The effect of expectancy versus actual gluten intake on gastrointestinal and extra-intestinal symptoms in non-coeliac gluten..., 2024, De Graaf et al.

Abstract
Background: Many individuals without coeliac disease or wheat allergy reduce their gluten intake because they believe that gluten causes their gastrointestinal symptoms. Symptoms could be affected by negative expectancy. Therefore, we aimed to investigate the effects of expectancy versus actual gluten intake on symptoms in people with non-coeliac gluten sensitivity (NCGS).

Methods: This randomised, double-blind, placebo-controlled, international, multicentre study was done at the University of Leeds (Leeds, UK), Maastricht University (Maastricht, the Netherlands), and Wageningen University and Research (Wageningen, the Netherlands). People aged 18-70 years with self-reported NCGS (ie, gastrointestinal symptoms within 8 h of gluten consumption) without coeliac disease and wheat allergy were recruited. Participants had to follow a gluten-free or gluten-restricted diet for at least 1 week before (and throughout) study participation and had to be asymptomatic or mildly symptomatic (overall gastrointestinal symptom score ≤30 mm on the Visual Analogue Scale [VAS]) while on the diet. Participants were randomly assigned (1:1:1:1; blocks of eight; stratified by site and gender) to one of four groups based on the expectation to consume gluten-containing (E+) or gluten-free (E-) oat bread for breakfast and lunch (two slices each) and actual intake of gluten-containing (G+) or gluten-free (G-) oat bread. Participants, investigators, and those assessing outcomes were masked to the actual gluten assignment, and participants were also masked to the expectancy part of the study. The primary outcome was overall gastrointestinal symptom score on the VAS, which was measured at and corrected for baseline (before breakfast) and hourly for 8 h, with lunch served after 4 h, and analysed per-protocol. Safety analysis included all participants incorporated in the per-protocol analysis. The study is registered at ClinicalTrials.gov, NCT05779358, and has ended.

Findings: Between Oct 19, 2018, and Feb 14, 2022, 165 people were screened and 84 were randomly assigned to E+G+ (n=21), E+G- (n=21), E-G+ (n=20), or E-G- (n=22). One person in the E+G+ group was excluded due to not following test day instructions, leaving 83 participants in the per-protocol analysis. Median age was 27·0 years (IQR 21·0-45·0), 71 (86%) of 83 people were women, and 12 (14%) were men. Mean overall gastrointestinal symptom score was significantly higher for E+G+ (16·6 mm [95% CI 13·1 to 20·0]) than for E-G+ (6·9 mm [3·5 to 10·4]; difference 9·6 mm [95% CI 3·0 to 16·2], p=0·0010) and E-G- (7·4 mm [4·2 to 10·7]; difference 9·1 mm [2·7 to 15·6], p=0·0016), but not for E+G- (11·7 mm [8·3 to 15·1]; difference 4·9 mm [-1·7 to 11·5], p=0·28). There was no difference between E+G- and E-G+ (difference 4·7 mm [-1·8 to 11·3], p=0·33), E+G- and E-G- (difference 4·2 mm [-2·2 to 10·7], p=0·47), and E-G+ and E-G- (difference -0·5 mm [-7·0 to 5·9], p=1·0). Adverse events were reported by two participants in the E+G- group (itching jaw [n=1]; feeling lightheaded and stomach rumbling [n=1]) and one participant in the E-G+ group (vomiting).

Interpretation: The combination of expectancy and actual gluten intake had the largest effect on gastrointestinal symptoms, reflecting a nocebo effect, although an additional effect of gluten cannot be ruled out. Our results necessitate further research into the possible involvement of the gut-brain interaction in NCGS.

Funding: Government of the Netherlands Topsector Agri & Food Top Consortium for Knowledge and Innovation, AB Mauri Global Bakery Ingredients, Baking Industry Research Trust, Borgesius-Albert Heijn, CSM Innovation Centre, the International Maize and Wheat Improvement Center (CIMMYT), DSM Food Specialties, Fazer, Healthgrain Forum, the International Association for Cereal Science and Technology, the International Wheat Gluten Association, Lantmännen, Mondelez International, Nederlands Bakkerij Centrum, Nutrition & Santé, Puratos, Rademaker, Sonneveld Group, and Zeelandia HJ Doeleman.

Link:
https://www.thelancet.com/journals/langas/article/PIIS2468-1253(23)00317-5/abstract

 

Interesting funding / conflicts there

I’m just not fully sure why they bother because if people think they feel better or worse on gluten free then telling them it’s just because they expect it to - whether that is nonsense or not - seems unlikely to make them suddenly buy loads of bread and cakes anyway. Well not enough to change their profits?

 

How can this study even be published with such obvious conflict of interest.

 

I have a regular habit of buying and eating bread on Monday because I like it. I definitely, 100% tend to be more symptomatic on Monday after lunch. Enough to be noticable, not enough to discourage me from continuing to eat bread.

It seems to depend on the specifics of the bread and might not have anything to do with gluten, but with other things in the bread or the way it has been prepared. Also two slices of bread is not a lot and it's not clear how much gluten is in oat bread. The test scenario seems a bit artificial and might not reflect the situations where people are actually noticing that bread is not good for them. If people expect a problem, maybe that is because they're observed it often enough to come to expect it.

The way they highlight how expectation affects things seems biased, because it's normal and expected and therefore not worthy of highlighting. It seems they're eager to be able to say that it's mostly imaginary.

Also I feel like saying: dear bakers, studies like this will do nothing to change the opinion of people like me because it's obvious that bread isn't healthy. Make a better product that is not unhealthy and I will eat it more. Trying to tell people they're imagining a problem will just make you even more unpopular.

 

I dreamed I ate some jam donuts the other night, I didn't have symptoms in the dream

Mindblown

 

I wonder what the patient information sheet said and whether it was ethical.

If the 'expectation part' of the study was 'masked' from the patients it sounds as if the information sheet said that they would be told whether or not to expect gluten - but not told that the information would be untrue.

If you tell people what they are going to get then they are likely to 'help' the investigators by giving the 'right answer' for reasons that have nothing whatever to do with the relation of expectation to symptoms in the real situation of eating stuff at home.

Conflicts of interest are fine. All drug trials done by drug companies are not so much a conflict of interest as just plain commercial interest, but if the trials are done properly that doesn't matter. The problem is bad methodology.

 

Related content:
In conversation with... Louise Dye
Louise Dye (University of Leeds) discusses a trial exploring the role of expectancy and gluten ingestion on symptoms in people with non-coeliac gluten sensitivity.

https://audio.buzzsprout.com/i91e1g8tggvkgw3jrecob866o0ip?response-content-disposition=inline&

23 minutes

 

Not terribly well controlled then, if some of the participants were completely off gluten at the time of the trial and some weren't?

 

Maybe people with non-coeliac gluten sensitivity live like that though? Some doing gluten free and some gluten restricted. As long as they were randomly assigned it wouldn't really affect controlling of the intervention.

 

I've always thought non celiac gluten sensitivity was a nocebo effect or misdiagnosed IBS.

 

On the few occasions I eat something that contains gluten unbeknownst to me, for example falafels made with wheat flour rather than gram flour, the effect is no different than that of knowingly eating gluten containing food.

However my gluten sensitivity is dose dependant, and though I can get away with small/trace amounts they can have a cumulative effect making a subsequent consumption of a larger amount have a more marked effect than it would if I had been previously totally gluten free, so I echo @Eleanor ’s point about the need to effectively control for previous gluten levels.

Also, if my memory of the situation some ten plus years ago, before I was consistently eating gluten free, I need to have eliminated gluten from my diet for much more than one week to get a very clear cut response to a challenge test.

Although I probably would not correspond to the subjects of this study as my gluten intolerance symptoms overlap and interact with my PEM symptoms and both have a cumulative impact.

[Note - I assume I have a non coeliac gluten intolerance, as I tested negative for coeliac disease and have a dose dependent response to gluten. However I did not know at the time of testing that I needed to have gluten in my diet for the test to be valid and had been gluten free for some months. I decided given management of both coeliac and non coeliac issues is to go gluten free, it did not seem worth making myself ill for a more reliable diagnosis.]

 

My husband is gluten sensitive and his experience is very much like yours, including not knowing that the test wouldn't be valid if he was gluten-free at the time (why don't they explain this to people?!).

 

Maybe this will finally get me to stop eating bread entirely, after spelling it out that I'm reliably a little bit worse on Mondays and that the only constant is the bread. My family buys bread from the same market and same baker every Monday and it has been this way for years.

 

Belief in the *cebo has to be continuously affirmed. This isn't about gluten, it's about the magical mind stuff that they badly want to believe is real.

Tests like this are garbage. A valid test, a scientific test, assures that all other things are equal. All of them. Not some of them, or most of them. Literally every single other factor. They aren't even close to that, there's way too much noise here. If anything, believing in the *cebo stuff is what leads people to affirm it, and this is what motivates people to do this stuff. Some in medicine have developed a fanatical obsession with this mind magic and they just can't accept that it was always noise, that the noises in the house were never ghosts, not even once, no, not even that one time that looked really convincing.

I don't know what it will take to end this silly nonsense. It's completely unfalsifiable, so it's not as if there is some point at which believers will say "welp, we've really tried it all, and it just can't be confirmed". It all rests on a combination of not knowing things, and random chaos. GI issues have the combined problem of being very hard to pin down for individuals, and sometimes even harder for clinicians. No one knows most of the time what the problem is, and this magical mind stuff is just perfect for it, it even has a huge cultural bandwagon effect encouraging it everywhere at all times.

The truth is that almost all studies that rely on subjective ratings need to have a huge effect size with minimal bias to be worth a damn, and they pretty much never are. But that basically invalidates about 90% of psychological studies, and close to that in general health studies. Noise noise noise. It's all just noise, like the faces on Mars and wanting to see faces where there's just shadows.

People will be trying to prop this nonsense up a century from now. It will be ignored as noise by then, but it will likely never die. The medical philosopher's stone isn't like with alchemy, some distant pre-science stuff, it's been baked in the fabric of modern medicine, it's too embarrassing to end it.

 

It's an interesting one of course because I've just ended up looking up coeliac disease, because when I was trying to see what NOn-coeliac gluten sensitivty was and involved one of the pages on this was from coeliac.org.uk . and it describes that as having similar symptoms to coeliac disease, but without the immunological : Gluten sensitivity - Coeliac UK

"Coeliac disease is not a food allergy or intolerance, it is an autoimmune disease.

Wheat allergy is a reaction to proteins found in wheat, triggered by the immune system and usually occurs within seconds or minutes of eating.

Non coeliac gluten sensitivity is when symptoms similar to coeliac disease are experienced, but it is not clear how the immune system might be involved because no antibodies are produced, and there does not appear to be damage to the gut lining."

The same website has a section on myths about coeliac disease, one of which is:
"You have to have gut symptoms such as diarrhoea to have coeliac disease’
Coeliac disease is known as a 'multi-system' disorder – symptoms can affect any area of the body. Symptoms differ between individuals in terms of type and severity. Read more on symptoms if coeliac disease. You don't need to have gut symptoms to have coeliac disease."

and the list of symptoms is:

SO I think what I'm noting is that on the following pages: Gluten sensitivity - Coeliac UK

it is defining this condition differently to wheat allergy / food allergies, and saying it is similar to coeliac and then pointing to testing needing 6 weeks of eating gluten before-hand for coeliac.

SO I don't know whether this has rolled a few things into one, or there is a definition issue going on (some just combining the intestinal type things, where others suggest one that isn't specifically intestinal) which would affect what time periods and ergo what symptoms - and what measures you might use. The description on these pages I'm not sure you'd immediately use 4 days on one then 3 off then 4 days on the other and asking people to list certain obvious symptoms that sound like they are more digestive?

 

I have learnt from experience some foods strongly disagree with me i had no expectations before eating said foods . after many unpleasant reactions i restricted them from my diet . simple i do not claim a specific cause/ingredient causes said symptoms because i have no real knowledge of all the processes used to make bread or cheese these days.

 

In the last year till December, I made my own sourdough bread from my own starter. It meant that my bread’s ingredients were flours, water and salt. I LOVE bread! Then in December I had to go on a liquid diet for a few weeks which meant no bread at all. I do lactose free dairy.The minute I changed diet, my gut started behaving more and more normally. It was like night and day.

now it is not perfect but I have been gluten free for 7 months. Still some sort of tummy distresses, some urgencies at time. I will try for gluten again because the gluten-free breads and products (pasta for instance) are not quite the same.

 

It might be worth shopping around for different gluten free breads as I had given up any bread for quite a number of years because in the past gluten free bread was inedible, but now there are a couple of brands whose brown bread and granary bread is to me as good as the ‘real thing’. Gluten free white bread though improving is still not quite there yet.

Also I find most gluten free pasta is not too bad if eaten when immediately cooked but very quickly as it cools it turns to cardboard, certainly no use for a salad. I also find rice noodles and Japanese soba or buckwheat noodles OK, as long as both are the genuine product without wheat added.

However it is worth trying gluten every now and again as it seems that food intolerances are less fixed than allergies and for some lucky people they can just disappear.

My godson trained as a Konditor (half way between a confectioner and a pastry chef) and when making gluten free cakes, gateaux or deserts usually mixes his own flour with different proportions of different flours (rice, potato, buckwheat, etc) depending on what he is aiming for. Usually what he cooks is as good as anything made with wheat flour, but I have not tried making any of his recipes myself. Unfortunately we don’t live in the same country, but he usually does me proud for special occasions like my birthday.

[I seem to have edited this whilst thinking I was still drafting it so I don’t know what was the original posting and what has been altered.]