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Thursday
Apr042013

You are what you eat, when you're 1 day old.

by Brooke Napier

Experiences in my childhood have resulted in me not liking mayonnaise, being scared of bathrooms without windows, and apparently the sensitivity of my colon to inflammation.I'm dead serious about this hate.

The idea of exposure to certain microbes affecting your adult life isn’t a new one, it’s called the “hygiene hypothesis”, which proposes that early-life exposure to specific microbes can result in a lower susceptibility to diseases such as inflammatory bowel disease (IBD) and asthma.

Basically, we (Americans specifically) are so clean as babies we’re making ourselves sick as adults.

But how are these two things tied together?

How does exposure to microbes as a baby influence your susceptibility to colon disease?

There have been tons of studies trying to answer these questions, but I found a beautiful article published in Science Magazine one year ago that enlightens the field by showing that microbial exposure at a young age (think the age of 1 day) can teach your immune system to avoid inflammatory disease in the colon as an adult.

Let’s break-it-down:

They already knew:

Previous epidemiological studies have already shown that exposure to microbes and a very young age is associated with lowered frequencies of immune-mediated inflammatory bowel disease (IBD).

They also knew that after birth, the gut is one of the first sites of microbial contact with human cells.

Basically, they knew there was a super interesting correlation between microbial exposures early in life equals less inflammation in the gut as an adult, but they had no idea why these two things would be correlated.

So what did they do to look at this correlation?

There are two major players in their study, Germ-Free (GF) mice and specific pathogen-free (SPF) mice. GF mice do not have any commensal bacteria in their gut, or anywhere, they’ve never seen a bacterium in their life. SPF mice have normal commensal bacterial cultures.

This is what Germ-Free (GF) mice live in. Yes, they are basically the bubble boy.

There are TONS of differences between these two mice, however this group of researchers was particularly interested in the difference they saw of a cell type that accumulates in the colonic lamina propria (da gut, yo) when the mice has ulcerative colitis.  They can induce ulcerative colitis in mice by administering a chemical that basically beats-up the epithelial lining of the gut, mimicking ulcers.

The infamous (or inflammous, har har) cell type associated with increased inflammation in the gut during this colitis model is known as invariant natural killer T (iNKT) cells.

invariant natural killer T-cell - it looks pretty menacing, don't you think?

Scared yet? I am.

Basically where there are more iNKT cells there is more inflammation, so the fact that GF mice had swarms of these cells in their gut meant that when GF mice had ulcerative colitis they died more frequently, or if not had worse symptoms, then SPF mice that also had ulcerative colitis (but less iNKT cells).

They go on to find that if they take GF mice (with no commensals) and expose them to microbiota at their first day of life they can reduce the frequency of iNKT cells in the gut during inflammation, and this is true throughout the rest of the mouse’s life.

However, when they exposed adult GF mice to microbiota they could not decrease the number of iNKT cells that were in the gut during inflammation – it was too late, the path was already paved for those mice.

Basically, super early exposure to microbiota led to a decrease in a life-time of gut inflammation due to lowered numbers of iNKT cells.

But why are there more iNKT cells in GF mice compared to SPF mice during inflammation of the gut?

Good question, they say.

What they found was that CXCL16, basically a molecule that beckons iNKT cells to the place of inflammation when they’re needed is extremely high in GF mice compared to their SPF friends. This means that the microbes in your colon are directing traffic of inflammatory cells (iNKT cells) by influencing the levels of molecules that attract them!

How can the microbiota tell the human cell to produce CXCL16 in order to influence the iNKT cells to migrate to the colon?

Your DNA is wrapped tightly around what is essentially a group of little protein balls (histones) that have tons of little repressor molecules (called methyl groups) that bind the DNA to the histones. When DNA is wrapped tight around these heavily methylated histones there is no access to the genes, therefore genes cannot be expressed.However, with the modification of removing some methyl groups, the DNA will loosen from around the histones and allow the appropriate machinery to access those genes and be expressed.

This is the bread and butter of eukaryotic genetics, in this one tiny picture.

This group of profound scientific researchers found that under GF conditions the gene that encodes cxcl16 is hypermethylated, therefore there is tons of gene expression, THEREFORE there is tons of the CXCL16 protein being produced and when there is CXCL16 there are iNKT cells!

Not to anyone’s surprise, when you add back SPF microbiota to neonatal GF mice you no longer see this hypermethylation of the cxcl16 gene, therefore there is no expression of cxcl16 = no iNKT cells = no inflammation = no hurry up go the bathroom dance!

These data really drive home the idea that the first moments of our life can influence our adult lives in more ways then we can imagine.

It also drives home the “hygiene hypothesis”, which proposes that early-life exposure to specific microbe-enriched environments decreases susceptibility to diseases such as IBD and asthma. 

 

 

 

 

 

ResearchBlogging.org Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, Glickman JN, Siebert R, Baron RM, Kasper DL, & Blumberg RS (2012). Microbial exposure during early life has persistent effects on natural killer T cell function. Science (New York, N.Y.), 336 (6080), 489-93 PMID: 22442383

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