Gut Microbial Ecology: Disease

Mediation and Causation

Daniel Hedge
Biology 223 A
Cushman

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Introduction
With the advent of cheap gene sequencing the notions of personalized medicine and
personal genomics have caught the imagination of the world but now with the expansion
of genomic studies to our surrounding and internal ecologies the image of the human
body is beginning to change dramatically in a way much like how the view of the
universe expanded from the world, to the solar system to the galaxy and beyond. Now
the understanding the human body is moving from the notion of a systems of human
cells bound in membranes interfacing an environment to a complex and rich ecology of
interacting permeable populations some sharing a common human genotype and some
not.
The human body is estimated to contain an internal microbial population of up to a
hundred trillion cells, that means there are ten times the microbial organisms in our
bodies than human cells, representing a combined genome a hundred times that of the
human genome (Shen et al., 2012). While Macdonald and Monteleones research finds
that these organisms interact with nearly every system of the body in ways never before
imagined and add capabilities to our bodies that our own cells cannot.(Macdonald and
Monteleone, 2005) The microbial content of the human body is increasingly being
recognized as an essential contributor to the human phenotype.
It has long been known that humans cannot produce all of the enzymes needed for
digestion. However their importance in many other aspects is only beginning to be
discovered. The potential breadth of relationships and interactions our internal
microbiological populations represent is of a magnitude that is only beginning to be
imagined and a great rush of research is now taking place to try to begin the long

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process of mapping out these relationships. Of particular interest is the rich and
complex role these microbial organisms have in the maintenance of our bodys
homeostasis, mediating diseases and sometimes even becoming pathogenic
themselves.

Body
It is hard to overemphasize the diversity and magnitude of the guts microbiome
called the gut microbiota but there are some surprising discoveries about that diversity.
While research has long since established the gut microbiotas diversity using ribosomal
DNA (Eckburg et al., 2005) it shockingly appears to be largely independent of human
population or geography (Lay et al., 2005). In fact it appears that gut microbiota upon
examination can be separated into three rough categories called enterotypes, which
according to the research done by Manimozhiyan and others appears to be a wellbalanced hostmicrobial symbiotic state driven by different patterns in species variation
of the gut microbiota (Manimozhiyan et. al., 2011) and these enterotypes appear
variable with age and potentially diet. It appears the healthy gut microbiota change by
making transitions between enterotypes presumably to adapt to differences in lifestyle
and diet. The degree in which such transitions are directly facilitated by the human body
are unknown.
Interestingly enough these same enterotypes are not just a human trait but appear to
be present in chimpanzees (Moeller et al., 2012) while there is of course variance
between the composition of human and chimp enterotypes they are compositionally
very similar and the three general specie compositional patterns remain intact and

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potentially are retained throughout the greater apes. It would be interesting to see if
similar enterotypes can be identified in more distant mammals, at this time however
sufficient research on this hasnt been done.
While a healthy humans gut microbiome can be characterized by their enterotypes
there does still exist variation within these homeostatic states in fact the variation within
enterotypes in modern humans appear to be changing. Amazingly it is possible to
recover the gut microbiota content from ancient human remains and analysis of these
gut microbiota show that little variance has occurred between ancient humans and
modern rural communities which is understandable considering the general
commonality in diet and lifestyle. It is only with modern cosmopolitan communities that a
marked increase in variance occurs (Tito et al., 2012) implying that with the radical
changes in diet and environment of modern human urban and suburban life the human
gut microbiota is undergoing increasing changes in order to adapt to this new situation.
This then begs the question what might be the consequences of such a transition and
its ensuing inevitable destabilizing effects on the guts microbiota, and what happens to
us as our guts microbiotic content moves out of those three homeostatic states a state
called dysbiosis?
The composition of the gut microbiota has been implicated in a variety of
increasingly common modern ailments like obesity, autoimmune disease like diabetes,
and inflammatory diseases like irritable bowel syndrome and Crohns disease. It has
even been implicated in playing an important role in increasingly common cancers of
the gastrointestinal tract such as pancreatic and colon cancer.

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These disease have been found to be fundamentally tied to variance in gut
microbiota to the point where it is possible to use metagenomic assays of the gut
microbiota to classify type 2 diabetes(Qin et al., 2012) demonstrating a direct
association between gut microbial dysbiosis and type 2 diabetes. This association
doesnt stop with type 2 diabetes but is even observed with type 1 diabetes where the
composition of the gut microbiota was found to be a strong factor in predisposing those
susceptible to type 1 diabetes(Hara et al., 2013). Significant differences in gut
microbiota are even found in autoimmune and inflammatory diseases not normally
associated with the gut. Rheumatoid arthritis sufferers are found to have significant
variance from healthy individuals (Vaahtovuo et al., 2008) and the activation of
pathogen recognition receptors in the gut from the translocation of gut microbiota has
been found to be the key pathogenic event triggering the transition from nonpathogenic
HIV to AIDs(Marchetti et al., 2013).
In order to understand these consequences of the activity, arising variance, and
dysbiosis in human gut microbiota something of their roles must be understood. These
roles are remarkably diverse. Gut microbiota recognize and synthesize neuroendocrine
hormones and there is strong evidence that there is direct interaction with the human
nervous system by such chemical signaling pathways. Gut microbiota produce
neurotransmitters like GABA and even produce precursors like tyrosine and tryptophan,
precursors to mood altering compounds (Norris et al., 2012). Such neuroendocrine
interaction is deeply implicated in the regulation of hunger and the feedback between
diet and mood.

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Gut microbiota do not just function in the gut, they play an essential role in creating
its very structure, particularly the epithelial structures of the gut. Gut microbiotaepithelial interactions through CCR7 signaling even have great influence over the
formation of gut-associated lymphoid tissues (Pabst et al., 2006) and have a powerful
influence on the formation goblet cells which in germ free models are nearly absent and
greatly diminished in size and activity(Kandori et al., 1996).
An important example of this mediation is that through gut microbiota fermentation
byproducts gut microbiota can regulate the gene expression for the production of
mucins in the gut (Burger-van Paassen et al., 2009). Mucins are of particular
importance as they form gels like coatings in the intestinal tract that play an essential
role in lubrication and signaling(Marin et al., 2007) the overproduction of which has
been linked to several kinds of cancer including pancreatic cancer and colon cancer
(Niv, 2008) Another effect of such byproducts is in the positive regulation of
inflammation particularly in the resolution of inflammatory responses where if certain
byproducts are not present or their receptors are not activated the body will not cease
its inflammatory response (Maslowski et al., 2009).
Such interactions have been discovered to be mediated by several classes of
pattern recognition receptor. The mechanism of such regulators are poorly understood
though research is beginning to make some headway in this. Toll-like receptors (Tlrs)
are receptors which recognize different pathogenic bacteria by responding to the
presence of various lipopolysaccharides are responsible for behavior such as positive
inflammatory regulation (Maslowski et al., 2009) and the transition of HIV into AIDs.
Another class of such receptors called Nucleotide-binding, Oligomerization Domain

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containing proteins or NOD are found to function through the recognition of
peptidoglycan structures(Clarke et al., 2010). NOD1 for instance is found to play a key
role in anti-bacterial immune regulation and response by capturing samples of
potentially pathogenic bacteria and transporting them through vesicles into the
circulatory system to train the immune system in their recognition. Whether a similar
mechanism for NOD2 receptors is occurring or not is unknown but it has been
implicated in the regulation of the variance within the gut microbiota being shown to
play a major role in recognizing and regulating pathogenic bacteria (Couturier-Maillard
et al., 2013) and mutations in NOD2 genes are the strongest known genetic factors
predisposing someone to Crohns disease (Petnicki-Ocwieja et al., 2009) and can cause
serious dysbiosis giving rise to colon-rectal cancers and gastrointestinal inflammatory
diseases(Couturier-Maillard et al., 2013). Emphasizing the importance of the pathways
by which the body recognizes and responds the gut microbiota.
This leads to another essential aspect of the interaction between the body and
the gut microbiota. The gastrointestinal tract doesnt just respond to gut microbiota but
actively attempts to regulate the population content. There a number of ways by which
this regulation is accomplished. Commensal bacteria, bacteria in positive symbiotic
relationships with the epithelial cells of the gastroitnestinal tract, produce byproducts
which induce the production and release of beneficial nutrients like fucosylated glycans
which encourage the colonization of those bacteria (Hooper et al., 1999). The
gastrointestinal tract also excretes antibiotic compounds to regulate the composition
and density of gut microbiota (Vaishnava et al., 2011)

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Conclusion
While there remains much to be discovered about the interaction between gut
microbiota and the rest of the body that such interaction is occurring and is reciprocal is
no longer in question. Indeed the many levels of such interactions with the rest of the
body are astounding; from interaction with the nervous system altering perception and
mood to the formation of tissues with the influencing of gastrointestinal epithelial
structures, and even the direct regulation of gene expression of human cells the
boundaries of the interaction between the gut microbiota and the rest of the body is ever
expanding. With the discover of correlations to diseases such as rheumatoid arthritis
and AIDs the involvement of such interactions with the immune system in regulating and
causing disease has far reaching implications for the very nature of disease and its
potential treatment.
As can be observed by a quick purview of this papers references most of the
research on this topic is within the last two years. There is a great deal yet to be
discovered as to the interactions between the human body and its microbiome and the
pathways for many of those interactions are poorly understood with many uncertain and
some even unknown let alone the underlying mechanisms. What is certain is the
importance of this research and its impact on our understanding of the human body.

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