May 2019 Issue

The Gut Microbiome’s Link to Celiac Disease
By Jamie Santa Cruz
Today’s Dietitian
Vol. 21, No. 5, P. 24

To what extent do genetics, the environment, and diet lead to this condition’s development?

For people to develop celiac disease, they have to have two strikes against them: First, they have to inherit genes that put them at risk, and second, they have to eat the protein that triggers the disease (gluten). However, genetic predisposition and gluten consumption aren’t sufficient in and of themselves to cause celiac disease, as evidenced by the fact many people with the genetic risk factors don’t develop the disease even after eating gluten. Clearly, other factors play a role in determining susceptibility. A growing body of research now suggests that one of those key factors may be the bacteria in the gut.

Genes and Gluten Exposure
Celiac disease is a chronic autoimmune condition in which ingestion of gluten prompts an immune reaction that causes damage to the small intestine. It’s a relatively common food intolerance, affecting 0.71% of the US population overall, according to the National Health and Nutrition Examination Survey. The disease is most common among non-Hispanic whites, where it affects about 1% of the population.1

The biggest genetic risk factor for celiac disease is variants located in the human leukocyte antigen (HLA) region of the genome. For a long time, variants in the HLA region were the only confirmed genetic risk factor. However, these HLA genes account for only about 40% of the heritability of the disease, and only a small percentage of the carriers of these genes develop celiac disease.2

More recent research has uncovered several dozen additional non-HLA regions of the genome that also are associated with celiac disease risk. Most of these genomic regions associated with celiac disease contain genes with immune-related functions, and significantly, several are known to play a role in shaping the composition of the gut microbiome.3

While genetic factors are important components of the disease, environmental factors also are key. The main environmental trigger of celiac disease is exposure to gluten, and celiac disease typically manifests in young children after their first gluten exposures. However, a significant number of individuals don’t develop celiac disease until later in life, after decades of consuming gluten. Furthermore, there are significant differences in the prevalence of celiac disease between populations that are geographically close, have similar genetic backgrounds, and have similar levels of wheat consumption. These facts are strong evidence that additional environmental factors besides genes and gluten consumption are in play.4

Environmental Factors That Influence Risk
Significantly, most of these factors also are known to impact the composition of bacteria in the human gut. Consider, for instance, mode of delivery (vaginal birth vs cesarean section). Infants born vaginally pass through the mother’s birth canal and acquire microbial communities similar to their mothers’ vaginal microbiota, whereas infants born via C-section acquire very different microbial communities.5 Some research has found that infants born via elective cesarean section are more likely to develop celiac disease.6

Antibiotic exposure also alters bacterial composition in the gut, and several studies likewise have linked antibiotic exposure to increased risk of celiac disease in both children and adults.7-9 Other factors that influence microbial composition and that also have been linked to higher risk of celiac disease include proton pump inhibitor use, gastrointestinal infections, and a higher number of respiratory infections in the first 18 months of life.10 The data on several of these factors are conflicting, and thus it’s not yet clear which environmental factors ultimately play a role in celiac disease. But the fact that so many environmental factors known to influence the composition of the microbiome have been linked to celiac disease in at least some studies is suggestive that microbiota composition is a significant factor in celiac disease development.4

How Microbial Composition Differs in Celiac Disease
Repeated studies by multiple research groups have demonstrated that the bacterial composition in the guts of individuals with celiac disease differs from that of individuals without the disease. Specifically, both children and adults with celiac disease have increased proportions of more harmful bacteria (especially bacteroides and proteobacteria), and decreased proportions of beneficial bacteria (especially lactobacilli and bifidobacteria).11,12

In addition, the microbiomes of individuals with different manifestations of celiac disease also show different patterns of microbial composition. For instance, celiac patients with classic gastrointestinal symptoms have lower diversity of microbes and greater predominance of proteobacteria in the upper part of their small intestines than celiac patients with other (nongastrointestinal) symptoms.13 Furthermore, celiac disease patients with persistent symptoms have higher levels of proteobacteria than those who are asymptomatic.14 Studies such as these suggest that intestinal microbiota likely play a role in how the disease manifests.

Some studies also suggest that the microbiomes of individuals with celiac disease may contain a higher percentage of pathogenic or proinflammatory bacteria than those without the disease. In one study, for example, researchers took fecal samples from 31 children, some with celiac disease and some without. They found that all of the samples contained various strains of E coli. However, the samples from children with celiac disease had a less diverse array of E coli strains, and the strains of E coli that the children with celiac disease did have were more virulent than the strains in the samples from children without the condition.15 Other studies have shown that patients with celiac disease similarly have more virulent strains of both Staphylococcus spp and Bacteroides fragilis.16,17

Altered Microbiota: Cause or Consequence?
While there are clear differences in the patterns of intestinal microbial composition between individuals with celiac disease and those without, it’s not yet certain whether such differences are the cause or the consequence of the disease. “What comes first, the change in the microbiota, or the disease?” asks Heather Galipeau, PhD, a research associate at McMaster University in Hamilton, Ontario, Canada. “Whether those differences come before the disease or as a consequence of inflammation (as a result of the disease) is an area of ongoing research.”

At least some of the variation between the microbiomes of individuals with celiac disease and those without is explained by the gluten-free diet that celiac patients must adopt, according to Maria del Carmen Cenit, PhD, a researcher in the Microbial Ecology, Nutrition and Health Research Unit at the Institute of Agrochemistry and Food Technology at the National Research Council in Valencia, Spain. Diet in general heavily impacts composition of intestinal microbiota, and adherence to a gluten-free diet in particular has been shown to cause a reduction in several bacterial communities, including Bifidobacterium spp, Clostridium lituseburense, Faecalibacterium prausnitzii, Lactobacillus spp, and Bifidobacterium longum, along with an increase in E coli, enterobacteriaceae, Bifidobacterium angulatum, and B fragilis.18,19 Thus, according to Cenit, “gut microbiota alterations detected in celiac disease patients on a gluten-free diet could be partly due to the dietary effect and not only to the underlying disease.”

But while some differences in the microbiome may be a consequence of celiac disease, there’s also reason to think that differences in intestinal microbiota may play a causal role in the disease’s development. There are two major types of studies that suggest this hypothesis. The first is gnotobiotic animal studies—that is, studies in which animals (namely, mice) are kept under germ-free conditions and then various microbes of interest are introduced into their intestines. Several such studies suggest that intestinal microbial composition may influence whether animals at genetic risk of gluten intolerance go on to develop an intolerance.20-22 According to Joanna Harnett, MHlthSc, PhD, a lecturer in the Sydney School of Pharmacy at Australia’s University of Sydney, the implication of these studies is that “specific intestinal microbial compositions can interact with the ‘celiac genes’ to trigger the immune-pathological reaction characteristic of celiac disease.”

The other type of study that suggests the intestinal microbiota potentially may influence the onset of celiac disease is human infant studies—ie, studies that compare the microbiota of infants who are genetically low risk with those who are genetically high risk. In such studies, researchers not only can observe how infant microbiomes differ at a single point in time early in life but also can track how the microbiome matures differently in infants who go on to develop celiac disease vs those who don’t.

Several infant studies suggest that high-risk and low-risk infants have different intestinal microbiota from very early on, before disease diagnosis. In one study, infants with genes that put them at high risk of celiac disease were shown to have lower levels of Bifidobacterium spp and B longum and greater numbers of Staphylococcus spp, even though none of them had yet developed celiac disease.23 Another infant study found that healthy infants with the high-risk genotype showed increases in firmicutes and proteobacteria along with decreases in actinobacteria (including the genus Bifidobacterium).24

Yet another study just last year found that infants who later went on to develop celiac disease showed an altered trajectory of microbial development compared with infants who didn’t develop celiac disease, and that this altered trajectory coincided with immune changes.25 “We observed that when these infants were only 1 month old, the gut microbiota was already imbalanced compared to the microbiota of those infants who did not carry these genes,” says Marta Olivares, PhD, also a researcher in the Microbial Ecology, Nutrition and Health Research Unit at the Institute of Agrochemistry and Food Technology at the National Research Council in Valencia, Spain. According to Olivares, it appears that the early differences in microbiota composition “could influence the immune maturation process and predispose to the disorder.”

Not all studies, however, have produced consistent results. In one study, the fecal microbiota composition of infants aged 9 to 12 months who later went on to develop celiac disease was similar to infants in the same age range who didn’t develop the disease.26 Thus, more research in larger populations is needed to clarify exactly how the composition and development of intestinal microbiota is altered in individuals who eventually develop the disease.

How Microbiome Disruptions Lead to Increased Risk
The mechanisms behind the possible causal influence of the gut microbiota in celiac disease still are being determined. However, three mechanisms have been proposed, according to Cenit. The first relates to the role of gut microbiota in digesting gluten. Microbiota release enzymes that aid in the digestion of gluten and other proteins, but the enzymes released by some microbiota generate gluten peptides that are toxic and/or tolerogenic, thus prompting the immune response characteristic of celiac disease.27,28

A second possibility is that alterations in gut microbiota precipitate celiac disease by impacting intestinal permeability. Some of the microbes (such as E coli) that appear in greater concentrations in the intestines of individuals with celiac disease seem to have a detrimental impact on the function of the intestinal barrier and contribute to greater permeability.28 Gliadin proteins (which are a component of gluten) are then able to permeate the intestinal barrier, triggering the immune responses associated with celiac disease.

Finally, gut microbiota may influence celiac disease development via inflammatory processes. For instance, B fragilis, which is known to be present in elevated concentrations in individuals with celiac disease, prompts greater production of inflammatory cytokines during digestion of gluten.17

Can Probiotics Play a Treatment Role?
The fact that the gut microbiome appears to play some role in celiac disease raises the question of whether probiotics can be used as a treatment. Could ingestion of beneficial bacteria help to restore the proper balance of the gut microbiome?

Some research suggests the answer is yes. A recent intervention trial led by Olivares examined the effects of B longum CECT 7347 on children who were newly diagnosed with celiac disease.19 “We observed that this bacterium tended to reduce the levels of one cytokine related to inflammation (tumor necrosis factor),” Olivares says. She and her colleagues further observed that the children’s diets (all were on a gluten-free diet) were associated with increases in B fragilis, a potential pathogenic bacteria, but that administration of the Bifidobacterium probiotic prevented this diet-related increase.19

A separate intervention by Argentinian researchers examined the effects of Bifidobacterium NLS on a cohort of adult patients who had been diagnosed with celiac disease but were still consuming at least 12 g of gluten per day. They found that the probiotic didn’t affect intestinal permeability (the study’s primary outcome), but it did result in significant improvement of gastrointestinal symptoms.29

But while the idea that probiotics could help treat celiac disease is an intriguing possibility, “the evidence so far is pretty weak,” according to Galipeau. One recent review found that most of the evidence on the effects of probiotics in celiac disease comes from animal studies, and that human intervention trials, while promising, are few in number.30

As for whether probiotics might ever be able to replace the need for a gluten-free diet, Galipeau suggests the answer is no. The introduction of beneficial bacteria in the form of a probiotic might legitimately aid celiac individuals in being able to digest gluten, she says, but the average person eats so much gluten that it would be difficult for a probiotic to fully compensate.

Olivares agrees: While science has been able to show that probiotics “can bring certain benefits to [celiac disease] patients,” consumption of probiotics is “a dietary strategy that complements the gluten-free diet but never replaces it.”

Takeaways for Dietitians
The main takeaway from research on the role of microbiota in celiac disease is the importance of eating in such a way as to support the health of the gut microbiome. “The care of the microbiota through the diet is fundamental for our well-being,” Olivares says. Several specific strategies can support microbiome health, including the following:

Encourage breast-feeding. It’s unclear whether or not breast-feeding ultimately impacts celiac disease risk (research has been mixed).28 What is clear, according to Olivares, is that “breast milk is the best ally to induce a healthy pattern of intestinal colonization.”31 Establishing a healthy microbiome right from the beginning is important because intestinal microbiota affect the development of the immune system. “The role of the microbiota in educating the immune system is particularly relevant in the first months of life,” Olivares says.

Recommend fiber consumption—especially in the celiac population. High-fiber diets promote the growth of beneficial bacteria such as bifidobacteria, Olivares says. A focus on fiber consumption is especially important in the celiac population because adherence to a gluten-free diet easily can lead to reduced fiber intake.

Harnett agrees on the value of high-fiber foods (ie, whole plant foods): “We know that diets rich in a range of vegetables, fruits, nuts and seeds, and whole grains play a critical role in both the development and ongoing maintenance of a ‘healthy’ microbiome,” she says. Individuals with celiac disease obviously cannot eat grains such as wheat, rye, and barley that contain gluten. However, according to Harnett, they can and should continue to eat whole grains that don’t contain gluten, including corn, millet, rice, and sorghum.

Consider probiotics as an option for promoting intestinal health. Although research is limited on the benefits of probiotics for individuals with celiac disease, the existing studies suggest probiotics can promote intestinal colonization of beneficial bacteria, Olivares says.

According to Harnett, probiotics may be particularly valuable for individuals with celiac disease who also have the common comorbidity irritable bowel syndrome (IBS). A range of probiotics have been studied for use in IBS (although, as Harnett notes, these trials haven’t been specific to people who also have celiac disease).32 Among the probiotics that have been shown to be beneficial in IBS, many are strains of either Lactobacillus or Bifidobacterium, including L plantarum 299v, L plantarum NCIMB 30173, L rhamnosus NCIMB 30174, L acidophilus NCIMB 30175, and Bifidobacterium infantis 35624.33-35

One word of caution, though: Some probiotics contain gluten, Galipeau says, so make sure to counsel clients with celiac disease to search for those without gluten.

Don’t worry about delaying the introduction of gluten to infants. At one time, researchers thought that waiting to introduce gluten until infants were older might reduce the risk of celiac disease, but subsequent research hasn’t borne out this theory.36 “Whether you introduce gluten later or earlier, it doesn’t really seem to be playing a role,” Galipeau says.

— Jamie Santa Cruz is a freelance writer of health and medical topics based in Parker, Colorado.


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