Gut microbiome studies lend significance to the idiom “you are what you eat”

The human intestine is an ecosystem that supports up to 100 trillion microbes—a cell number that is roughly ten times greater than the human cells that comprise our bodies. In addition to the vast number of cells comprising the microbial community of the gut, there may be over 100 times the number of bacterial genes present compared with the number of genes in our own DNA (Bäckhed et al., 2005). These beneficial microbes are instrumental in our ability to extract nutrients from food, and also play an important role in the development of our immune systems.

In a study conducted by Eckburg et al. (2005), 16S rRNA genes were obtained from DNA extracted from gut mucous or feces via PCR primers targeted to broad phylogenetic groups of bacteria.  The data indicated seven divisions (phyla) of bacteria, but by far the most dominant groups were the Bacteroidetes and Firmicutes.  Figure 1 from a review by Ley et al. (2006) highlights the Eckburg et al. finding by comparing the percent representation of divisions in a variety of environments.

Figure 1.  Comparison of Microbial Diversity in the Human Colon, Mouse Cecum, Fish Gut, Ocean, Stromatolite and Soil

Eckburg’s research team discovered that there were high levels of strain variation, but far fewer intermediate and deep lineages, supporting the idea that gut bacteria evolution is a classic case of adaptive radiation, where a few successful colonists gave rise to a variety of descendants, thus there was diversification of an initial population bottleneck into various strains that likely correspond to ecotypes.

A logical question then arises— How do the microbes withstand attack, by a bacteriophage for example, with such low levels of diversity?  It is suggested that genomic and/or transcriptomic diversity at the subspecies level results in a broad collection of responses to various environmental factors.  In other words, the microbes are functionally diverse in their adaptive responses despite relatively low levels of phylogenetic diversity (Bäckhed et al., 2005).  A fascinating example of microbial genetic differentiation via LGT was recently recovered by Jan-Hendrik Hehemann et al. (2010).  Working with Zobellia galactanivorans, a member of the marine Bacteroidetes, investigators discovered an enzyme (porphyranase) responsible for breaking down porphyran, an abundant polysaccharide in the red algal species Porphyra, on which Z. galactanivorans is often found.  While searching gene-sequence databases, investigators came across predicted porphyranase sequences in metagenomes derived from human feces and in the genome of the resident human gut bacterium Bacteroides plebeius, suggesting B. plebeius acquired the genes laterally from marine bacteria.  Because it turned out these sequences were present in Japanese individuals but not in residents of the United States, Hehemann et al. concluded that Z. galactanivorans were introduced via Porphyra (“nori”), the traditional seaweed used to wrap sushi and a common component of the Japanese diet.  The researchers hypothesize that by constantly consuming seaweeds, Japanese communities produced a selective force that led to retaining the beneficial porphyranase genes in their gut microbiomes.

But, if lateral gene transfer is considered to be a homogenizing evolutionary force, and we assume Bacteroidetes and Firmicutes have continually swapped genes over their evolutionary history, wouldn’t we expect to see little variability in the makeup and function of their genomes?  To the contrary, these two groups have a known difference in the GC content of their DNA, evidence that despite selection for functional redundancy, they are distinct enough genetically to occupy different niches in the gut environment.  It is likely they have complementary roles as well, where the product of one microbe becomes the substrate for another, and a complex yet efficient chemical food web results. Experiments that aim to quantify rates of LGT among key members of the gut microbiota will help to elucidate the degree to which microbes differ between these gut niches.

In general, the ability to aid the host in extracting energy and nutrients from food is considered an important benefit that has resulted in a long history of coevolution between humans and gut microbes.  However, recent research has demonstrated that resident microbial communities can become pathogenic within the context of other factors, such as host genotype, diet and behavior.  For example, groups that are highly efficient at extracting calories from food may confer a health advantage to human individuals or communities with limited access to food resources.  Conversely, these same groups could have negative health consequences (e.g. obesity) for those who have ready access to many types of food.  Ley and Turnbaugh et al. (2006) found that the proportion of genetic material from Firmicutes was higher in obese individuals than in lean individuals, and further, when obese individuals lost weight, the proportion of Firmicutes decreased to a level more like that of lean individuals.

The research team of Carlotta De Filippo et al. (2010) took the work of Ley et al. a step further by honing in on the coevolution of microbiota associated with different diets in human populations.  The study compared the gut microbiota of children aged 1-6 living in a village in rural Africa with those from European children of the same age group living in a typical modern western environment. The diets of the African children were characterized as low in fat and animal protein and high in starch, fiber, and plant polysaccharides, whereas the European children’s diets were high in animal protein, sugar, starch and fat and low in fiber.  Both groups of children were breast-fed, for up to two years in the African group and up to 1 year in the European group.  Researchers sequenced 16S rRNA from the fecal matter of several children in each population, and thought they found very similar bacterial phyla across groups, the African children had significantly more abundant Bacteroidetes and lower levels of Firmicutes compared with European children.


Figure 2.  Dendogram clustering of samples from African and European populations based on their genera.  Note that the subcluster at the middle of the tree are samples taken from the three youngest African children (aged 1-2 yrs) and two 1-year old European children, all of which represent children that are breast-fed rather than receiving the respective African or European solid food diets. 

Additionally, the African children contained bacterial genes for hydrolysis of cellulose and xylan (plant fibers), which the European children completely lacked.  De Filippo et al. suggest that the gut microbiota of the African children coevolved with their polysaccharide-rich diet.  The investigators propose that the European children may be predisposed to obesity due to the increased Firmicutes/Bacteroides ratio in their gut, likely resulting from their diet.  Most intriguingly, they found that short-chain fatty acids produced in the gut from the bacterial fermentation of whole grains were abundant in only the African children’s feces, noting the connection between these molecules and their protective role against gut inflammation.

Many hypotheses regarding the evolution of the human gut microbiome still remain to be tested.  Among these, what I find particularly interesting are potential connections between the makeup of the gut microbiome and cultural differences between developing and industrialized countries.  What are the impacts of improved sanitation on the gut microbiomes in developed nations, assuming we are reducing exposure to hosts of microbes that may have been able to set up shop in our gut?  What impact does this have on the development of the host immune system?  What about frequent use of antibiotics during postnatal development in western cultures? How might use of antibiotic treatments affect the establishment of long-term microbe communities in the gut?  Furthermore, might it be possible to establish particular microbial assemblages within the gut as a therapeutic strategy to treat health conditions such as inflammatory gut disease or autoimmune disorders?

Literature Cited:

 
Backhed, F. (2005). Host-Bacterial Mutualism in the Human Intestine Science, 307 (5717), 1915-1920 DOI: 10.1126/science.1104816

De Filippo, C., Cavalieri, D., Di Paola, M., Ramazzotti, M., Poullet, J.B., Massart, S., Collini, S., Pieraccini, G., & Lionetti, P.  (2010).  Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa.  PNAS, 107 (33): 14691-14696.

Eckburg, P.B., Bik, E.M., Bernstein, C.N., Purdom, E., Dethlefsen, L., Sargent, M., Gill, S.R., Nelson, K.E., & Relman, D.A. (2005).  Diversity of the human intestinal microbial flora.  Science, 308: 1635-1638.

Hehemann, J.H., Correc, G., Barbeyron, T., Helbert, W., Czjezek, M., & Michel, G.  (2010).  Transfer of carbohydrate-active enzymes from marine bacteria to Japanese gut microbiota.  Nature, 464:  908-912.

Ley, R.E., Peterson, D.A., & Gordon, J.I.  (2006).  Ecological and Evolutionary Forces Shaping Microbial Diversity in the Human Intestine.  Cell, 124: 837-848.

Ley, R.E. Peter J. Turnbaugh, P.J., Klein, S., & Gordon, J.I. (2006).  Microbial ecology: Human gut microbes associated with obesity. Nature, 444: 1022-1023.

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