The Problems With Dr. Fasano's Latest Paper :sigh:

[tex]

Hi All,

Someone recently posted about Dr. Fasano's latest research report, titled Divergence of gut permeability and mucosal immune gene expression in two gluten associated conditions: celiac disease and gluten sensitivity.

I've been distracted by work obligations lately, and so I didn't really have time to analyze that report until this weekend, after Rosie, with impeccable timing, pointed out some of her concerns about the research project. I have to agree with the points she raised - they point to some serious problems with some of the choices made during the project, and especially with the conclusions that were reported. It almost appears as though Dr. Fasano knew what he wanted the report to show, before the project was even begun, so the constraints and assumptions were carefully orchestrated in order to verify those "preconceived" notions. A link to the original published report is available at the end of this post.

Since Rosie's work experience involves biological research, (if I recall correctly), one of her concerns is the way that subjects for the GS portion of the study were selected. According to their criteria:

GS patients are defined as those patients in which CD, wheat allergy and other clinically overlapping diseases (type 1 diabetes, inflammatory bowel diseases and Helicobacter pylori6 infection) have been ruled out and whose symptoms were triggered by gluten exposure and alleviated by gluten withdrawal. ……GS were considered in those patients with negative autoantibody serology (endomysium antibodiesimmunoglobulin A (EMA-IgA) and tTG-IgA), normal mucosa (Marsh stage 0) or increased intraepithelial lymphocytes (Marsh stage 1) and improvement of symptoms within days of the implementation of the diet. To avoid any possible selection bias and to prove that these patients are different from CD patients, we elected to enroll every patient fulfilling the above-described definition of gluten sensitivity.

The emphasis in red is mine, of course, but as you can see, by ruling out anyone who had one of the common antoimmune diseases mentioned, and anyone who had small intestinal damage exceeding a Marsh stage 1 level, and anyone who did not respond to the GF diet promptly, the outcome was rather "closely regulated", shall we say, before the research was even begun.

Part of the problem with this criteria, of course, is that it surely includes some subjects who were in the early stages of CD, rather than true non-celiac GS. And, as Rosie correctly points out:

In support of this, I find it interesting that at the start, the GS cohort were all tissue transglutaminase negative, but that after a 4-month gluten challenge, almost half were now positive.

Hmmmmmmm. That sounds suspiciously like celiac disease in the making, doesn't it. But of course, that's impossible, because it doesn't agree with what he was trying to prove with this research.

Of course, as she points out, (and I agree),

Or it could be possible that there are several different mechanisms of GS in addition to the type that the article describes. Because of the selection criteria, they didn’t include those with MC, and that might yield different results.

And, of course, that caveat applies to the other categories that they excluded, in addition to subjects with MC.

IMO, one of the biggest problems with the study, is the conclusion that those with GS, (but not CD), don't have any issues with intestinal permeability, (maybe this is why he cut out any potential subjects with IBDs, since many of them have the leaky gut syndrome). So it's not clear to me just where this leaves us. Are we in the GS group or not? Clearly we're not in the CD group, (except for a few of us, of course). If we are in the GS group, then as Rosie so aptly points out:

If you believe the conclusions of the study, then Dr. Faisano’s zonulin-modulating drug won’t help to those of us with non-celiac gluten sensitivity, since apparently we don’t have any issues with intestinal permeability.

Also, as she points out, the following comment from the report gives support to my and Polly’s suspicions that MC can be triggered by infections, like MAP.

These findings might indicate that GS is an inflammatory condition mostly supported by innate immune mechanisms.

Another very big issue that I have with the report is the fact that he talks out of both sides of his mouth, and makes contradictory claims. For example, as background information, he initially claims

Gluten-sensitive individuals (GS) cannot tolerate gluten and may develop gastrointestinal symptoms similar to those in CD, but the overall clinical picture is generally less severe and is not accompanied by the concurrence of tissue transglutaminase autoantibodies or autoimmune comorbidities.

The red emphasis is mine. The fact that the GS category is generally less severe, and is not accompanied by the additional risk of autoimmune disease comes as news to those of us with severe symptoms, and numerous autoimmune diseases, of course. And obviously, the claim that tissue transglutaminase autoantibodies do not exist is simply incorrect - all they would have had to do was to look in the stool to find those antibodies. But of course, they couldn't do that, because Dr. Fasano refuses to recognize the work of Dr. Fine.

And then at another point in the report, he says that

In itself, the absence of autoantibodies and intestinal lesions does not rule out the intrinsic toxicity of gluten, whose intake, even in non-CD individuals, has been associated with damage to other tissues, organs and systems besides the intestine.

Which, of course, makes a lot more sense.

The report also mentions:

Interestingly, 48% of GS patients were anti-gliadin antibody (AGA)-positive, and 57% were HLA-DQ2-positive and/or HLA- DQ8-positive. Fifty-six percent of AGA-positive GS patients were HLA-DQ2-positive and/or HLA-DQ8-positive, while the remaining 44% were HLA-negative, suggesting that AGA production was not associated with a HLA-DQ2-restricted and/or HLA-DQ8-restricted presentation.

Again, the red emphasis is mine. Well, whatta ya know - he's saying that Dr. Fine's work showing that various other genes may indeed relate to gluten-sensitivity, is correct, after all. How about that?

I note that Dr. Fasano had no qualms about using the same wording that Dr. Fine used in his well-known talk about CD being "the tip of the iceberg", but for some strange reason, neither he nor any of the researchers working under him were able to figure out how to detect antibodies in the case of non-celiac gluten-sensitivity, so he makes this obviously incorrect statement:

Differently from CD, though, in GS the adverse reactions that develop while eating gluten are not followed by the appearance of autoantibodies

Well doh! I guess it never dawned on them to check stool samples for antibodies.

We could probably point out a lot more problems with this report, if we wanted to take the time to analyze it in more depth, but the bottom line seems to be that it is so full of holes, that it could be used as a sieve to strain GF spaghetti. At the very least, though, it appears that Dr. Fasano has finally stepped down off his high horse, and admitted the existence of non-celiac gluten-sensitivity,which is a huge step for the medical community in general. His progress at ironing out the details, though, seems to be excruciatingly slow. At this rate, it will probably take him at least another 10 or 20 years to get it all right.

http://www.biomedcentral.com/content/pd ... 5-9-23.pdf

Thanks, Rosie, for all your help.

Tex

[JLH]

Would you please link to Rosie's thread? Thanks very much.

[Rosie]

Tex, I have a few more comments to make on the paper.

First of all, I made a mistake that I want to correct:

Rosie wrote:

In support of this, I find it interesting that at the start, the GS cohort were all tissue transglutaminase negative, but that after a 4-month gluten challenge, almost half were now positive.

It should be anti-gliadin antibodies....I just had a "brainfart".....

Dr Fasano makes the case that non-celiac gluten sensitivity is not associated with increased intestinal permeability. But then in his discussion, he mentions that GS is associated with systemic issues and that could only be the case if gluten were escaping the intestine and getting systemic. This would require increased intestinal permeability. So he is contradicting himself, as you can see in the quotes below.

Patients with GS do not present significant autoimmune or allergic comorbidities………

That's because by definition for his study he discarded any patient with co-existing autoimmune conditions. That's circular reasoning.............

And below he mentions toxicity of gluten in other parts of the body in association with non-celiac gluten sensitivity.

In itself, the absence of autoantibodies and intestinal lesions does not rule out the intrinsic toxicity of gluten, whose intake, even in non-CD individuals, has been associated with damage to other tissues, organs and systems besides the intestine [6, 30, 31].

…….signs and symptoms associated with non-CD gluten sensitivity, have also been reported for schizophrenia [39] and autism spectrum disorders [40].

Also, if you take a look at the figures showing data, I noticed something else.

Although the paper states that there were 30 controls, 42 with CD, and 26 with GS, the numbers for the figures report varying numbers, in some cases half of the total pool. No reason is given in the paper, which makes one wonder if “outliers” were discarded. Especially since the range of data is pretty high, and only a small subset of the data has statistical significance. Outliers would make it more difficult to document statistical significance.

The good news is that gluten sensitivity is now being accepted in the mainstream medical community. And as Dr. Fasano and other researchers continue to investigate, hopefully those of us suffering from GS will gain some respect and some help in dealing with it.

Rosie

[tex]

Would you please link to Rosie's thread? Thanks very much.

Joan, there's no thread - she PM'ed me.

Tex

[tex]

Rosie,

All in all, the paper seems to be rather disorganized and somewhat sloppily done. I agree with you, it appears that there are a lot of discrepancies.

Note that there are 16 authors listed, but apparently no one was in charge of proofreading for data accuracy (and I just now happened to notice that virtually all of them seem to have Italian-sounding names). That seems rather odd, doesn't it. Hmmmmmmm. I certainly have nothing against Italians, but it almost seems as though he's created a "Little Italy" in his research department. Maybe he needs some more diversified blood in the group, in order to escape the "closed shop, (and rather convoluted), thinking", that seems to prevail there.

I wonder if he even read the report, before putting his stamp of approval on it. It doesn't appear to be a professional-level publication, in fact, I would call it rather disappointing, for a man in his position.

Tex

[Rosie]

Tex, in my scientific career I've seen all too many examples of sloppy work coming out of "major" labs with well-connected researchers. It seems like they are often held to a more lenient standard.........

Rosie

[tex]

It seems like they are often held to a more lenient standard.........

That may well be the case, because I'm sure that many of their peers are a lot more forgiving when they review such work, since they hold the authors in such high esteem. I, on the other hand, (and maybe this fits you as well), tend to hold them to a higher standard than researchers who have not yet attained such celebrity, because for someone so well qualified, there's really no justifiable excuse for such sloppy work. They, of all people, should know better, and I, for one, see no reason to grant them a free pass, and ignore their mistakes. I realize that no one is perfect, and I don't expect perfection, but "perfect" is not even on the table, with that paper.

Tex

[JLH]

No wonder I couldn't find it! I spent a lot of time trying......