The Human Gut Microbiome and Obesity
Obesity is a growing phenomenon in many industrialized countries  and is associated with fatal diseases which are categorized as preventable including heart disease, stroke, type 2 diabetes, and certain types of cancer . Research into the causes of obesity has shown that the composition of the gut microbiome plays a significant role in weight gain. Changes in the gut microbiome can result from variations in diet that induce alterations in the gut environment and mucosal immune responses, selectively limiting certain species of microbes    . Studies have demonstrated a complex system of interactions between the human body and microbial community of the gut and their role in maintaining a healthy body weight.
Human Gut Microbiome
It is estimated that there are approximately 100 trillion cells living in the human gut . These microbes represent roughly 160 different microbial species out of a possible selection of 1000 to 1150 gut-associated species present in the gut . Each species is adapted to a different niche, utilizing a slightly different subset of nutrients . Environmental sensing systems allow the bacteria to adjust their metabolism according to which nutrients or other species are present, permitting a large number of different microbial species to co-exist in the dynamic gut environment without out-competing each other . The two most abundant bacterial phyla in the gut are Bacteroidetes and Firmicutes, together constituting approximately 92.6% of the total gut population . These are also the two groups of bacteria that have been linked to obesity    .
A mutualistic relationship exists between the human host and the gut microbes: the host provides a consistent and amenable environment and, in return, is provided with access to otherwise inaccessible energy and carbon     . This mutualism is best demonstrated by studies involving germ-free mice, where it has been shown that mice with no microbes present in their gut obtain less energy from food than normal mice with microbes when both groups have been fed the same diet . This phenomenon is primarily due to the fermentation processes utilized by gut microbes    , which are able to ferment complex carbohydrates that human enzymes are not able to degrade    . These otherwise indigestible carbohydrates are degraded by microbes into short chain fatty acids (small carbon-containing molecules) that can then be absorbed by the host and utilized as energy sources    . Gut microbes are also able to induce fat storage in the host by increasing the absorption of simple sugars into the host’s serum . The increased sugar concentration in the host’s serum helps to induce lipogenesis (the formation of fat) in the liver . In these ways, the microbes living in the human gut maintain a mutualistic relationship with their host.
Microbiome Composition and Obesity
Obesity is associated with changes in the composition of the gut microbiome    . Although exact mechanisms are not yet known, it has been observed that obesity due to a high fat or high polysaccharide diet correlates with a decrease in the amount of Bacteroidetes and a proportional increase in Firmicutes. This was shown by Ley et al.  in mouse models with obese and normal genotypes, and was later supported by Ley et al.  in studies of human fecal matter. Obesity is also associated with a decrease in the overall microbial diversity of the gut, although the total amount of microbes remains the same    . This indicates that certain groups of bacteria, such as Firmicutes, are taking the place of the bacterial groups that have decreased in abundance, such as Bacteroidetes  . The replacing bacteria are more efficient at harvesting energy from food than the bacteria they replaced, resulting in increased calorie intake by the host  and ultimately, an increase in weight .
The Immune System-Microbe Interaction
In more recent studies, a link between the host immune system and obesity has been realized. Upadhyay et al. , demonstrated with mouse models that a fully functioning immune system makes the host vulnerable to obesity induced by a high fat diet. However, mice that are deficient in lymphotoxin protein are resistant to obesity due to diet . Lymphotoxin is an essential component of the mucosal immune system which controls the production of vital interleukin proteins . Interleukin proteins, in turn, are needed for a functional mucosal immune response . It is thought due to these observations in mouse models, that mucosal immunity controls the microbes in the gut, and therefore, the level of energy harvest occurring . Although the exact mechanism is not known, a high fat diet somehow induces an immune response in the gut that appears to diminish many bacterial species, allowing specific bacterial groups associated with obesity to increase in abundance . These groups increase energy uptake by the host, causing weight gain . This association between the host immune system and obesity is supported by other studies that demonstrate the prevalence of mucosal immune system components such as Toll-like Receptor 5  and tumor necrosis factor   in obese individuals.
The goal of most research on obesity and the gut microbiome is to discover new therapies for treating obesity. Current treatments involve surgery, drugs, and hormones that inhibit certain digestive pathways or reduce the patient’s appetite . These therapy types have multiple risk factors, and new, safer methods are needed . Given the importance of gut bacteria in weight gain, manipulating the microbial content of the gut is a newly favoured potential treatment . Probiotics, antibiotics, and prebiotics are currently being evaluated as the best means of changing the abundance of particular groups of microbes in the gut  . However, the development of these agents has proven difficult as they must be very specific in order to target the correct organisms without negatively disrupting the normal flora of the patient  . Much more needs to be known about gut-microbe interactions in order for these proposed microbial therapies to eventually be used as safe and efficient treatments for obesity.
(1) World Health Organization (WHO). Global Infobase. <https://apps.who.int/infobase/?id=1> (2005).
(2) Centers for Disease Control and Prevention (CDC). Adult Obesity Facts. <http://www.cdc.gov/obesity/data/trends.html#State> (2012).
(3) Upadhyay, V., Poroyko, V., Kim, T., Devkota, S., Fu, S., Liu, D., Tumanov, A.V., Koroleva, E.P., Deng, L., Nagler, C., Chang, E.B.,Tan, H. and Fu, Y.X. “Lymphotoxin regulates commensal responses to enable diet-induced obesity.” Nature Immunology, 2012, DOI:10.1038/ni.2403
(4) Mahajan, A., Tabassum, R., Chavali, S., Dwivedi,O. P., Chauhan, G., Tandon, N. and Bharadwaj, D. “Obesity-dependent association of the TNF/LTA locus with type 2 diabetes in North Indians.” J. Mol. Med., 2010, 88(5):515–522.
(5) Norman, R.A., Bogardus, C. and Ravussin, E. “Linkage between obesity and a marker near the tumor necrosis factor-alpha locus in Pima Indians.” J. Clin. Invest., 1995, DOI:10.1172/JCI118016
(6) Vijay-Kumar, M., Aitken, J.D., Carvalho, F.A., Cullender, T.C., Mwangi, S., Srinivasan, S., Sitaraman, S.V., Knight, R., Ley, R.E. and Gewirtz, A.T. “Metabolic Syndrome and Altered Gut Microbiota in Mice Lacking Toll-Like Receptor 5.” Science, 2010, DOI: 10.1126/science.1179721
(7) Gill, S.R., Pop, M., DeBoy, R.T., Eckburg, P.B., Turnbaugh, P.J., Samuel, B.S., Gordon, J.I., Relman, D.A., Fraser-Liggett, C.M. and Nelson, K.E. “Metagenomic Analysis of the Human Distal Gut Microbiome.” Science, 2006, 312(5778):1355-1359.
(8) Xu, J., Bjursell, M.K., Himrod, J.,Deng, S.,Carmichael, L.K.,Chiang, H.C.,Hooper, L.V. and Gordon, J.I. “A Genomic View of the Human: Bacteroides thetaiotaomicron Symbiosis.” Science, 2003, 299(5615):2074-2076.
(9) Ley, R. E., Peterson, D. A. and Gordon, J. I. “Ecologicaland evolutionary forces shaping microbialdiversity in the human intestine.” Cell, 2006, 124(4): 837-848.
(10) Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K.S., Manichanh, C., Nielsen, T., Pons, N., Levenez, F., Yamada, T., Mende, D.R., L,i J., Xu, J., Li, S., Li, D., Cao, J., Wang, B., Liang, H., Zheng, H., Xie, Y., Tap, J., Lepage, P., Bertalan, M., Batto, J.M., Hansen, T., Le Paslier, D., Linneberg, A., Nielsen, H.B., Pelletier, E., Renault, P., Sicheritz-Ponten, T., Turner, K., Zhu, H., Yu, C., Li, S., Jian, M., Zhou, Y., Li, Y., Zhang, X., Li, S., Qin, N., Yang, H., Wang, J., Brunak, S., Doré, J., Guarner, F., Kristiansen, K., Pedersen, O., Parkhill, J., Weissenbach, J., Bork, P., Ehrlich, S.D. and Wang, J. “A human gut microbial gene catalogue established by metagenomic sequencing.” Nature, 2010, 464(7285):59-65.
(11) Thomas, F., Hehemann,J.H., Rebuffet, E., Czjzek, M. and Michel, G. “Environmental and Gut Bacteroidetes: The Food Connection.” Frontiers in Microbiology, 2011, DOI:10.3389/fmicb.2011.00093
(12) Ley, R.E., Turnbaugh, P.J., Klein, S. and Gordon, J.I. “Microbial ecology: Human gut microbes associated with obesity.” Nature, 2006, DOI:10.1038/4441022a
(13) Eckburg, P.B., Bik, E.M., Bernstein, C.N., Purdom, E., Dethlefsen, L., Sargent, M., Gill, S.R., Nelson, K.E. and Relman, D.A. “Diversity of the Human Intestinal Microbial Flora” Science, 2005, 308(5728): 1635-1638.
(14) Turnbaugh, P.J., Bäckhed, F., Fulton, L. and Gordon, J.I. “Diet-Induced Obesity Is Linked to Marked but Reversible Alterations in the Mouse Distal Gut Microbiome.” Cell Host Microbe, 2008, 3(4): 213-223.
(15) Mahowald, M.A., Rey, F.E., Seedorf, H., Turnbaugh, P.J.,Fulton, R.S.,Wollam, A., Shah, N., Wang,C., Magrini, V., Wilson, R.K., Cantarel, B.L., Coutinho, P.M., Henrissat, B., Crock, L.W., Russell, A., Verberkmoes, N.C., Hettich, R.L. and Gordon, J.I. “Characterizing a model human gut microbiota composed of members of its two dominant bacterial phyla.” Proc Natl Acad Sci U S A., 2009, DOI: 10.1073/pnas.0901529106
(16) Bäckhed, F., Ding, H., Wang, T., Hooper, L.V.,Koh, G.Y., Nagy, A., Semenkovich, C.F. and Gordon, J.I. “The Gut Microbiota as an Environmental Factor That Regulates Fat Storage.” Proc. Natl. Acad. Sci. U. S. A., 2004, 101(44): 15718-15723.
(17) Ley, R.E., Bäckhed, F., Turnbaugh, P., Lozupone, C.A., Knight, R.D. and Gordon, J.I. “Obesity alters gut microbial ecology.” Proc. Natl Acad. Sci. USA, 2005, DOI: 10.1073/pnas.0504978102
(18) Faith, J.J., McNulty, N.P., Rey, F.E., Gordon, J.I. “Predicting a Human Gut Microbiota’s Response to Diet in Gnotobiotic Mice.” Science, 2011, DOI: 10.1126/science.1206025
(19) Turnbaugh, P.J., Ley, R.E., Mahowald, M.A., Magrini, V., Mardis, E.R. and Gordon, J.I. “An obesity-associated gut microbiome with increased capacity for energy harvest.” Nature, 2006, DOI:10.1038/nature05414
(20) McGavigan, A.K. “Gut hormones: the future of obesity treatment?” British journal of clinical pharmacology, 2012, DOI:10.1111/j.1365-2125.2012.04278.x
(21) Murphy, E.F., Cotter, P.D., Hogan, A., O'Sullivan, O., Joyce, A., Fouhy, F., Clarke, S.F., Marques, T.M., O'Toole, P.W., Stanton, C., Quigley, E.M.M., Daly, C., Ross, P.R., O'Doherty, R.M. and Shanahan, F. “Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity.” Gut, 2012, DOI: 10.1136/gutjnl-2011-300705
(22) Holmes, E., Kinross, J., Gibson, G.R., Burcelin, R., Jia, W., Pettersson, S. and Nicholson, J.K. “Therapeutic Modulation of Microbiota-Host Metabolic Interactions.” Sci. Transl. Med., 2012, DOI: 10.1126/scitranslmed.3004244