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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The science of microbiomics

A very short post to plug... well, to plug me really, and my very, very small contribution to an article featuring in the Pharmaceutical Journal titled: Microbiomics: its growing significance in the world of medicines testing. The article is only open-access for a short period of time, so if you happen to have stumbled across this post years and years into the future (today is Tuesday 26th February 2013 according to my flux-capacitated DeLorean) sorry.

But just so you don't feel to left out, a few article highlights: yoghurt and C.diff infection, the human microbiome project (HMP), gut bacteria and immune function, dysbiosis, the microbiota-gut-brain axis, fecal transplants (yuck factor 10) and pharmacometabonomics.

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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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

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.