balls of dough


BCM7: beta-casomorphin-7

FODMAP: fermentable Oligo-, Di- and Mono-saccharides and Polyols

MCP1: monocyte chemotactic protein 1

MPO: myeloperoxidase

NCGS: Non-celiac gluten sensitivity

SIBO: small intestinal bacterial overgrowth


Today’s post is about an Italian trial confirming that all may not be right with the Western world’s favorite grain. The study is titled Small Amounts of Gluten in Subjects With Suspected Nonceliac Gluten Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. (1)

Sixty-one patients were selected from a group of 118 people self-reporting gastrointestinal symptoms whenever eating any amount of gluten. In other words, these are people claiming to be suffering from non-celiac gluten sensitivity (NCGS).

All were screened to be free from the following: celiac disease, wheat allergy, lactose intolerance, FODMAP intolerance, Helicobacter pylori infection, pregnancy and Giardiasis.

Patients were asked to refrain from eating any gluten one week before the trial started until one week after gluten or placebo challenge ended.

In the first arm of the study participants were either instructed to consume capsules containing purified wheat gluten equivalent to two slices of white bread no more than twice daily, or an identical number of capsules containing an equivalent amount of rice starch. This was a double-blind, placebo-controlled trial so both the participants and the physicians administering the pills were unaware of who was getting what.

During this and the subsequent arm of the study, participants were asked to rate 15 intestinal and 13 extraintestinal symptoms. Extraintestinal means symptoms not directly related to GI function like changes to mood or energy levels for example.

At the end of week one, the pills were discontinued for another week and the patients were instructed to continue with their gluten-free diet before the next arm of the study commenced. During week three, those who initially took the gluten capsules were now told to take the rice starch capsules and those who had consumed the placebo were instructed to take the capsules containing gluten.

Of the sixty-one patients who started the trial, two withdrew leaving fifty-nine participants. Now, before I get to the results I need to report that of the fifty-nine patients only three, yes three, consistently showed a statistically significant reaction to gluten for both intestinal and extraintestinal symptoms. That comes out to only 5% of participants.

When separating out the two broad categories, eight patients (13%) experienced worsening intestinal symptoms. Six (10%) suffered negative extraintestinal symptoms.

The others were reporting symptoms both under gluten challenge and when consuming the rice starch placebo. The authors of this study point to a nocebo effect for this finding, meaning that the mere thought of ingesting something perceived as harmful, in this case gluten, was enough to elicit negative symptoms even in its absence.

There is no question that stress caused by anxiety, and that includes food anxiety, can elicit uncomfortable gastrointestinal symptoms which is why cognitive behavior therapy has been proven effective in helping control certain aspects of irritable bowel syndrome. (2) For that reason, those who consult with me are often asked about any psychological factors that may be contributing to their problem.

But let’s not forget that these were people suffering from some form of gut dysbiosis or they wouldn’t have been admitted to the trial in the first place. I find that some people with gut dysbiosis often react negatively to starch despite its source.

Does this mean that true non-celiac gluten sensitivity is far less common than thought? Perhaps, although when symptom data were aggregated for all fifty-nine participants, those consuming gluten still reported a higher level of negative outcomes in certain categories:


Courtesy: Small Amounts of Gluten in Subjects With Suspected Nonceliac Gluten Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial

Courtesy: Small Amounts of Gluten in Subjects With Suspected Nonceliac Gluten Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial


Here we see a series of graphs depicting overall symptomatology alongside five specific changes in health states for all fifty-nine patients. In all five metrics, those consuming gluten experienced higher negative scores than they did when consuming the rice starch placebo.

Also note the three areas where placebo or nocebo responses remained closer to baseline: foggy mind, depression and aphthous stomatitis (canker sores). All of these extraintestinal disorders were quite pronounced in the gluten consuming group.

The disturbing increase in depression seen in this trial closely resembles a similar finding in a 2013 Australian study:

“Short-term exposure to gluten specifically induced current feelings of depression with no effect on other indices or on emotional disposition. Gluten-specific induction of gastrointestinal symptoms was not identified. Such findings might explain why patients with non-coeliac gluten sensitivity feel better on a gluten-free diet despite the continuation of gastrointestinal symptoms.” (3)

Following is a complete list of reported symptoms. The highest symptom occurrence is at the top decreasing as you go down the list. Note how common abdominal bloating and pain were, as well as headaches and tiredness:
Gluten list

These researchers were unable to identify any biomarkers to pinpoint who would react to gluten. They go on to state:

“…neither serum IgG AGA nor intraepithelial lymphocytes correlated with either the overall response to gluten or the overall delta score, and in clarifying the pathogenic mechanisms underlying NCGS. Experiments aimed at defining the cytokine milieu in the duodenal mucosa of the patients enrolled in this trial are being conducted in our laboratory, and preliminary data do not seem to support the involvement of either innate or adaptive immune mechanisms in this condition.”

Now let’s keep in mind that the gluten dose administered was relatively low, equivalent to what you would get in two slices of bread eaten twice a day. Many people often consume more wheat during a typical day, especially in the land of pasta.

It’s conceivable that at higher intake levels, and for a duration lasting longer than a week, immune activation could become apparent driven by a worsening of gut dysbiosis.

But that still leaves the question of what could possibly be driving these particular symptoms in such a short time absent any proof of immune stimulation. My guess is gluten opioid peptides. (4) (5)

Opioids are never kind to the gastrointestinal tract because of their negative effects on peristalsis, the migrating motor complex, and their epigenetic effects on epithelial stem cells.

And we know some of this from animal and human studies investigating another dietary opioid peptide, beta-casomorphin-7 (BCM7). BCM7 is formed from the digestion of dairy containing A1 casein protein.

As I wrote in part two of my GERD series:

“…gluten opioids and adenosine aren’t the only dietary substances impacting stomach emptying and GERD incidence. Another class of opioid is formed from the digestion of a certain type of dairy:

UntitledCourtesy: Devil in the Milk: Illness, Health, and the Politics of A1 and A2 Milk.

This is an illustration of one section of the milk protein casein found in two different types of dairy. The casein at the top is derived from A2 dairy. The milk protein below from A1 dairy.

Each of these circles represent the different amino acids that make up this protein. Both are identical except for position 67. In A2 dairy, this position is occupied by the amino acid proline. In A1 dairy, this position is occupied by the amino acid histidine.

As humans, we are quite adept at producing enzymes capable of breaking apart or cleaving histidine bonds. Not so proline, which is why gluten, being very rich in this amino acid, is so difficult for us to digest into harmless peptides or individual amino acids.

The seven amino acid structure formed by the cleaving of the histidine bond in A1 dairy forms an opioid by the name of beta-casomorphin-7 (BCM7). The number seven refers to the number of amino acids in this peptide.

Just as gluten opioid peptides would be expected to have an effect on gastrointestinal function, including stomach emptying, so too BCM7. A1 dairy is derived from the milk of cows that originated in Europe. Although it contains the number 1 in its name, it’s actually a more recent evolutionary variant of older A2 cattle.”

Feeding mice dairy containing A1 casein was found to up-regulate several inflammatory markers like myeloperoxidase (MPO), monocyte chemotactic protein 1 (MCP1) and interleukin 4. (6) I’m pretty sure that what drove this increase in inflammation was intestinal dysbiosis likely caused by impaired peristalsis.

A study in male Wistar rats also found increased inflammatory markers along with increased intestinal transit time when these rats were fed dairy containing A1 casein in contrast to rats fed A2 dairy. (7) Constipation was alleviated when these animals were administered Naloxone, an opioid antagonist.

A 2014 pilot study in humans found that those consuming A1 casein dairy reported stool that was firmer than those who consumed dairy from A2 casein cows. (8) This is significant because firmer stool signifies constipation. The longer stool sits in the colon, the more water is withdrawn from it making it harder to pass. This is why severe constipation is often associated with dry, nugget-like feces.

Those consuming A1 casein dairy also reported more abdominal pain and discomfort although anyone reporting lactose intolerance or a milk allergy was excluded from participating in the study. The researchers theorized that a propensity to constipation would allow fiber to sit longer in the colon and be fermented by gut flora. This in turn would allow the buildup of gas resulting in sensations of visceral pain. In other words, the same gas and bloating symptoms that were observed in the gluten sensitive group were also seen in humans reacting to BCM7.

Delayed transit time can be a real problem for those with undiagnosed small intestinal bacterial overgrowth (SIBO), itself a condition that is overwhelmingly caused by compromised gastrointestinal motility. In those with SIBO, an overgrowth of bacteria in the small intestine means gas is produced in both the small and large intestine whenever fiber passes through either area.

Returning to the Italian gluten study, a major limitation was that none of the patients were screened for SIBO. That may explain the worsening of symptoms even under placebo. The addition of gut stopping opioids derived from consuming gluten was just further icing on an already dysbiotic cake.

Another limitation was that consumption of A1 dairy was not controlled for. It’s conceivable that this would confound the results. This is Italy after all, a country replete with cheeses, sauces and deserts made with milk.

But can gluten opioid peptides also explain the foggy brain, depression and canker sores that were reported by many?

Well it surely can account for foggy thinking. Opioids have obvious effects on brain function outside of pain suppression. They can make you feel quite spacey as well as tired, with the latter also being a common symptom reported by those consuming gluten. And it’s also not unusual for those on opioid pain medication to report depressed moods.

Opioids are also well known to suppress immune function, which might very well account for the outbreak of canker sores in those eating gluten. From a review on opioid side effects we learn:

“The immunomodulatory effects of opioids were initially demonstrated in the 1890s when Cantacuzene showed cellular immune suppression and decreased resistance to bacterial infection in guinea pigs treated with morphine. Opioids have been implicated in the increased incidence of infections in heroin addicts and as a cofactor in the pathogenesis of human immunodeficiency virus. Interestingly, although exogenous opioids may generate immunosuppression, their endogenous counterparts (e.g., endorphins), induce immunoactivation. It is known that acute and chronic opioid administration can cause inhibitory effects on antibody and cellular immune responses, natural killer cell activity, cytokine expression, and phagocytic activity. The immunologic effects of opioids are mediated by central and peripheral mechanisms. The potential mechanism by which central opioid receptors mediate peripheral immunosuppression may involve the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. (9)

Of course immune suppression caused by opioids would also be expected to hamper the body’s ability to prevent an overgrowth of pathogenic gut flora over time. Recall that approximately 80% of total immune cells are located in or near the GI tract. (10)

So does this study point to the possible effects of gluten opioid peptides as a cause for certain GI and non-GI abnormalities in those confirmed free from celiac disease?

I believe it does.

Will it be enough to change the mind of Dr. Carroll?

I haven’t a clue.

Until next time.


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