The current estimation of microbes in the human body is at 100 trillion cells and they are extremely diverse (Ley and Peterson, 2006). Thus, the genes that they encode may be as many as 100 times as our own genome. Most of these organisms reside within the human gastrointestinal tract and are crucial for many of the basic functions of the digestive system. Many foods we eat would simply not be absorbed without the gut microbiota. More importantly, these organisms have been found to play part in the prevention (and in some instances, causal roles) of diseases such as inflammatory bowel disease (IBD), cancer and obesity. The destruction of the microbiota by antibiotics has consequences in the health of the individual. Intake of probiotics (eg. yogurt), has become an interesting therapeutic treatment. Due to the importance of its functional roles, O'Hara and Shanahan (2006) have suggested that the gut microbiota should be viewed as a human organ in its own right. The only exception is that they are not controlled by the human genome, but rather by the 100 times more unique bacterial genes.
Just last month, the deep sequencing of the human gut microbiota full metagenome was published (Qin et al., 2010). This marks an important milestone that expands the use of genomic technologies in nutritional sciences. Since the organisms of the gut microbiota are of hundreds of different species, it is difficult to culture an individual species and sequence it. "Metagenomics" refers to the study of the sequences of a collection of organism taken from their environment (in this case, the human GI tract). The individual genes are of interest regardless of the species of the organism. Therefore, sequencing the metagenome is the most practical way to get access to the full genetic information of our microbial "organ".
With these sequences in hand, I propose the following analyses so nutritional scientists may better understand and make use of the gut microbiota in studying related diseases. There are two scopes of analyses: gene-specific and transcriptomic.
Gene specific analyses:
1. perform multiple sequence alignments (MSA) of each gene against known bacterial genomes, because most of the already sequenced gut bacterial genes are included in this metagenome (Qin et al., 2010). Most of the high frequency genes in this metagenome have already been mapped to NCBI-NR, KEGG, COG, and eggNOG databases (Qin et al., 2010).
2. find homologs and establish phylogenies in relation to known genomes from the MSA
3. study the genes whose homologs are of relevant significance under relevant conditions. Such genes would have bacterial homologs that are known to be involved in fat metabolism, inflammation-repressing functions (Guarner and Malagelada, 2003), carcinogen metabolism (O'Hara and Shanahan, 2006). Relevant conditions would include in the presence of colorectal cancer, probiotic treatment, drug treatment, high fat diet, etc. These studies would begin with qRT-PCR.
Transcriptomic analyses:
1. make microarrays from this gene sequence catalogue
2. produce metagenomic co-expression profiles of different conditions of the GI tract. For example, in the presence of colorectal cancer, probiotic treatment, drug treatment, high fat diet, etc.
3. compare the global transcriptome changes in these conditions, especially relating to metabolic pathways.
The outcome of these analyses may allow us to evaluate drugs and probiotics aimed at the GI tract. Furthermore, new treatments can be devised after the identification of key factors produced by the microbiota that prevent or repress disease malignancy. Most importantly, many studies are easy to do in humans (except for certain inducing treatments that needs to be done in mouse), because the analyses of gut microbiota require no invasive procedure, as human fecal samples are simple to collect.
References:
Qin, J, et al. (2010). A human gut microbial gene catalogue established by metagenomic sequencing. Nature, 464: 59-65.
Ley, R. E., Peterson, D. A.&Gordon, J. I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124, 837-848 (2006).
O'Hara, A. M., & F. Shanahan. (2006). The gut flora as a forgotten organ. European Molecular Biology Organization Reports, 7(7): 688-693.
Guarner, F., & JR. Malagelada. (2003). Role of bacteria in experimental colitis. Best Practice & Research Clinical Gastroenterology, 17(5): 793-804.
