Metabonomics and Celiac Disease: A New Frontier

Celiac.com 03/29/2019 - What are we looking for when we ask for testing for celiac disease? The primary objective is usually to discover whether a given set of troubling symptoms are the result of eating gluten. With asymtomatic family members, the objective is likely to avoid developing the many health problems that are in the offing for those with untreated celiac disease. But maybe there is another reason to test for celiac disease. Perhaps some people could achieve optimum health— a better and longer life—through eliminating gluten from their diets. Two relatively new developments in the field of celiac disease research may open the path to testing aimed at optimal health. These discoveries may offer a better understanding of the dynamics of celiac disease and others who are genetically susceptible to gluten’s negative impact on human health. In 2009, Dr. Ivano Bertini and colleagues reported their discovery of a metabonomic signature of celiac disease (1). Metabonomics is a field of study involving an examination of blood and urine looking for signs of multiple metabolic changes caused by a biological irritant or perturbation. These signs are formed by the products of food digestion, cellular assimilation of these nutrients, and the by-products of cellular conversion of  food products to energy, as well as the enzymes produced to facilitate these conversions. These metabolites are identified, quantified, and the patterns they form are determined through a process of nuclear magnetic resonance and subsequent statistical analysis of these findings.  

Bertini et al discovered that those with untreated celiac disease show a pattern of these various  substances in both their blood and urine (1). This offers a new, holistic approach to the study and understanding of celiac disease. Although, for diagnostic purposes, it is not as accurate as serum antibody tests. This is partly because it does not do as well at distinguishing between latent and active celiac disease. However, this investigative approach does explain some of the variations in the many manifestations of celiac disease, while it transcends many of the controversies that currently surround appropriate treatment of celiac disease, potential celiac disease, latent celiac disease, and asymptomatic celiac disease. It may even offer insight into some elements of non-celiac gluten sensitivity. 

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I have previously described some of the problems with the diagnosis of celiac disease on the basis of intestinal biopsy. In short, these problems include improper sample orientation or harvesting damage done during the endoscopic procedure. Sometimes an inadequate number of biopsies (in the past a single sample was often considered adequate to exclude celiac disease) impedes accurate diagnosis or exclusion. Sampling errors can also cause problems due to patchy villous atrophy in the intestine. There are still some pathologists who do not use the Marsh system, or one of its derivatives, or refuse to count intra-epithelial lymphocytes. They also inhibit accurate diagnosis of this common disease. Sometimes, just getting a referral to see a gastroenterologist can also pose a diagnostic problem. General practitioners can serve as gate-keepers who will not refer patients to gastroenterologists for a variety of reasons. If patients are demonstrating symptoms of celiac disease but are overweight or even of normal weight, or if the patient is demonstrating signs and symptoms of celiac disease with which the practitioner is unfamiliar, they are often refused a referral. These same practitioners will also resist ordering serological antibody testing, despite requests from their patients, citing similar reasons.  When patients have experienced improvements after a trial of a gluten free diet, and now want a diagnosis, they will likely be disappointed. Whether under the supervision of specialists or general practitioners, gluten challenges are particularly difficult as nobody can predict the duration or quantity of gluten that should be consumed to ensure an accurate test.   

The problems with serum antibody tests are at least equally perplexing. They will often miss milder cases of celiac disease and sometimes fail to identify serious cases, both of which might have been caught if an endoscopic biopsy had been done. Without a concurrent measurement of total IgA, those with IgA deficiency will also be overlooked. IgA deficiency has been reported to constitute about 14% of celiac patients (2). False positive serological tests can also pose a diagnostic problem. Some reports contend that these false positive antibody tests constitute potential or latent celiac disease, while others report them in the context of other bowel diseases, arthritis, and other autoimmune diseases. Still others insist that a gluten free diet should only be recommended to people who have celiac disease with demonstrable villous atrophy. 

To further confound this issue, some of these antibody tests require the technician to make subtle color distinctions while others are impugned because intestinal parasites and other autoimmune diseases will also cause production of these antibodies, and for any of a number of other reasons. Further, no antibody tests produce results that are completely congruent with intestinal biopsies, so they carry the added problem of being dismissed by many practitioners who recognize celiac disease only on the basis of intestinal biopsies. To further confound this situation, the cyclic nature of celiac disease may also interfere with diagnosis on the basis of either intestinal biopsies or blood tests. This is because a series of intestinal biopsies may appear normal, or blood tests may produce normal results, at one time, yet subsequent testing will reveal celiac disease. 

Testing for the metabonomic signature of celiac disease, on the other hand, identifies specific metabolite patterns in the urine and blood, and may someday circumvent every one of these problems. The metabonomic signature may prove to be unsurpassed as a tool for increasing our understanding of celiac disease. This investigative process has already reflected three important components of  untreated celiac disease: malabsorption; changes to cellular energy metabolism, and; altered gut microflora/intestinal permeability. 

While some of this information has been found by other means, this research has produced some new insights into impaired glycolysis at the cellular level, in the context of active celiac disease. This leads to reduced pyruvate and lactate with concurrent increases in blood glucose levels. This compromises our ability to make full use of one of our two main sources of cellular energy. Because of fat malabsorption, which is characteristic of celiac disease, the other major source of cellular nutrients is also compromised. Ketone bodies, a by-product of cellular use of fat, also become an important source of brain fuel in cases of active celiac disease.  Thus, we now know a little more about the lethargy and malaise that often accompanies celiac disease. Our cells are starving for energy and we are incurring much of the same damage that is seen in poorly controlled diabetes, due to chronically elevated blood glucose levels, while some brain functions may be spared through utilizing ketone bodies.  

Such features of this metabonomic signature are abolished after a year of gluten avoidance.  In subsequent research reported in December of 2010, metabonomic testing has shown similar metabolite patterns in latent or potential celiac disease, which also normalize after a year of following a gluten free diet (3). This is powerful evidence that those with latent or potential celiac disease can benefit as much from the gluten free diet as those who already have villous atrophy. It also opens the door for understanding the dynamics whereby some celiac patients can be overweight while others are underweight but both suffer malnutrition with respect to some micro-nutrients. And it clarifies the importance and therapeutic value of a gluten free diet for those who might otherwise be told that they have potential or latent celiac disease and therefore don’t need the diet.

Susan, a friend of mine in Arizona who has celiac symptoms and a suggestive family history, was recently told by her gastro that “we don’t believe in gluten sensitivity where there is no villous atrophy”.  Bertini and colleagues comment on their findings with respect to patients such as Susan saying: “They already experience some subtle alteration of the enterocytes (at the microscopic functional level but not at the macroscopic level) and metabolically appear similar to overt celiac disease also without any histological evidence of intestinal damage.” Yet their blood and urine carries a metabonomic signature that clearly demonstrates they would benefit from a gluten-free diet. So despite her negative biopsy, Susan really should follow a gluten-free diet. Bertini and colleagues have demonstrated the benefits through metabolic research.    

Metabonomics is an exciting new field of research that is poised to reveal hidden facets of many ailments, but it may be particularly helpful to improving our understandings of intestinal ailments and a variety of psychiatric illnesses where we are already aware of altered urinary peptide profiles. Perhaps we will soon see support for the therapeutic use of the gluten free diet in many intestinal, autoimmune, and psychiatric illnesses because of this unique approach to understanding the exquisitely complex machinations of our bodies in sickness and in health.  

Sources: 
1. Bertini I, Calabrò A, De Carli V, Luchinat C, Nepi S, Porfirio B, Renzi D, Saccenti E, Tenori L. The metabonomic signature of celiac disease. J Proteome Res. 2009 Jan;8(1):170-7.
2. Bahari A, Karimi M, Sanei-Moghaddam I, Firouzi F, Hashemi M. Prevalence of celiac disease among blood donors in Sistan and Balouchestan Province, Southeastern Iran. Arch Iran Med. 2010 Jul;13(4):301-5.
3. Bernini P, Bertini I, Calabrò A, la Marca G, Lami G, Luchinat C, Renzi D, Tenori L. Are Patients with Potential Celiac Disease Really Potential? The Answer of Metabonomics.  J Proteome Res. 2010 Dec 13.