More study in celiac disease patients is needed first
By Amy Ratner, Medical and Science News Analyst
As scientists search for additional ways to treat celiac disease, a new review of existing studies suggests that probiotics may have the potential to help patients in three ways.
Possible roles for probiotics include improving symptoms, modulating the immune response and altering the composition of bacteria in the gut microbiome, researchers from the University of Parma in Italy found.
The Italian study review, published in the journal Frontiers in Immunology, emphasized that much more investigation is needed to determine which probiotics, in what doses and for how long would be beneficial in celiac disease. But researchers’ conclusions were optimistic.
Probiotics are live microorganisms that are intended to have health benefits when consumed, according to the National Institutes of Health. They can be found in yogurt and other fermented foods and dietary supplements. Many of the microorganisms in probiotics are the same as or similar to microorganisms that naturally live in our bodies.
“Knowledge of the role of intestinal bacteria in the development of celiac disease opens new possibilities for its treatment through probiotic administration,” the authors wrote.
Meanwhile, those with celiac disease should get probiotics and prebiotics from foods such as chicory, yogurt and kimchee, according to Maureen Leonard, MD, clinical director, Center for Celiac Research and Treatment (CFCR) at Massachusetts General Hospital for Children, who was not involved in the review study. Leonard is leading the Celiac Disease Genomic Environmental Microbiome and Metabolic Study (CDGEMM) being done at the celiac center.
“The probiotic field is still in its infancy,” Leonard said. Consequently, randomized trials in large populations or smaller trials with personalized probiotics in patients are necessary before probiotics should be recommended or used in treating celiac disease patients, she said.
Benjamin Lebwohl, MD, director of clinical research, The Celiac Disease Center at Columbia University, who was also not involved with the review study, said he does not advise patients to take probiotics because it’s unknown how effective the supplements are in celiac disease or, due to minimal federal testing requirements, how safe.
“But some patients have ongoing symptoms and have tried a number of medications without success and have experimented with probiotics and found a particular one that seems to help maintain their regularity or help alleviate certain symptoms,” Lebwohl said. When that is the case, Lebwohl tells celiac disease patients it’s OK to continue as long as they understand that probiotics are not highly regulated.
While Lebwohl is dubious about the effectiveness of probiotic-containing foods due to lack of evidence about their role in celiac disease, he said eating these kinds of foods is harmless and preferable to taking probiotic supplements, whose safety is more questionable.
The gut microbiome is the collection of microorganisms, bacteria, viruses, fungi and more in the gastrointestinal tract. It plays an important role in nutrient and mineral absorption, synthesis of enzymes, vitamins and amino acids.
Changes in the composition and function of the colony of bacteria in the gut have been linked to chronic inflammatory disease and the researchers set out to review what’s known about relationships between changes in the microbiota and celiac disease and what role probiotics might play.
The HLA-DQ genes related to celiac disease can alter the composition of the microbiome from birth, with some studies showing that children at genetic risk have higher portions of bacteria associated with inflammatory conditions compared to infants not at risk.
Environmental factors that influence the make-up of the microbiome from birth include type of delivery, infections and exposure to antibiotics, which have also been associated with the risk of developing celiac disease in those with the necessary genes. Diet also plays a role in the composition and diversity of the microbiome and some studies have shown that the gluten-free diet can result in reductions in beneficial gut bacteria.
While acknowledging that the gluten-free diet may explain some differences in the microbiome in celiac disease, authors of the review note that several studies support the hypothesis that the microbiota plays a role in the risk of getting celiac disease, as well as its origination, development and symptoms. Studies have also found evidence of altered microbiomes in patients who continue to have symptoms on a long term diet and those in who have celiac disease but do not follow the gluten-free diet.
Recent studies evaluating the composition of the microbiome in those with celiac disease have found a decrease in beneficial Lactobacillus and Bifidobacterium and an increase in harmful Bacteroides and E. coli compared to healthy people. Studies of children with celiac disease have identified bacteria not found in healthy children. One found that even after following a gluten-free diet for two years, the microbiome of children with celiac disease was not completely restored.
These studies suggest that the microbiota influence the way that celiac disease manifests and evolves, according to study authors. They note that Leonard’s CDGEMM study holds hope for a better understanding of the role of the gut microbiome in the early stages of celiac disease.
Lactobacilli and Bifidobacterium, the most frequently studied bacteria in celiac disease, may play a role in breaking down gluten and its harmful fragments to modify its potential to cause an immune reaction.
For example, Lactobacillus has been shown to detoxify gliadin fragments after partial digestion by enzymes in the body and Bifidobacteria may have the potential to reduce the abnormal opening of tight junctions in the lining of the gut caused by gluten in those who have celiac disease, according to the study review.
Bifidobacterium Longum reduce the production of inflammatory cytokines, which are small secreted proteins released by cells that have a specific effect on the interactions and communications between cells, according to the study review.
“Findings on the gluten-processing activities of specific microbial strains could suggest the use of probiotics as a complementary therapy for celiac disease,” the authors wrote, though they note that much of the work related to probiotic use has been done in laboratory test tubes and petri dishes or in animal studies. Meanwhile, data from human trials is scarce. The review included a number of laboratory studies published from 2009 to 2019 but only eight that investigated the effectiveness of probiotic supplementation in trials with celiac disease patients.
A few showed that probiotics might be beneficial in improving symptoms of celiac disease. One involving 78 celiac disease patients who were not following a strict gluten-free diet found that a strain of Bifidobacterium resulted in significant improvement in gastrointestinal symptoms compared to a placebo. Two studies that measured changes in the microbial DNA in stool after study participants were given probiotics showed improvements, while a third found no differences in fecal microbial counts or the severity of symptoms between probiotic and placebo groups. The risk of developing celiac disease was not affected by the use of probiotics compared to a placebo in two large studies of children.
“Which probiotics are more effective, at what dose and how long they should be administered are yet to be definitively clarified,” the study review concludes. It calls for more investigation to understand the role of probiotics in treating and preventing celiac disease.
Lebwohl noted that an earlier review of studies related to probiotics and celiac disease “similarly offers glimmers of an effect but leaves open great uncertainty” regarding which patients might benefit and in what situations, as wells as which specific probiotic to use.
“So, my takeaway is that it remains not at all clear that probiotics are effective in treating patients with celiac disease,” he said. “What to do in the midst of uncertainty? Probiotics are either helpful, harmful or inert. That makes them an ideal subject for study in clinical trials.” The fact that clinical trials are expensive and probiotic makers are not required to conduct extensive studies to determine safety and effectiveness before selling their product explains why there are few of these studies, Lebwohl said.
CDGEMM is a prospective, observational, multi-center study of the genetic makeup, environmental conditions, and gut microbiome of participating babies and children. The goal of the ongoing study is to identify how these factors contribute to disease development so that, in the future, it may be possible to predict who will develop celiac disease before it happens.
Early data from the CDGEMM study suggests that changes in the microbiome that could be linked to subsequent development of celiac disease can be identified more than a year before celiac disease develops, said Leonard, study lead. She said this is the most important thing researchers have learned from the study so far.
Alterations in the microbiome of infants who have gone on to develop celiac disease have been observed in the CDGEMM study, but this work needs to be repeated with a large sample size. Researchers also need to continue to explore how identified changes could be connected to the development of celiac disease.
Leonard and colleagues are finding that genetics and early environmental factors such as antibiotic use and the way in which a newborn is delivered alter the developing microbiome soon after birth. “Some of these changes persist until at least six months of age, which is the end of our current investigations,” Leonard said, noting that future research is designed to extend the timeline for investigating changes in the microbiome.
It’s not yet known exactly how the microbiome may contribute to the development of celiac disease, but the CDGEMM study is looking for an answer. Possibilities include increased leakiness of the gut, alterations in the immune response through the production of pro-inflammatory cytokines and alterations in the digestion of gluten.
Leonard noted that the study review from Italy points out that probiotics have also been shown to alter the immune response and the digestion of gluten peptides. “This demonstrates how much we have to learn about the complex interactions of probiotics in an individual microbiome,” Leonard said. It is possible that beneficial Bifidobacterium may be used in the future in conjunction with other probiotics and a gluten-free diet, but larger studies are needed before this could be considered as a treatment, she added.
The future may also hold the possibility of early interventions to alter the microbiome to prevent celiac disease, but much more research would be needed, according to Leonard. “As with many chronic autoimmune disorders, it is very likely that there are many paths to developing celiac disease,” she said. “Children at-risk of celiac disease will need personalized approaches mitigating environmental exposure and altering the microbiome, possibly through probiotics, to prevent celiac disease.”
You can read more about the study from Italy here.
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