Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter March 28, 2014

Obesity and the gut microbiome: pathophysiological aspects

H. Leon Bradlow

Abstract

While there is a large volume of literature describing a role for obesity as a risk factor for breast cancer and many other cancers, in the main a causal relationship has not been established. If the study is limited to breast cancer risk, it has been suggested that the increase in sex steroid formation that occurs in postmenopausal women plays a role. Obesity is known to be associated with chronic low grade inflammation, but no reason for this association has been offered in the past. The gut microbiome, while known to be enormous, has not in the past been considered as a metabolic role player in the body. This is now recognized to be the case. Recent studies have found the obesity is correlated with an alteration in the gut microbiome. In obese individual there is a change in the relative proportions of the two major classes of bacteria – bacteroides and firmacutes – with the latter dominant in obesity and resulting in the formation of increased amounts of metabolic endotoxins like deoxycholic acid and lipopolysaccharides (LPS). Obese individuals show a decrease in the concentration of Akkermansia muciniphila in the mucus that lines the intestinal wall, resulting in thinner mucus and a weakened intestinal lining and permitting metabolic endotoxins formed by other bacterial flora like LPS to enter the blood steam and cause the chronic inflammation associated with obesity. The change in the microbiome profile results in increases in bacterial strains that are more efficient at generating energy, leading to increased obesity. In mice, it has been shown that introducing gut bacterial flora from the cecum of obese mice into germ-free mice results in increased obesity with lesser food consumption while the reverse, introducing bacterial flora from lean mice results in a loss in weight. This raises the attractive possibility that manipulating the gut microbiome could facilitate weight loss or prevent obesity in humans.


Corresponding author: H. Leon Bradlow, Hackensack University Medical Center, Hackensack, NJ, USA, E-mail:

References

1. Barreira TV, Staiano AE, Harrington DM, Heymsfield SB, Smith SR, Bouchard C, Katzmarzyk PT. Anthropometric correlates of total body fat, abdominal adiposity, cardiovascular disease risk factors in a biracial sample of men and women. Proc Mayo Clin 2012;87:452–60.10.1016/j.mayocp.2011.12.017Search in Google Scholar PubMed PubMed Central

2. KathBritton KA, Massaro JM, Murabito JM, Kreger BE, Hoffmann U, Fox CS. Body Fa2 distribution, incident cardiovascular disease, cancer, all-cause mortality. J Am Coll Cardiol 2013;62:921–5.10.1016/j.jacc.2013.06.027Search in Google Scholar PubMed PubMed Central

3. Lean MJ. Prognosis in obesity. BMJ 2005;330:1339–40.10.1136/bmj.330.7504.1339Search in Google Scholar PubMed PubMed Central

4. Sinicrope FA, Dannenber AJ. Obesity and breast cancer prognosis: weight of the evidence. J Clin Oncol 2;29:4–7.10.1200/JCO.2010.32.1752Search in Google Scholar PubMed

5. Foxhall LE. The obesity-cancer connection, what we can do about it. American Cancer Society 2013. Available from: http://www.cancer.org/cancer/news/expertvoices/post/2013/02/28/the-obesity-cancer-connection-and-what-we-can-do-about-it.aspx.Search in Google Scholar

6. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature 2007;449:804–10.10.1038/nature06244Search in Google Scholar PubMed PubMed Central

7. Faith JJ, Guruge JL, Charbonneau M, Subramanian S, Seedorf H, Goodman AL, Clemente JC, Knight R, Heath AC, Leibel RL, Rosenbaum M, Gordon JL. The long-term stability of the human gut microbiota. Science 2013;341:DOI:10.1126/science.1237439.10.1126/science.1237439Search in Google Scholar PubMed PubMed Central

8. Turnbaugh PJ, Quince C, Faith JJ, McHardy AC, Yatsunenko T, Niazi F, Affourtit J, Egholm M, Henrissat B, Knight R, Gordon JI. Organismal, genetic, transcriptional variation in the deeply sequenced gut microbiomes of identical twins PNAS 2010;107:7503–8.10.1073/pnas.1002355107Search in Google Scholar PubMed PubMed Central

9. 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;457:480–4.10.1038/nature07540Search in Google Scholar PubMed PubMed Central

10. Cani PD, Bibilont R, Knauf C, Waget A, Neyrinck AM. Changes in gut microbiota controls metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470–81.10.2337/db07-1403Search in Google Scholar PubMed

11. Karlsson FH, Tremaroli V, Nookaew I, Bergström G, Behre CJ, Fagerberg B, Nielsen J, Bäckhed F. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013;498:99–103.10.1038/nature12198Search in Google Scholar PubMed

12. Musso G, Gambino R, Cassader M. Obesity, diabetes, gut microbiota. The hygiene hypothesis expanded? Diabetes Care 2010;33:2277–84.10.2337/dc10-0556Search in Google Scholar PubMed PubMed Central

13. Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, de Vos WM, Cani PD. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA 2013;110:9066–71.10.1073/pnas.1219451110Search in Google Scholar PubMed PubMed Central

14. Everard A, Lazarevic V, Derrien M, Girard M, Muccioli GG, Neyrinck AM, Possemiers S, Van Holle A, François P, de Vos WM, Delzenne NM, Schrenzel J, Cani PD. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obemse and diet-induced leptin-resistant mice. Diabetes 2011;60:2775–86.10.2337/db11-0227Search in Google Scholar PubMed PubMed Central

15. Cani PD, Possemiers S, Van d Wiele T, Guiot Y, Everard A, Rottier O, Geurts L, Naslain D, Neyrinsk A, Lambert DM, Muccioli GG, Delzenne NM. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability Gut 2009;58:1091–103.10.1136/gut.2008.165886Search in Google Scholar PubMed PubMed Central

16. Million M, Lagier J-C, Yahav D, Paul M. Gut bacterial microbiota and obesity. Clin Microbiol Infect 2013;19:305–13.10.1111/1469-0691.12172Search in Google Scholar PubMed

17. Bäckhed 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 2004;101:15718–23.10.1073/pnas.0407076101Search in Google Scholar PubMed PubMed Central

18. Looft T, Allen HK. Gut microbes. Collateral effects of antibiotics on mammalian gut microbiomes Gut Microbes 2012;3:463–7.Search in Google Scholar

19. Turnbaugh PJ, Ridura VK, Faith JJ, Rey FE, Knight R, Gordon JI. The effect of diet on the human gut microbiome: a metagenomic assay in humanized gnotobiotic mice. Sci Transl Med 2009;1:6ra14.10.1126/scitranslmed.3000322Search in Google Scholar PubMed PubMed Central

20. Bäckhed F, Manchester JK, Semenkovich CF, Gordon J. Jeffrey Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA 2007;104:979–84.10.1073/pnas.0605374104Search in Google Scholar PubMed PubMed Central

21. Huang EY, Leone VA, Devkota S, Wang Y, Brady MJ, Chang EB. Composition of dietary fat source, shapes gut microbiota architecture and alters host inflammatory mediators in mouse adipose tissue. J Parenter Enteral Nutr 2013;37:746–54.10.1177/0148607113486931Search in Google Scholar PubMed PubMed Central

22. Maurice CF, Haiser HJ, Turnbaugh PJ. Xenobiotics shape the physiology and gene expression of the active human gut microbiome. Cell. 2013;152:39–50.10.1016/j.cell.2012.10.052Search in Google Scholar PubMed PubMed Central

23. Freter R, Abrams GD. Function of various intestinal bacteria in converting germfree mice to the normal state. Infect Immun 1972;6:119–26.10.1128/iai.6.2.119-126.1972Search in Google Scholar PubMed PubMed Central

24. Mahowald MA, Rey FE, Seedorf H, Turnbaugh PJ, Fulton RS, Wollam A, Shah N, Wang C, Magrini V, Wilson RK, Cantarel BL, Coutinho PM, Henrissat B, Crock LW, Russell A, Verberkmoes NC, Hettich RL, Gordon JI. Characterizing a model human gut microbiota composed of members of its two dominant bacterial phyla. Proc Natl Acad Sci USA 2009;106:5859–64.10.1073/pnas.0901529106Search in Google Scholar PubMed PubMed Central

25. Turnbaugh PJ, Ruth E, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027–103.10.1038/nature05414Search in Google Scholar PubMed

26. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Nature 2005;102:11070–5.Search in Google Scholar

27. Devkota S, Turnbaugh PJ. Cancer: an acidic link. Nature 2013;499:37–8.10.1038/nature12404Search in Google Scholar PubMed

28. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, Iwakura Y, Oshima K, Morita H, Hattori M, Honda K, Ishikawa Y, Hara E, Ohtani N. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499:97–101.10.1038/nature12347Search in Google Scholar PubMed

29. Bernstein H, Bernstein C, Payne CM, Dvorakova K, Garewal H. Bil acids as carcinogens in human gastrointestinal cancer. Mutat Res 2005;589:47–65.10.1016/j.mrrev.2004.08.001Search in Google Scholar PubMed

30. Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, Antonopoulos DA, Jabri B, Chang EB. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature. 2012;87:104–8.10.1038/nature11225Search in Google Scholar PubMed PubMed Central

31. Fox JG, Feng Y, Theve EJ, Raczynski AR, Fiala JLA, Doernte AL, Williams M, McFaline JL, Essigmanm JM, Schauer DB, Tannenbaum SR, Dedone PC, Weinman SA, Lemon SM, Fry RC, Rogers AB. Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens. Gut 2010;59:88–97.10.1136/gut.2009.183749Search in Google Scholar PubMed PubMed Central

32. Modi SR, Lee HH, Spina CS, Colllins JJ. Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature 2013;499:219–22.10.1038/nature12212Search in Google Scholar PubMed PubMed Central

33. Million M, Lagier JC, Yahav D, Paul M. Gut bacterial microbiota and obesity. Clin Microbiol Infect 2013;19:305–13.10.1111/1469-0691.12172Search in Google Scholar PubMed

34. Ng KM, Ferreyra JA, Higgenbottom SK, Lynch JB, Kashyap PC, Gopinath S, Naidu N, Choudhury B, Weimer BC, Monack DM, Sonnenburg JL. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 2013;502:96–9.10.1038/nature12503Search in Google Scholar PubMed PubMed Central

35. Micioli GG, Naslain D, Bäckhed F, Reigstad CS, Lambert DM, Delzenne NM, Cani PD. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol 2010;6:392–8.10.1038/msb.2010.46Search in Google Scholar PubMed PubMed Central

36. Chen G, Pang Z. Endocanabinoids and Obesity. Vitm Horm 2013;91:325–68.10.1016/B978-0-12-407766-9.00014-6Search in Google Scholar PubMed

37. Liou AP, Paziuk M, Luevano JM, 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;5:178ra41.10.1126/scitranslmed.3005687Search in Google Scholar PubMed PubMed Central

38. Li JV, Ashrafian H, Bueter M, Kinross J, Sands C, le Roux CW, Bloom SR, Darzi A, Athanasiou T, Marchesi JR, Nicholson JK, Holmes E. Metabolic surgery profoundly influences gut microbial-host metabolic cross-talk. Gut 2011;60:1214–23.10.1136/gut.2010.234708Search in Google Scholar PubMed PubMed Central

39. Wesemann DR, Portuguese AJ, Meyers RM, Gallagher MP, Cluff-Jones K, Magee J, Panchakshari RA, Rodig SJ, Kepler TB, Alt FW. Microbial colonization influences early B–lineage development in the gut lamina propria. Nature 2013;501:112–5.10.1038/nature12496Search in Google Scholar PubMed PubMed Central

40. Haiser HJ, Gootenberg DB, Chatman K, Sirasani G, Balskus EP, Turnbaugh PJ. Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta. Science 2013;341:295–8.10.1126/science.1235872Search in Google Scholar PubMed PubMed Central

41. Heijtz RD, Wang S, Oian Y, Bjorkholm B, Samuelsson A, Hibberd ML, Fosberg H, Pettersson S. Normal gut microbiota modulates brain development and behavior. PNAS 2011;108:3047–52.10.1073/pnas.1010529108Search in Google Scholar PubMed PubMed Central

42. Elahi S, Ertelt JM, Kinder JM, Jiang TT, Zhang X, Xin L, Charturvedi V, Strong BS, Qualls JE, Steinbrecher KA, Kalfa TA, Shaaban AF. Immunosuppressive CD71+ erythroid cells compromise neonatal host defense against infection. Nature (2013) DOI:10.1038/nature12675.10.1038/nature12675Search in Google Scholar PubMed PubMed Central

43. Greenblum S, Turnbaugh PJ, Borenstein E. Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease. Proc Natl Acad Sci USA 2012;109:594–9.10.1073/pnas.1116053109Search in Google Scholar PubMed PubMed Central

44. Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Urself LK, Clement JC, Vantreuren W, Walters WA, Knight R, Newgard CB, Heath AC, Gordon JI. Gut Microbiota from Twins Discordant for Obesity Modulate Metabolism in Mice. Science 2013;341:1241214.10.1126/science.1241214Search in Google Scholar PubMed PubMed Central

45. Le Chatelier E, Nielson T, Priti E, Hildebrand F, Falony G, Almeida M, Arumugam M, Batto J-M, Kenedy S, Leonard S, Li J, Burgdorf K, Grarup N, Jorgensen T, Branslund I, Nielsen HB, Sunagawa S, Tap J, Tims S. Richness of human gut microbiome correlates with metabolic markers. Nature 2013;500:541–6.10.1038/nature12506Search in Google Scholar PubMed

46. Cotillard A, Kennedy SP, Kong LC, Prifti E, Pons N, Le Chatelier E, Almeida, Quinquis aB, Levenz L, Galleron N, Gougis S, Rizkalla S, Batto J-M, Renault P, ANR MicroObes consortium, Dore J, Zucker J-D, Clement K, Ehrlich SD, Blottiere H, Leclerc M, Juste C, Wouters T, Lepage P, Fouqueray C. Dietary intervention impact on gut microbial gene richness. Nature 2013;500;585–8.10.1038/nature12480Search in Google Scholar PubMed

47. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE. Diet rapidly and reproducibly alters the human gut microbiome Nature doi:10.1038/nature12820.10.1038/nature12820Search in Google Scholar PubMed PubMed Central

48. Lee SM, Donaldson GP, Mikulski Z, Bovaiian S, Leym K, Mazmanian SK. Bacterial colonization factors control specificity and stability of the gut microbiota. Nature 2013;501;426–9.10.1038/nature12447Search in Google Scholar PubMed PubMed Central

49. Naukkarinen J, Heinonen S, Hakkarainen A, Lundbom J, Vuolteenaho K, Saarinen L, Hautaniemi S, Rodriguez A, Frühbeck G, Pajunen P, Hyötyläinen T, Orešič M, Moilanen E, Suomalainen A, Lundbom N, Kaprio J, Rissanen A, Pietiläinen KH. Characterising metabolically healthy obesity in weight-discordant monozygotic twins. Diabetologia 2014;57:167–76.10.1007/s00125-013-3066-ySearch in Google Scholar PubMed

50. Moore T, Rodriguez A, Bakken JS. Fecal Microbiota Transplantation: A Practical Update for the Infectious Disease Specialist. Clin Infect Dis 2014;58:541–5.10.1093/cid/cit950Search in Google Scholar PubMed

51. Borody TJ, Warren EF, Leis S, Surace R, Ashman O. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol 2003;37:42–7.10.1097/00004836-200307000-00012Search in Google Scholar PubMed

52. Anderson JL, Edney RJ, Whelan K. Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharmacol Ther 2012;36:503–16.10.1111/j.1365-2036.2012.05220.xSearch in Google Scholar PubMed

53. Louie T. Fecal Transplant Pills Effective for C difficile ID Week 2013. Abstract 89. Presented October 3, 2013.Search in Google Scholar

54. Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, Molina DA, Salcedo R, Back T, Cramer S, Dai RM, Kiu H, Cardone M, Naik S, Patri AK, Wang E, Marincola FM, Frank KM, Belkaid Y, Trinchieri G, Goldszmid RS. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 2013;342:967–70.10.1126/science.1240527Search in Google Scholar PubMed PubMed Central

55. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, Enot DP, Pfirschke C, Engblom C, Pittet MJ, Schlitzer A, Ginhoux F, Apetoh L, Chachaty E, Woerther PL, Eberl G, Bérard M, Ecobichon C, Clermont D, Bizet C, Gaboriau-Routhiau V, Cerf-Bensussan N, Opolon P, Yessaad N, Vivier E, Ryffel B, Elson CO, Doré J, Kroemer G, Lepage P, Boneca IG, Ghiringhelli F, Zitvogel L. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 2013;342: 971–6.10.1126/science.1240537Search in Google Scholar PubMed PubMed Central

56. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, Patterson PH, Mazmanian SK. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013;155:1451–63.10.1016/j.cell.2013.11.024Search in Google Scholar PubMed PubMed Central

57. Faith JJ, Ahern PP, Ridura VK, Cheng J, Gordon JI. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci Transl Med 2014:6:p. 220ra11.10.1126/scitranslmed.3008051Search in Google Scholar PubMed PubMed Central

58. Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis. A pathological and clinical entity. J Am Med Assoc 1932;9:1323–9.10.1001/jama.1932.02740680019005Search in Google Scholar

59. Erickson AR, Cantarel BL, Lamendella R, Darzi Y, Mongodin EF, Pan C, Shah M, Halfvarson J, Tysk C, Henrissat B, Raes J, Verberkmoes NC, Fraser CM, Hettich RL, Jansson JK. Integrated metagenomics/metaproteomics reveals human host–microbiota signatures of Crohn’s disease. PLoS One 2012;7:e49138.10.1371/journal.pone.0049138Search in Google Scholar PubMed PubMed Central

Received: 2013-10-18
Accepted: 2014-2-14
Published Online: 2014-3-28
Published in Print: 2014-1-1

©2014 by Walter de Gruyter Berlin/Boston