Cytokines and gut motility

A relatively short post this one.

I think most people would understand why gastrointestinal motility is important to our health and wellbeing. Too fast or too slow a transit time is likely to lead to some pretty uncomfortable symptoms and indeed could signal the presence of one of a number of complications.

A recently published review paper on motility in gastrointestinal disorders by Akiho and colleagues* (full-text here) caught my eye. I was interested in this paper because it reviews the association between gastrointestinal motility and the expression of cytokines as a function of which way the immune system might be skewed.

I should perhaps back-up slightly here and provide some commentary on the way the immune system can be poised (according to our current knowledge) and in particular the concepts of Th1 and Th2. A good overview of the T helper cells is here. In brief, it's all to do with different kinds of immunity and how our immune system attempts to strike a balance between cell-mediated immunity (Th1) and humoral immunity (Th2) depending on what particular pathogen the immune system is up against.

The Akiho review paper lists a number of the most common GI disorders currently in the medical dictionary and details what particular types of response and cytokines are tied into the disease state. So for coeliac (celiac) disease and Crohn's disease there is a predominantly Th1 skewed cytokine profile either associated with disease onset or perpetuation. In ulcerative colitis, it is more of a Th2-like response in terms of cytokines associated with the condition. The authors do make mention also about Th17-mediated inflammation (possibly linked to autoimmunity) but this is still very much an emerging area of investigation.

The authors then proceed to review the evidence that Th1-related cytokines seem to show more of an affinity with hypocontractality of inflamed intestinal smooth muscle (slowing down) and Th-2 show a more hypercontractility (speeding up).  This is perhaps too simplistic a view to take, one linked to one but not the other, given the number of cytokines tied into various GI states and the complexity of the whole thing. But their analysis of the current evidence base is an interesting one.

What work like this serves to show is that the our immune system is a fantastic piece of engineering constantly trying to strike a balance between fighting off pathogens and infections and invaders, whilst at the same time keeping the host (us) in working order, trying not to destroy us also. The presentation of GI conditions, many GI conditions, seem to reflect the inner workings (and malfunctions) of the immune system and when establishing how the immune system manifests itself in individual conditions, offers some tantilising insights into potential therapies.

* Akiho H. et al. Cytokine-induced alterations of gastrointestinal motility in gastrointestinal disorders. World J Gastrointest Pathophysiol. October 2011

I, claudin

There is no way that I can blog about the gastrointestinal (GI) tract without making mention of that wonderful barrier separating gut contents from the other recesses of our body. Without being too dramatic, I could probably say that I owe my livelihood to the gut barrier; as a consequence of much of my research career heading towards some involvement for the gut barrier at least in some cases of autism spectrum conditions.

A recent paper brought all the years of reading on this subject back to me with the suggestion of a link between intestinal inflammation and claudin-1. The paper by Poritz and colleagues* describes how key tight junction proteins like occludin and zonula occludens-1 (ZO-1) are decreased in inflammatory bowel diseases and how treatment of intestinal epithelial cells with the inflammatory cytokine TNF-alpha (sorry about the lack of Greek characters) seems to increase permeability (leaky gut). With all due respect to the authors, these findings are nothing new.

What was slightly more interesting from Poritz however were the findings in relation to the ratio of claudin-1 and occludin (C:O) as a consequence of cell treatment with TNF-a and what this ratio looked like in real life when comparing different intestinal diseases like Crohn's disease (CD) and ulcerative colitis (UC). Answer: decreased occludin and increased claudin-1 in diseased UC vs. non-diseased UC and normal colons and nothing spectacularly different in different disease-states of CD or controls.

Even to an interested amateur like me, this data indicate some things potentially very important: (a) ratios between multiples rather than independent statistics might yield more diagnostic information, and (b) there may be some underlying differences in the way that tight junctions might be affected in UC vs. CD.

I will come back to the leaky gut and various other things related to it at some point in the future no doubt. But for now if you really, really want some extra credits bedtime reading, here is an article that I always found invaluable on the subject (long yawn, adjust reading glasses and reach for that glass of scotch on the bedside table).

* Poritz LS. et al. Increase in the tight junction protein claudin-1 in intestinal inflammation. Dig Dis Sci. October 2011.