Celiac disease is an autoimmune gastroenteritis disorder that affects many individuals worldwide. There are many approaches used to explain the reasons for the prevalence of celiac disease. Evidence from current research links genetic factors involved in our body's inflammatory response to predisposition for celiac disease. From an evolutionary perspective, the genes for celiac disease should have been selected against, but celiac disease remains as one of the most prevalent diseases with a strong genetic predisposition. Evolutionary biologists are particularly interested in celiac disease because they speculate that the increased prevalence of celiac disease in the modern population could be explained by evolutionary biology. Evolutionary scientists offer several hypotheses that are based on a mismatch between past and current diets, evolutionary compromises, and a novel environment, explaining why celiac disease exists today and offering insight into factors that could have contributing to the increased prevalence of celiac disease. Some of these hypotheses fall short of explaining the increase in prevalence of celiac disease. Based on analyzing these hypotheses using the adaptationist program, a mismatch between our ancestor's diet and our current diet offer more convincing argument for the increase in the number of patients with celiac disease.
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In order to fully explore a multifaceted disease such as celiac disease, the etiology of the disease needs to be addressed. Celiac disease is a common gastroenteritis disease that affects 1% of the Western populations. The medical community identifies celiac disease as an autoimmune disease - a category of diseases that rise from an individual's overactive immune system. In general, autoimmune diseases affect 5% to 8% of the United States population and are regarded as the third most common category of diseases after cancer and heart disease (Catassi et al., 2010). Most autoimmune diseases are more common in females. Similar to other autoimmune diseases, females are twice as more vulnerable to celiac disease than males (Fabris et al., 2010; Matysiak-Budnik et al., 2007; Marild, Frostell & Ludvigsson, 2010).
Patients suffering from celiac disease have adverse reaction to gluten, a protein present in wheat, barley, and rye. Simply, celiac patient's immune system reacts negatively to gluten. Once an individual with celiac disease ingests food that contains gluten, the gluten is partially digested to another protein called gliadin. This molecule is responsible for activating the T-cell mediated inflammatory response, which with continued exposure to gluten, will eventually result in damage to the microvilli of the small intestine. Once the microvilli are damaged, the body is incapable of absorbing necessary nutrients for survival (Fasano, 2004). As a result, celiac disease patients show various symptoms including anemia, diarrhea, malnutrition, vomiting, nutrient deficiency and weight loss. With continued consumption of gluten, these patients suffer from damaged microvilli and eventually develop osteopenia, a disease caused by insufficient absorption of calcium. Even young children with celiac disease may develop osteoporosis or osteopenia if they are not immediately placed on a gluten free diet (Matysiak-Budnik et al., 2007).
Diagnosing and immediate treatment plan for celiac disease patients are crucial because undiagnosed celiac disease is associated with four times the risk of developing other health issues (Wu et al., 2010). Studies have also shown that untreated celiac disease could lead to development of other autoimmune diseases among celiac disease patients (Nalui et al., 2008). One example of common autoimmune diseases among celiac disease patients is malignant lymphoma, which is frequent among individuals who are diagnosed with celiac disease at an older age Some researchers believe that "upregulated immunological activity in untreated [celiac disease] may contribute to the development of autoimmune disease in genetically susceptible individuals" (Nalui, Ascher, Nilsson & Wahlstrom, 2008). Once the physician believes that a patient has celiac disease, physicians utilize the serological criteria tests. These tests measure levels of two different proteins - the IgA anti-tissue transglutaminase antibodies and IgG anti-gliadin antibodies with the absence of IgA antibodies (Catassi et al., 2010; Wu et al., 2010).
Currently, the only treatment option for patients suffering from celiac disease is restricting them to a life long gluten free diet. This treatment option has been implemented since the 1950s, and even today, it is the only viable option for patients with celiac disease (Matysiak-Budnik et al., 2007). Because of the pros and cons associated with the gluten free diet, physicians face a difficult choice when suggesting gluten free diet to patients, especially for young children and adolescents, (Matysiak-Budnik et al., 2007). Following a gluten free diet may lead to nutrition deficiency, stunted growth, and immunological imbalance (Matysiak-Budnik et al., 2007; Pinier, Fuhrmann, Verdu & Leroux, 2010). However, physicians tend to recommend gluten free diet because patients who were for "a few years on a [gluten free diet] during childhood may reduce the severity of [celiac disease] at adulthood" (Matysiak-Budnik et al., 2007). For some of these patients, reintroduction of gluten into their diet has been feasible without showing symptoms of "active celiac disease" such as vomiting, abdominal pains, and diarrhea (Matysiak-Budnik et al., 2007).
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Because the gluten free diet is restrictive pose problems of sufficient nutrient intake for celiac disease patients, there is a strong motive for researchers to explore other treatment options. Modifying wheat to make it safe for celiac disease patients, administering bacterial enzymes via tablets for complete degradation of gluten, interfering with gliadin's damaging activities to the intestinal wall, and disrupting the method of immune recognition of gliadin are some avenues that researchers are currently exploring as alternative methods to treat celiac disease (Pinier, Fuhrmann, Verdu & Leroux, 2010). The most promising of the proposed options is creating a tablet with bacterial enzymes, which has shown to sufficiently degrade gluten. Since ingesting gluten triggers adverse activation of the T-cell mediated inflammatory response in celiac disease patients, the inflammatory response may be subdued by modifying the chemical pathway gluten follows once it is ingested. Developing a tablet containing the exogenous enzyme prolyl endopeptidases (PEP) that would target gluten and cause its complete degradation would detoxify gluten peptides and prevent gliadin uptake in the gut (Pinier, Fuhrmann, Verdu & Leroux, 2010). Because PEP has only been only studied in vitro, further research is necessary to observe its in vivo effects before it can be clinically tested to celiac disease patients.
In order to explore better treatment options for celiac disease patients, it is necessary to gain better understanding of the origin and the causes of the disease. Among the celiac disease patients, there is a strong correlation between predisposition to the disease and certain genetic factors. The genetic basis for the disease is supported by twin studies that have found a 75% concordance rate of celiac disease between identical twins and genetic research showing a 40% concordance rate among siblings (Naluai, Ascher, Nilsson & Wahlstrom, 2008). The genes strongly associated with celiac disease express human leukocyte agent (HLA) DQ 2 heterodimers and HLA DQ 8 heterodimers. It has been found that 90% of the patients with celiac disease test positive for the HLA DQ 2 gene and almost all celiac patients who are negative for the HLA DQ 2 gene are positive for the HLA DQ8 gene (Naluai, Ascher, Nilsson & Wahlstrom, 2008). This phenomenon suggests that the HLA DQ 2 gene is a stronger indicator of celiac disease predisposition than the HLA DQ 8 gene (Fabris et al., 2010).
In addition to the HLA DQ 2 and HLA DQ 8 genes, another study shows that there are new loci in the genome that influence the genetic factors that contribute to development of celiac disease. One particular research study concludes that there eight newly discovered loci that are believed to contribute to immune response (Romanos et al., 2008). Romanos et al. predict that "60% of the genetic heritability" of celiac disease is due to non-HLA genes, but "each of [the eight loci] is estimated to contribute only a small risk effect" (2008). This supports the claim that non-HLA genes may be more influential than previously thought (Ivarsson, Persson, Nystrom & Hernell, 2002). Because this study concentrated on the southern European population, the authors also speculate that there may be a population difference in genetic predisposition to celiac disease (Romanos et al., 2008).
Recent research has been conducted to find more gene sequences associated with celiac disease. Scientists estimate that the genetic heritability of celiac disease is explained 40% by the HLA DQ 2 and HLA DQ 8 genes and 60% by a combination of other genes (Romanos et al., 2008). One of those gene sequences is the14-base pair (bp) insertion allele in the HLA-G gene. The recessive allele of the HLA-G gene has been observed to occur more frequently among individuals with celiac disease than in normal population. The study showed that 14-bp allele followed a recessive genetic model and the recessive allele is "significantly more frequent in celiac disease patients than in healthy controls" (Fabris et al., 2010). There was no difference in genotype frequencies between men and women for the HLA-G 14-bp insertion pattern (Fabris et al., 2010). The study also looked at individuals with the 14-bp insertion in addition to the HLA DQ 2 gene. Fabris et al. conclude that individuals with both genes have higher predisposition to celiac disease compared to the individuals with just the HLA DQ-2 gene (2010). They believe that increased level of HLA-G among celiac disease patients may be due to HLA-G's role in "restoring tolerance toward dietary gluten" (2010). In addition, another recent study explores SH2B3 as a locus that is associated with having a protective effect from diseases (Zhernakova et al., 2010). Research shows that the SH2B3 gene plays a significant role in increasing cytokines response and thus associated with various autoimmune and metabolic disorders (Zhernakova et al., 2010). Although genetics alone cannot be used to predict at risk individuals due to complex genetic inheritance pattern, genetics play a significant role in predisposition to celiac disease.
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These genetic sequences prevalent among celiac disease patients serve as proximate causes of the disease that predispose certain individuals to celiac disease. However, genetics alone cannot be used to explain the high prevalence of celiac disease. There is still a small percentage of the healthy population who have the gene sequences associated with celiac disease, but do not display any symptoms (Nalui, Ascher, Nilsson &Wahlstrom, 2008). There is also an increasing number of individuals who become immunologically intolerant to gluten as they age, suggesting that certain environmental factors are triggering the onset of celiac disease (Catassi et al., 2010). Thus, the researchers believe that about 40-50% of the susceptibility of celiac disease is due to environmental causes (Fabris et al., 2010).
To show that environmental causes contribute greatly to development of celiac disease, there is evidence to support that seasonal pattern affect infants' exposure to infections and their development of the immune system. One particular study looked at sunlight exposure as well as varying temperature of the seasons as factors affecting celiac disease occurrence (Ivarsson, Hernell, Nystrom & Persson, 2003). For infants diagnosed before the age of 2 years, the frequency of celiac disease was higher among those born in the summer (Ivarsson, Hernell, Nystrom & Persson, 2003). Researchers believe that this is due to the seasonal effect on immune system and to the variations in both infectious and non-infectious exposure level between seasons (Ivarsson, Hernell, Nystrom & Persson, 2003). For example, the infants born in the summer are in utero during the winter when mothers are more vulnerable to infections (Ivarsson, Hernell, Nystrom & Persson, 2003). It is possible that interactions with adenoviruses, which are upper respiratory infections such as common colds, contribute to celiac disease development due to immunological cross reactivity between the virus and A-gliadin, a protein that's present in the body and responsible for post-gluten consumption inflammatory response among celiac disease patients (Ivarsson, Hernell, Nystrom & Persson, 2003).
Another possible environmental factor is the infant's diet and the variation in the infant's diet based on what season they were born in. Researchers predict that about half of celiac disease is due to the individual's infant dietary pattern (Ivarsson, Hernell, Nystrom & Persson, 2003). Studies have shown that delayed introduction of gluten in an infant's diet could reduce the possibility of developing celiac disease (Matysiak-Budnik, 2007). Since it is a common practice among the mothers to wean their infants off breast milk and introduced them to gluten during the winter, celiac disease is more common among infants born in the summer (Ivarsson, Hernell, Nystrom & Persson, 2003). Since changes in infant feeding practices vary with season, the infant's diet is also affected seasonally.
Theses genetic and environmental factors are used to explain why an individual may develop celiac disease. However, these factors cannot explain why celiac disease has persisted in today's population or what contributed to the rise in the prevalence of celiac disease. Because predisposition for celiac disease has been established to be highly genetic, natural selection should have selected against these genes. Having celiac disease is not a positive trait, but why is there a rise in number of celiac disease patients? In attempt to address these questions, evolutionary biologists utilize the adaptationist program to offer hypotheses as to how celiac disease fits into the larger evolutionary context to draw conclusions as to why celiac disease exists in today's populations.
One hypothesis to explain why celiac disease is so common in today's population is the theory that the gene sequences that are common among celiac disease patients may also have a protective effect. This hypothesis would suggest that these genes are examples of evolutionary compromises. There is evidence to show that having celiac disease is a form of protection from bacterial infections since genes associated with celiac disease play a role in the immune responses (Zhernakova et al., 2010). The previous mentioned gene sequence, specifically the SH2B3 loci, could have been selected for 1200-1700 years ago due to greater mortality from an infectious disease (Zhernakova et al., 2010). Research shows that SH2B3 loci was under positive selection during that time period and could have resulted in "population differences in selective pressure resulting in global allele frequency variations" (Zhernakova et al., 2010).
Similar to the SH2B3 gene, one study shows that having the HLA DQ 2 gene could be advantageous if an individual lacks some other HLA molecules since the HLA DQ 2 molecules has procytokine functions and plays a role in the inflammatory response (Nalui, Ascher, Nilsson & Wahlstrom, 2008). Research evidence suggests that the HLA DQ 2 gene is a "wildtype" gene and thus the presence of this gene would be explained as both an evolutionary compromise and an evolutionary legacy (Naluai, Ascher, Nilsson & Wahlstrom, 2008). Although celiac disease is not optimal for an individual's survival, the HLA DQ 2 gene could have offered protection as some infections and these individuals have survived to reproduce and pass on their genes to their offspring (Naluai, Ascher, Nilsson & Wahlstrom, 2008). Therefore, having this gene could be a benefit in terms of protection from infections. However, there is insufficient evidence to suggest why the gene was selected against for certain populations while it persisted in other populations.
Evolutionary biologists also propose several hypotheses to explain why there is a rise in prevalence in celiac disease in today's population. In the last thirty years, the population of individuals with celiac disease in the United States has doubled every 15 years with a total of 4-fold increase in thirty years, and a similar trend has been observed in other Western countries (Catassi et al., 2010). One hypothesis used to explain this rise in celiac disease patients is the new modern method of giving birth. In the last decade, specifically between the years 1991 to 2007, the rate of Cesarean delivery increased by 15% to 30% and with this increase was accompanied by an increased rate of celiac disease (Decker et al., 2010). Thus the increased rate of infants born via Cesarean delivery could be linked to increased prevalence of celiac disease. This hypothesis suggests that birthing through Cesarean delivery would expose infants to a novel environment, as opposed to infants birthed by vaginal birth. One study examined Cesarean delivery contributing to celiac disease due to alterations of intestinal microflora among infants born by Cesarean delivery. The study showed that Cesarean delivery influences postnatal bacterial colonization in the infants' intestines (Decker et al., 2010). There are noted differences between the infants born via Cesarean delivery and the infants born via natural birth when researchers analyzed the infants' microbial flora in their enteric epithelial surface (Decker et al., 2010). Alterations of microbial flora composition and anatomic localization of the epithelial lining could explain why infants born via Cesarean section are more vulnerable to intestinal complications, including celiac disease (Decker et al., 2010).
Although it may seem that the increase in Cesarean delivery is a valid explanation for the recent rise in prevalence of celiac disease in the United States, this trend still doesn't explain why there are increasing number of celiac disease patients. The increased Cesarean delivery may be due to other factors such as higher prevalence of women with celiac disease giving birth to preterm babies and having no choice but to deliver their babies via Cesarean delivery (Decker et al., 2010). There is no research that compares the prevalence of celiac disease among infants of women with celiac disease born via Cesarean delivery versus vaginal delivery. Without evidence from such research, the rise in prevalence of infants born via Cesarean delivery and of individuals with celiac disease could be mere coincidence.
The hypothesis that offers the best argument for the rise in celiac disease in today's population suggests a mismatch in the dietary patterns between our ancestors and today's population. Our ancestors' genetic composition did not account for domestication and therefore high gluten consumption. Studies show that compared to the wheat in the early days of domestication, the amount of gluten present in the wheat today is much greater (Nalui, Ascher, Nilsson & Wahlstrom, 2008). This is possibly due to genetic engineering of wheat to develop efficient crops. It is possible that the wheat in our ancestors' diet didn't contain enough gluten to trigger an autoimmune response (Nalui, Ascher, Nilsson & Wahlstrom, 2008). In today's world, celiac disease is more common among populations where gluten is a more substantial part the population's diet. One study observed that celiac disease was more prevalent in the regions of China with high levels of gluten in the region's main crops (Wu et al., 2010).
This hypothesis can be used to explain the rise of adults who are diagnosed with celiac disease in their adult years. Since celiac disease is an autoimmune disease, the diagnosis for the disease in most patients is determined in the first two years of infancy. In the recent years, there has been an increase of individuals who develop autoimmunity towards gluten in their adulthood (Fasano, 2004). Throughout an individual's lifetime, gradual increase in exposure to gluten can trigger an autoimmune response to result in celiac disease.
Although the mismatch theory is a compelling explanation, further research needs to be conducted to test this theory. As of now, this theory is mostly based on observations of populations with increasing prevalence of celiac disease. To show association between increased gluten intake and development of celiac disease, it would be necessary to conduct a controlled study to look at different amounts of gluten in the diet and the pattern of celiac disease development among individuals with no family history of celiac disease as well as among individuals who are genetically predisposed to celiac disease but without the disease. This may be a difficult study to conduct, but it may strengthen the mismatch theory.
The need to understand the origin and the causes of celiac disease rises from the lack of efficient treatment plans other than gluten free diet. In the scientific community, there is a general consensus that genetic factors play a significant role in predisposition of celiac disease. However, there is no clear explanation for why these genes are still present in today's population when celiac disease is not a favorable trait and natural selection should have selected against these genes. Among the numerous hypotheses that attempt to explain why celiac disease exists in today's population and why there is an upward trend of the disease, most hypotheses fail to sufficiently explain this phenomenon. Of the numerous hypotheses to explain the increased prevalence of celiac disease, the best explanation is provided by the mismatch between the diet of our ancestors and the diet of the current population. This is a highly compelling hypothesis that can be bolstered by further research.