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Is Gluten Causing Your Depression?

We sort out the confusing research to date.

Gluten, a major protein in wheat, rye, and barley, is great for baking, allowing for lovely, elastic, fluffy breads and the like. However, as a food item for humans, the jury is still out. The problem really begins because gluten is a long, wound up tangle, and we can only partially digest it, leading to large and possibly damaging segments that may irritate the gut and cause immune reactions and allergies.

In a few people (roughly 1% of the population), gluten is frankly poisonous. These folks have celiac disease, which is actually an autoimmune condition where the gut lining is destroyed in the presence of gluten. Celiac disease can be deadly, and those who have it can present not only with weight loss, diarrhea, and malnutrition, but also neurological and skin manifestations. Sometimes the neurologic or skin issues conditions present by themselves. I have several patients whose psychiatric symptoms seem to resolve after eliminating gluten (and, perhaps critically, most grains and therefore most processed foods) from the diet, but admittedly this is anecdotal and unusual. Several popular books have gone after gluten as the great evil of our times, and now 18% of adults are buying gluten free packaged foods (1).

The issue seemed a little more clear in irritable bowel syndrome, a condition where people have gastrointestinal discomfort, flatulence, diarrhea, and/or constipation with no cause found for the problem. Depression and anxiety goes hand in hand with irritable bowel, suggesting it is a condition related to stress in many, researchers suspected diet might be a cause for irritable bowel as well. A while back, a study was done trying to see if there is such a thing as gluten causing irritable bowel in people without celiac disease. The researchers used gold standard techniques to exclude celiac, then gave people either gluten-containing food or non-gluten containing food in a blinded fashion. Low and behold, some folks with irritable bowel reported getting better on the gluten-free diet. The new problem was called non-celiac gluten sensitivity and made big news. See! Told you so said a bunch of gluten-free fans of the research. However, the very same researchers figured out their paper had a big problem, and the problem was FODMAPs.

FODMAPs? Yes, fermentable oligo di mono-saccharides and polyols. These are short carbohydrate chains (such as fructose and fructans) and sugar alcohols that can cause both irritable bowel syndrome, and probably depression. Wheat, the major source of gluten in the diet, also contains plenty of FODMAPs. When the researchers did the first experiment, they didn’t isolate gluten separately from FODMAPs, and when they redid the experiment a couple of years later, they exhaustively proved that non-celiac gluten sensitivity doesn’t exist (at least as a cause of irritable bowel). An even larger study put the nail in the coffin on gluten as the culprit, once FODMAPs were excluded.

This second paper was popularized in the media as well, causing such quotes as “you can go ahead and smell your bread and eat it too.” What seemed to be missed in the whole controversy is that while it wasn’t the gluten, wheat itself was still a problem for many, and most commercial breads are made with both wheat and high fructose corn syrup, potent sources of FODMAPs. A commentary in Gastroenterology made the point: Non-celiac wheat sensitivity is a more appropriate label than non-celiac gluten sensitivity. Gluten-free processed foods sometimes contain plenty of FODMAPs, by the way, and FODMAPs are tolerated well by a lot of people, just not by all. In fact, many FODMAPs are a great source of prebiotics that help keep the gut healthy by providing food for the microbiome in the colon.

Confused and frustrated yet? It’s about to get murkier. Earlier this year, a paper was published in Alimentary Pharmacology and Therapeutics called “Randomised clinical trial: gluten may cause depression in subjects with non-celiac gluten sensitivity—an exploratory study.”

These researchers were following up on an unpublished observation from the second large study that proved gluten didn’t cause non-celiac irritable bowel symptoms in the absence of FODMAPs. This observation was that even though the research subjects were definitively proven not to be sensitive to gluten with respect to irritable bowel symptoms, many continued to follow gluten-free diets because they subjectively described “feeling better.”

In celiac patients, depression and anxiety symptoms have been linked to gluten consumption. But what about in non-celiac patients? Could gluten be causing anxiety and depression in folks without celiac disease? There’s very little research on this issue. One study had patients diagnosed with non-celiac gluten sensitivity eat gluten bread for 3 days, and there was no change in feelings of anxiety or depression. In the newest paper, 22 participants were recruited from another study of self-reported non-celiac gluten sensitive patients with irritable bowel. Celiac disease was excluded previously, and all the participants reported their irritable bowel was stable and they were on a gluten free diet for at least six weeks.

Now the patients were put on a gluten-free and low FODMAP diet, and, after a few days, were asked (in a blinded fashion) to add certain “challenge” foods for three days, with a washout period between challenges. One food was supplemented with carbohydrate-depleted wheat gluten (minimal FODMAPs), another with whey (lactose-free and also low FODMAP), and the other was placebo. Participants tracked their mental state, gastrointestinal symptoms, and cortisol, a stress hormone, was also measured.

What did they find? Well, there was no difference in cortisol measurements of the subjects during any of the three challenges. There was also no difference in gastrointestinal symptoms for the three challenge foods all told, though (interestingly), no matter what the first challenge was (whey, gluten, or placebo), the participants reported the most gastrointestinal distress during the first challenge, less during the second, and even less during the third.

But what about depression? 90% of the final participants reported more depressed mood while eating gluten compared to placebo, and the differences in the scale measurements of depression did reach statistical significance. There was a smaller but non-significant increase in reported depression while eating whey compared to placebo.

Now this is a very small, very short study, but that’s an interesting finding. Certainly the gluten didn’t seem to increase cortisol, which would have indicated the gluten stressed the body in some way, leading to depressed mood. Why else could gluten ingestion cause depression? Well, perhaps the excess gluten (which is relatively low in tryptophan) depleted the study participants’ serotonin, leading to feelings of depression. The mechanism is plausible, and for the exact way it might work, please read this article. Another theory is the “exorphin” theory. Small bits of partially digested gluten can have deleterious psychological effects in rodent studies, but I’ve never seen any compelling evidence for this theory in humans. Lastly, its possible the gluten affected the gut mircobiota in some way, causing depressed feelings. There is some evidence changes in the microbiota can affect mood, particularly anxiety, but in general, unless there is direct communication between the microbiota and the brain leading to depressed mood, an off-kilter microbiota is thought to induce depression by inducing stress and an inflammatory state, and we should be able to measure that. The exorphin theory could be tested by using an opiate-blocker called naloxone or naltrexone.

Certainly, more study is needed, and more examination of inflammatory state (not just cortisol) possibly induced by gluten must be tested. In the mean time, if you feel better in body or mind not eating gluten, by all means, don’t eat it. But keep in mind that FODMAPs might be an issue for you as well, and there are now some good resources online about how to do a low FODMAP test on yourself. A mostly whole foods, low grain diet will be low in FODMAPs as well with the exception of certain foods such as high-lactose dairy, artichokes, certain nuts, and sweeter fruits.

While some people believe FODMAP intolerance is a common genetic issue (specifically an inability of the upper part of the gut to absorb fructose efficiently), I’ve also spoken to folks who had changes in what they could tolerate after serious gastrointestinal infection, suggesting that FODMAP intolerance might also be related to the microbiota. Or both!

In short, while gluten may not be the end all evil of our modern times, highly processed foods may be. And don’t be embarrassed if you feel better on a gluten-free diet, even if it is accidentally a low FODMAP one.

Image credit: flikr creative commons

Copyright Emily Deans, MD

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