Kathryn Peterson ’22 and Lynsey Randolph ’22


When I was younger, I was convinced my father was lying when he swore that salads made him sick, yet he could eat a ribeye-steak with no problem. It was comical then, but with age I learned that this was his harsh reality with Crohn’s Disease. Chronic Crohn’s Disease impacts half a million US individuals1 and is a heritable form of inflammatory bowel disease known to cause symptoms such as abdominal pain and weight loss. These symptoms can be managed with proper dietary restrictions, but the wide variability in both personal food-triggers and tolerance levels makes full treatment difficult. With similar disruptive symptoms and heritability, Celiac’s Disease impacts about 1% of the US population2 and is also difficult to treat. Despite the only restriction being food containing gluten, this protein is found in wheat, barely, and rye3, so many foods contain it. Additionally, an individual’s tolerance to gluten may vary. Both Crohn’s and Celiac’s diseases often feel like an invisible battle, with each dietary choice needing to be made with care. This heightened awareness is only half the battle though, as beneficial treatment is often difficult to find given each person’s variability in symptom severity, dietary options, and tolerance levels.   

Whole thirty, keto, vegetarian, dairy free, gluten free, and plant-based are just a few of the many diet choices out there. Despite the variations, at the end of the day, we are all trying to feel comfortable and energized by the food we consume. When a person is struggling to do so for whatever reason, the quick fix is usually to cut that item out of their diet. Implications can get blurry, however, when a person claims a food intolerance. By medical standards, intolerance is a far weaker claim than allergic because the reaction is less clear. Nonetheless, intolerant reactions can force people to deal with serious consequences beyond an uncomfortable trip to the bathroom. Although people are free to claim food intolerances as they please, Crohn’s disease and Celiac disease have scientific bases that should not be overlooked due to the gaps in knowledge surrounding their treatment. In recent years, studies on these diseases have drastically increased allowing us to understand their pathology, the science behind the cause and effects of these diseases.

Humans vary in traits (ex. hair color) due to small changes in their DNA sequence, or genetic code, and we inherit genetic code from our biological parents in a process of gene inheritance. In the case of inflammatory-related diseases, genes that influence how a parent responds to certain foods are passed on to their children, which can influence their response to food as well. Apart from changes to the genetic code itself, reversible DNA modifications change how the body reads its genetic code. These DNA modifications act like a car’s gas cap by allowing in or blocking the levels of gas (or genes) in the body. Epigenetics is a field that studies how a person’s environment can modify DNA in this way by changing gene levels (otherwise known as the amount of gene expression), which results in behavioral changes. The specific subfield of Nutriepigenetics focuses on DNA modifications made when food serves as the environment. There is evidence that both gene inheritance and epigenetic changes drive the symptoms of both Crohn’s and Celiac disorders.

In general, certain genes inherited at birth can influence the onset of Crohn’s Disease around the ages of 15-30. Following disease onset, an individual with Crohn’s typically restricts certain foods if it triggers inflammation, which is the cause of symptoms. Although the inflammatory response mechanism to certain foods is not fully known, recent data shows that inflammation is partially influenced by diet-driven changes in gene expression. In other words, once Crohn’s-specific genes are inherited and the disease has onset, diet can change the levels of these specific genes throughout a person’s lifetime, thereby influencing the effectiveness of dietary treatment/remission. This may explain why a single prescribed diet to alleviate all inflammatory responses is difficult. Several studies show that a person can vary in how their gene expression levels change in response to different diets, such that one food type (like salad), but not another (like steak), can increase gene expression in a way to cause an inflammatory response in the gut microbiome4 (This pathway is shown below). Inflammation of the gut responds to adverse bacterial conditions and the DNA modifications of specific microbial genes is shown to affect these bacteria levels5. In other words, a gas cap (DNA modification) can be added to prevent a much needed gas (genes) from being in the car’s body, and the motor (the gut microbiome) can respond by working improperly (inflammation). Since these microbial genes are in constant interaction with different foods like salad or steak that cause varying states of DNA modification (cap on or off), a person’s inflammatory symptoms can be driven by nutriepigenetics. 

(Ferguson et al., 2012)

Recent data has also found that prior to Crohn’s Disease onset, both a mother and child’s diet can drive changes of gene expression and affect an individual’s disease course. That is, the combination of gene inheritance, a mother’s diet during pregnancy, and the child’s diet before the ages of 15-30 can determine an individual’s later symptom severity. In a study using rats, it was shown that adolescents with Crohn’s gene inheritance (genes such as Ptpn22) did not have an increased severity in inflammation when they alone were given a diet of high methyl-donor foods (methyl donor foods influence the state of DNA modification (cap on or off), which was previously described to harm bacteria levels in the gut and cause Crohn’s inflammation). However, when the mother had a high methyl-donor diet during pregnancy, and the offspring also had this diet, the inflammation did increase in severity. This finding suggested that, following Crohn’s-specific gene inheritance, a mother and child’s diet can lead to DNA methylation and changes in microbial gene expression in a way that determines how the individual experiences symptoms and their tolerance to certain foods later in life6.  

Taken together, these studies show how the treatment of Crohn’s Disease can be complex. Although dietary choices can influence inflammatory-response symptoms through changing gene expression, no single food choice among everyone has an equal influence on symptom severity. Furthermore, the diet of a mother while pregnant– long before an individual is able to make diet choices themselves– is able to influence the symptom sensitivity of an individual through prenatal DNA modifications in microbial genes. However, no evidence suggests that a mother’s diet increases the likelihood of an individual having Crohn’s Disease later in life. Positively, an individual’s personal diet can prevent symptoms due to the microbiome’s constant interaction with food and the ability to maintain healthy bacterial levels that do not spark inflammation. Overall, the nutrigenomics of Crohn’s has societal implications for understanding how current patients can partially prevent the effects of microbial gene expression changes through diet in order to prevent painful inflammation. Presently, long-chain n-3 fatty acids (found in fish-oil supplements) have been linked to anti-inflammation and reduced symptom severity in rats (see ref. [4]). In the future, available treatment options may benefit from Nutrigenomics research by allowing more personalized prescriptive diet treatment in humans to prevent inflammatory responses to specific foods. Additionally, preventive diets could be identified for pregnant mothers to take in cases of their offspring having a high risk for Crohn’s gene inheritance.

Similar in symptomatology, Celiac’s Disease is the heritable result of a person’s genetic makeup and how their environment influences their genes. In this case, the factor which contributes to their genomic environment is gluten consumption. Official Celiac diagnosis requires a person to possess the allele encoding for either HLA-DQ2 or HLA-DQ8 which are proteins made by human leukocyte antigen (HLA) genes. HLA genes are significant in the body’s defense against molecules which make their way into the body without an invite to be there. However, presence of these alleles in a person does not guarantee Celiac disease (see ref. [3]). In other words, on a person’s sixth chromosome of organized DNA, at the area specific to HLA genes (labeled as 6p21.3), HLA-DQ (in class 2) version 2 or version 8 needs to be there. It is notable that as of 2017, researchers described the HLA gene as the most variable area in human DNA, and that it plays an important role in our immune system7.

Gluten is a protein rich in glutamine and proline, which are amino acids that can cause digestive issues in a person’s upper gastrointestinal tract (see ref. [3]). Amino acids are a group of 20 building blocks that uniquely combine to form proteins. A toxic component of gluten, called gliadin, which consists of these two amino acids, can resist degradation and pass into the intestine to interact with antigen-presenting cells. These cells are a part of our immune system, and treat the gliadin fragments as unwelcome guests in the body, like they might treat the flu, when the body possesses the HLA-DQ2 or HLA-DQ8 gene characteristic. This interaction causes inflammation, or irritation, which might leave patients feeling sick (see ref. [3]). The inflammation as a result of gliadin increases gene expression of pro-inflammatory cytokines, which are signaling proteins that lead to oxidative stress. Think of cytokines as signals given by a conductor which cause the orchestra to play music in a louder, more obnoxious style. This stress creates a molecular imbalance which can cause cell damage in the intestine8. (The mechanism can be seen below as gliadin leads to NF-kappaB transcription factor activation, which causes further inflammation in the form of oxidative stress.)

(Ferretti et al., 2012)

Consumption of vitamins C and E found in vegetable food and oil can modulate immune responses in people with Celiac Disease by decreasing the release of pro-inflammatory cytokines to gluten. This would be a conductor signaling to the orchestra to play their music more peacefully and quietly. Ultimately, this leads to down regulation of the transcription factor NF-kappaB, which is a molecule responsible for turning genes on. When NF-kappaB is decreased, there is further oxidative stress in response to gliadin’s interaction with antigen-presenting cells. These vitamins can also be absorbed by the intestinal walls to prevent further inflammatory damage (see ref. [8]). Additionally, plant based molecules called Polyphenols and Carotenoids in fruits and vegetables can cause anti-inflammatory effects by suppressing that same transcription factor. Another example of DNA regulation against the effects of gluten is seen in n-3 fatty acid consumption. Similar to vitamins C and E, and Polyphenols and Carotenoids, n-3 fatty acids inhibit NF-kappaB transcription factor activation, halting pro-inflammatory cytokine production  (see ref. [8]). This would be like putting the conductor in a very calm mood so that he will not tell the orchestra to play their music in an aggressive way. It is interesting that the effects of gluten consumption in those with celiac can be reversed, however, the main form of treatment is simply to avoid consumption. This is likely because in the more serious cases of Celiac Disease, oxidative stress may damage tissue further than repair allows. Although it is up to one of two possible genes to decide for sure if a person is Celiac, it seems possible that aside from these two, some genes may be more likely to cause struggles with breaking down glutamine and proline in gluten and experience adverse inflammatory effects than others. Through this approach, it makes sense why we see more people cut gluten out of their diet than those with Celiac diagnosis. 

Both Crohn’s and Celiac’s Disease present symptoms following inflammatory response. Therefore, assessing how diet can influence these changes through Nutriepigenetics provides interesting avenues for treatment. A diagnosis of these diseases requires a certain set of genes to be inherited, and these genes are implicated in the inflammatory responses that drive symptoms. Rather than focus on observable symptoms such as abdominal pain, it could be helpful to instead analyze how these genes respond to certain diets in a given individual. Furthermore, although a certain criteria of gene inheritance must be met for a diagnosis, it is likely that individuals outside of a diagnosis experience food intolerance due to a few inflammatory-related genes. People often cut foods out of their diets because they feel that it does not sit quite with their bodies. Perhaps we can look at our genetic makeup as a spectrum for our ability to consume without a cascade of inflammatory events inside our bodies making us wish we had not done so.

References

  1. MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); [updated 2022 Feb 14]. Crohn disease; [updated 2022 Jan 3; reviewed 2022 Jan 3; cited 2022 Feb 16]; [about 7 p.]. Available from: https://medlineplus.gov/genetics/condition/crohn-disease/
  2. Celiac Disease: Fast Facts | BeyondCeliac.org. (n.d.). Beyond Celiac. Retrieved March 24, 2022, from https://www.beyondceliac.org/celiac-disease/facts-and-figures/
  3. Green HR, Cellier C. Celiac Disease, New England Journal of Medicine. 2007 Oct 25;357(17):1731-43. doi:10.1056/NEJMra071600. PMID: 17960014
  4. Ferguson, Lynnette R. “Potential value of nutrigenomics in Crohn’s disease.” Nature Reviews Gastroenterology & Hepatology, vol. 9, no. 5, May 2012, pp. 260+. Gale Academic OneFile, link.gale.com/apps/doc/A289722656/AONE?u=umuser&sid=bookmark
  5. Ryan FJ, Ahern AM, Fitzgerald RS, et al. Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease. Nat Commun. 2020;11(1):1512. Published 2020 Mar 23. doi:10.1038/s41467-020-15342-5-AONE&xid=0740c0d8.
  6. Schaible TD, Harris RA, Dowd SE, Smith CW, Kellermayer R. Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes. Hum Mol Genet. 2011;20(9):1687-1696. doi:10.1093/hmg/ddr044
  7. Crux, NB, Elahi S. “Human Leukocyte Antigen (HLA) and Immune Regulation: How Do Classical and Non-Classical HLA Alleles Modulate Immune Response to Human Immunodeficiency Virus and Hepatitis C Virus Infections?” Frontiers in Immunology, vol 8, 2017. doi:10.3389/fimmu.2017.00832.
  8. Ferretti G, Bacchetti T, Masciangelo S, Saturni L. Celiac disease, inflammation and oxidative damage: a nutrigenetic approach. Nutrients. 2012 Apr;4(4):243-57. doi: 10.3390/nu4040243.