The gut microbiota has emerged as an environmental factor that modulates the host's energy balance. It increases the host's ability to harvest energy from the digested food, and produces metabolites and microbial products such as short-chain fatty acids, secondary bile acids, and lipopolysaccharides. These metabolites and microbial products act as signaling molecules that modulate appetite, gut motility, energy uptake and storage, and energy expenditure. Several findings suggest that the gut microbiota can affect the development of obesity. Germ-free mice are leaner than conventionally raised mice and they are protected against diet-induced obesity. Furthermore, obese humans and rodents have an altered gut microbiota composition with less phylogeneic diversity compared to lean controls, and transplantation of the gut microbiota from obese subjects to germ-free mice can transfer the obese phenotype. Taken together, these findings indicate a role for the gut microbiota in obesity and suggest that the gut microbiota could be targeted to improve metabolic diseases like obesity. This review focuses on the role of the gut microbiota in energy balance regulation and its potential role in obesity.

1.
Sender R, Fuchs S, Milo R: Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 2016;164:337-340.
2.
Gill SR, Pop M, Deboy RT, Eckburg PB, Turnbaugh PJ, Samuel BS, Gordon JI, Relman DA, Fraser-Liggett CM, Nelson KE: Metagenomic analysis of the human distal gut microbiome. Science 2006;312:1355-1359.
3.
Backhed F, Roswall J, Peng Y, Feng Q, Jia H, Kovatcheva-Datchary P, et al: Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 2015;17:690-703.
4.
David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, Ling AV, Devlin AS, Varma Y, Fischbach MA, Biddinger SB, Dutton RJ, Turnbaugh PJ: Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014;505:559-563.
5.
Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, Beaumont M, Van Treuren W, Knight R, Bell JT, Spector TD, Clark AG, Ley RE: Human genetics shape the gut microbiome. Cell 2014;159:789-799.
6.
Donaldson GP, Lee SM, Mazmanian SK: Gut biogeography of the bacterial microbiota. Nat Rev Microbiol 2016;14:20-32.
7.
Li J, Jia H, Cai X, Zhong H, Feng Q, Sunagawa S, et al: An integrated catalog of reference genes in the human gut microbiome. Nat Biotechnol 2014;32:834-841.
8.
Ley RE, Turnbaugh PJ, Klein S, Gordon JI: Microbial ecology: human gut microbes associated with obesity. Nature 2006;444:1022-1023.
9.
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;444:1027-1031.
10.
Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI: A core gut microbiome in obese and lean twins. Nature 2009;457:480-484.
11.
Duncan SH, Lobley GE, Holtrop G, Ince J, Johnstone AM, Louis P, Flint HJ: Human colonic microbiota associated with diet, obesity and weight loss. Int J Obes (Lond) 2008;32:1720-1724.
12.
Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, et al: Richness of human gut microbiome correlates with metabolic markers. Nature 2013;500:541-546.
13.
Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, et al: Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 2013;341:1241214.
14.
Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI: The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 2004;101:15718-15723.
15.
McNeil NI: The contribution of the large intestine to energy supplies in man. Am J Clin Nutr 1984;39:338-342.
16.
Backhed 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;104:979-984.
17.
Kubeck R, Bonet-Ripoll C, Hoffmann C, Walker A, Muller VM, Schuppel VL, Lagkouvardos I, Scholz B, Engel KH, Daniel H, Schmitt-Kopplin P, Haller D, Clavel T, Klingenspor M: Dietary fat and gut microbiota interactions determine diet-induced obesity in mice. Mol Metab 2016;5:1162-1174.
18.
Suarez-Zamorano N, Fabbiano S, Chevalier C, Stojanovic O, Colin DJ, Stevanovic A, et al: Microbiota depletion promotes browning of white adipose tissue and reduces obesity. Nat Med 2015;21:1497-1501.
19.
Collins SM, Surette M, Bercik P: The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 2012;10:735-742.
20.
Koda S, Date Y, Murakami N, Shimbara T, Hanada T, Toshinai K, Niijima A, Furuya M, Inomata N, Osuye K, Nakazato M: The role of the vagal nerve in peripheral PYY3-36-induced feeding reduction in rats. Endocrinology 2005;146:2369-2375.
21.
Schele E, Grahnemo L, Anesten F, Hallen A, Backhed F, Jansson JO: The gut microbiota reduces leptin sensitivity and the expression of the obesity-suppressing neuropeptides proglucagon (GCG) and brain-derived neurotrophic factor (BDNF) in the central nervous system. Endocrinology 2013;154:3643-3651.
22.
Wichmann A, Allahyar A, Greiner TU, Plovier H, Lunden GO, Larsson T, Drucker DJ, Delzenne NM, Cani PD, Backhed F: Microbial modulation of energy availability in the colon regulates intestinal transit. Cell Host Microbe 2013;14:582-590.
23.
Bucinskaite V, Tolessa T, Pedersen J, Rydqvist B, Zerihun L, Holst JJ, Hellstrom PM: Receptor-mediated activation of gastric vagal afferents by glucagon-like peptide-1 in the rat. Neurogastroenterol Motil 2009;21:978.
24.
Flak JN, Myers MG Jr: Minireview: CNS mechanisms of leptin action. Mol Endocrinol 2016;30:3-12.
25.
Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, et al: Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 2012;122:153-162.
26.
Valdearcos M, Robblee MM, Benjamin DI, Nomura DK, Xu AW, Koliwad SK: Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep 2014;9:2124-2138.
27.
Erny D, Hrabe de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, et al: Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 2015;18:965-977.
28.
Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Toth M, Korecka A, Bakocevic N, Ng LG, Kundu P, Gulyas B, Halldin C, Hultenby K, Nilsson H, Hebert H, Volpe BT, Diamond B, Pettersson S: The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med 2014;6:263ra158.
29.
Tremaroli V, Backhed F: Functional interactions between the gut microbiota and host metabolism. Nature 2012;489:242-249.
30.
Caesar R, Nygren H, Oresic M, Backhed F: Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism. J Lipid Res 2016;57:474-481.
31.
Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, et al: The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 2003;278:11312-11319.
32.
Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda T, et al: The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun 2013;4:1829.
33.
Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK, Hammer RE, Williams SC, Crowley J, Yanagisawa M, Gordon JI: 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;105:16767-16772.
34.
Xiong Y, Miyamoto N, Shibata K, Valasek MA, Motoike T, Kedzierski RM, Yanagisawa M: Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc Natl Acad Sci USA 2004;101:1045-1050.
35.
Psichas A, Sleeth ML, Murphy KG, Brooks L, Bewick GA, Hanyaloglu AC, Ghatei MA, Bloom SR, Frost G: The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int J Obes (Lond) 2015;39:424-429.
36.
Donohoe DR, Garge N, Zhang X, Sun W, O'Connell TM, Bunger MK, Bultman SJ: The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab 2011;13:517-526.
37.
Osaka T, Endo M, Yamakawa M, Inoue S: Energy expenditure by intravenous administration of glucagon-like peptide-1 mediated by the lower brainstem and sympathoadrenal system. Peptides 2005;26:1623-1631.
38.
Secher A, Jelsing J, Baquero AF, Hecksher-Sorensen J, Cowley MA, Dalboge LS, et al: The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest 2014;124:4473-4488.
39.
Wahlstrom A, Kovatcheva-Datchary P, Stahlman M, Khan MT, Backhed F, Marschall HU: Induction of farnesoid X receptor signaling in germ-free mice colonized with a human microbiota. J Lipid Res 2017;58:412-419.
40.
Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, et al: TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009;10:167-177.
41.
Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K, Angelin B, Hyotylainen T, Oresic M, Backhed F: Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013;17:225-235.
42.
Parseus A, Sommer N, Sommer F, Caesar R, Molinaro A, Stahlman M, Greiner TU, Perkins R, Backhed F: Microbiota-induced obesity requires farnesoid X receptor. Gut 2017;66:429-437.
43.
Mawe GM, Hoffman JM: Serotonin signalling in the gut-functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol 2013;10:473-486.
44.
Sumara G, Sumara O, Kim JK, Karsenty G: Gut-derived serotonin is a multifunctional determinant to fasting adaptation. Cell Metab 2012;16:588-600.
45.
Reigstad CS, Salmonson CE, Rainey JF 3rd, Szurszewski JH, Linden DR, Sonnenburg JL, Farrugia G, Kashyap PC: Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J 2015;29:1395-1403.
46.
Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al: Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007;56:1761-1772.
47.
Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R: Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470-1481.
48.
Caesar R, Tremaroli V, Kovatcheva-Datchary P, Cani PD, Backhed F: Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metab 2015;22:658-668.
49.
Ghoshal S, Witta J, Zhong J, de Villiers W, Eckhardt E: Chylomicrons promote intestinal absorption of lipopolysaccharides. J Lipid Res 2009;50:90-97.
50.
Breton J, Tennoune N, Lucas N, Francois M, Legrand R, Jacquemot J, et al: Gut commensal E. coli proteins activate host satiety pathways following nutrient-induced bacterial growth. Cell Metab 2016;23:324-334.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.