Monday, 5 March 2012

Strong intestinal barrier and the big C?

I enjoy reading the odd newspaper now and again just to find out what's going on in the world. Having said that I do take some of the headlines with a pinch of salt as evidenced by a recent UK headline about autism which has been roundly brought up on its inaccuracy.

With such things in mind, I approach this post with very much more caution than usual given the subject matter - cancer - and the propensity for such headlines to become 'over inflated'. The headline in question came from this news piece on the recent publication by Lin and colleagues* (open-access) on a possible connection between the compound guanylyl cyclase C (GC-C) and the integrity of the intestinal barrier which might have onward repercussions outside of just malabsorption issues.

Let's start from the beginning on this one. Guanylyl cyclase C (GC-C) is, as its -ase name suggests, an enzyme found in gut and brain. It plays a role in regulating intestinal fluid and balancing electolytes. For those brave souls who quite like a bit of heavy biochemsitry, quite a thorough description of the whole guanyly cyclase family can be found here. Going back to GC-C, more recently, evidence has been accumulating to suggest that GC-C might also have some connection to intestinal barrier function** based on knockout mice studies.

The recent study by Lin went one stage further suggesting that in a mouse model GC-C did indeed link to barrier integrity through its effect on various junction proteins. It also however affected oxidative DNA damage when silenced subsequently ".. associated with increased spontaneous and carcinogen-induced systemic tumorigenesis".

Some details:

  • Various mouse models were used; the important ones being mice deficient in GC-C (called GUCA2A in this paper) which will be called GC-C-/- (the -/- denoting zygosity for the receptor, as in homozygous for deficiency) and mice GC-C+/+ (denoting homozygous for no deficiency).
  • A few differences came to light between the -/- and +/+ mice: the -/- mice produced less tight junction proteins including occluden, claudin-2, claudin-4 and JAM-A. In English, these are some of the main constituents that keep the gut barrier in good integral health. This was confirmed when looking at intestinal permeability which was increased (more leaky) in the -/- mice.
  • When trying to chemically induce intestinal barrier issues via DSS, the severity of the colitis produced was increased in the -/- mice compared with the +/+ mice; something also seen in the mortality-survival rates between the two models.
  • A quote from the paper: "Impaired basal epithelial barrier integrity producing systemic genotoxicity was associated with spontaneous extra-intestinal tumorigenesis, including tumors in mesenteric lymph nodes, livers, and lungs, in 50% of Gucy2c−/− mice, but in only 10% of Gucy2c+/+ mice". Translation: more permeability in the gut of the -/- mice led to more tumours in other organs compared to +/+ mice.

There is a lot more to this paper which I unable to cover in this short post. The one obvious point to make is that this was a mouse model of GC-C deficiency and hence needs a little more investigation into whether such processes transpose so readily on to humans. GC-C already has a possible link to metastatic cancer cells as per articles like this one so one would already expect quite a bit of interest in this compound in cancer research circles.

Combined with my previous post on diabetes and leaky gut, it is heartening to see some novel research is being done on how gut barrier permeability might not necessarily just manifest in intestinal symptoms. I leave you with another quote from one of the authors: ".. if you want to prevent inflammation or cancer in humans, then we need to start thinking about feeding people hormones that activate GC-C to tighten up the [intestinal] barrier.” I am certainly not advocating this or any other 'advice' at this time but perhaps this is fodder for further research and a later post methinks.

* Lin JE. et al. GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity. PLoS ONE. February 2012.
DOI: 10.1371/journal.pone.0031686

** Han X. et al. Loss of guanylyl cyclase C (GCC) signaling leads to dysfunctional intestinal barrier. PLoS ONE. 6: e16139
DOI: 10.1371/journal.pone.0016139

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