What Causes Crohn’s Disease? Is IBD Determined by Genetics?

Genes Mentioned

• IL10
• NOD2

Crohn’s disease is complex, chronic disorder primarily affecting the digestive system and with no single known cause. What we do know, though, is that this disease occurs more often in people with northern European ancestry and of eastern and central European (Ashkenazi) Jewish descent. When epidemiologists (who study disease development) identify this type of pattern for a disease, it gives them a clue that suggests genetics are at play. Add to that the fact that if one identical twin has Crohn’s disease, there is a 58.3% chance the other has it too, while the rate of concordance is just 3.9% for non-identical twins, and you have yourself a pretty solid case suggesting the involvement of genes. ¹ It’s no big surprise, then, that in recent years, scientists have uncovered hundreds of genetic locations and at least 10 genes significantly involved in Crohn’s disease. Before we get to those, let’s look at the symptoms of Crohn’s disease and whom it affects.

What is Crohn’s disease?

Crohn’s disease is a form of inflammatory bowel disease (IBD) and is characterized by an abnormal immune system response that leads to excessive inflammation in the digestive tract. Typically, this occurs in the intestinal walls, especially in the ileum (the lower part of the small intestine), but it can also affect tissue anywhere from the mouth to the anus. Ulcerative colitis is another form of IBD, but, unlike in Crohn’s disease, ulcerative colitis is typically isolated to the colon. Crohn’s disease can arise at any age, but usually appears when a person is an older teenager or in their 20s. ² And, because inflammation waxes and wanes according to a whole heap of factors, symptoms of Crohn’s disease tend to flare up throughout life, and especially at times of stress. ³ As tissues become inflamed and ulcers develop in the digestive tract, symptoms such as abdominal pain, cramping, weight loss, fever, loss of appetite, and persistent diarrhea can occur. Bleeding may also lead to discolored stools and anemia, if blood loss is persistent and/or severe. Some people with Crohn’s disease also experience symptoms related to inflammation in other parts of the body, such as in the joints, skin, and eyes. Scar tissue and inflammation can also cause intestinal blockages, and ulceration can lead to the development of fistulae, bridge-like connections between areas of tissue such as the intestine, skin, bladder, or vagina.

Crohn’s disease and genetics

If you have Crohn’s disease, chances are that it also affects other people in your family. About 15% of people with Crohn’s disease have a parent or sibling who also has Crohn’s. And, as mentioned, if you have an identical twin with the disease, you have a 58.3% chance of also having Crohn’s disease. ¹ At least 200 genetic variations have been identified that affect your risk of developing Crohn’s disease. These appear to modulate risk via the immune system, and through changes to the microbiome. Some of the genes identified so far that have been associated with an increased risk of developing Crohn’s disease include:

• G16L1
• HLA-DRB1
• IL10
• IL12B
• IL23R
• IRGM
• JAK2
• LRRK2
• MUC2
• NOD2
• SLC22A4
• SLC22A5
• STAT3
• TYK2

Around 30-50% of people in the western hemisphere carry a disease-causing mutation in at least one allele of NOD2, and people who have two mutated alleles have a 20- to 40-fold increased risk of developing Crohn’s disease. ^{4 5} Data from 51 studies involving over 28,000 people, including more than 12,000 with Crohn’s disease, revealed that people with the ATG16L1 variant rs2241880 had a 38% increased risk of Crohn’s disease. The ATG16L1 mutation also has been associated with an increased risk of necrotizing enterocolitis in premature infants. ⁶ In contrast, people with the IL23R variant rs11209026 were 54% less likely to develop Crohn’s disease. ⁷

Crohn’s disease and other health issues

Considering just how many genes are involved in Crohn’s disease, it’s understandable that there is some overlap with other health issues. A genetic link has been found between Crohn’s disease and diabetes, as well as rheumatoid arthritis and psoriasis. Crohn’s disease also seems to be linked to Ankylosing Spondylitis, with the two disorders sharing at least seven genes, four of which involve immune function. ⁸

Risk factors for Crohn’s disease

Lifestyle, diet, environment, and genetics seem to be co-conspirators when it comes to Crohn’s disease.

Smoking

Smoking, for instance, doubles the likelihood of developing Crohn’s and increases the frequency and severity of flare-ups. ⁹

Urban living

People who live in urban areas have also been found to be 42% more likely to have Crohn’s disease, which suggests that factors such as pollution, sedentary lifestyles, and diet might play a role in the disease. ¹⁰

High animal fat and high sugar diets

Indeed, diets high in animal fat and low in fruits and vegetables are most strongly associated with an increased risk of IBD. ¹¹ It makes sense that a diet high in sugars and saturated fats (especially pro-inflammatory animal fats) and lacking in antioxidants and other vital nutrients, could contribute to Crohn’s disease by promoting intestinal inflammation, altering the gut microbiome, and impairing healing and immune function. ¹¹ Fiber is a contentious issue for people with IBD, given that some types of fiber can exacerbate symptoms while others may help reduce inflammation. Diets high in soluble fiber, for instance, can help lessen inflammation because they increase production of the anti-inflammatory short-chain fatty acid butyrate in the intestine. ¹¹ Diets high in FODMAPs may, however, exacerbate symptoms in some people, with a low-fiber diet often advised during flares of IBD.

FODMAPS

FODMAPs (Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols) are types of fiber that are poorly absorbed in the gut, which can lead to excess gas production, bloating, abdominal pains, cramps, diarrhea, and constipation. Many people with Crohn’s disease, as well as irritable bowel syndrome, have success with a low-FODMAP diet, although this should be done under the guidance of a qualified nutritionist as cutting out a wide range of foods puts you at risk of nutrient deficiencies.

Addressing nutrient deficiencies caused by Crohn’s

Crohn’s disease itself presents an increased risk of nutrient deficiencies, likely through malabsorption and increased demand for certain nutrients to facilitate healing. Nutrients that are particularly problematic include:

• iron,
• calcium,
• zinc,
• magnesium,
• vitamin D,
• vitamin B12,
• folic acid,
• and vitamin A. ¹²

Low levels of vitamin D have also been linked to an increased risk of IBD, and a regimen of vitamin D and curcumin supplementation appears to be an effective way to enhance treatment for IBD. ¹³

Adherent invasive Escherichia coli and Crohn’s disease

There are more than 3 million unique genes within the gut, courtesy of the microbiome and sometimes referred to as our “second genome.” ¹⁴ These genes vastly outnumber your own genes and, thanks partly to the transient nature of some gut bacteria, create a somewhat moving target for epigenetic and nutrigenomic interventions. One target that has been identified is adherent invasive Escherichia coli (AIEC), a pathogen found in a staggering number of people with Crohn’s disease. In one study, AIEC was isolated from 36% of lesions in people undergoing surgery for Crohn’s disease, compared to just 6% of healthy controls. ¹⁵ Taking steps to control or eradicate AIEC may be useful in Crohn’s disease, therefore, with studies showing that the probiotic E. coli Nissle 1917 (EcN) may do just that. ¹⁶

Geographic location and Crohn’s

Early on in this article, we mentioned how Crohn’s disease disproportionately affects people with specific ethnic backgrounds. While where you live might not seem, at first glance, to fundamentally alter your immune function, the truth is that a person’s microbiome is greatly dependent on their geographic location and diet. In one study, researchers found that African children had a gut microbiome rich in Bacteroidetes species but poor in Firmicutes and Enterobacteriaceae. The guts of European children were completely opposite however, with ramifications for how each population would digest food and interact with intestinal pathogens, as well as how genes would be expressed in the gut. ¹⁷ What’s more, the increased prevalence and spread of IBD coincides with decreased biodiversity in the gut microbiome, in large part due to a western-style diet. ¹⁸ While association isn’t causation, it seems likely that environment, diet, your microbiome, and genetic factors interact in complex ways to alter a person’s risk of Crohn’s disease and to affect how the disease progresses. ¹⁹ See also: Probiotics aren’t the only way to restore healthy gut bacteria

Fighting Crohn’s disease with diet

In conclusion, while research is ongoing into the relationship between Crohn’s disease and genetics, sufficient evidence exists to support the idea that dietary measures could influence the expression and impact of genes (whether yours or those of your second genome) involved in the condition. For some people, green tea and DHA may help. In general, though, the smart move seems to be to eat a predominantly plant-based diet that is low in animal fats and sugar, and high in fiber, prebiotic, and probiotic foods. ²¹