There seems to be some confusion about how to appropriately interpret ex vivo studies, which are studies that are not conducted in a living organism.
Worse than that, there appears to be a common and rather dramatically misleading presentation of the data in Dr. Allesio Fasano's excellent study linking gluten to zonulin production. But I'll cover that in my next gluten post.In any case, some people construe this study as showing that eating wheat or gluten causes leaky gut in people who do not have celiac, when in actuality the authors treated isolated tissues and tissue models with gluten rather than feeding gluten to people and seeing what happened.
A study conducted in isolated human cells or tissues is not a “human study.” A study conducted in isolated human cells or tissues is useful for three things:
generating the hypothesis that the effect also occurs in live humans.
providing a possible explanation for existing data obtained from live humans.
characterizing the mechanistic details of the molecular biology of some phenomenon that would be impossibly invasive to characterize in living humans.
Whatever such a study is, it is not a test of the hypothesis that the phenomenon occurs in humans.
Let's say we obtain data showing that gluten or wheat causes intestinal permeability in non-celiac patients. And say we also have a study showing that it does so in an ex vivo model by stimulating zonulin release. In this case, we can interpret the second study as suggesting a possible mechanism for the phenomenon uncovered by the first. Our next step would be to try to show that gluten increases zonulin production in live humans under the same conditions under which it causes leaky gut.
The definitive way to demonstrate the role of zonulin would be to show in a double-blind, randomized, controlled trial that gluten or wheat causes increased zonulin and intestinal permeability in the absence of any co-treatment, but that if the gluten or wheat is fed alongside a zonulin inhibitor, intestinal permeability will remain normal.
Lest anyone think this is an unrealistic burden of evidence, Dr. Fasano's group has already published such a study conducted in celiac patients. There is no reason someone couldn't conduct such a study in non-celiac gluten-sensitive patients, and indeed, I'm sure that if Dr. Fasano found that these patients actually have leaky gut, his group would probably perform exactly this type of study on them.
If we did not have any data showing that gluten or wheat causes intestinal permeability in humans, we could interpret an ex vivo study showing that it causes this phenomenon in isolated tissues as a justification to investigate the hypothesis that it also does so in live humans.
Of course, we already have evidence directly refuting such an effect in live humans. Dr. Fasano's most recent study shows that increased intestinal permeability simply does not exist in non-celiac gluten-sensitive patients. Yes, this is the same Dr. Fasano who published the 2006 ex vivo study.
Likewise, a double-blind, randomized, placebo-controlled trial just showed that purified and chemically deamidated gluten (deamidation makes the gluten similar to what would appear in a celiac patient's intestines) does not alter intestinal permeability in non-celiac gluten-sensitive patients (though they provided poorly reported evidence that it may increase some symptoms).
Does that mean no one develops leaky gut in response to gluten except celiacs? Not necessarily.
Emily Deans left a comment on my last gluten post linking to an interesting study showing very high rates of leaky gut among autistics and their first-degree relatives. The fact that leaky gut was also seen in their relatives suggests that there is an element of biological inheritance, although without identifying the specific way in which this inheritance is transmitted, it does not necessarily imply anything about genetics because not all biological inheritance is genetic.
And, in fact, there is some inheritance even in intestinal bacteria, which outnumber human cells 10-to-1 and substantially contribute to our phenotype, even though they for some reason are never considered part of the human organism.
The study identified 55 out of 88 autistic subjects who were not on gluten-free, casein-free (GFCF) diets who did not have leaky gut, and two out of two autistic subjects who were on GFCF diets and also did not have leaky gut. Perhaps gluten or casein contributes to intestinal permeability in autistics. Or, perhaps gluten-sensitive autistics, like the gluten-sensitive patients in Dr. Fasano's study, simply have stronger intestinal barriers than non-gluten-sensitive controls regardless of whether they are consuming gluten. The study sheds no light on this matter.
Incidentally, Emily Deans rocks not simply because she drives a lot of traffic to this blog, but because her own blog and her new Psychology Today blog are awesome, and because her kids are so darn cute.
Any biological truth is intrinsically elusive. Consequently, neither Dr. Fasano's most recent study showing that non-celiac gluten-sensitive patients do not have leaky gut nor the double-blind controlled trial showing that gluten does not cause leaky gut in non-celiac gluten-sensitive patients rule out the possibility that there is some subset of non-celiac subjects, somewhere on the face of the earth, perhaps autistics, perhaps not, who actually do respond to gluten by developing leaky guts. But to my knowledge there is no solid evidence of this and if anyone knows of some, again, please post it in the comments.
Thus, the situation in which we are faced is one where the available data suggest that people identified as having non-celiac gluten sensitivity do not have leaky guts. It therefore makes no sense to use a tissue study to explain a phenomenon that does not exist, nor to characterize the molecular biology of a phenomenon that does not exist.
We can use Dr. Fasano's tissue study as a justification to hypothesize that there may be non-celiac subjects in whom gluten causes leaky gut, but so far the available tests of this hypothesis have refuted it.
This does not mean that gluten is not problematic, nor that wheat is not problematic. Nor is it an invalidation of anyone's dietary choices. It's simply an honest, logical, and straightforward appraisal of the existing evidence.
And of course, if someone identifies wheat as a problem food, they should not be dissuaded from eliminating it from their diet based on a lack of evidence supporting the leaky gut hypothesis.
Ultimately the purpose of understanding why a food is a problem is to understand how to properly identify other problem foods, whether it is possible or even desirable to recover tolerance for a given problem food, and if so, how to do it. Thus understanding the why's and how's can often help people resolve residual health problems, and enjoy a healthier life to a fuller extent. There will always, however, be uncertainty in the mechanistic details, and this uncertainty should never stop someone from acting in their best judgment to improve their health.