Friday, November 14, 2014

Microbiome- Follow up post


  In my previous post, I talked about the growing field of microbiome and tried to put important concepts of virome in a snapshot pattern. I realized that I should have cited more examples and some concentrated a bit more on microbiome, to get the reader a full picture. So, this post is a follow up for my previous post.

First, let me revisit the debated question of microbiome. "Is it worth to call our microbiome a yet another organ"? This is a well discussed question with science thinkers and practitioners taking both sides of opinion and there is no consensus. However more and more of the scientific community is beginning to accept the yes part of it. The point that the microbiome is more than significantly associated with multiple physiological components is striking enough to be called as an organ. Gnotobiotic rats are maintained in such artificial conditions, shows that natural life without microbiome is probably impossible. That argument delivered, let us at least tentatively agree it as another organ (But unlike other organs, in terms of dynamic nature).

I'm pretty sure you have heard at least one example similar to the following. Two identical persons with similar exposure to environmental factors (Let's say mosquito bite), and one of them keeps getting infection. Th other appears resistant always. The earliest of the arguments was "Genetics". With more research pouring in this seems to be possible even if the genetics was much similar (Say in siblings) and genetics may not account, nor chance. Such questions have led researchers to question if there is more to it. A set of gene similarity don't mean much these days, since concepts such as epigenetics has to be considered for variability. But microbiome probably produces a gene pool that can account for a million more variation to be considered, and that is why the the hypothesis of "microbiome influence" is damn attractive.

Not convinced yet? In addition to the previous post citing articles (I have previously posted multiple blogs on the same concept, Indeed this blog site is full of such examples), here I will present a couple of examples that stress on what I have said.

Perhaps the most compelling of the evidence is microbiome influence on weight. Obesity is considered as a disease in the current era and there is enough genetic factors that lie around the whole concept. However, off late evidence has begun to accumulate that microbe gene pool is also important. Studies have been conducted on humanized mice to show that microbiome can have a significant impact on obesity. It has been demonstrated that by transferring the microbiome, from gut obesity can be influenced. Lean mice can be made obese and other way around. More recently deep sequencing from human gut has shown supportive results.

In a recent example I cited, C difficile has got an important rival C scindens, which can reduce the C diff effect (Read my previous post here). This is not the only such study. For example Ruminococcus obeum is shown to significantly effect the virulence of V cholerae. This is mediated through a inter species quorum sensing, specifically R obeum AI-2 which repress V cholerae virulence genes. There are more such examples in literature, and more on coming. You just need to look.

There are more examples. For example, microbial composition is shown to influence how frequently you will get a mosquito bite. Skin flora metabolites are the cause of odor, signatures of which can be detected by the mosquito, It has been shown that a particular pattern of microbiota composition is more attractive to mosquito. Another one, bacterial colonization in the wound is common concurrence. The type of composition has been shown to impact the healing capabilities in terms of time and quality.

The first question that has been often raised is why can't we get such data for every condition? Is it reliable. I have already discussed the dynamic nature and the technical challenge in evaluating the flora composition in previous post. Additionally understanding the pathways between every microbial entity is currently out of the technical capabilities. Working with more than a million connections is simply a challenge.

More recently the whole concept of microbiome has met with a challenge of addressing contamination. In a article published in nature, there is a lot of discussion on issue of contaminating sequences, based on papers published in BMC biology and PloS One. The point basically boils down to the fact that the reagents used in two commonly used sequencing techniques -16S rRNA and whole-genome shotgun metagenomics, contain contaminating sequences. The lack of negative control sequence has impacted the way we look into the deep sequencing technique. The point is illustrated in the statement by Walker, "We haven’t challenged anyone directly. We hope the message will stand for itself. We’re trying to nip it in the bud now before it becomes more of an issue.” Source

So what are the implications?

One of the microbiota based therapy is projected to be Fecal transplantation (FTM). The success story of treating C diff infection, by FTM has led many people to argue that probably "microbiota transfer", can be the answer to many of the conditions. In other words, there is a tendency to designate "Good" & "Bad" microbiome. My projection was that, if we can recolonize with "Good microbiota", for other conditions such as asthma, where it can be influential, that would be great. Of course we don't know at this point what is that combination in any of our normal flora system. However, A post in ASM blog (Link), has led me to rethink this. Probably, just like genes its not good or bad. Its the context that matters.

Story has just begun to uncover, and am sure I will be revisiting these concepts.
Baquero, F., & Nombela, C. (2012). The microbiome as a human organ Clinical Microbiology and Infection, 18, 2-4 DOI:10.1111/j.1469-0691.2012.03916.x

Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Muehlbauer MJ, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Ursell LK, Clemente JC, Van Treuren W, Walters WA, Knight R, Newgard CB, Heath AC, & Gordon JI (2013). Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science, 341 (6150) PMID:24009397

Hsiao A, Ahmed AM, Subramanian S, Griffin NW, Drewry LL, Petri WA, Haque R, Ahmed T, & Gordon JI (2014). Members of the human gut microbiota involved in recovery from Vibrio cholerae infection. Nature PMID: 25231861

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