et al. Analysis of gut microbial regulation of host gene expression along the length of the gut and regulation of gut microbial ecology through MyD88. Gut 2012; 61(8): 1124-31. [http://dx.doi.org/10.1136/gutjnl-2011-301104]. [PMID: 22115825].
[57]
Boulangé CL, Neves AL, Chilloux J, Nicholson JK, Dumas ME. Impact of the gut microbiota on inflammation, obesity, and metabolic disease. Genome Med 2016; 8(1): 42. [http://dx.doi.org/10.1186/s13073-016-0303-2]. [PMID: 27098727].
[58]
Le Chatelier E, Nielsen T, Qin J, et al. Richness of human gut microbiome correlates with metabolic markers. Nature 2013; 500(7464): 541-6. [http://dx.doi.org/10.1038/nature12506]. [PMID: 23985870].
[59]
Khan MJ, Gerasimidis K, Edwards CA, Shaikh MG. Role of Gut Microbiota in the Aetiology of Obesity: Proposed Mechanisms and Review of the Literature. J Obes 2016; 2016: 7353642. [http://dx.doi.org/10.1155/2016/7353642]. [PMID: 27703805].
[60]
Jacobs DM, Gaudier E, van Duynhoven J, Vaughan EE. Non-digestible food ingredients, colonic microbiota and the impact on gut health and immunity: A role for metabolomics. Curr Drug Metab 2009; 10(1): 41-54. [http://dx.doi.org/10.2174/138920009787048383]. [PMID: 19149512].
[61]
Krajmalnik-Brown R, Ilhan ZE, Kang DW, DiBaise JK. Effects of gut microbes on nutrient absorption and energy regulation. Nutr Clin Pract 2012; 27(2): 201-14. [http://dx.doi.org/10.1177/0884533611436116]. [PMID: 22367888].
[62]
Rowland I, Gibson G, Heinken A, et al. Gut microbiota functions: Metabolism of nutrients and other food components. Eur J Nutr 2018; 57(1): 1-24. [http://dx.doi.org/10.1007/s00394-017-1445-8]. [PMID: 28393285].
[63]
De Vadder F, Kovatcheva-Datchary P, Goncalves D, et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 2014; 156(1-2): 84-96. [http://dx.doi.org/10.1016/j.cell.2013.12.016]. [PMID: 24412651].
[64]
Hur KY, Lee MS. Gut microbiota and metabolic disorders. Diabetes Metab J 2015; 39(3): 198-203. [http://dx.doi.org/10.4093/dmj.2015.39.3.198]. [PMID: 26124989].
[65]
Delaere F, Duchampt A, Mounien L, et al. The role of sodium-coupled glucose co-transporter 3 in the satiety effect of portal glucose sensing. Mol Metab 2012; 2(1): 47-53. [http://dx.doi.org/10.1016/j.molmet.2012.11.003]. [PMID: 24024129].
[66]
Frost G, Sleeth ML, Sahuri-Arisoylu M, et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun 2014; 5: 3611. [http://dx.doi.org/10.1038/ncomms4611]. [PMID: 24781306].
[67]
Roberfroid M, Gibson GR, Hoyles L, et al. Prebiotic effects: Metabolic and health benefits. Br J Nutr 2010; 104(Suppl. 2): S1-S63. [http://dx.doi.org/10.1017/S0007114510003363]. [PMID: 20920376].
[68]
Cani PD, Neyrinck AM, Maton N, Delzenne NM. Oligofructose promotes satiety in rats fed a high-fat diet: Involvement of glucagon-like Peptide-1. Obes Res 2005; 13(6): 1000-7. [http://dx.doi.org/10.1038/oby.2005.117]. [PMID: 15976142].
[69]
Cani PD, Joly E, Horsmans Y, Delzenne NM. Oligofructose promotes satiety in healthy human: A pilot study. Eur J Clin Nutr 2006; 60(5): 567-72. [http://dx.doi.org/10.1038/sj.ejcn.1602350]. [PMID: 16340949].
[70]
Keenan MJ, Zhou J, McCutcheon KL, et al. Effects of resistant starch, a non-digestible fermentable fiber, on reducing body fat. Obesity (Silver Spring) 2006; 14(9): 1523-34. [http://dx.doi.org/10.1038/oby.2006.176]. [PMID: 17030963].
[71]
Zhou J, Martin RJ, Tulley RT, et al. Dietary resistant starch upregulates total GLP-1 and PYY in a sustained day-long manner through fermentation in rodents. Am J Physiol Endocrinol Metab 2008; 295(5): E1160-6. [http://dx.doi.org/10.1152/ajpendo.90637.2008]. [PMID: 18796545].
[72]
Shen L, Keenan MJ, Martin RJ, et al. Dietary resistant starch increases hypothalamic POMC expression in rats. Obesity (Silver Spring) 2009; 17(1): 40-5. [http://dx.doi.org/10.1038/oby.2008.483]. [PMID: 18948970].
[73]
Dewulf EM, Cani PD, Neyrinck AM, et al. Inulin-type fructans with prebiotic properties counteract GPR43 overexpression and PPARγ-related adipogenesis in the white adipose tissue of high-fat diet-fed mice. J Nutr Biochem 2011; 22(8): 712-22. [http://dx.doi.org/10.1016/j.jnutbio.2010.05.009]. [PMID: 21115338].
[74]
Bergman EN. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol Rev 1990; 70(2): 567-90. [http://dx.doi.org/10.1152/physrev.1990.70.2.567]. [PMID: 2181501].
[75]
Aronsson L, Huang Y, Parini P, et al. Decreased fat storage by Lactobacillus paracasei is associated with increased levels of angiopoietin-like 4 protein (ANGPTL4). PLoS One 2010; 5(9): 5. [http://dx.doi.org/10.1371/journal.pone.0013087]. [PMID: 20927337].
[76]
Winder WW, Hardie DG. AMP-activated protein kinase, a metabolic master switch: Possible roles in type 2 diabetes. Am J Physiol 1999; 277(1): E1-E10. [PMID: 10409121].
[77]
Fu X, Zhu M, Zhang S, Foretz M, Viollet B, Du M. Obesity Impairs Skeletal Muscle Regeneration Through Inhibition of AMPK. Diabetes 2016; 65(1): 188-200. [PMID: 26384382].
[78]
Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002; 8(11): 1288-95. [http://dx.doi.org/10.1038/nm788]. [PMID: 12368907].
[79]
Noga AA, Vance DE. A gender-specific role for phosphatidylethanolamine N-methyltransferase-derived phosphatidylcholine in the regulation of plasma high density and very low density lipoproteins in mice. J Biol Chem 2003; 278(24): 21851-9. [http://dx.doi.org/10.1074/jbc.M301982200]. [PMID: 12668679].
[80]
Dumas ME, Barton RH, Toye A, et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci USA 2006; 103(33): 12511-6. [http://dx.doi.org/10.1073/pnas.0601056103]. [PMID: 16895997].
[81]
Cole LK, Vance JE, Vance DE. Phosphatidylcholine biosynthesis and lipoprotein metabolism. Biochim Biophys Acta 2012; 1821(5): 754-61. [http://dx.doi.org/10.1016/j.bbalip.2011.09.009]. [PMID: 21979151].
[82]
Bellahcene M, O’Dowd JF, Wargent ET, et al. Male mice that lack the G-protein-coupled receptor GPR41 have low energy expenditure and increased body fat content. Br J Nutr 2013; 109(10): 1755-64. [http://dx.doi.org/10.1017/S0007114512003923]. [PMID: 23110765].
[83]
Bindels LB, Dewulf EM, Delzenne NM. GPR43/FFA2: Physiopathological relevance and therapeutic prospects. Trends Pharmacol Sci 2013; 34(4): 226-32. [http://dx.doi.org/10.1016/j.tips.2013.02.002]. [PMID: 23489932].
[84]
Inoue D, Tsujimoto G, Kimura I. Regulation of Energy Homeostasis by GPR41. Front Endocrinol (Lausanne) 2014; 5: 81. [http://dx.doi.org/10.3389/fendo.2014.00081]. [PMID: 24904531].
[85]
Samuel BS, Shaito A, Motoike T, et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci USA 2008; 105(43): 16767-72. [http://dx.doi.org/10.1073/pnas.0808567105]. [PMID: 18931303].
[86]
Tolhurst G, Heffron H, Lam YS, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 2012; 61(2): 364-71. [http://dx.doi.org/10.2337/db11-1019]. [PMID: 22190648].
[87]
Neves AL, Chilloux J, Sarafian MH, Rahim MB, Boulangé CL, Dumas ME. The microbiome and its pharmacological targets: Therapeutic avenues in cardiometabolic diseases. Curr Opin Pharmacol 2015; 25: 36-44. [http://dx.doi.org/10.1016/j.coph.2015.09.013]. [PMID: 26531326].
[88]
Janssen AW, Kersten S. The role of the gut microbiota in metabolic health. FASEB J 2015; 29(8): 3111-23. [http://dx.doi.org/10.1096/fj.14-269514]. [PMID: 25921831].
[89]
Kimura I, Ozawa K, Inoue D, et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun 2013; 4: 1829. [http://dx.doi.org/10.1038/ncomms2852]. [PMID: 23652017].
[90]
Kaska L, Sledzinski T, Chomiczewska A, Dettlaff-Pokora A, Swierczynski J. Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome. World J Gastroenterol 2016; 22(39): 8698-719. [http://dx.doi.org/10.3748/wjg.v22.i39.8698]. [PMID: 27818587].
[91]
Chiang JY. Bile acid metabolism and signaling. Compr Physiol 2013; 3(3): 1191-212. [PMID: 23897684].
[92]
Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006; 439(7075): 484-9. [http://dx.doi.org/10.1038/nature04330]. [PMID: 16400329].
[93]
Swann JR, Want EJ, Geier FM, et al. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci USA 2011; 108(Suppl. 1): 4523-30. [http://dx.doi.org/10.1073/pnas.1006734107]. [PMID: 20837534].
[94]
Dawson PA, Karpen SJ. Intestinal transport and metabolism of bile acids. J Lipid Res 2015; 56(6): 1085-99. [http://dx.doi.org/10.1194/jlr.R054114]. [PMID: 25210150].
[95]
Lorenzo-Zúñiga V, Bartolí R, Planas R, et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology 2003; 37(3): 551-7. [http://dx.doi.org/10.1053/jhep.2003.50116]. [PMID: 12601352].
[96]
Clements WD, Parks R, Erwin P, Halliday MI, Barr J, Rowlands BJ. Role of the gut in the pathophysiology of extrahepatic biliary obstruction. Gut 1996; 39(4): 587-93. [http://dx.doi.org/10.1136/gut.39.4.587]. [PMID: 8944570].
[97]
Wahlström A, Sayin SI, Marschall HU, Bäckhed F. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. Cell Metab 2016; 24(1): 41-50. [http://dx.doi.org/10.1016/j.cmet.2016.05.005]. [PMID: 27320064].
[98]
Li T, Chiang JY. Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev 2014; 66(4): 948-83. [http://dx.doi.org/10.1124/pr.113.008201]. [PMID: 25073467].
[99]
Cătoi AF, Pârvu A, Mureşan A, Busetto L. Metabolic Mechanisms in Obesity and Type 2 Diabetes: Insights from Bariatric/Metabolic Surgery. Obes Facts 2015; 8(6): 350-63. [http://dx.doi.org/10.1159/000441259]. [PMID: 26584027].
[100]
Long SL, Gahan CGM, Joyce SA. Interactions between gut bacteria and bile in health and disease. Mol Aspects Med 2017; 56: 54-65. [http://dx.doi.org/10.1016/j.mam.2017.06.002]. [PMID: 28602676].
[101]
Sagar NM, Cree IA, Covington JA, Arasaradnam RP. The interplay of the gut microbiome, bile acids, and volatile organic compounds. Gastroenterol Res Pract 2015; 2015: 398585. [http://dx.doi.org/10.1155/2015/398585]. [PMID: 25821460].
[102]
Massafra V, van Mil SWC. Farnesoid X receptor: A “homeostat” for hepatic nutrient metabolism. Biochim Biophys Acta Mol Basis Dis 2018; 1864(1): 45-59. [http://dx.doi.org/10.1016/j.bbadis.2017.10.003]. [PMID: 28986309].
[103]
Inagaki T, Moschetta A, Lee YK, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci USA 2006; 103(10): 3920-5. [http://dx.doi.org/10.1073/pnas.0509592103]. [PMID: 16473946].
[104]
Gonzalez FJ, Jiang C, Bisson WH, Patterson AD. Inhibition of farnesoid X receptor signaling shows beneficial effects in human obesity. J Hepatol 2015; 62(6): 1234-6. [http://dx.doi.org/10.1016/j.jhep.2015.02.043]. [PMID: 25747705].
[105]
Sayin SI, Wahlström A, Felin J, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013; 17(2): 225-35. [http://dx.doi.org/10.1016/j.cmet.2013.01.003]. [PMID: 23395169].
[106]
Parséus A, Sommer N, Sommer F, et al. Microbiota-induced obesity requires farnesoid X receptor. Gut 2017; 66(3): 429-37. [http://dx.doi.org/10.1136/gutjnl-2015-310283]. [PMID: 26740296].
[107]
Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007; 56(7): 1761-72. [http://dx.doi.org/10.2337/db06-1491]. [PMID: 17456850].
[108]
Cani PD, Possemiers S, Van de Wiele T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009; 58(8): 1091-103. [http://dx.doi.org/10.1136/gut.2008.165886]. [PMID: 19240062].
[109]
Festi D, Schiumerini R, Eusebi LH, Marasco G, Taddia M, Colecchia A. Gut microbiota and metabolic syndrome. World J Gastroenterol 2014; 20(43): 16079-94. [http://dx.doi.org/10.3748/wjg.v20.i43.16079]. [PMID: 25473159].
[110]
Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008; 57(6): 1470-81. [http://dx.doi.org/10.2337/db07-1403]. [PMID: 18305141].
[111]
Brun P, Castagliuolo I, Di Leo V, et al. Increased intestinal permeability in obese mice: New evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2007; 292(2): G518-25. [http://dx.doi.org/10.1152/ajpgi.00024.2006]. [PMID: 17023554].
[112]
Erridge C, Attina T, Spickett CM, Webb DJ. A high-fat meal induces low-grade endotoxemia: Evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr 2007; 86(5): 1286-92. [http://dx.doi.org/10.1093/ajcn/86.5.1286]. [PMID: 17991637].
[113]
Amar J, Burcelin R, Ruidavets JB, et al. Energy intake is associated with endotoxemia in apparently healthy men. Am J Clin Nutr 2008; 87(5): 1219-23. [http://dx.doi.org/10.1093/ajcn/87.5.1219]. [PMID: 18469242].
[114]
de Punder K, Pruimboom L. Stress induces endotoxemia and low-grade inflammation by increasing barrier permeability. Front Immunol 2015; 6: 223. [http://dx.doi.org/10.3389/fimmu.2015.00223]. [PMID: 26029209].
[115]
Neves AL, Coelho J, Couto L, Leite-Moreira A, Roncon-Albuquerque R Jr. Metabolic endotoxemia: A molecular link between obesity and cardiovascular risk. J Mol Endocrinol 2013; 51(2): R51-64. [http://dx.doi.org/10.1530/JME-13-0079]. [PMID: 23943858].
[116]
Tilg H, Kaser A. Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest 2011; 121(6): 2126-32. [http://dx.doi.org/10.1172/JCI58109]. [PMID: 21633181].
[117]
Moreira AP, Texeira TF, Ferreira AB, Peluzio Mdo C, Alfenas Rde C. Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia. Br J Nutr 2012; 108(5): 801-9. [http://dx.doi.org/10.1017/S0007114512001213]. [PMID: 22717075].
[118]
de Kort S, Keszthelyi D, Masclee AA. Leaky gut and diabetes mellitus: What is the link? Obes Rev 2011; 12(6): 449-58. [http://dx.doi.org/10.1111/j.1467-789X.2010.00845.x]. [PMID: 21382153].
[119]
Everard A, Lazarevic V, Gaïa N, et al. Microbiome of prebiotic-treated mice reveals novel targets involved in host response during obesity. ISME J 2014; 8(10): 2116-30. [http://dx.doi.org/10.1038/ismej.2014.45]. [PMID: 24694712].
[120]
Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: A systematic review and meta-analysis. JAMA 2004; 292(14): 1724-37. [http://dx.doi.org/10.1001/jama.292.14.1724]. [PMID: 15479938].
[121]
Sjöström L, Narbro K, Sjöström CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007; 357(8): 741-52. [http://dx.doi.org/10.1056/NEJMoa066254]. [PMID: 17715408].
[122]
Heneghan HM, Nissen S, Schauer PR. Gastrointestinal surgery for obesity and diabetes: Weight loss and control of hyperglycemia. Curr Atheroscler Rep 2012; 14(6): 579-87. [http://dx.doi.org/10.1007/s11883-012-0285-5]. [PMID: 23054661].
[123]
Lau E, Carvalho D, Pina-Vaz C, Barbosa JA, Freitas P. Beyond gut microbiota: Understanding obesity and type 2 diabetes. Hormones (Athens) 2015; 14(3): 358-69. [http://dx.doi.org/10.14310/horm.2002.1571]. [PMID: 26188221].
[124]
Tadross JA, le Roux CW. The mechanisms of weight loss after bariatric surgery. Int J Obes 2009; 33(Suppl. 1): S28-32. [http://dx.doi.org/10.1038/ijo.2009.14]. [PMID: 19363504].
[125]
Anhê FF, Varin TV, Schertzer JD, Marette A. The Gut Microbiota as a Mediator of Metabolic Benefits after Bariatric Surgery. Can J Diabetes 2017; 41(4): 439-47. [http://dx.doi.org/10.1016/j.jcjd.2017.02.002]. [PMID: 28552651].
[126]
Angrisani L, Santonicola A, Iovino P, Formisano G, Buchwald H, Scopinaro N. Bariatric Surgery Worldwide 2013. Obes Surg 2015; 25(10): 1822-32. [http://dx.doi.org/10.1007/s11695-015-1657-z]. [PMID: 25835983].
[127]
Albaugh VL, Flynn CR, Tamboli RA, Abumrad NN. Recent advances in metabolic and bariatric surgery. F1000 Res 2016; 5: 5. [http://dx.doi.org/10.12688/f1000research.7240.1]. [PMID: 27239296].
[128]
Liou AP, Paziuk M, Luevano JM Jr, Machineni S, Turnbaugh PJ, Kaplan LM. Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity. Sci Transl Med 2013; 5(178): 178ra41. [http://dx.doi.org/10.1126/scitranslmed.3005687]. [PMID: 23536013].
[129]
Islam KB, Fukiya S, Hagio M, et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology 2011; 141(5): 1773-81. [http://dx.doi.org/10.1053/j.gastro.2011.07.046]. [PMID: 21839040].
[130]
Zhang H, DiBaise JK, Zuccolo A, et al. Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci USA 2009; 106(7): 2365-70. [http://dx.doi.org/10.1073/pnas.0812600106]. [PMID: 19164560].
[131]
Palleja A, Kashani A, Allin KH, et al. Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota. Genome Med 2016; 8(1): 67. [http://dx.doi.org/10.1186/s13073-016-0312-1]. [PMID: 27306058].
[132]
Tremaroli V, Karlsson F, Werling M, et al. Roux-en-Y Gastric Bypass and Vertical Banded Gastroplasty Induce Long-Term Changes on the Human Gut Microbiome Contributing to Fat Mass Regulation. Cell Metab 2015; 22(2): 228-38. [http://dx.doi.org/10.1016/j.cmet.2015.07.009]. [PMID: 26244932].
[133]
Graessler J, Qin Y, Zhong H, et al. Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: Correlation with inflammatory and metabolic parameters. Pharmacogenomics J 2013; 13(6): 514-22. [http://dx.doi.org/10.1038/tpj.2012.43]. [PMID: 23032991].
[134]
Kong LC, Tap J, Aron-Wisnewsky J, et al. Gut microbiota after gastric bypass in human obesity: Increased richness and associations of bacterial genera with adipose tissue genes. Am J Clin Nutr 2013; 98(1): 16-24. [http://dx.doi.org/10.3945/ajcn.113.058743]. [PMID: 23719559].
[135]
Furet JP, Kong LC, Tap J, et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: Links with metabolic and low-grade inflammation markers. Diabetes 2010; 59(12): 3049-57. [http://dx.doi.org/10.2337/db10-0253]. [PMID: 20876719].
[136]
Jahansouz C, Staley C, Bernlohr DA, Sadowsky MJ, Khoruts A, Ikramuddin S. Sleeve gastrectomy drives persistent shifts in the gut microbiome. Surg Obes Relat Dis 2017; 13(6): 916-24. [http://dx.doi.org/10.1016/j.soard.2017.01.003]. [PMID: 28279578].
[137]
Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA 2013; 110(22): 9066-71. [http://dx.doi.org/10.1073/pnas.1219451110]. [PMID: 23671105].
[138]
Yan M, Song MM, Bai RX, Cheng S, Yan WM. Effect of Roux-en-Y gastric bypass surgery on intestinal Akkermansia muciniphila. World J Gastrointest Surg 2016; 8(4): 301-7. [http://dx.doi.org/10.4240/wjgs.v8.i4.301]. [PMID: 27152136].
[139]
Everard A, Lazarevic V, Derrien M, et al. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes 2011; 60(11): 2775-86. [http://dx.doi.org/10.2337/db11-0227]. [PMID: 21933985].
[140]
Guo Y, Huang ZP, Liu CQ, Qi L, Sheng Y, Zou DJ. Modulation of the gut microbiome: A systematic review of the effect of bariatric surgery. Eur J Endocrinol 2018; 178(1): 43-56. [http://dx.doi.org/10.1530/EJE-17-0403]. [PMID: 28916564].
[141]
Magouliotis DE, Tasiopoulou VS, Sioka E, Chatedaki C, Zacharoulis D. Impact of Bariatric Surgery on Metabolic and Gut Microbiota Profile: A Systematic Review and Meta-analysis. Obes Surg 2017; 27(5): 1345-57. [http://dx.doi.org/10.1007/s11695-017-2595-8]. [PMID: 28265960].
[142]
Damms-Machado A, Mitra S, Schollenberger AE, et al. Effects of surgical and dietary weight loss therapy for obesity on gut microbiota composition and nutrient absorption. BioMed Res Int 2015; 2015: 806248. [http://dx.doi.org/10.1155/2015/806248]. [PMID: 25710027].
[143]
Peck BCE, Seeley RJ. How does ‘metabolic surgery’ work its magic? New evidence for gut microbiota. Curr Opin Endocrinol Diabetes Obes 2018; 25(2): 81-6. [http://dx.doi.org/10.1097/MED.0000000000000392]. [PMID: 29337705].
[144]
Murphy R, Tsai P, Jüllig M, Liu A, Plank L, Booth M. Differential Changes in Gut Microbiota After Gastric Bypass and Sleeve Gastrectomy Bariatric Surgery Vary According to Diabetes Remission. Obes Surg 2017; 27(4): 917-25. [http://dx.doi.org/10.1007/s11695-016-2399-2]. [PMID: 27738970].
[145]
Liu H, Hu C, Zhang X, Jia W. Role of gut microbiota, bile acids and their cross-talk in the effects of bariatric surgery on obesity and type 2 diabetes. J Diabetes Investig 2018; 9(1): 13-20. [http://dx.doi.org/10.1111/jdi.12687]. [PMID: 28434196].
[146]
Sinclair P, Brennan DJ, le Roux CW. Gut adaptation after metabolic surgery and its influences on the brain, liver and cancer. Nat Rev Gastroenterol Hepatol 2018; 15(10): 606-24. [http://dx.doi.org/10.1038/s41575-018-0057-y]. [PMID: 30181611].
[147]
Garcia-Rios A, Torres-Peña JD, Perez-Jimenez F, Perez-Martinez P. Gut Microbiota: A New Marker of Cardiovascular Disease. Curr Pharm Des 2017; 23(22): 3233-8. [http://dx.doi.org/10.2174/1381612823666170317144853]. [PMID: 28317481].
[148]
Haro C, Rangel-Zúñiga OA, Alcalá-Díaz JF, et al. Intestinal Microbiota Is Influenced by Gender and Body Mass Index. PLoS One 2016; 11(5): e0154090. [http://dx.doi.org/10.1371/journal.pone.0154090]. [PMID: 27228093].
[149]
Santos-Marcos JA, Haro C, Vega-Rojas A, et al. Sex differences in the gut microbiota as potential determinants of gender predisposition to disease. Mol Nutr Food Res 2019; 63(7): e1800870. [http://dx.doi.org/10.1002/mnfr.201800870]. [PMID: 30636111].
[150]
Rizzo M, Nikolic D, Patti AM, et al. GLP-1 receptor agonists and reduction of cardiometabolic risk: Potential underlying mechanisms. Biochim Biophys Acta Mol Basis Dis 2018; 1864(9 Pt B): 2814-21. [http://dx.doi.org/10.1016/j.bbadis.2018.05.012]. [PMID: 29778663].
[151]
Mancini MC, de Melo ME. The burden of obesity in the current world and the new treatments available: Focus on liraglutide 3.0 mg. Diabetol Metab Syndr 2017; 9: 44. [http://dx.doi.org/10.1186/s13098-017-0242-0]. [PMID: 28580018].
[152]
Pafili K, Rizzo M, Papanas N. New antihyperglycaemic agents and cardiovascular disease: Let’s be optimistic. Curr Opin Cardiol 2018; 33(4): 444-54. [http://dx.doi.org/10.1097/HCO.0000000000000524]. [PMID: 29702499].
[153]
Lu Y, Hajifathalian K, Ezzati M, Woodward M, Rimm EB, Danaei G. Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: A pooled analysis of 97 prospective cohorts with 1·8 million participants. Lancet 2014; 383(9921): 970-83. [http://dx.doi.org/10.1016/S0140-6736(13)61836-X]. [PMID: 24269108].
[154]
Claus SP. Will Gut Microbiota Help Design the Next Generation of GLP-1-Based Therapies for Type 2 Diabetes? Cell Metab 2017; 26(1): 6-7. [http://dx.doi.org/10.1016/j.cmet.2017.06.009]. [PMID: 28683295].
[155]
Morales P, Fujio S, Navarrete P, et al. Impact of Dietary Lipids on Colonic Function and Microbiota: An Experimental Approach Involving Orlistat-Induced Fat Malabsorption in Human Volunteers. Clin Transl Gastroenterol 2016; 7: e161. [http://dx.doi.org/10.1038/ctg.2016.20]. [PMID: 27054579].
[156]
Scholtes RA, van Baar MJB, Lytvyn Y, et al. Sodium glucose cotransporter (SGLT)-2 inhibitors: Do we need them for glucose-lowering, for cardiorenal protection or both? Diabetes Obes Metab 2019; 21(Suppl. 2): 24-33. [http://dx.doi.org/10.1111/dom.13692]. [PMID: 30843294].
[157]
Lee DM, Battson ML, Jarrell DK, et al. SGLT2 inhibition via dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice. Cardiovasc Diabetol 2018; 17(1): 62. [http://dx.doi.org/10.1186/s12933-018-0708-x]. [PMID: 29703207].
[158]
Du F, Hinke SA, Cavanaugh C, et al. Potent Sodium/Glucose Cotransporter SGLT1/2 Dual Inhibition Improves Glycemic Control Without Marked Gastrointestinal Adaptation or Colonic Microbiota Changes in Rodents. J Pharmacol Exp Ther 2018; 365(3): 676-87. [http://dx.doi.org/10.1124/jpet.118.248575]. [PMID: 29674332].
[159]
Katsiki N, Mikhailidis DP, Theodorakis MJ. Sodium-glucose Cotransporter 2 Inhibitors (SGLT2i): Their Role in Cardiometabolic Risk Management. Curr Pharm Des 2017; 23(10): 1522-32. [http://dx.doi.org/10.2174/1381612823666170113152742]. [PMID: 28088910].
[160]
Liao X, Song L, Zeng B, et al. Alteration of gut microbiota induced by DPP-4i treatment improves glucose homeostasis. EBioMedicine 2019; 44: 665-74. [http://dx.doi.org/10.1016/j.ebiom.2019.03.057]. [PMID: 30922964].
[161]
Xourgia E, Papazafiropoulou A, Papanas N, Melidonis A. Anti-diabetic treatment leads to changes in gut microbiome. Front Biosci 2019; 24: 688-99. [http://dx.doi.org/10.2741/4743]. [PMID: 30844705].

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy