Gluten exclusion for cases of diarrhoea predominant IBS

If I had the intellect I would try and deliver this very concise entry in the form of a witty poem or ditty just to try and make things a little more entertaining for readers rather than enduring yet another dry excuse for not making a proper "chatty" post. Unfortunately, I am to poetry what chocolate is to teapot material, so won't even try.

Instead I offer a link to a potentially very, very interesting trial by Maria Vazquez–Roque and colleagues* (open-access) reporting physiological results based on the use of a gluten-free diet for cases of irritable bowel syndrome (IBS) diarrhoea predominant type. The accompanying editorial by Lowe and Moseley** does a great job of summing up what Vazquez-Roque et al found, so leaves me very little to add.

Basically, under randomised-controlled conditions, "Patients on the gluten-containing diet exhibited greater small intestinal permeability than those on the gluten-free diet. The study was able to measure significant changes that provided physiologic support for a gluten-free diet in patients with IBS-D without celiac disease".

Whilst small intestinal permeability - also known as gut hyperpermeability or leaky gut - is already discussed in coeliac disease (CD) circles, the added-value from this recent trial is the suggestion that the effect of gluten on permeability might extend slightly outside of just diagnosed CD. I'm not getting into the nitty-gritty of the MHC and those CD-related serotypes at this point even though they were important to the findings. Also too were some interesting results based on those tight junction proteins including 'General' zonulin.

I do wonder how far outside of CD and indeed IBS-D we might venture with these findings. Y'know that very interesting paper from Laura de Magistris and colleagues*** (discussed here) with autism in mind; bearing in mind of course the experimental differences between the studies and that autism is not IBS....

Maybe also at this point I'll also introduce the latest study by Jessica Biesiekierski and colleagues**** on non-coeliac gluten sensitivity (see here) in relation to FODMAPs and gluten as further fodder for consumption.

Now, 'the boy stood on the burning deck....' (scroll down the link to see the Spike Milligan parody).

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* Vazquez–Roque MI. et al. A Controlled Trial of Gluten-Free Diet in Patients With Irritable Bowel Syndrome-Diarrhea: Effects on Bowel Frequency and Intestinal Function. Gastroenterology. 2013; 144: 903-911.

** Lowe AW. & Moseley RH. Covering the Cover. Gastroenterology. 2013; 144: 859-862.

*** de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010; 51: 418-424.

**** Biesiekierski JR. et al. No Effects of Gluten in Patients with Self-Reported Non-Celiac Gluten Sensitivity Following Dietary Reduction of Low-Fermentable, Poorly-Absorbed, Short-Chain Carbohydrates. Gastroenterology. May 2013.

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General Zod? No, General Zonulin

I hold my hands up and admit that gut hyperpermeability - leaky gut - is a bit of an obsession of mine. I know to some the mere mention of leaky gut conjures up images of 'alternative medicine' and all things tree-hugging. Just for the record I've never knowingly hugged any tree and am a meat eating, petrol car driving, house dwelling regular guy who has yet to dabble in anything 'alternative' assuming that the odd vitamin D tablet and probiotic counts as regular. Still I remain very interested in how abnormal gastrointestinal (GI) permeability might be tied into quite a few conditions.

One aspect of GI permeability in particular has surfaced quite recently on my research radar, an interesting compound called zonulin.

A description first. Zonulin enjoys quite a special place in the science of the tight junctions. Tight junctions (TJs) among other roles, serve quite an important barrier function in lots of parts of the body; so making sure that things stay in and other things stay out. Zonulin seems to be part and parcel of the chemistry of tight junctions and in particular sharing quite an important relationship with the enhanced permeability of TJs.

With the gut in mind, zonulin has found quite a bit of interest. A familiar name to this blog, Dr Alessio Fasano, seems to have been present right at the beginning of interest in zonulin, with a particular focus on gut permeability tied into the presence of coeliac (celiac) disease as per this article* and write-up.

Ever since then, zonulin has just been making wave** (full-text) after wave*** (full-text) after wave**** as per its 'disassembly' activity when it comes to TJs. The initial link with coeliac disease is an interesting one given that later work suggested that gluten, or rather the gliadin fraction of gluten, has the propensity to induce zonulin release***** (at least under certain laboratory conditions).

But coeliac disease was just the starting point for zonulin, as more recent research has suggested a potential role for this protein in relation to gut permeability in type-1 diabetes (here and here), obesity (here) and potentially quite a few other conditions (here) with a specific focus on autoimmune conditions. General Zod? No, General Zonulin.

Accepting that there still remains some work to do on zonulin with regards to the methods and mode of action of zonulin on gut permeability******* this is a very interesting protein.

With my 'wondering' hat on, I have a few questions:

• Assuming the link between type-1 diabetes, gut permeability and zonulin holds up, does this mean that a gluten-free diet might be 'advantageous' for at least some people with type-1 diabetes? I'm thinking about this recent case study******* as a template. I would also add that no medical advice is given or intended by  this question.
• Gut hyperpermeability, leaky gut, has been documented in other conditions including one close to my research heart, autism spectrum conditions (see here). Again noting the suggestions by de Magistris and colleagues (here) on how a gluten- & casein-free diet seemed to affect measures of gut permeability in their cohort, is it perhaps time to look at zonulin with regards to conditions like autism? How about schizophrenia also? 
• Finally(!), the amino acid glutamine and its proposed tie up with gut permeability. Might glutamine affect zonulin production or even the other way around? Or am I just confusing things and heading out a step too far? 

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* Fasano A. et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000; 355: 1518-1519.

** Wang W. et al. Human zonulin, a potential modulator of intestinal tight junctions. Journal of Cell Science. 2000; 113: 4435-4440.


*** Fasano A. Intestinal zonulin: open sesame! Gut. 2001; 49: 159-162.


**** El Asmar R. et al. Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure. Gastroenterology. 2002; 123: 1607-1615.


***** Clemente MG. et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003; 52: 218-223.


****** Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences. 2012; 1258: 25-33.


******* Sildorf SM. et al. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Reports. June 2012

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Gut microflora, coeliac disease and introducing gluten

A new paper by Sellitto and colleagues* (full-text) has been causing quite a bit of interest in certain circles. The paper as the name suggests is [partially] a 'proof of concept' study which includes several topics of interest for this blog with its focus on gut microflora (and dysbiosis), coeliac (celiac) disease (CD) and some interesting metabolomics science. The added value comes with the name Alessio Fasano as part of the authorship list.

There is quite a bit of details to this paper but in essence the aims were: (i) to characterise the changes from birth to 24 months in terms of gut bacteria to genetically at-risk of coeliac disease children as a function of early or delayed introduction of gluten to the diet, and (ii) to undertake a range of analytical methods to map such bacterial populations with the hope of further informing on any relationship between gut bacteria and coeliac disease.

The paper is full-text but a quick summary of proceedings and findings:

• Forty-seven infants who had one parent with biopsy-proven CD were initially recruited before weaning had commenced. All were breastfed from birth to at least 6 months of age. From 6-12 months of age, 30 infants positive for either the HLA DQ2 and/or HLA DQ8 genotypes were randomly allocated to either a gluten-free - delayed gluten exposure - group (n=13) or a gluten load - early exposure - group (n=17).
• A smaller number of children from each group (n=8 each) were selected randomly for the analytical side of the study (which is what this paper in essence reports) where stool samples were collected at various points over the study period ranging from 7 days in to 24 months.
• The results: none of the 8 infants from the delayed gluten exposure group developed CD over the course of the study. One of the 8 infants in the early gluten introduction group did go on to develop CD at 2 years of age as measured by various serological panels and went on to a gluten-free diet with a remission of serology at follow-up.
• When levels of anti-gliadin antibodies (AGA) (IgG) were examined and corrected for gluten exposure time, the early gluten introduction group showed a higher number of IgG-AGA positive results than the delayed exposure group. The authors discuss how AGA is not necessarily a particularly good measure of CD but could indicate greater levels of intestinal hyperpermeability (leaky gut) as a result of exposure to the gliadin fraction of the gluten protein in the same way that IgG levels have been interpreted in other studies (see Sutterella and autism post). 
• Pyrosequencing of the various species and families of bacteria present across the groups at different time frames suggested some interesting goings-on. To quote: "the GI tract microbiota in DQ2+/DQ8+ infants appears to be lacking significant numbers of member of the phylum Bacteroidetes". That and a higher abundance of Firmicutes, implies that maturationally, the gut microflora of children at elevated risk of CD is different from lower risk groups as determined by comparison with an external dataset** (full-text).
• The application of 1H-Nuclear Magnetic Resonance Spectroscopy (NMR) to proceedings added that metabolomic touch as "..SCFA succinate, acetate, propionate and butyrate are found in the feces" following the introduction of solid foods. Having said that little distinguishing data was found to categorise the two groups in any significant, universal way.

It's taken me a while to get my head around all the findings from this recent paper because there was a lot of data produced bearing in mind the small participant group and preliminary status of the paper. One of the first things that did strike me is the overlap in these findings and some fairly recent data published looking at carbohydrate metabolism and autism included in this post. Decreasing Bacteriodetes and increasing Firmicutes was the preliminary finding from Williams and colleagues*** bearing in mind the difference in samples being analysed and the lack of data on HLA DQ2 / HLA DQ8 genotype provided in the group with autism being studied. I'm not going to say too much more of this 'similarity' aside from the fact that screening for coeliac disease and/or excessive intestinal permeability perhaps ought to be much more commonly undertaken in cases of autism spectrum conditions just to rule them out.

Quite a few mentions of the word 'dysbiosis' are also recorded in the current paper which reaffirms the possibility of a connection between the various populations of bacteria that reside within us and our potential risk of disease. I like the idea that this study looked at both the metabolomic and genomic side of things even if it was just based on the HLA DQ geneotypes.

So from the starting point of a genetic susceptibility to gluten, we have preliminary data on functional changes to the microbiome in susceptible people and some interesting tools for looking at how this might be expressed functionally. I look forward to more studies of this type with greater participant numbers, and in particular how such findings might extend into other autoimmune conditions and even beyond just somatic presentation.

* Sellitto M. et al. Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants. PLoS ONE. March 2012
DOI: 10.1371/journal.pone.0033387

** Palmer C. et al. Development of the human infant intestinal microbiota. PLoS Biology. 2007; 5:e177
DOI: 10.1371/journal.pbio.0050177

*** Williams B. et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS ONE. September 2011.
DOI: 10.1371/journal.pone.0024585

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

Does diabetes start in the intestines?

The findings of an interesting paper by Wei and colleagues* (full-text) pose a question: are the origins of diabetes in the intestines?

For those that don't know too much about diabetes, here is a link that should help. The concise version (if there is such a thing) is that diabetes normally manifests as either type-1 diabetes or type-2 diabetes with insulin being the key compound in controlling blood sugar, and corresponding issues either with its production or when resistance is built up to it.

The crux of the paper by Wei et al is that an insulin-responsive super enzyme called fatty acid synthase (FAS) involved in lipogenesis is also involved in gut barrier regulation through its action on Mucin 2 (Muc2), a gel-forming component of mucus. The authors' suggestion is that becoming resistant to insulin is associated with issues with FAS and correspondingly problems with mucus in the gut, inflammation and diabetes. No pressure then.

The paper summarised (deep breath):

• Several groups of mice were included for study: (a) mice with chemically-induced (tamoxifen induction of Cre recombinase) decreases of FAS protein and mRNA, (b) mice bred with inactivated FAS in the intestine and (c) control germ-free mice. For group (b) mice, diabetes was induced by administration of streptozotocin, a toxin to the beta cells which produce insulin in the pancreas.
• Assays looking at gut bacteria, intestinal permeability, cytokine release and protein S-palmitoylation were used to investigate various parameters.
• The findings: a chemically-induced deficiency of FAS in mice started a cascade of events linked to inflammation. One of the primary cytokine markers of this inflammation was elevated levels of TNF-α although animals were also noted to show weight loss and other gastrointestinal symptoms. A quarter of these mice actually died within 14 days.
• The authors deduced that although some changes were noted to the intestinal bacterial makeup of FAS reduced mice, these changes were not enough to cause the inflammation observed but rather were as a result of the inflammation. They demonstrated this via a previously discussed method on this blog, bacterial transplantation; in this case to the germ-free mice (group c) who did not show the accompanying inflammation as a result of their donor bacteria. That is not however to say that gut microbiota did not have some effect, as per the reduction in inflammation noted in the FAS deficient mice following administration of the antibiotics ciprofloxacin and metronidazole.
• The link between FAS deficiency and Muc2 was evidenced by the lower levels of Muc2 shown in FAS deficient mice and reduced inner mucus layer thickness in the colon of affected mice. 
• Looking at the inactivated FAS (group b) diabetic mice, a similar pattern of issues with Muc2 and reductions in the mucus layer was seen alongside penetration of bacteria indicating intestinal hyperpermeability (leaky gut). Interestingly, insulin supplementation seemed to positively affect some of the permeability issues.

This is quite a complicated paper and so please do not take my summary as gospel. It is intriguing that inflammation is at the heart of their theory and in particular, inflammation as a result of not having enough FAS present in the gut with the knock-on effects on gut permeability. Indeed not for the first time has it been suggested that diabetes and leaky gut are connected as per articles like this one. Makes you wonder also about any other possible dietary inter-related connections?

* Wei X. et al. Fatty acid synthase modulates intestinal barrier function through palmitoylation of mucin. Cell Host & Microbe. February 2012.
DOI:  10.1016/j.chom.2011.12.00

Gut bacteria and heart health?

Happy (belated) New Year! Welcome back to Gutness Gracious Me in 2012. I start this year with a post on something pretty central to the ethos of this blog: gut bacteria.

I should perhaps first apologise to Alex Gazzola (#HealthJourno) who very kindly asked if I would be discussing the new Codex standards for labelling foods and gluten-free and the 20 parts per million threshold introduced. I did say I would have a look at this and I am still looking. I do however think that Alex has done a wonderful job of covering this topic on his own blog (see here) as per the reader response he has received.

Back to task. Despite being only 13 days into the New Year (Friday 13th...mmm?), already the research is coming thick and fast. Over at my Questioning Answers blog, the big news recently has been on the bacteria Sutterella and its detection via various methods in quite a few biopsy samples from children with autism and gastrointestinal (GI) issues. I say big news but in among the very detailed explanation of how that team came to find Sutterella, the main story for me is the suggestion that gut hyperpermeability in some cases of autism might be a route through which the immune system meets gut bacteria in places it really shouldn't and onwards formulates an antibody response. The template for this is Crohn's disease and leads into some interesting suggestions about whether gut bacteria itself might not necessarily be the bad guy but rather what happens when it is allowed to roam.

The other quite interesting news is from this paper by Vy Lam and colleagues* suggesting that different amounts and varieties of gut bacteria might influence the severity of and recovery from heart attacks in rats. I am well used to seeing papers talk about gut bacteria in relation to GI issues and conditions, even conditions like autism where functional and more systemic bowel disorders have been noted in some cases. This is however one of the first times that I have come across gut bacteria potentially so directly influencing the physical health of an organ like the heart.

So what did the researchers do?

• Three groups of rats were fed three different types of diet: a standard diet, a standard diet plus quite a powerful antimicrobial (vancomycin) and a standard diet plus a probiotic very aptly named GoodBelly. 
• The primary probiotic constituent of GoodBelly is Lactobacillus plantarum 299v quite commonly found in fermented foods like sauerkraut and subject to a few claims. One of those claims is that the bacteria might be able to reduce the production of leptin among other things.
• Both the vancomycin and GoodBelly supplemented groups showed a decrease in circulating leptin levels (38% and 41% respectively) alongside some changes to gut bacteria as one might expect.
• The vancomycin and GoodBelly supplemented groups also showed evidence of smaller heart attacks and improved recovery after heart attack compared with the standard diet group.

Whilst the authors describe this as a 'proof-of-concept' study, there are potentially many implications from this work not least that our gut bacteria might do far more than call us home and help digest our food. I have previously (jokingly) referred to gut bacteria as being our 'masters'. Assuming the results from this study are pertinent to humans as well as rats, I might well be offering a sacrifice to 'those who must be obeyed' in the near future.

Should we be surprised that the human body is interconnected? No probably not, although it might take a while and a few more bits of evidence of effect before cardio health care professionals start giving probiotics to help treat (prevent?) myocardial infarction (please note I am not giving any medical advice about this). Going back to the Sutterella post and the proposed link between bacterial translocation and gut permeability, I do wonder whether research should also be looking more closely at gut permeability and lots of other conditions just to see if findings such as these might provide a few more clues about health and illness.

*Lam V. et al. Intestinal microbiota determine severity of myocardial infarction in rats. The FASEB Journal. January 2012

Diagnosis by gut bacteria?

Please don't take the title of this post too literally. Sciences is only just beginning to unravel the first strands of the complicated universe that is our gut microbiota but two recent papers certainly do make for some interesting reading.

The first paper by Iebba and colleagues* provides quite a nice summary of where we stand (research-wise) with regards to different bacterial species seemingly predominating in different childhood conditions. The second paper by Jeffery and colleagues** details the intriguing possibility that irritable bowel syndrome (IBS), or some phenotypes of IBS based on the presence of functional bowel disturbances, might be classifiable by the predominating types of gut bacteria.

The Iebba paper was of double (triple) interest to me because it mentioned autism, coeliac disease (CD) and inflammatory bowel disease (IBD) in the same sentence. In particular, the prevalence of Bacteroidetes alongside a parallel decrease of Firmicutes was a commonality between these three conditions; the first time I've seen a research group looking (bacterially) at these conditions together. I have to point out that autism is an extremely heterogeneous condition with quite a lot of scope for comorbidity; hence I am careful with any generalisations.

By contrast the Jeffery paper, although based on quite a small participant group, suggested quite a few things including that cluster analysis might be able to 'pick out' those cases of IBS associated with diarrhoea compared with those where constipation or alternating bowel habits were more common. Interestingly, their analysis also reported the opposite trend in terms of an increase of Firmicutes-associated taxa and a depletion of Bacteroidetes-related taxa in some of their participant cases. This alongside other related findings which perhaps indicate that the so-called 'leaky gut' (gut hyperpermeability) might also show some differences in terms of site when sub-categorising IBS on the basis of predominant functional bowel patterns.

Aside from factors such as different ages, different populations, different genders, et al, all of this makes me wonder about things like the immune system differences between conditions like IBD and CD compared with IBS. Indeed a few open questions: do the gut bacteria findings in autism perhaps reflect similar immune features to CD and IBD or is it all merely a coincidence? Is IBS an immune-mediated condition the same way as CD or IBD are or are other forces at work?

Without getting too Arthur C. Clarke, there are lots of potential possibilities to these collected works based on our individual and collected patterns of gut microbiota. Unlike fingerprints or retinal scans, gut bacteria is perhaps slightly more dynamic as a function of diet, environment, etc. and so is probably not going to be biometrically encoded onto your passport any time soon. Having said that, if the subtle differences between our gut bacteria might also be reflective of our condition or disease, this could potentially offer some quite startling insights into the way medicine diagnoses and also manages a wide variety of conditions.

Finally, this is probably my last post on this blog until the New Year. I would like to wish readers Merry Christmas and a Happy New Year. I raise a glass of water to your good digestive health over the holiday period!

* Iebba V. et al. Gut microbiota and pediatric disease. Digestive Diseases. December 2011.

** Jeffery IB. et al. An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. Gut. December 2011.

The leaky gut and chronic fatigue syndrome

I've mentioned the TV programme called the Food Hospital before on this blog in a post not so long ago about Crohn's disease and the LOFFLEX diet. Having watched the episodes so far as well as the various social networking chatter about the series, my conclusion is that it is rather a brave programme to broadcast in terms of 'treating' various medical conditions simply with adjustments to diet. I will perhaps lay my stall out to you in that I am swayed by some of the arguments that food, certain foods, do place certain people at a health disadvantage outside of known food-related conditions such as coeliac (celiac) disease and PKU. The emerging data, albeit preliminary, on some cases of autism and ADHD seems to be pointing in that direction for example.

The latest programme aired on Tuesday 13 December (2011) again presented some interesting 'cases' and the potential link to food. One particular cases was that of a woman diagnosed with Chronic Fatigue Syndrome (CFS). I don't want to get too bogged down with a description of CFS (and CFS/ME) because it is quite complicated. Without blowing my own trumpet, I was involved in a paper on trying to describe CFS a while back which suggested that quite a few symptoms might be variably expressed including physical, somatic features alongside other more cognitive issues. The bottom line is that CFS/ME is a real and very often complicated condition.

The Food Hospital suggested a few things in terms of diet which might be useful for the particular lady with CFS in question. Outside of chocolate being suggested (and not doing particularly well in this case) I thought I also heard the suggestion that a glutamine-rich diet might also be something to try. My attention was grabbed by this suggestion for a very good reason: glutamine (also called L-glutamine) has some interesting effects on the gastrointestinal (GI) tract and in particular, intestinal permeability.

Maybe I should back up a little here. Glutamine is an amino acid, a building block of protein. For quite a few years, glutamine has been finding some favour in relation to improving the structural integrity of the intestinal barrier in both humans and animals and potentially relieving the so-called 'leaky gut'. Leaky gut is a bit of a misnomer because everyone has leaky gut to some degree; the better description would perhaps be gut hyperpermeability or excessive leakiness.

With regards to CFS/ME, as with other conditions, leaky gut has been reported in the research literature and commented on elsewhere. One name seems to crop up quite a lot in this area of investigation, Dr Michael Maes and not just with regards to CFS/ME. It seems leaky gut might have the potential to do all manner of things. So putting leaky gut, CFS/ME and glutamine together might make some sense? Aside from the paper from Maes, I have been unable to find any other published trials of glutamine for CFS/ME which is a shame really, given that a double-blind, placebo-controlled trial of a solitary supplement like glutamine should be a pretty straight-forward experiment to do (he says with a straight face). Any budding researchers out there with a few hundred thousand pounds to spare could do a lot worse than put such an experiment to their boss and local ethics committee.

I would finally add that as per the tenets of this and my other blogs, I don't give out medical advice and am not suggesting for one minute that glutamine is a cure-all for CFS/ME. I do however reiterate that for a condition like CFS/ME where more questions are being asked than answered, every experimental and research avenue should be explored.

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.