Non-celiac gluten sensitivity

Gluten is protein, not carbs.  A gluten-free diet is frequently low-carb, because most dietary gluten comes in the form of bread (and wheaty foods).  But believe it or not, bread is an incredibly complex food… many different proteins, carbohydrates, and nutrients that could be problematic for some people (more on this later).

Gluten is not a FODMAP, but most gluten-containing foods are.  Gluten is actually very rich in the amino acid glutamine.  Gluten, not bread.

So we have three studies on purified “gluten,” asking if it’s the gluten, FODMAPs, or something else in wheaty food that is problematic.

Study #1. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of FODMAPs (Biesiekierski et al., 2013)

Strong study design; patient population was people who thought they were gluten sensitive (but definitely not celiac).

This is the study which led journalists to claim non-celiac gluten sensitivity doesn’t exist, and it’s really sensitivity to FODMAPs, in part, because of this:



low FODMAPs and gluten free



Baseline = low gluten diet
Run-in = low gluten and low FODMAPs


Here’s the fly in the ointment:


symptoms returned in all participants


After the run-in period, subjects still followed their gluten-free diets but also received either 16g relatively pure gluten/d (High gluten), 2g gluten + 14g whey protein (Low gluten), or 16g whey protein (placebo).  GI symptoms returned in all participants.  So, low FODMAPs worked for about a week, but then symptoms returned regardless of whether they were eating gluten or not.  In other words, neither low FODMAPs nor low/no gluten worked very well in this study.

But this study may have introduced a brilliant new confounder: food intake was strictly controlled — the experimental diets were different from their normal diets.  Restricting gluten and FODMAPs may have provided some transient benefit, but if the new experimental diet introduced something else that caused problems, then that may explain the gradual return of symptoms…




Study #2. Small Amounts of Gluten in Subjects with Suspected Nonceliac Gluten Sensitivity: a Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial (Di Sabatino et al., 2015)

It was another high quality study design: “Randomized, Double-Blind, Placebo-Controlled, Cross-Over.”  And it was addressing a basic question: do people who strongly suspect they have non-celiac gluten sensitivity (NCGS) really have NCGS?  Alternatively, is NCGS real?

Intervention was strong:

1) 4.375 grams of gluten or placebo (rice starch) daily for a week.  This is roughly equivalent to two slices of bread (note: this is way more than enough gluten to destroy the intestines of a patient with bona fide celiac disease).

2) important: they defined the what they would classify as NCGS prior to starting the trial.  A priori.

61 patients strongly suspected of NCGS started the trial, and one withdrew due to gluten-related symptoms in both the gluten and placebo groups.


Results:  regardless of whether they were assigned to gluten or placebo FIRST (prior to the crossover), most patients reported gluten-related symptoms.  More importantly, 3 of the 59 patients exhibited significantly worse symptoms on gluten relative to placebo according to the endpoint they defined prior starting the trial.  In one sense, this could be interpreted to mean 5% of people who strongly believe they have NCGS actually have NCGS.


gluten sensitive patients


Two patients reacted just as selectively strongly to the placebo as the three “real” NCGS patients did to gluten.  Rice-starch sensitivity?


See here for a more detailed description of the statistics involved in this study.  I’m willing to accept the “5%” rate, despite the strength of the placebo-responders, whereas the author of that blog post is not.  That’s fair, imo.

And here is another article which questions the legitimacy of NCGS based on this study.  I don’t think that’s totally fair.

And Raphael’s post, where he humorously concludes: “[Gluten-free] does not include advice to sport a gas mask when walking past bakeries.”



Study #3. Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity (Hollon et al., 2015)



gluten increases intestinal permeability



“Delta TEER” is basically the amount of intestinal permeability in intestinal explants exposed to media + gluten (experimental condition) minus those exposed to plain media (control condition).  A better control condition, imo, would’ve been something like they did above: substitute gluten with another protein like whey protein.


NC: healthy people
RCD: celiac patients in remission
ACD: celiac patients with active disease
GS: non-celiac gluten sensitivity


Active celiac samples responded significantly worse than those in remission, which is good as it functions as a positive control for the experimental protocol.


However, gluten sensitive samples responded significantly worse than celiac remission samples; actually, they responded just as badly as celiac samples with active disease.  Celiac disease is supposed to be a million times worse than non-celiac gluten sensitivity… and statistically speaking, even permeability the normal samples declined as much as NCGS samples.


This led some to conclude that gluten is bad for EVERYONE.  I’d say it means the assay is bollixed.  Occam’s razor?



My advice: don’t be anti-science, but don’t use bad science to justify diet choices.  We simply need better studies on non-celiac gluten sensitivity and FODMAPs.

If bread doesn’t work for you, don’t eat bread.  You’re not missing much.


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  • >If bread doesn’t work for you, don’t eat bread. You’re not missing much.

    Ha, you’d think the stuff was the prime source of oxygen and unicorn sweat the way people obsess about needing the stuff.

    Via Donaldson (dunno if this will embed correctly):

    “Bread addiction is little different from that of alcohol or cocaine or heroin addiction, and sometimes it seems even more dangerous.

    Did you even see a fat man praying for the soul of some poor alcoholic or drug addict? Yet he couldn’t stop his own helping of whole wheat toast for breakfast to save his soul.” ~ Blake F Donaldson, 1962

    • This Old Housewife


  • TechnoTriticale

    re: Rice-starch sensitivity?

    One of the first things I look for in a nutrition trial paper is what the placebo (if any) was. Whey protein and rice, if their effects have been well-characterized in prior trials, might be “controls”. They are NOT “placebos”, and the first two referenced papers make this error.

    Whey protein is known for insulinemia, allergy, BSA, and possible hormone and antibiotic contamination. Mayo has a longer rap sheet, including “Use cautiously in people with stomach or intestine disorders.”

    Rice contains wheat germ agglutinin, and many rices have strikingly high levels of inorganic arsenic contamination. Pesticide uptake and GMO concerns could also arise unless clearly disclaimed.

    When I see placebos that aren’t, the obvious question is:
    what else don’t they know?

    • “we need better studies on NCGS”

      I think whey was a better control than rice starch, because it’s protein. They chose rice starch because it’s rapidly absorbed; not a FODMAP (which was more important in this study).

      perhaps gelatin and purified maltodextrin would’ve been better controls in the respective studies.

      • rs711

        I’m undecided on that…whey *may* also be immunoreactive. 4.375g of starch is pretty innocuous, all considering – even for parts of IBS/FODMAP sensitive populations. furthermore, the point of a placebo is to exert no actual effect, not to mimic properties of its (supposedly) active counterpart without causing sh*t to happen. Yes, sometimes taste & texture are important to reproduce but in this case it wasn’t because it was an indistinct encapsulation.

        Gelatin or maltodextrin could also work I guess…it’s an interesting point though – probably one that’ll become way more important when we start figuring out wtf is happening with the placebo/nocebo effect(s).

        • “4.375g of starch is pretty innocuous”

          as long as it’s rapidly digesting. That much GOS will impact the ‘biome, transit time, etc., especially in IBS/FODMAP populations

          • rs711

            good point, individual differences in intestinal motility may act as a substantial confounder

      • Whey may also cause problems for people sensitive to gluten. Very reactive protein with endorphin qualities. I have not tested wheyiphrenia like I have wheatiphrenia but I get massively stimulated from pure whey protein similar tew the high I get from wheat protein.

        As stated, ice repeatedly demonstrated wheat protein disinhibited ketosis just like opiate medication. Something to this.

        • Several years ago there was a surge of interest in cross reactivity of gluten and coffee I think. I consume neither habitually so IDGAF but maybe worth investigating for some, it may have been bogus, dunno, never cared.

        • I’ve heard of this with casein (eg, GFCF diet), but not whey. Interesting.

  • The Dietary Intake of Wheat and other Cereal Grains and Their Role in Inflammation

    • Sky King

      Reading books like “Grain Brain” and “Wheat Belly” has convinced me to stay away from ALL wheat and avoid the grasses ( corn, oats, etc.) as much as possible. It’s not just the gluten that could be the problem. Genetic engineering over the years has created other foreign proteins that may be problematic and causing problems….now or eventually down the road.

  • Wheat gluten was used by bodybuilders as a source of glutamine dipeptides, which were supposed to be significantly better than glutamine alone.
    Problem was, it tasted like shit and didn’t work very well.

  • This Old Housewife

    This is what I have–problems with ALL grains, not just the gluten-containing ones. Gluten bothers me, and I’m allergic to grains to boot. Gluten sets off my arthritis, and all grains (except psyllium) lead to anaphlaxis. I’ve never had any of the symptoms of Celiac disease, so I had no idea grains were a hazard to me until I stopped them.

  • Gerard Pinzone

    Unfortunately, the nocebo effect is a very real confounder. Maybe the placebo used wasn’t a proper once since it triggered a sensitivity, too, or maybe these food issues are mostly in people’s heads. A similar thing happened in the 80s and 90s with MSG and Chinese food. Gulf War Syndrome is another. And of course, some people subconsciously (or even consciously) WANT to be gluten intolerant so they can be “special snowflakes.”

    • rs711

      “maybe these food issues are mostly in people’s heads.” ==> history shows this is a risky position to take. I see where you’re coming from – I do hehe – but it’s also a bit of a facile dismissal

      • Gerard Pinzone

        I was trying to think up a better answer, but I’m too close to my internet router and the radio waves are upsetting the glucose balance in my brain. It must be the reason since there’s a demonstrable biological effect.

        • rs711

          OK point taken :)…to be perfectly honest, I’m agnostic about EMFs – I don’t have a good enough Physics background (yet) to intelligently weigh the arguments & very few people do (as it requires BioPhysics)

  • rs711

    So far, this is what it comes down to:

    – gluten-containing foods are much more the problem rather than gluten by itself (I’ve readjusted some of my views on gluten-alone but not on gluten-containing foods)
    – we don’t how much of a part gluten plays in these foods, generally speaking (this is where I agree with Bill on the sorry state of most of the science behind it)
    – we do know that it does play some kind of role within different models (Celiac, gluten-ataxia)
    – Gluten transiently increases gut permeability in everyone (yes, everyone – from in vivo/ex vivo data mainly) ==> yet, we lack good data on what this means for long-term overall permeability (which is key, obviously)
    – There is 0 upside to consuming gluten or gluten containing foods (except the caloric value & “but I rreeaally like bread”)
    – There is a significant potential downside & a non-trivial actual downside depending on ones genes & current health status
    – Not related to medicine/health directly but nonetheless important depending on what you care about ===> the sustainability piece is a no brainer: you ain’t helping nobody consuming major monocrop grains/legumes
    – [Except for the “I like bread” excuse] I fail to see why anyone would recommend NOT avoiding gluten-breads. Not shying away from a bite every once in a while is NO BIG DEAL in the grand scheme of things; choosing to make it a daily or weekly occurrence isn’t nothing…

    • Upside to gluten? glutamine dipeptides! make moar gainz!

      “Gluten transiently increases gut permeability in everyone”
      …I don’t think that assay is very reliable.

      but yeah, most gluten-containing foods are crap.

      • rs711

        lol if the bro’s do it, must be right :p

        what specific assay are you referring to? And what issue specifically? I’m talking about multiple studies where different methods (W. Blot, gel electrophoresis, immunoblot staining etc.) used to detect the cascade of zonulin & occludens’. I *think* I’m not wrong saying its been confirmed in animals in vitro, ex vivo and in human cells in vitro.

        If i missed something in the methodology, please point it out, i’d like to dig into it. Thanks!

        Just to clarify – that gluten transiently activates the permeability cascade doesn’t imply that everyone will automatically suffer from it equally. We know it doesn’t since typical responses to gluten aren’t BIG IN YO FACE ones. These processes are very responsive and a 1-celled gut lining has wickedly fast turnover. How we handle the ‘insult’ makes all the difference in the world.

        I think it’s smarter to avoid the win-nothing conflict all together (especially when dispensing nutrition advice).

        Maybe I’m overly cautious – but I think not.


        • “what specific assay are you referring to?”

          the Hollon study on intestinal explants from active CD, CD in remission, NCGS, and healthy px.

          Most of the work showing negative effects of gluten is done in intestinal cell lines, and is relatively weak (imo)… gluten might be bad, but no one has figured out the MOA. (tons of things disrupt tight junctions).

          I don’t disagree with your general advice to avoid gluten, but perhaps not bc of the gluten lol 🙂

          • rs711

            OK thanks – I’ll have to get back to your over the MOA, in case I make a fool of myself.

            you’re absolutely right, tons of things disrupt pandora’s box. HIIT will for e.g…

  • Great post Bill.

    Pretty obvious the gluten free fad is over the top…most benefits are clearly from going lc, reducing insulin thus inflammation.

    Although, interesting anecdote, I have discovered gluten acts like a mu old receptor agonist to enhance keto, assuming one consumes a keto meal with the gluten. The effect of gluten on keto is redundant with opiate medication or mu opiod agonist.

    Perhaps people imagining gi symptoms are actually responding to psychological distress from ,maybe, endorphin system effects of gluten? I have repeatedly verified in myself gluten has powerful MOR effects.

    FWIW, I find gluten to be a high and enjoy it without gi distress. However, unlike the past where I was sure wheat restriction was a stupid fad, I have no choice now but to be open minded it’s found suffering unlike normal food perhaps in a subset of individuals. I suspect it’s mediated via endorphin system, and its important to note endorphin regulates gi somewhat.

    • rs711

      I’m leaning more & more towards itsthewooo’s angle, which as I understand it is more preoccupied with behavioral changes related to opiate responses…after all, the growing importance of the gut-brain axis is undeniable (but as always, often mis/over-extrapolated).

  • In the Gibson study – 8% of participants were classified as NCGS & more were reporting symptoms of depression.

    “It is also worth noting that in our study on NCGS, wheat protein did cause current feelings of depression – a finding that is currently being re-examined in a larger and more complete study (the other was another ‘pilot’)”

    (From an interview Gibson did). The same team went on to do another study that linked gluten to depression and no one bothers to pay attention to that.

    I’ve spoken to a few doctors before – when they test people for gluten sensitivity or celiacs – that person, if they were gluten free, has to resume consumption of gluten for 3 weeks in order to see the response.

    Neither the Gibson study or the 2nd (more recent one) you mentioned do that. They take gluten free people and give them a few grams of gluten and expect to see negative effects. And to say “Well – this would upset a celiac” is nonsense. NCGS is not celiacs disease. If it were, it would simply be called celiacs.

    If someone can make the case that gluten is a protein worth eating I’m all ears. Also, if they could please identify which enzyme exists in the human body that can effectively convert gluten into the proper amino acids, I’m curious to know what that enzyme is.

    And for the gluten sensitivity cynics – please eat 8 servings of wheat per day and drink a gluten protein shake daily. Stay as committed to eating wheat and gluten as we are to avoiding it. Enjoy!

    I can easily eat 8 servings of complex carbs from oats, potatoes, rice etc. without any issues. Even legumes. I think most people can do the same but would really struggle doing that with wheat.

    I’d really like to see a study done on wheat in general and how people fare on it compared to other complex carbs.

  • Kerrie Levanger Cobain

    Here’s my problem. Going gluten free might be great for adults, even if they aren’t really intolerant, but when you start seeing more and more children being put on gluten free diets that can be a problem and more than one pediatrician has expressed their concern that children’s caloric intake is being significantly curtailed by parents who believe they are gluten andor lactose intolerant. Not eating a ton of carbs is great when you’re 30 or 40 or 50, but what about when you’re 5 or 6? I think this allergy obsession has started to get out of control and no one seems to realize children are being put at risk of not getting enough calories to grow properly. I know kids who have had both gluten and dairy removed from their diet. After awhile it gets difficult to find anything they are allowed to eat and I think that should be a real concern and we need to start talking about it. In some cases this has become a legal way for people with Munchhausen by Proxy to get attention at the expense of their children’s health without breaking any laws.