View source for The Human Gut Microbiome and Obesity

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=Introduction=

Obesity is a growing phenomenon in many industrialized countries [[#References|[1]]] and is associated with fatal diseases which are categorized as preventable including [http://en.wikipedia.org/wiki/Cardiovascular_diseases heart disease], [http://en.wikipedia.org/wiki/Stroke stroke], [http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 type 2 diabetes], and certain types of [http://en.wikipedia.org/wiki/Cancer cancer] [[#References|[2]]]. 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 [http://en.wikipedia.org/wiki/Mucosal_immune_system mucosal immune responses], selectively limiting certain species of microbes [[#References|[3]]] [[#References|[4]]] [[#References|[5]]] [[#References|[6]]]. 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. 
[[File: The_Global_Obesity_Problem.gif‎|thumb|400px|right|Figure 1. Prevalence of obesity in nations across the world. [[#References|[1]]] ]]

=Human Gut Microbiome=

It is estimated that there are approximately 100 trillion cells living in the human gut [[#References|[9]]]. These microbes represent roughly 160 different microbial species out of a possible selection of 1000 to 1150 gut-associated species present in the gut [[#References|[10]]]. Each species is adapted to a different niche, utilizing a slightly different subset of nutrients [[#References|[11]]]. 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 [[#References|[11]]]. The two most abundant bacterial phyla in the gut are [http://en.wikipedia.org/wiki/Bacteroidetes ''Bacteroidetes''] and [http://en.wikipedia.org/wiki/Firmicutes ''Firmicutes''], together constituting approximately 92.6% of the total gut population [[#References|[12]]]. These are also the two groups of bacteria that have been linked to obesity [[#References|[3]]] [[#References|[12]]] [[#References|[13]]] [[#References|[14]]].

=Microbe-Host Mutualism=

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 [[#References|[7]]] [[#References|[8]]] [[#References|[11]]] [[#References|[15]]] [[#References|[16]]]. This mutualism is best demonstrated by studies involving [http://en.wikipedia.org/wiki/Germ-free_animal 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 [[#References|[16]]]. This phenomenon is primarily due to the [http://en.wikipedia.org/wiki/Fermentation_%28biochemistry%29 fermentation] processes utilized by gut microbes [[#References|[7]]] [[#References|[8]]] [[#References|[11]]] [[#References|[15]]], which are able to ferment [http://en.wikipedia.org/wiki/Fermentation_%28biochemistry%29 complex carbohydrates] that human enzymes are not able to degrade [[#References|[7]]] [[#References|[8]]] [[#References|[11]]] [[#References|[15]]]. These otherwise indigestible carbohydrates are degraded by microbes into [http://en.wikipedia.org/wiki/Short-chain_fatty_acid short chain fatty acids] (small carbon-containing molecules) that can then be absorbed by the host and utilized as energy sources [[#References|[7]]] [[#References|[8]]] [[#References|[11]]] [[#References|[15]]]. Gut microbes are also able to induce fat storage in the host by increasing the absorption of simple sugars into the host’s [http://en.wikipedia.org/wiki/Serum_%28blood%29 serum] [[#References|[16]]]. The increased sugar concentration in the host’s serum helps to induce [http://en.wikipedia.org/wiki/Lipogenesis lipogenesis] (the formation of fat) in the liver [[#References|[16]]]. In these ways, the microbes living in the human gut maintain a mutualistic relationship with their host.

=Microbiome Composition and Obesity=

[[File: Changes_in_Faecal_Microbiota.jpg‎|thumb|400px|right|Figure 2. Results from Ley et al. [[#References|[12]]]. a) Faecal microbiota of different individuals (different colours) as grouped by their 16S rRNA sequences during the course of two different diets. b) Changes in ''Firmicutes'' and ''Bacteroidetes'' abundance in dieting individuals and lean individuals. c) Change in the relative abundance of Bacteroidetes  at different changes in body weight in two different diets.]]

Obesity is associated with changes in the composition of the gut microbiome [[#References|[3]]] [[#References|[12]]] [[#References|[14]]] [[#References|[17]]]. Although exact mechanisms are not yet known, it has been observed that obesity due to a high fat or high [http://en.wikipedia.org/wiki/Polysaccharide polysaccharide] diet correlates with a decrease in the amount of ''Bacteroidetes'' and a proportional increase in ''Firmicutes''. This was shown by Ley et al. [[#References|[17]]] in mouse models with obese and normal genotypes, and was later supported by Ley et al. [[#References|[12]]] 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 [[#References|[3]]] [[#References|[12]]] [[#References|[14]]] [[#References|[17]]]. 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'' [[#References|[3]]] [[#References|[18]]]. The replacing bacteria are more efficient at harvesting energy from food than the bacteria they replaced, resulting in increased calorie intake by the host [[#References|[19]]] and ultimately, an increase in weight [[#References|[19]]]. 

=The Immune System-Microbe Interaction=

In more recent studies, a link between the host immune system and obesity has been realized. Upadhyay et al. [[#References|[3]]], 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 [http://en.wikipedia.org/wiki/Lymphotoxin lymphotoxin] protein are resistant to obesity due to diet [[#References|[3]]]. Lymphotoxin is an essential component of the [http://en.wikipedia.org/wiki/Mucosal_immune_system mucosal immune system] which controls the production of vital [http://en.wikipedia.org/wiki/Interleukin interleukin proteins] [[#References|[3]]].  Interleukin proteins, in turn, are needed for a functional mucosal immune response [[#References|[3]]]. 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 [[#References|[3]]]. 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 [[#References|[3]]]. These groups increase energy uptake by the host, causing weight gain [[#References|[3]]]. 
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 [http://en.wikipedia.org/wiki/TLR_5 Toll-like Receptor 5] [[#References|[6]]] and [http://en.wikipedia.org/wiki/Tumor_necrosis_factors tumor necrosis factor] [[#References|[4]]] [[#References|[5]]] in obese individuals.
[[File: Mechanism for Weight Gain.jpg|thumb|400px|left|Figure 3. A general mechanism for weight gain in normal mice fed a high polysaccharide or high fat diet compared to mice with a deficient mucosal immune system fed a similar diet.]]

=Current Research=

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 [[#References|[20]]]. These therapy types have multiple risk factors, and new, safer methods are needed [[#References|[20]]]. Given the importance of gut bacteria in weight gain, manipulating the microbial content of the gut is a newly favoured potential treatment [[#References|[21]]]. [http://en.wikipedia.org/wiki/Probiotic Probiotics], [http://en.wikipedia.org/wiki/Antibacterial antibiotics], and [http://en.wikipedia.org/wiki/Prebiotic_%28nutrition%29 prebiotics] are currently being evaluated as the best means of changing the abundance of particular groups of microbes in the gut [[#References|[21]]] [[#References|[22]]]. 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 [[#References|[21]]] [[#References|[22]]]. 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.




=References=

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(2) Centers for Disease Control and Prevention (CDC). Adult Obesity Facts. <http://www.cdc.gov/obesity/data/trends.html#State> (2012).


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