Gluten intolerance or gut dysbiosis? 

The role of the gut microbiome in celiac disease and non-celiac gluten sensitivity

BY LUCY MAILING, MD/PHD STUDENT

Disclosure: I went gluten-free in 2015 and found that it significantly improved my eczema and mental clarity. I have not yet formally attempted to reintroduce gluten, but no longer have the same issues that I used to when eating out in restaurants that may have gluten cross-contamination.

Are you gluten sensitive? Or is it really your gut microbes? Recent research suggests that a disrupted gut microbiome may play a key role in celiac disease and non-celiac gluten/wheat sensitivity, and that gut dysbiosis may be involved in the onset, progression, and refractory nature of these conditions. Read on to learn why wheat intolerance may be a sign of a larger problem, and how it might be resolved by treating the root cause.

As of 2014, more than 11 percent of U.S. households choose to eat gluten-free. Celiac disease now affects at least 3 million Americans, while non-celiac gluten/wheat sensitivity (NCG/WS) has been estimated to affect up to 18 million Americans.

If you’ve been following my work for a while, you probably know that I advocate removing wheat and other grains from the diet for a short period of time. While I don’t think that wheat necessarily needs to be avoided 100 percent of the time by everyone, I do think that everyone should do their due diligence to carefully assess whether wheat consumption is safe for them.

Obviously, those with celiac disease need to avoid gluten much more strictly, but even these individuals may be able to worry less about cross-contamination by taking positive steps to support ongoing remission. To determine what these steps are, we’ll first need to understand how celiac disease and NCG/WS develop in the first place.

In this article, I’ll discuss all of the nuances of celiac disease and NCG/WS, the role of genetics and environment, FODMAPs, leaky gut, and more. I’ll also identify the best probiotics for these conditions and provide a step-by-step protocol for assessing your personal wheat tolerance.

Celiac disease vs. wheat allergy vs. non-celiac gluten/wheat sensitivity

Before we dive into the research, it’s important to distinguish between three different wheat-related conditions:

Celiac disease (CD) is an autoimmune condition where gliadin, a protein found in gluten, triggers the gut immune system to produce antibodies that damage the small intestine and cause atrophy of the intestinal villi. The most common symptoms include weight loss, fatigue, joint pain, iron-deficiency anemia, skin rashes, abdominal pain, and seizures. CD is typically diagnosed by the presence of antibodies against transglutaminase 2 (TG2) and confirmed with a biopsy of the small intestine.

Wheat allergy (WA) is an allergy to one or more proteins in wheat that is typically mediated by IgE antibodies and may cause anaphylaxis, a severe allergic response requiring immediate medical treatment. True wheat allergy is quite rare and usually appears very early in life. I will discuss the role that the gut microbiome plays in the development of food allergies in a future article; but for the purposes of this article, I will not be discussing wheat allergy.

Non-celiac gluten/wheat sensitivity (NCG/WS) describes individuals who experience symptoms either in the gut or elsewhere in response to gluten or wheat consumption. Common symptoms include abdominal pain, bloating, altered bowel movements, fatigue, headache, brain fog, joint and muscle pain, eczema or other skin rashes, depression, and anemia. While these individuals lack the characteristics of true celiac disease or wheat allergy, their symptoms subside on a gluten-free diet. Scientists have struggled to properly diagnose NCG/WS because of the lack of common biomarkers.

The gut microbiome and oral tolerance to foods

The gut microbiome is critically important for the proper development of the immune system and tolerance to different foods. Altering the gut microbiota, particularly early in life, can increase susceptibility to chronic inflammatory conditions, food sensitivities, and autoimmune diseases.1,2 Let’s start by taking a look at celiac disease.

Celiac disease: beyond just genes and gluten

Many people think of CD as a genetic condition brought on by gluten exposure alone. However, genetics only explain about a third of the heritability of CD. For instance, the two haplotypes (HLA-DQ2 an HLA-DQ8) represent the primary genetic predispositions to CD. Yet, while these genes underlie almost every case of CD, only 2-5 percent of people who carry these genes will develop CD.

This suggests that environmental factors play a major role in the development of CD, a notion supported by a number of published studies:

  • Early-life antibiotic use and birth by Cesarean section both increase the risk of developing CD.3–5
  • Early-life antibiotic treatment has been shown to lead to an expansion of the phylum Proteobacteria and enhance the severity of responses to gluten in animal studies.6
  • Longer breastfeeding and the maintenance of breastfeeding when gluten is introduced may reduce the risk of delay the onset of CD.7

Several independent research groups have found that CD is associated with an altered gut microbiome8–11. Studies in infants have confirmed that this dysbiosis appears to precede the development of the disease. In a cohort study of human infants that were genetically at risk for CD, relative decreases in the abundance of Bifidobacterium and increases in Staphylococcus and Bacteroides fragilis in fecal samples early in life were associated with a higher risk of developing CD.12 More recent analyses have shown that high-risk HLA genes themselves may influence the composition of the gut microbiota.13 Infants with HLA-DQ2 haplotype showed an increase of Firmicutes and Proteobacteria and a decrease in Actinobacteria (including the genus Bifidobacterium).

The FUT2 gene is also associated with CD and influences gut microbial composition. Individuals who have two copies of a particular variant of the FUT2 gene fail to secrete certain compounds into the mucus layer of the gut. This results in altered mucus-associated microbes and reduced diversity, richness, and abundance of Bifidobacterium species.14–16

Gut permeability also plays a major role in CD. Dr. Alessio Fasano, an Italian researcher and gastroenterologist, has postulated that autoimmune diseases like CD are always preceded by leaky gut.17  In 2006, his laboratory found that gliadin, a component of gluten, can cause intestinal permeability by upregulating the signaling molecule zonulin. Zonulin then disrupts the tight junction proteins that link adjacent epithelial cells.18

Research in humans has confirmed that CD patients have leaky gut and further shown that most CD patients gut barrier function is restored after adhering to a gluten-free diet.19 However, other factors may also contribute to impaired gut barrier function, including certain medications, environmental toxins, chronic stress, hyperglycemia, and a highly refined diet.

In a later section, I’ll discuss how adding back some of these “missing microbes” might be beneficial for CD. For now, we’ll transition to a discussion of NCG/WS.

Shared symptoms between NCG/WS and IBS

Non-celiac gluten/wheat sensitivity has been a hot topic of debate over the last decade. Despite initial skepticism that NCG/WS existed, it has recently been recognized as an independent disorder of clinical relevance.20 While the overall prevalence of NCG/WS remains unknown, it has been estimated to range from 0.6 to 6 percent of the population.21

A group of experts that convened in 2014 in Salerno, Italy recommended that NCG/WS diagnosis should be made after a positive double-blind, placebo-controlled gluten challenge with crossover.20 This essentially means a test trial where neither doctor nor patient knows which treatment (gluten or placebo) he or she is receiving, followed by a second trial with the other treatment condition, and the assessment of symptoms after each trial with validated questionnaires. However, in clinical practice, the diagnosis of NCG/WS is typically based solely on exclusion of CD and wheat allergy, and self-reported improvement of symptoms after eliminating gluten and wheat from the diet.

Many of the symptoms of NCG/WS, including abdominal pain, bloating, and flatulence make it difficult to distinguish from irritable bowel syndrome (IBS), and at least two studies have found that IBS patients have improved symptoms control on a gluten-free diet.22,23 Indeed, there may quite a bit of overlap between NCG/WS and IBS, leading to questions about whether NCG/WS is an independent condition. I’ll discuss some of the research supporting this is the next few sections.

Is gluten the true culprit of NCG/WS?

FODMAPS, fructans, amylase trypsin inhibitors, and wheat germ agglutinin have all been suggested to be possible triggers for NCG/WS, leading to increasing doubt among the scientific and medical community that gluten is the true cause of symptoms in these individuals.

But what does the research really say? Let’s take a closer look at a few of these studies and the evidence for the gluten protein itself as the trigger for NCG/WS.

FODMAPs

FODMAPs are fermentable oligosaccharides, disaccharides, monosaccharides, and polyols. These carbohydrates tend to be rapidly fermentable in the gut and for many individuals, can cause bloating, gas, and other unpleasant GI symptoms. In recent years, these have been highlighted for their ability to trigger symptoms in NCG/WS patients.

In 2013, a group of Australian researchers recruited 37 subjects with NCG/WS and IBS for a randomized crossover study.24 The participants were placed on a two-week gluten-free, low-FODMAP diet before completing one week of a high-gluten (16 grams carbohydrate-depleted, isolated wheat gluten/day), low-gluten (2 grams gluten/day and 14 grams low-FODMAP whey protein/day), or placebo (16 grams whey protein/day) diet, followed by a washout period of at least 2 weeks. The researchers summarized their findings:

“In all participants, gastrointestinal symptoms consistently and significantly improved during reduced FODMAP intake, but significantly worsened to a similar degree when their diets included gluten or whey protein.” 24

In 2018, a group of Norwegian researchers published a randomized crossover study of 59 individuals on a self-instituted gluten-free diet for at least 6 months.25 Participants were assigned to one of three 7-day challenges with gluten (5.7 grams carbohydrate-free wheat gluten), the FODMAP fructan (2.1 grams fructo-oligosaccharides), or placebo (nothing added) given in a muesli bar, followed by a minimum one-week washout period (or until symptoms resolved).

The researchers assessed the participants’ self-reported symptoms using a detailed GI symptom and IBS questionnaire. They found that the average IBS score and bloating score for participants consuming fructans was significantly higher than participants consuming gluten. However, 13 participants had the highest IBS score after consuming gluten, 24 had the highest after consuming fructan, and 22 had the highest score after consuming the placebo.

This suggests that some individuals with self-diagnosed NCG/WS may be reacting to gluten itself, while others may be reacting to the FODMAPS in wheat. Still others may react to other wheat components. In other words, while some individuals will benefit from a low FODMAP diet, some may additionally benefit from removing both gluten and dairy proteins. A 2017 review summarized this well:

“In our opinion, rather than triggers, FODMAPs should be considered as possible additional elements of disturbance.” 26

Amylase trypsin inhibitors

Some researchers have suggested that wheat amylase trypsin inhibitors (ATIs) could also play a role in gluten-related disorders. ATIs are proteins in plants that support the natural defense against predators and pests. They may also regulate starch metabolism during seed formation and germination.

ATIs are strong activators of several different types of immune cells, including dendritic cells, macrophages, and monocytes, stimulating the classical NF-kB inflammatory pathway and the release of pro-inflammatory cytokines.27 Gluten-containing staples like bread and pastries have as much as 100-fold higher levels of innate immune system-activating ATIs than most gluten-free foods. Interestingly, older wheat variants, like Emmer or Einkorn wheat, have much lower ATI activity than modern wheat varieties.28

Currently, there are no studies that have assessed the effects of ATIs in humans. However, a group of German researchers fed mice ATIs isolated from wheat and found that it increased the release of inflammatory molecules in the small and large intestine and activated immune cells in the gut and mesenteric lymph nodes.28

Wheat germ agglutinin

Another potential culprit for adverse reactions to wheat is a lectin called wheat germ agglutinin (WGA). Lectins are proteins found in a wide variety of plants and are widely recognized as anti-nutrients; they can bind to virtually all cell types and, in large enough quantities, potentially cause damage to organs. Even very small concentrations of WGA have been shown to impair the integrity of the intestinal barrier29, and several uptake mechanisms allow transport of this lectin into the periphery where it can potentially damage other cells.

Feeding large amounts of WGA to mice has been shown to cause abnormal growth of the small intestine and pancreas and atrophy of the thymus, an important immune organ.30 In cell culture studies, WGA also stimulates histamine secretion and degranulation of mast cells, and the release of inflammatory cytokines from several different types of immune cells.31 Unfortunately, no studies have assessed the effects of WGA ingestion in humans; however, antibodies to WGA have been detected in the blood of healthy individuals, suggesting that their ingestion provokes a systemic immune response.32

Gluten

While all of these studies point to NCG/WS as a broad condition with many potential triggers, at least one double-blind, placebo-controlled trial has found a significant effect of the gluten on symptoms in NCG/WS patients.33 A total of 34 participants with IBS who were on a gluten-free diet received either carbohydrate-depleted wheat gluten (16g/day) or placebo (nothing) in the form of bread or muffins. Of patients in the gluten group, 13 out of 19 (68%) reported that symptoms were not adequately controlled, compared to 6 of 15 (40%) of patients in the placebo group. Patients in the gluten group had significantly worse pain, bloating, satisfaction with stool consistency, and fatigue. The authors concluded:

“gluten is indeed a trigger of gut symptoms and tiredness. […] Non-celiac gluten intolerance may exist, but no clues to the mechanism were elucidated.” 33

Other wheat proteins

While gluten receives the most attention, other proteins in wheat may be just as problematic. Wheat can be broken down into hundreds of different compounds, many of which can cause inflammatory immune responses. These include beta-, gamma-, and omega-gliadin, deamidated gliadin, glutenin, gluteomorphin, and prodynorphin.

Research by Lambert et al. have shown that patients with antibodies against these proteins in wheat often have cross-reactivity with tissues – in other words, these antibodies can cause autoimmune damage to the body. If these patients are not properly tested, told that they don’t have CD and that they can eat gluten in moderation, they may do irreversible damage to organs and put themselves at risk for a whole host of very serious autoimmune diseases. More on that later.

All of the above

The reality is that all of these compounds could potentially contribute to NCG/WS. This does not mean that NCG/WS doesn’t exist; rather, it suggests that NCG/WS has several potential etiologies and therefore requires individualized diagnosis and treatment. For instance, one individual may only be reacting to fructans and would do best on a diet that limits (but does not necessarily eliminate) all FODMAPs, including wheat. Another individual might be reacting to ATIs and could safely consume Emmer or Einkorn wheat, but not modern wheat varieties. Yet another individual might have antibodies to gliadin or other gluten proteins and a genetic predisposition to autoimmune disease. This individual would want to avoid wheat completely.

Later, I’ll discuss how to assess your personal response to wheat and help determine which of these factors might most contribute to symptoms. First, though, we’ll discuss a few mechanisms that might explain why someone is reacting to these various compounds in wheat.

Could gluten sensitivity be gut dysbiosis?

In a review published in 2017, Leccioli et al. pieced together recent evidence into a new proposed mechanism for the development of NCG/WS. They hypothesize that the root cause of NCG/WS is gut dysbiosis, particularly characterized by reduced numbers of Firmicutes and Bifidobacterium, leading to low levels of butyrate in the gut and increased intestinal permeability.

The Firmicutes phylum includes many known butyrate-producing microbes, including Faecalibacterium prausnitzii, Eubacterium rectale, and Roseburia. These microbes are typically detected in healthy adult fecal samples at about 2-15 percent relative abundance compared to total bacteria, but are likely even more prevalent in the gut mucus layer.34

Bifidobacterium, a genus belonging to the phylum Actinobacteria, contribute to gut butyrate production by producing acetate and lactate. Butyrate-producing Firmicutes then convert these molecules to butyrate by cross-feeding interactions. (It’s important to note, however, that many non-Western populations do not appear to have significant amounts of Bifidobacterium, yet produce plenty of butyrate.35)

Unfortunately, few studies have assessed the fecal microbiota of NCG/WS patients, but low levels of butyrate-producing Firmicutes and Bifidobacterium are found in IBS and are negatively associated with IBS symptoms.36,37

If the researchers’ hypothesis is true and NCG/WS is caused by low levels of these microbes, this suggests that NCG/WS is transient and treatable, related to the overall quality of the diet and health of the gut microbiome. In other words, if you’re currently sensitive to wheat but improve the health of your gut, you may be able to tolerate wheat in the future.

Is glyphosate killing off our native microbes and inhibiting digestion of wheat?

Glyphosate is the active ingredient in the popular herbicide Roundup, and its usage on wheat in the United States has risen sharply in the last decade. Several animal studies have increased our understanding of the potential effects of glyphosate on the gut microbiome. Unfortunately, opportunistic pathogens like Salmonella appear to be highly resistant to glyphosate, whereas Bifidobacterium, Lactobacillus, and Enterococcus species seem to be especially susceptible.38 This may be particularly true in cases of insufficient protein intake.39

Glyphosate may also reduce the activity of protease, lipase, and amylase, enzymes responsible for the digestion of protein, fats, and carbohydrates, and disrupt the structure of microvilli. This may also impact the immune response:

“Glyphosate may interfere with the breakdown of complex proteins in the human stomach, leaving larger fragments of wheat in the human gut that will then trigger an autoimmune response.” 40

In this way, glyphosate may act as an adjuvant, making gut immune cells hyper-reactive to gluten, ATIs, or other wheat compounds I mentioned previously. This hyperactivity may be particularly pronounced if the gut is already in a state of increased permeability.

Many people with NCG/WS have leaky gut and autoimmunity

A recent study performed by Uhde et al. provided some additional insight relative to NCG/WS.41 They found that individuals with NCG/WS had:

  • Increased LPS-binding protein and soluble CD14 in the blood
  • Enhanced antibody reactivity to bacterial components LPS and flagellin
  • Increased levels of serum FABP2

In other words, NCG/WS patients had widespread inflammation and leaky gut:

 “The results demonstrate the presence of objective markers of systemic immune activation and gut epithelial cell damage in individuals who report sensitivity to wheat in the absence of coeliac disease.” 41

Moreover, these markers decreased dramatically after a six-month period of strict gluten avoidance. This was not the first study to identify the presence of leaky gut in NCG/WS patients. In 2015, Hollon et al. demonstrated that intestinal biopsies from patients with active CD or NCG/WS had a greater increase in intestinal permeability in response to gliadin than healthy controls or CD patients in remission.42

Other studies have found that high proportions of people with NCG/WS have autoimmune disease or antinuclear antibodies (ANA, antibodies against their own cells). In a large retrospective study of patients with NCG/WS, 46 percent of patients had elevated ANA and 29 percent went on to develop autoimmune disease during the ten year follow-up period.43

Unfortunately, because of current confusion and misunderstanding surrounding NCG/WS, many doctors fail to test NCG/WS patients for the presence of these antibodies. Some may even mistakenly suggest that these patients are okay eating wheat in moderation, leading to potentially irreversible organ damage.

In a later section, I’ll describe the best commercially available tests for these antibodies, to determine whether you should be concerned about potential autoimmunity. First, I want to briefly discuss the research we have on gluten-free diets and the composition of the gut microbiota.

Gluten intake modestly affects the gut microbiome and host immunity

Few studies have assessed how gluten consumption itself changes the gut microbiome. One 2009 study found that in healthy subjects, a gluten-free diet was associated with lower Bifidobacterium and Lactobacillus spp. and higher amounts of Enterobacteriaceae and E. coli.44 However, the study only included ten participants, and the gluten-free diet significantly reduced intake of polysaccharides. This decrease in fiber intake is a common occurrence among those who switch directly from processed gluten-containing bread, pastries, and sweets to processed gluten-free alternatives (as opposed to adopting a whole foods diet) but is still a significant confounding variable in this study.

Notably, the gluten-free diet also reduced cytokine production by cultured blood immune cells when exposed to fecal samples. In particular, the gluten-free diet reduced production of pro-inflammatory cytokines TNFα, IFNγ, and IL-8:

“Thus, a GFD could contribute to reduce the pro-inflammatory signals in the gut by introducing modifications in the microbiota structure.”

Another study published in 2018 compared sixty Danish adults that underwent eight weeks on a low-gluten diet and eight weeks on a high-gluten diet.45 The low-gluten diet altered the fecal microbiome, reducing relative abundance of Bifidobacterium, two species of Dorea, one species of Blautia, two species of Lachnospiraceae, and two butyrate-producing bacteria Anerostipes hadrus and Eubacterium hallii. However, the low-gluten diet also increased the relative abundance of Clostridiales and an unclassified species of Lachnospiraceae, two butyrate-producing taxa. There were no changes in microbial diversity or fecal short-chain fatty acid production.

Notably, total energy, polysaccharide, and FODMAP intake did not change between the two different dietary conditions. Most interestingly, the low-gluten diet reduced breath hydrogen after a meal and self-reported bloating, even though these individuals did not have any diagnosed digestive issues! It also significantly increased production of the satiety hormone PYY and resulted in weight loss, which was attributed to enhanced generation of heat (thermogenesis).

There were no major changes in inflammatory markers, though serum IL-1β, a molecule involved in the inflammatory response, was reduced on the low-gluten diet. Overall, more studies are needed to understand how different gluten-free diets might impact the fecal microbiome and immune system, and how other therapies might improve tolerance to gluten. Study of mucus-associated microbes and those that reside in the small intestine may also provide key insights, as we’ll see in the next section.

High prevalence of SIBO and gut pathologies in CD and NCG/WS

Up to a third of CD patients continue to experience symptoms after adopting a gluten-free diet. While many of these cases are due to accidental gluten contamination, studies suggest that some ongoing symptoms may be due to small intestinal bacterial overgrowth (SIBO) or other gut pathologies.

The small intestine is the primary site of nutrient absorption and normally contains relatively few microbes, while the large intestine, or colon, contains a dense microbial ecosystem. SIBO is characterized by abnormally large numbers of microbes in the small intestine and/or the presence of microbes normally found in the large intestine in the small intestine. These microbes can ferment food in the small intestine, producing unpleasant GI symptoms like bloating, abdominal pain, and gas.

In 2003, a group of Italian researchers studied 15 CD patients who continued to experience GI symptoms after at least 6-8 months of consuming a gluten-free diet.46 Intestinal biopsies revealed that the gut tissue had healed, and no longer had the characteristic atrophy of CD, suggesting that they did not have a reoccurrence of active disease. Of the 15 patients, 10 tested positive for SIBO by breath test, two had lactose intolerance, and two had parasitic infections (one had an accidental gluten exposure and was not treated). After being treated for these conditions, all of the patients were symptom-free.

However, the true prevalence of SIBO in non-responsive CD is widely debated and may actually be much lower. While breath testing is the easiest non-invasive way to assess SIBO in clinical practice, it may result in over-diagnosis. A study in 2009 used the gold standard for assessing the presence of SIBO, quantitative culture of intestinal aspirate, and estimated that only 11 percent of patients with non-responsive CD have SIBO.47

To my knowledge, only one study has assessed the prevalence of SIBO in patients with NCG/WS. Of the 84 patients, 16 (19%) were positive for SIBO by breath test, five had fructose intolerance, and three had lactose intolerance.48 Overall, this suggests that doctors should be screening for other gut pathologies in cases of refractory CD or ongoing NCG/WS.

Could probiotics improve gluten tolerance?

Probiotics may also have the potential to make wheat less allergenic or mitigate the effects of gluten in sensitive individuals. Certain strains of Bifidobacterium longum (NCC2705 and CECT 7347), Bifidobacterium animalis (subspecies lactis), and Lactobacillus rhamnosus (GG) have been found to attenuate the damaging effects of gliadin on the gut mucosa in cell culture and animal studies.49–52

In a randomized, placebo-controlled trial of children with newly diagnosed CD, Bifidobacterium longum CECT 7347 supplementation for three months improved growth parameters, reduced abundance of the potentially pro-inflammatory species Bacteroides fragilis, and reduced fecal secretory IgA, suggesting that the gut immune system was no longer on “high alert”.

Another study in children with CD on a gluten-free diet found that three months of supplementation with Bifidobacterium breve (BR03 and B632) significantly reduced circulating TNFα, a marker of systemic inflammation. Three months after stopping probiotic supplementation, TNFα levels were again elevated.53

In 2013, Smecuol et al. found that Bifidobacterium infantis (NLS strain) alleviated some of the symptoms of untreated CD in adults, including indigestion, constipation, and reflux, but was not able to significantly alleviate intestinal permeability.54

Overall, these studies suggest that there is great potential for probiotic supplementation to mitigate the damage caused by gluten and improve overall health in gluten-sensitive individuals. In the summary and takeaways section, I’ll provide my top four probiotics for gluten intolerance.

Soaking, sprouting, and fermenting wheat

For centuries, traditional cultures had the wisdom to prepare wheat and other grains to make them more digestible and more nutritious. The most common approach includes soaking, grinding, removing most of the bran, fermenting, and cooking. Modern nutritional science has confirmed that this process indeed improves the digestibility and nutrient value of grains, reducing the level of toxins and anti-nutrients, including lectins, phytates, and many of the most immunogenic proteins.

For example, a series of experiments by a group of Italian researchers found that the fermentation of wheat flour with the probiotic VSL#3 for 24 hours resulted in almost complete degradation of several immunogenic proteins in wheat.55 The release of zonulin from cultured intestinal epithelial cells treated with this pre-digested wheat was considerably lower than epithelial cells treated with un-treated wheat flour, and the agglutinating ability of the wheat was lost. Moreover, CD biopsies exposed to the VSL#3-digested wheat did not show an inflammatory response. VSL#3 also partially, but not completely, attenuated gliadin-induced intestinal permeability in mice.

This suggests that long-time fermented wheat products, such as authentic sourdough bread, are best if you plan to consume wheat regularly. Note that most bread marketed as sourdough is not actually authentically fermented, so be sure to look for sourdoughs that do not contain yeast, and that allow the dough to rise naturally for at least 4-6 hours before baking.

Summary and takeaways

I know I covered a lot in this article, so here’s a brief summary of the most important points and takeaways:

Gut dysbiosis likely plays a significant role in the development of celiac disease and non-celiac gluten sensitivity. Decreases in the abundance of Bifidobacterium, increases in Bacteroides fragilis are associated with CD, while low levels of Bifidobacterium and butyrate-producing Firmicutes may contribute to NCG/WS.

Removing gluten from the diet is usually necessary, but not sufficient to restore gut health. Going gluten-free will quiet the immune response and reduce symptoms, but it does not correct the underlying gut dysbiosis or leaky gut, especially if you simply switch to a diet of processed gluten-free foods. Those with CD or NCG/WS should be screened for additional gut pathologies, such as SIBO and parasitic infections.

NCG/WS should be accepted as a real condition and viewed as a collective group of signs and symptoms with many potential triggers. Some NCG/WS patients may react to lectins, ATIs, or FODMAPs in wheat, while others may react directly to wheat-related peptides. This does not mean that NCG/WS doesn’t exist!

Many patients with NCG/WS have autoimmunity and may do long-term damage by continuing to eat wheat. The antibodies that our immune system produces against wheat can often cross-react with our own body tissues, causing potentially irreversible organ damage.

NCG/WS may be reversible. Improving gut health by increasing levels of beneficial microbes, supporting a strong gut barrier, and regulating the gut immune system may allow some people that did not previously tolerate wheat to tolerate it in future.

Probiotics may help improve gluten tolerance and reduce inflammation. While I do not advocate that anyone with CD eat wheat, probiotic supplementation may prevent the detrimental effects of gluten cross-contamination in restaurants or accidental gluten exposure. Probiotics can also reduce inflammation and help address the underlying causes of gluten intolerance and autoimmunity in both CD and NCG/WS.

The top four evidence-based, commercially-available probiotics I have been able to identify for those with CD or NCG/WS are:

  • Bifibaby (Bifidobacterium Breve BR03 and B632) – reduced inflammation in children with CD
  • Natren LifeStart (Bifidobacterium infantis NLS strain, available in several forms, some of which contain dairy) – alleviated CD symptoms in adults
  • Visbiome (previously known as VSL#3*) – breaks down immunogenic gluten proteins
  • Enterogermina (Bacillus clausii OC, NR, SIN, and T) – enhances SIBO clearance and reduces functional abdominal pain

*IMPORTANT NOTE: VSL#3, as studied in clinical trials, is now manufactured by Visbiome. Other products that are marketed as VSL#3 are likely fake. 

How to evaluate your own wheat tolerance

If you do not have celiac disease and want to continue to consume wheat on occasion, I highly recommend a comprehensive evaluation of wheat tolerance. This includes:

  • A 2-week low-FODMAP, gluten-free diet followed by a blinded gluten (wheat gluten), fructan (FOS), or placebo (rice flour) challenge. This is particularly useful for those who have IBS or who primarily experience bloating and GI discomfort after wheat consumption. Enlist a family member or friend to randomly provide one of these three powders at a meal or baked into a food. Record any symptoms you experience or ideally use a validated GI symptom questionnaire. Go back to the baseline diet for at least three days or until symptoms subside; then try the next challenge agent.
  • A 60-day strict elimination of gluten, wheat, barley, and rye, followed by staged reintroduction, starting with sourdough and ancient varieties, and finally modern wheat. This will allow you to assess your own subjective improvement on a gluten-free diet and any symptomatic changes upon reintroduction. This is most accurate when also removing other immunogenic foods, such as dairy, soy, corn, and other grains.
  • A Cyrex Array 3 gluten sensitivity panel. This tests for IgG and IgA immune reactivity to gluten, gliadin, glutenin, gluteomorphin, and other related peptides. It also screens for antibodies to transglutaminase 2, a marker of celiac disease, and other transglutaminase enzymes. The Cyrex Array 14 mucosal immunology panel also tests for many wheat-related antibodies, in addition to antibodies against dairy, corn, soy, heavy metals, aflatoxin, and rotavirus. Note: you need to have consumed wheat recently for the results to be accurate, so it often makes sense to do this the week after wheat reintroduction.

Interpreting the results:

  • If you have NCG/WS due to FODMAP intolerance, you can likely consume wheat safely in small amounts, but should identify and treat underlying gut pathologies such as SIBO and gut dysbiosis. After these have been addressed, you may be able to tolerate wheat and other FODMAPs in larger quantities.
  • If you have NCG/WS due to antibodies against wheat proteins or transglutaminase enzymes, wheat and gluten should be strictly avoided in the short term to prevent the possibility of irreversible autoimmune damage to organs. Antibodies to cross-reactive foods should also be assessed. However, improving the health of the gut microbiome and gut barrier may reduce antibody responses and allow for the safe consumption of gluten months or years later. Repeat antibody testing should be performed before including wheat in the diet on a regular basis.
  • If you have celiac disease (elevated anti-TG2 and confirmed biopsy), gluten and wheat should be avoided for life. While there is some intriguing evidence suggesting that Lactobacillus and Bifidobacterium supplementation can improve tolerance to small amounts of gluten, the detrimental effects of gluten consumption in individuals with celiac are not worth experimenting with.
  • If you have no issues with FODMAPs, no antibodies against wheat proteins or transglutaminase, and no symptomatic changes after reintroduction of wheat, you can feel comfortable including wheat in your diet. Note that wheat contains anti-nutrients that can impair mineral absorption and can still cause transient intestinal permeability, so it should be seen as more of a condiment, rather than a dietary staple. When possible, choose ancient varieties of wheat or traditionally sprouted or fermented preparations like authentic sourdough, which are less likely to cause permeability and impair mineral absorption.

That’s all for now! Let me know what you thought in the comments and be sure to share your experience if you try this gluten challenge. I am currently performing my own gluten challenge and will be reporting back with my own results in a few weeks!

Sources:

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  4. Canova, C. et al. Association of maternal education, early infections, and antibiotic use with celiac disease: a population-based birth cohort study in northeastern Italy. Am. J. Epidemiol. 180, 76–85 (2014).
  5. Mårild, K., Stephansson, O., Montgomery, S., Murray, J. A. & Ludvigsson, J. F. Pregnancy outcome and risk of celiac disease in offspring: a nationwide case-control study. Gastroenterology 142, 39-45.e3 (2012).
  6. Galipeau, H. J. et al. Intestinal Microbiota Modulates Gluten-Induced Immunopathology in Humanized Mice. Am J Pathol 185, 2969–2982 (2015).
  7. Akobeng, A. K., Ramanan, A. V., Buchan, I. & Heller, R. F. Effect of breast feeding on risk of coeliac disease: a systematic review and meta-analysis of observational studies. Arch. Dis. Child. 91, 39–43 (2006).
  8. Nistal, E. et al. Differences in faecal bacteria populations and faecal bacteria metabolism in healthy adults and celiac disease patients. Biochimie 94, 1724–1729 (2012).
  9. Di Cagno, R. et al. Duodenal and faecal microbiota of celiac children: molecular, phenotype and metabolome characterization. BMC Microbiol. 11, 219 (2011).
  10. Collado, M. C., Donat, E., Ribes-Koninckx, C., Calabuig, M. & Sanz, Y. Imbalances in faecal and duodenal Bifidobacterium species composition in active and non-active coeliac disease. BMC Microbiol. 8, 232 (2008).
  11. Collado, M. C., Donat, E., Ribes-Koninckx, C., Calabuig, M. & Sanz, Y. Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease. J. Clin. Pathol. 62, 264–269 (2009).
  12. Palma, G. D. et al. Influence of milk-feeding type and genetic risk of developing coeliac disease on intestinal microbiota of infants: the PROFICEL study. PLoS ONE 7, e30791 (2012).
  13. Olivares, M. et al. The HLA-DQ2 genotype selects for early intestinal microbiota composition in infants at high risk of developing coeliac disease. Gut 64, 406–417 (2015).
  14. Wacklin, P. et al. Faecal microbiota composition in adults is associated with the FUT2 gene determining the secretor status. PLoS ONE 9, e94863 (2014).
  15. Wacklin, P. et al. Secretor genotype (FUT2 gene) is strongly associated with the composition of Bifidobacteria in the human intestine. PLoS ONE 6, e20113 (2011).
  16. Rausch, P. et al. Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype. Proc. Natl. Acad. Sci. U.S.A. 108, 19030–19035 (2011).
  17. Fasano, A. Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol 42, 71–78 (2012).
  18. Drago, S. et al. Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scandinavian Journal of Gastroenterology 41, 408–419 (2006).
  19. Duerksen, D. R., Wilhelm-Boyles, C. & Parry, D. M. Intestinal Permeability in Long-Term Follow-up of Patients with Celiac Disease on a Gluten-Free Diet. Dig Dis Sci 50, 785 (2005).
  20. Catassi, C. et al. Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts’ Criteria. Nutrients 7, 4966–4977 (2015).
  21. Volta, U., Caio, G., Karunaratne, T. B., Alaedini, A. & De Giorgio, R. Non-coeliac gluten/wheat sensitivity: advances in knowledge and relevant questions. Expert Rev Gastroenterol Hepatol 11, 9–18 (2017).
  22. Vazquez–Roque, M. I. et al. A Controlled Trial of Gluten-Free Diet in Patients With Irritable Bowel Syndrome-Diarrhea: Effects on Bowel Frequency and Intestinal Function. Gastroenterology 144, 903-911.e3 (2013).
  23. Shahbazkhani, B. et al. Non-Celiac Gluten Sensitivity Has Narrowed the Spectrum of Irritable Bowel Syndrome: A Double-Blind Randomized Placebo-Controlled Trial. Nutrients 7, 4542–4554 (2015).
  24. Biesiekierski, J. R. et al. No Effects of Gluten in Patients With Self-Reported Non-Celiac Gluten Sensitivity After Dietary Reduction of Fermentable, Poorly Absorbed, Short-Chain Carbohydrates. Gastroenterology 145, 320-328.e3 (2013).
  25. Skodje, G. I. et al. Fructan, Rather Than Gluten, Induces Symptoms in Patients With Self-Reported Non-Celiac Gluten Sensitivity. Gastroenterology 154, 529-539.e2 (2018).
  26. Leccioli, V., Oliveri, M., Romeo, M., Berretta, M. & Rossi, P. A New Proposal for the Pathogenic Mechanism of Non-Coeliac/Non-Allergic Gluten/Wheat Sensitivity: Piecing Together the Puzzle of Recent Scientific Evidence. Nutrients 9, (2017).
  27. Junker, Y. et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J. Exp. Med. 209, 2395–2408 (2012).
  28. Zevallos, V. F. et al. Nutritional Wheat Amylase-Trypsin Inhibitors Promote Intestinal Inflammation via Activation of Myeloid Cells. Gastroenterology 152, 1100-1113.e12 (2017).
  29. Dalla Pellegrina, C. et al. Effects of wheat germ agglutinin on human gastrointestinal epithelium: insights from an experimental model of immune/epithelial cell interaction. Toxicol. Appl. Pharmacol. 237, 146–153 (2009).
  30. Pusztai, A. et al. Antinutritive effects of wheat-germ agglutinin and other N-acetylglucosamine-specific lectins. Br. J. Nutr. 70, 313–321 (1993).
  31. Lansman, J. B. & Cochrane, D. E. Wheat germ agglutinin stimulates exocytotic histamine secretion from rat mast cells in the absence of extracellular calcium. Biochemical Pharmacology 29, 455–458 (1980).
  32. Tchernychev, B. & Wilchek, M. Natural human antibodies to dietary lectins. FEBS Letters 397, 139–142 (1996).
  33. Biesiekierski, J. R. et al. Gluten Causes Gastrointestinal Symptoms in Subjects Without Celiac Disease: A Double-Blind Randomized Placebo-Controlled Trial. The American Journal of Gastroenterology 106, 508–514 (2011).
  34. Van den Abbeele, P. et al. Butyrate-producing Clostridium cluster XIVa species specifically colonize mucins in an in vitro gut model. ISME J 7, 949–961 (2013).
  35. Schnorr, S. L. et al. Gut microbiome of the Hadza hunter-gatherers. Nature Communications 5, 3654 (2014).
  36. Rajilić-Stojanović, M. et al. Intestinal microbiota and diet in IBS: causes, consequences, or epiphenomena? Am. J. Gastroenterol. 110, 278–287 (2015).
  37. Chassard, C. et al. Functional dysbiosis within the gut microbiota of patients with constipated-irritable bowel syndrome. Aliment. Pharmacol. Ther. 35, 828–838 (2012).
  38. Shehata, A. A., Schrödl, W., Aldin, A. A., Hafez, H. M. & Krüger, M. The effect of glyphosate on potential pathogens and beneficial members of poultry microbiota in vitro. Curr. Microbiol. 66, 350–358 (2013).
  39. Nielsen, L. N. et al. Glyphosate has limited short-term effects on commensal bacterial community composition in the gut environment due to sufficient aromatic amino acid levels. Environmental Pollution 233, 364–376 (2018).
  40. Samsel, A. & Seneff, S. Glyphosate, pathways to modern diseases II: Celiac sprue and gluten intolerance. Interdisciplinary Toxicology 6, 159–184 (2013).
  41. Uhde, M. et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut 65, 1930–1937 (2016).
  42. Hollon, J. et al. Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity. Nutrients 7, 1565–1576 (2015).
  43. Carroccio, A. et al. High Proportions of People With Nonceliac Wheat Sensitivity Have Autoimmune Disease or Antinuclear Antibodies. Gastroenterology 149, 596-603.e1 (2015).
  44. De Palma, G., Nadal, I., Collado, M. C. & Sanz, Y. Effects of a gluten-free diet on gut microbiota and immune function in healthy adult human subjects. Br. J. Nutr. 102, 1154–1160 (2009).
  45. Hansen, L. B. S. et al. A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults. Nature Communications 9, 4630 (2018).
  46. Tursi, A., Brandimarte, G. & Giorgetti, G. High Prevalence of Small Intestinal Bacterial Overgrowth in Celiac Patients With Persistence of Gastrointestinal Symptoms After Gluten Withdrawal. The American Journal of Gastroenterology 98, 839–843 (2003).
  47. Rubio-Tapia, A., Barton, S. H., Rosenblatt, J. E. & Murray, J. A. Prevalence of Small Intestine Bacterial Overgrowth Diagnosed by Quantitative Culture of Intestinal Aspirate in Celiac Disease. J Clin Gastroenterol 43, 157–161 (2009).
  48. Tavakkoli, A., Lewis, S. K., Tennyson, C. A., Lebwohl, B. & Green, P. H. R. Characteristics of patients who avoid wheat and/or gluten in the absence of Celiac disease. Dig. Dis. Sci. 59, 1255–1261 (2014).
  49. McCarville, J. L. et al. A Commensal Bifidobacterium longum Strain Prevents Gluten-Related Immunopathology in Mice through Expression of a Serine Protease Inhibitor. Appl Environ Microbiol 83, (2017).
  50. Laparra, J. M., Olivares, M., Gallina, O. & Sanz, Y. Bifidobacterium longum CECT 7347 modulates immune responses in a gliadin-induced enteropathy animal model. PLoS ONE 7, e30744 (2012).
  51. Lindfors, K. et al. Live probiotic Bifidobacterium lactis bacteria inhibit the toxic effects induced by wheat gliadin in epithelial cell culture. Clinical & Experimental Immunology 152, 552–558 (2008).
  52. Orlando, A., Linsalata, M., Notarnicola, M., Tutino, V. & Russo, F. Lactobacillus GG restoration of the gliadin induced epithelial barrier disruption: the role of cellular polyamines. BMC Microbiology 14, 19 (2014).
  53. Klemenak, M., Dolinšek, J., Langerholc, T., Di Gioia, D. & Mičetić-Turk, D. Administration of Bifidobacterium breve Decreases the Production of TNF-α in Children with Celiac Disease. Dig. Dis. Sci. 60, 3386–3392 (2015).
  54. Smecuol, E. et al. Exploratory, randomized, double-blind, placebo-controlled study on the effects of Bifidobacterium infantis natren life start strain super strain in active celiac disease. J. Clin. Gastroenterol. 47, 139–147 (2013).
  55. Angelis, M. D. et al. VSL#3 probiotic preparation has the capacity to hydrolyze gliadin polypeptides responsible for Celiac Sprue probiotics and gluten intolerance. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 1762, 80–93 (2006).

Gluten intolerance or gut dysbiosis? 

The role of the gut microbiome in celiac disease and non-celiac gluten sensitivity

BY LUCY MAILING, MD/PHD STUDENT

Disclosure: I went gluten-free in 2015 and found that it significantly improved my eczema and mental clarity. I have not yet formally attempted to reintroduce gluten, but no longer have the same issues that I used to when eating out in restaurants that may have gluten cross-contamination.

Are you gluten sensitive? Or is it really your gut microbes? Recent research suggests that a disrupted gut microbiome may play a key role in celiac disease and non-celiac gluten/wheat sensitivity, and that gut dysbiosis may be involved in the onset, progression, and refractory nature of these conditions. Read on to learn why wheat intolerance may be a sign of a larger problem, and how it might be resolved by treating the root cause.

As of 2014, more than 11 percent of U.S. households choose to eat gluten-free. Celiac disease now affects at least 3 million Americans, while non-celiac gluten/wheat sensitivity (NCG/WS) has been estimated to affect up to 18 million Americans.

If you’ve been following my work for a while, you probably know that I advocate removing wheat and other grains from the diet for a short period of time. While I don’t think that wheat necessarily needs to be avoided 100 percent of the time by everyone, I do think that everyone should do their due diligence to carefully assess whether wheat consumption is safe for them.

Obviously, those with celiac disease need to avoid gluten much more strictly, but even these individuals may be able to worry less about cross-contamination by taking positive steps to support ongoing remission. To determine what these steps are, we’ll first need to understand how celiac disease and NCG/WS develop in the first place.

In this article, I’ll discuss all of the nuances of celiac disease and NCG/WS, the role of genetics and environment, FODMAPs, leaky gut, and more. I’ll also identify the best probiotics for these conditions and provide a step-by-step protocol for assessing your personal wheat tolerance.

Celiac disease vs. wheat allergy vs. non-celiac gluten/wheat sensitivity

Before we dive into the research, it’s important to distinguish between three different wheat-related conditions:

Celiac disease (CD) is an autoimmune condition where gliadin, a protein found in gluten, triggers the gut immune system to produce antibodies that damage the small intestine and cause atrophy of the intestinal villi. The most common symptoms include weight loss, fatigue, joint pain, iron-deficiency anemia, skin rashes, abdominal pain, and seizures. CD is typically diagnosed by the presence of antibodies against transglutaminase 2 (TG2) and confirmed with a biopsy of the small intestine.

Wheat allergy (WA) is an allergy to one or more proteins in wheat that is typically mediated by IgE antibodies and may cause anaphylaxis, a severe allergic response requiring immediate medical treatment. True wheat allergy is quite rare and usually appears very early in life. I will discuss the role that the gut microbiome plays in the development of food allergies in a future article; but for the purposes of this article, I will not be discussing wheat allergy.

Non-celiac gluten/wheat sensitivity (NCG/WS) describes individuals who experience symptoms either in the gut or elsewhere in response to gluten or wheat consumption. Common symptoms include abdominal pain, bloating, altered bowel movements, fatigue, headache, brain fog, joint and muscle pain, eczema or other skin rashes, depression, and anemia. While these individuals lack the characteristics of true celiac disease or wheat allergy, their symptoms subside on a gluten-free diet. Scientists have struggled to properly diagnose NCG/WS because of the lack of common biomarkers.

The gut microbiome and oral tolerance to foods

The gut microbiome is critically important for the proper development of the immune system and tolerance to different foods. Altering the gut microbiota, particularly early in life, can increase susceptibility to chronic inflammatory conditions, food sensitivities, and autoimmune diseases.1,2 Let’s start by taking a look at celiac disease.

Celiac disease: beyond just genes and gluten

Many people think of CD as a genetic condition brought on by gluten exposure alone. However, genetics only explain about a third of the heritability of CD. For instance, the two haplotypes (HLA-DQ2 an HLA-DQ8) represent the primary genetic predispositions to CD. Yet, while these genes underlie almost every case of CD, only 2-5 percent of people who carry these genes will develop CD.

This suggests that environmental factors play a major role in the development of CD, a notion supported by a number of published studies:

  • Early-life antibiotic use and birth by Cesarean section both increase the risk of developing CD.3–5
  • Early-life antibiotic treatment has been shown to lead to an expansion of the phylum Proteobacteria and enhance the severity of responses to gluten in animal studies.6
  • Longer breastfeeding and the maintenance of breastfeeding when gluten is introduced may reduce the risk of delay the onset of CD.7

Several independent research groups have found that CD is associated with an altered gut microbiome8–11. Studies in infants have confirmed that this dysbiosis appears to precede the development of the disease. In a cohort study of human infants that were genetically at risk for CD, relative decreases in the abundance of Bifidobacterium and increases in Staphylococcus and Bacteroides fragilis in fecal samples early in life were associated with a higher risk of developing CD.12 More recent analyses have shown that high-risk HLA genes themselves may influence the composition of the gut microbiota.13 Infants with HLA-DQ2 haplotype showed an increase of Firmicutes and Proteobacteria and a decrease in Actinobacteria (including the genus Bifidobacterium).

The FUT2 gene is also associated with CD and influences gut microbial composition. Individuals who have two copies of a particular variant of the FUT2 gene fail to secrete certain compounds into the mucus layer of the gut. This results in altered mucus-associated microbes and reduced diversity, richness, and abundance of Bifidobacterium species.14–16

Gut permeability also plays a major role in CD. Dr. Alessio Fasano, an Italian researcher and gastroenterologist, has postulated that autoimmune diseases like CD are always preceded by leaky gut.17  In 2006, his laboratory found that gliadin, a component of gluten, can cause intestinal permeability by upregulating the signaling molecule zonulin. Zonulin then disrupts the tight junction proteins that link adjacent epithelial cells.18

Research in humans has confirmed that CD patients have leaky gut and further shown that most CD patients gut barrier function is restored after adhering to a gluten-free diet.19 However, other factors may also contribute to impaired gut barrier function, including certain medications, environmental toxins, chronic stress, hyperglycemia, and a highly refined diet.

In a later section, I’ll discuss how adding back some of these “missing microbes” might be beneficial for CD. For now, we’ll transition to a discussion of NCG/WS.

Shared symptoms between NCG/WS and IBS

Non-celiac gluten/wheat sensitivity has been a hot topic of debate over the last decade. Despite initial skepticism that NCG/WS existed, it has recently been recognized as an independent disorder of clinical relevance.20 While the overall prevalence of NCG/WS remains unknown, it has been estimated to range from 0.6 to 6 percent of the population.21

A group of experts that convened in 2014 in Salerno, Italy recommended that NCG/WS diagnosis should be made after a positive double-blind, placebo-controlled gluten challenge with crossover.20 This essentially means a test trial where neither doctor nor patient knows which treatment (gluten or placebo) he or she is receiving, followed by a second trial with the other treatment condition, and the assessment of symptoms after each trial with validated questionnaires. However, in clinical practice, the diagnosis of NCG/WS is typically based solely on exclusion of CD and wheat allergy, and self-reported improvement of symptoms after eliminating gluten and wheat from the diet.

Many of the symptoms of NCG/WS, including abdominal pain, bloating, and flatulence make it difficult to distinguish from irritable bowel syndrome (IBS), and at least two studies have found that IBS patients have improved symptoms control on a gluten-free diet.22,23 Indeed, there may quite a bit of overlap between NCG/WS and IBS, leading to questions about whether NCG/WS is an independent condition. I’ll discuss some of the research supporting this is the next few sections.

Is gluten the true culprit of NCG/WS?

FODMAPS, fructans, amylase trypsin inhibitors, and wheat germ agglutinin have all been suggested to be possible triggers for NCG/WS, leading to increasing doubt among the scientific and medical community that gluten is the true cause of symptoms in these individuals.

But what does the research really say? Let’s take a closer look at a few of these studies and the evidence for the gluten protein itself as the trigger for NCG/WS.

FODMAPs

FODMAPs are fermentable oligosaccharides, disaccharides, monosaccharides, and polyols. These carbohydrates tend to be rapidly fermentable in the gut and for many individuals, can cause bloating, gas, and other unpleasant GI symptoms. In recent years, these have been highlighted for their ability to trigger symptoms in NCG/WS patients.

In 2013, a group of Australian researchers recruited 37 subjects with NCG/WS and IBS for a randomized crossover study.24 The participants were placed on a two-week gluten-free, low-FODMAP diet before completing one week of a high-gluten (16 grams carbohydrate-depleted, isolated wheat gluten/day), low-gluten (2 grams gluten/day and 14 grams low-FODMAP whey protein/day), or placebo (16 grams whey protein/day) diet, followed by a washout period of at least 2 weeks. The researchers summarized their findings:

“In all participants, gastrointestinal symptoms consistently and significantly improved during reduced FODMAP intake, but significantly worsened to a similar degree when their diets included gluten or whey protein.” 24

In 2018, a group of Norwegian researchers published a randomized crossover study of 59 individuals on a self-instituted gluten-free diet for at least 6 months.25 Participants were assigned to one of three 7-day challenges with gluten (5.7 grams carbohydrate-free wheat gluten), the FODMAP fructan (2.1 grams fructo-oligosaccharides), or placebo (nothing added) given in a muesli bar, followed by a minimum one-week washout period (or until symptoms resolved).

The researchers assessed the participants’ self-reported symptoms using a detailed GI symptom and IBS questionnaire. They found that the average IBS score and bloating score for participants consuming fructans was significantly higher than participants consuming gluten. However, 13 participants had the highest IBS score after consuming gluten, 24 had the highest after consuming fructan, and 22 had the highest score after consuming the placebo.

This suggests that some individuals with self-diagnosed NCG/WS may be reacting to gluten itself, while others may be reacting to the FODMAPS in wheat. Still others may react to other wheat components. In other words, while some individuals will benefit from a low FODMAP diet, some may additionally benefit from removing both gluten and dairy proteins. A 2017 review summarized this well:

“In our opinion, rather than triggers, FODMAPs should be considered as possible additional elements of disturbance.” 26

Amylase trypsin inhibitors

Some researchers have suggested that wheat amylase trypsin inhibitors (ATIs) could also play a role in gluten-related disorders. ATIs are proteins in plants that support the natural defense against predators and pests. They may also regulate starch metabolism during seed formation and germination.

ATIs are strong activators of several different types of immune cells, including dendritic cells, macrophages, and monocytes, stimulating the classical NF-kB inflammatory pathway and the release of pro-inflammatory cytokines.27 Gluten-containing staples like bread and pastries have as much as 100-fold higher levels of innate immune system-activating ATIs than most gluten-free foods. Interestingly, older wheat variants, like Emmer or Einkorn wheat, have much lower ATI activity than modern wheat varieties.28

Currently, there are no studies that have assessed the effects of ATIs in humans. However, a group of German researchers fed mice ATIs isolated from wheat and found that it increased the release of inflammatory molecules in the small and large intestine and activated immune cells in the gut and mesenteric lymph nodes.28

Wheat germ agglutinin

Another potential culprit for adverse reactions to wheat is a lectin called wheat germ agglutinin (WGA). Lectins are proteins found in a wide variety of plants and are widely recognized as anti-nutrients; they can bind to virtually all cell types and, in large enough quantities, potentially cause damage to organs. Even very small concentrations of WGA have been shown to impair the integrity of the intestinal barrier29, and several uptake mechanisms allow transport of this lectin into the periphery where it can potentially damage other cells.

Feeding large amounts of WGA to mice has been shown to cause abnormal growth of the small intestine and pancreas and atrophy of the thymus, an important immune organ.30 In cell culture studies, WGA also stimulates histamine secretion and degranulation of mast cells, and the release of inflammatory cytokines from several different types of immune cells.31 Unfortunately, no studies have assessed the effects of WGA ingestion in humans; however, antibodies to WGA have been detected in the blood of healthy individuals, suggesting that their ingestion provokes a systemic immune response.32

Gluten

While all of these studies point to NCG/WS as a broad condition with many potential triggers, at least one double-blind, placebo-controlled trial has found a significant effect of the gluten on symptoms in NCG/WS patients.33 A total of 34 participants with IBS who were on a gluten-free diet received either carbohydrate-depleted wheat gluten (16g/day) or placebo (nothing) in the form of bread or muffins. Of patients in the gluten group, 13 out of 19 (68%) reported that symptoms were not adequately controlled, compared to 6 of 15 (40%) of patients in the placebo group. Patients in the gluten group had significantly worse pain, bloating, satisfaction with stool consistency, and fatigue. The authors concluded:

“gluten is indeed a trigger of gut symptoms and tiredness. […] Non-celiac gluten intolerance may exist, but no clues to the mechanism were elucidated.” 33

Other wheat proteins

While gluten receives the most attention, other proteins in wheat may be just as problematic. Wheat can be broken down into hundreds of different compounds, many of which can cause inflammatory immune responses. These include beta-, gamma-, and omega-gliadin, deamidated gliadin, glutenin, gluteomorphin, and prodynorphin.

Research by Lambert et al. have shown that patients with antibodies against these proteins in wheat often have cross-reactivity with tissues – in other words, these antibodies can cause autoimmune damage to the body. If these patients are not properly tested, told that they don’t have CD and that they can eat gluten in moderation, they may do irreversible damage to organs and put themselves at risk for a whole host of very serious autoimmune diseases. More on that later.

All of the above

The reality is that all of these compounds could potentially contribute to NCG/WS. This does not mean that NCG/WS doesn’t exist; rather, it suggests that NCG/WS has several potential etiologies and therefore requires individualized diagnosis and treatment. For instance, one individual may only be reacting to fructans and would do best on a diet that limits (but does not necessarily eliminate) all FODMAPs, including wheat. Another individual might be reacting to ATIs and could safely consume Emmer or Einkorn wheat, but not modern wheat varieties. Yet another individual might have antibodies to gliadin or other gluten proteins and a genetic predisposition to autoimmune disease. This individual would want to avoid wheat completely.

Later, I’ll discuss how to assess your personal response to wheat and help determine which of these factors might most contribute to symptoms. First, though, we’ll discuss a few mechanisms that might explain why someone is reacting to these various compounds in wheat.

Could gluten sensitivity be gut dysbiosis?

In a review published in 2017, Leccioli et al. pieced together recent evidence into a new proposed mechanism for the development of NCG/WS. They hypothesize that the root cause of NCG/WS is gut dysbiosis, particularly characterized by reduced numbers of Firmicutes and Bifidobacterium, leading to low levels of butyrate in the gut and increased intestinal permeability.

The Firmicutes phylum includes many known butyrate-producing microbes, including Faecalibacterium prausnitzii, Eubacterium rectale, and Roseburia. These microbes are typically detected in healthy adult fecal samples at about 2-15 percent relative abundance compared to total bacteria, but are likely even more prevalent in the gut mucus layer.34

Bifidobacterium, a genus belonging to the phylum Actinobacteria, contribute to gut butyrate production by producing acetate and lactate. Butyrate-producing Firmicutes then convert these molecules to butyrate by cross-feeding interactions. (It’s important to note, however, that many non-Western populations do not appear to have significant amounts of Bifidobacterium, yet produce plenty of butyrate.35)

Unfortunately, few studies have assessed the fecal microbiota of NCG/WS patients, but low levels of butyrate-producing Firmicutes and Bifidobacterium are found in IBS and are negatively associated with IBS symptoms.36,37

If the researchers’ hypothesis is true and NCG/WS is caused by low levels of these microbes, this suggests that NCG/WS is transient and treatable, related to the overall quality of the diet and health of the gut microbiome. In other words, if you’re currently sensitive to wheat but improve the health of your gut, you may be able to tolerate wheat in the future.

Is glyphosate killing off our native microbes and inhibiting digestion of wheat?

Glyphosate is the active ingredient in the popular herbicide Roundup, and its usage on wheat in the United States has risen sharply in the last decade. Several animal studies have increased our understanding of the potential effects of glyphosate on the gut microbiome. Unfortunately, opportunistic pathogens like Salmonella appear to be highly resistant to glyphosate, whereas Bifidobacterium, Lactobacillus, and Enterococcus species seem to be especially susceptible.38 This may be particularly true in cases of insufficient protein intake.39

Glyphosate may also reduce the activity of protease, lipase, and amylase, enzymes responsible for the digestion of protein, fats, and carbohydrates, and disrupt the structure of microvilli. This may also impact the immune response:

“Glyphosate may interfere with the breakdown of complex proteins in the human stomach, leaving larger fragments of wheat in the human gut that will then trigger an autoimmune response.” 40

In this way, glyphosate may act as an adjuvant, making gut immune cells hyper-reactive to gluten, ATIs, or other wheat compounds I mentioned previously. This hyperactivity may be particularly pronounced if the gut is already in a state of increased permeability.

Many people with NCG/WS have leaky gut and autoimmunity

A recent study performed by Uhde et al. provided some additional insight relative to NCG/WS.41 They found that individuals with NCG/WS had:

  • Increased LPS-binding protein and soluble CD14 in the blood
  • Enhanced antibody reactivity to bacterial components LPS and flagellin
  • Increased levels of serum FABP2

In other words, NCG/WS patients had widespread inflammation and leaky gut:

 “The results demonstrate the presence of objective markers of systemic immune activation and gut epithelial cell damage in individuals who report sensitivity to wheat in the absence of coeliac disease.” 41

Moreover, these markers decreased dramatically after a six-month period of strict gluten avoidance. This was not the first study to identify the presence of leaky gut in NCG/WS patients. In 2015, Hollon et al. demonstrated that intestinal biopsies from patients with active CD or NCG/WS had a greater increase in intestinal permeability in response to gliadin than healthy controls or CD patients in remission.42

Other studies have found that high proportions of people with NCG/WS have autoimmune disease or antinuclear antibodies (ANA, antibodies against their own cells). In a large retrospective study of patients with NCG/WS, 46 percent of patients had elevated ANA and 29 percent went on to develop autoimmune disease during the ten year follow-up period.43

Unfortunately, because of current confusion and misunderstanding surrounding NCG/WS, many doctors fail to test NCG/WS patients for the presence of these antibodies. Some may even mistakenly suggest that these patients are okay eating wheat in moderation, leading to potentially irreversible organ damage.

In a later section, I’ll describe the best commercially available tests for these antibodies, to determine whether you should be concerned about potential autoimmunity. First, I want to briefly discuss the research we have on gluten-free diets and the composition of the gut microbiota.

Gluten intake modestly affects the gut microbiome and host immunity

Few studies have assessed how gluten consumption itself changes the gut microbiome. One 2009 study found that in healthy subjects, a gluten-free diet was associated with lower Bifidobacterium and Lactobacillus spp. and higher amounts of Enterobacteriaceae and E. coli.44 However, the study only included ten participants, and the gluten-free diet significantly reduced intake of polysaccharides. This decrease in fiber intake is a common occurrence among those who switch directly from processed gluten-containing bread, pastries, and sweets to processed gluten-free alternatives (as opposed to adopting a whole foods diet) but is still a significant confounding variable in this study.

Notably, the gluten-free diet also reduced cytokine production by cultured blood immune cells when exposed to fecal samples. In particular, the gluten-free diet reduced production of pro-inflammatory cytokines TNFα, IFNγ, and IL-8:

“Thus, a GFD could contribute to reduce the pro-inflammatory signals in the gut by introducing modifications in the microbiota structure.”

Another study published in 2018 compared sixty Danish adults that underwent eight weeks on a low-gluten diet and eight weeks on a high-gluten diet.45 The low-gluten diet altered the fecal microbiome, reducing relative abundance of Bifidobacterium, two species of Dorea, one species of Blautia, two species of Lachnospiraceae, and two butyrate-producing bacteria Anerostipes hadrus and Eubacterium hallii. However, the low-gluten diet also increased the relative abundance of Clostridiales and an unclassified species of Lachnospiraceae, two butyrate-producing taxa. There were no changes in microbial diversity or fecal short-chain fatty acid production.

Notably, total energy, polysaccharide, and FODMAP intake did not change between the two different dietary conditions. Most interestingly, the low-gluten diet reduced breath hydrogen after a meal and self-reported bloating, even though these individuals did not have any diagnosed digestive issues! It also significantly increased production of the satiety hormone PYY and resulted in weight loss, which was attributed to enhanced generation of heat (thermogenesis).

There were no major changes in inflammatory markers, though serum IL-1β, a molecule involved in the inflammatory response, was reduced on the low-gluten diet. Overall, more studies are needed to understand how different gluten-free diets might impact the fecal microbiome and immune system, and how other therapies might improve tolerance to gluten. Study of mucus-associated microbes and those that reside in the small intestine may also provide key insights, as we’ll see in the next section.

High prevalence of SIBO and gut pathologies in CD and NCG/WS

Up to a third of CD patients continue to experience symptoms after adopting a gluten-free diet. While many of these cases are due to accidental gluten contamination, studies suggest that some ongoing symptoms may be due to small intestinal bacterial overgrowth (SIBO) or other gut pathologies.

The small intestine is the primary site of nutrient absorption and normally contains relatively few microbes, while the large intestine, or colon, contains a dense microbial ecosystem. SIBO is characterized by abnormally large numbers of microbes in the small intestine and/or the presence of microbes normally found in the large intestine in the small intestine. These microbes can ferment food in the small intestine, producing unpleasant GI symptoms like bloating, abdominal pain, and gas.

In 2003, a group of Italian researchers studied 15 CD patients who continued to experience GI symptoms after at least 6-8 months of consuming a gluten-free diet.46 Intestinal biopsies revealed that the gut tissue had healed, and no longer had the characteristic atrophy of CD, suggesting that they did not have a reoccurrence of active disease. Of the 15 patients, 10 tested positive for SIBO by breath test, two had lactose intolerance, and two had parasitic infections (one had an accidental gluten exposure and was not treated). After being treated for these conditions, all of the patients were symptom-free.

However, the true prevalence of SIBO in non-responsive CD is widely debated and may actually be much lower. While breath testing is the easiest non-invasive way to assess SIBO in clinical practice, it may result in over-diagnosis. A study in 2009 used the gold standard for assessing the presence of SIBO, quantitative culture of intestinal aspirate, and estimated that only 11 percent of patients with non-responsive CD have SIBO.47

To my knowledge, only one study has assessed the prevalence of SIBO in patients with NCG/WS. Of the 84 patients, 16 (19%) were positive for SIBO by breath test, five had fructose intolerance, and three had lactose intolerance.48 Overall, this suggests that doctors should be screening for other gut pathologies in cases of refractory CD or ongoing NCG/WS.

Could probiotics improve gluten tolerance?

Probiotics may also have the potential to make wheat less allergenic or mitigate the effects of gluten in sensitive individuals. Certain strains of Bifidobacterium longum (NCC2705 and CECT 7347), Bifidobacterium animalis (subspecies lactis), and Lactobacillus rhamnosus (GG) have been found to attenuate the damaging effects of gliadin on the gut mucosa in cell culture and animal studies.49–52

In a randomized, placebo-controlled trial of children with newly diagnosed CD, Bifidobacterium longum CECT 7347 supplementation for three months improved growth parameters, reduced abundance of the potentially pro-inflammatory species Bacteroides fragilis, and reduced fecal secretory IgA, suggesting that the gut immune system was no longer on “high alert”.

Another study in children with CD on a gluten-free diet found that three months of supplementation with Bifidobacterium breve (BR03 and B632) significantly reduced circulating TNFα, a marker of systemic inflammation. Three months after stopping probiotic supplementation, TNFα levels were again elevated.53

In 2013, Smecuol et al. found that Bifidobacterium infantis (NLS strain) alleviated some of the symptoms of untreated CD in adults, including indigestion, constipation, and reflux, but was not able to significantly alleviate intestinal permeability.54

Overall, these studies suggest that there is great potential for probiotic supplementation to mitigate the damage caused by gluten and improve overall health in gluten-sensitive individuals. In the summary and takeaways section, I’ll provide my top four probiotics for gluten intolerance.

Soaking, sprouting, and fermenting wheat

For centuries, traditional cultures had the wisdom to prepare wheat and other grains to make them more digestible and more nutritious. The most common approach includes soaking, grinding, removing most of the bran, fermenting, and cooking. Modern nutritional science has confirmed that this process indeed improves the digestibility and nutrient value of grains, reducing the level of toxins and anti-nutrients, including lectins, phytates, and many of the most immunogenic proteins.

For example, a series of experiments by a group of Italian researchers found that the fermentation of wheat flour with the probiotic VSL#3 for 24 hours resulted in almost complete degradation of several immunogenic proteins in wheat.55 The release of zonulin from cultured intestinal epithelial cells treated with this pre-digested wheat was considerably lower than epithelial cells treated with un-treated wheat flour, and the agglutinating ability of the wheat was lost. Moreover, CD biopsies exposed to the VSL#3-digested wheat did not show an inflammatory response. VSL#3 also partially, but not completely, attenuated gliadin-induced intestinal permeability in mice.

This suggests that long-time fermented wheat products, such as authentic sourdough bread, are best if you plan to consume wheat regularly. Note that most bread marketed as sourdough is not actually authentically fermented, so be sure to look for sourdoughs that do not contain yeast, and that allow the dough to rise naturally for at least 4-6 hours before baking.

Summary and takeaways

I know I covered a lot in this article, so here’s a brief summary of the most important points and takeaways:

Gut dysbiosis likely plays a significant role in the development of celiac disease and non-celiac gluten sensitivity. Decreases in the abundance of Bifidobacterium, increases in Bacteroides fragilis are associated with CD, while low levels of Bifidobacterium and butyrate-producing Firmicutes may contribute to NCG/WS.

Removing gluten from the diet is usually necessary, but not sufficient to restore gut health. Going gluten-free will quiet the immune response and reduce symptoms, but it does not correct the underlying gut dysbiosis or leaky gut, especially if you simply switch to a diet of processed gluten-free foods. Those with CD or NCG/WS should be screened for additional gut pathologies, such as SIBO and parasitic infections.

NCG/WS should be accepted as a real condition and viewed as a collective group of signs and symptoms with many potential triggers. Some NCG/WS patients may react to lectins, ATIs, or FODMAPs in wheat, while others may react directly to wheat-related peptides. This does not mean that NCG/WS doesn’t exist!

Many patients with NCG/WS have autoimmunity and may do long-term damage by continuing to eat wheat. The antibodies that our immune system produces against wheat can often cross-react with our own body tissues, causing potentially irreversible organ damage.

NCG/WS may be reversible. Improving gut health by increasing levels of beneficial microbes, supporting a strong gut barrier, and regulating the gut immune system may allow some people that did not previously tolerate wheat to tolerate it in future.

Probiotics may help improve gluten tolerance and reduce inflammation. While I do not advocate that anyone with CD eat wheat, probiotic supplementation may prevent the detrimental effects of gluten cross-contamination in restaurants or accidental gluten exposure. Probiotics can also reduce inflammation and help address the underlying causes of gluten intolerance and autoimmunity in both CD and NCG/WS.

The top four evidence-based, commercially-available probiotics I have been able to identify for those with CD or NCG/WS are:

  • Bifibaby (Bifidobacterium Breve BR03 and B632) – reduced inflammation in children with CD
  • Natren LifeStart (Bifidobacterium infantis NLS strain, available in several forms, some of which contain dairy) – alleviated CD symptoms in adults
  • Visbiome (previously known as VSL#3*) – breaks down immunogenic gluten proteins
  • Enterogermina (Bacillus clausii OC, NR, SIN, and T) – enhances SIBO clearance and reduces functional abdominal pain

*IMPORTANT NOTE: VSL#3, as studied in clinical trials, is now manufactured by Visbiome. Other products that are marketed as VSL#3 are likely fake. 

How to evaluate your own wheat tolerance

If you do not have celiac disease and want to continue to consume wheat on occasion, I highly recommend a comprehensive evaluation of wheat tolerance. This includes:

  • A 2-week low-FODMAP, gluten-free diet followed by a blinded gluten (wheat gluten), fructan (FOS), or placebo (rice flour) challenge. This is particularly useful for those who have IBS or who primarily experience bloating and GI discomfort after wheat consumption. Enlist a family member or friend to randomly provide one of these three powders at a meal or baked into a food. Record any symptoms you experience or ideally use a validated GI symptom questionnaire. Go back to the baseline diet for at least three days or until symptoms subside; then try the next challenge agent.
  • A 60-day strict elimination of gluten, wheat, barley, and rye, followed by staged reintroduction, starting with sourdough and ancient varieties, and finally modern wheat. This will allow you to assess your own subjective improvement on a gluten-free diet and any symptomatic changes upon reintroduction. This is most accurate when also removing other immunogenic foods, such as dairy, soy, corn, and other grains.
  • A Cyrex Array 3 gluten sensitivity panel. This tests for IgG and IgA immune reactivity to gluten, gliadin, glutenin, gluteomorphin, and other related peptides. It also screens for antibodies to transglutaminase 2, a marker of celiac disease, and other transglutaminase enzymes. The Cyrex Array 14 mucosal immunology panel also tests for many wheat-related antibodies, in addition to antibodies against dairy, corn, soy, heavy metals, aflatoxin, and rotavirus. Note: you need to have consumed wheat recently for the results to be accurate, so it often makes sense to do this the week after wheat reintroduction.

Interpreting the results:

  • If you have NCG/WS due to FODMAP intolerance, you can likely consume wheat safely in small amounts, but should identify and treat underlying gut pathologies such as SIBO and gut dysbiosis. After these have been addressed, you may be able to tolerate wheat and other FODMAPs in larger quantities.
  • If you have NCG/WS due to antibodies against wheat proteins or transglutaminase enzymes, wheat and gluten should be strictly avoided in the short term to prevent the possibility of irreversible autoimmune damage to organs. Antibodies to cross-reactive foods should also be assessed. However, improving the health of the gut microbiome and gut barrier may reduce antibody responses and allow for the safe consumption of gluten months or years later. Repeat antibody testing should be performed before including wheat in the diet on a regular basis.
  • If you have celiac disease (elevated anti-TG2 and confirmed biopsy), gluten and wheat should be avoided for life. While there is some intriguing evidence suggesting that Lactobacillus and Bifidobacterium supplementation can improve tolerance to small amounts of gluten, the detrimental effects of gluten consumption in individuals with celiac are not worth experimenting with.
  • If you have no issues with FODMAPs, no antibodies against wheat proteins or transglutaminase, and no symptomatic changes after reintroduction of wheat, you can feel comfortable including wheat in your diet. Note that wheat contains anti-nutrients that can impair mineral absorption and can still cause transient intestinal permeability, so it should be seen as more of a condiment, rather than a dietary staple. When possible, choose ancient varieties of wheat or traditionally sprouted or fermented preparations like authentic sourdough, which are less likely to cause permeability and impair mineral absorption.

That’s all for now! Let me know what you thought in the comments and be sure to share your experience if you try this gluten challenge. I am currently performing my own gluten challenge and will be reporting back with my own results in a few weeks!

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By |2018-12-29T18:08:42+00:00December 29th, 2018|

One Comment

  1. Jacquie Walburn December 30, 2018 at 5:48 pm - Reply

    Fabulously written article!
    I actually had 15 different conditions/symptoms before I started my journey. With each change I made I waited 60 days. I started by removing wheat gluten from my diet & lost 20 lbs in 30 days. I then removed all gluten/grains & lost 20 more lbs in 60 days. My biggest loss was when I also deleted cow dairy & lost 30 more lbs in 90 days. Almost all symptoms reversed in this time. I tried, after a year with confirmed leaky gut healed, to reintro organic corn & tore my gut up again & gained 10 lbs in 90 days but no other symptoms. So, I am back to gluten/grain/cow dairy free.

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