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Researchers have spent decades trying to better understand Crohn’s disease, a type of chronic inflammatory bowel disease (IBD). But while its exact causes remain murky, scientists are learning more and more about the 100-plus genes that may play a role in its development. And they've got their sights on one in particular: NOD2.
Of the genes linked to Crohn's so far, having an altered NOD2 has been shown to result in the highest risk for developing the disease, with a higher risk for complications, says Gabriel Núñez, M.D., professor in the department of pathology at the University of Michigan Medical School in Ann Arbor, MI. In fact, between 30% and 50% of people diagnosed with Crohn's carry this specific marker.
But simply having a mutated NOD2 gene does not guarantee that Crohn's is in your future. Far from it: Only 3% of those who carry it go on to develop the condition. There's definitely something else—or, rather, trillions of something elses—at play.
What Is NOD2, Anyway?
First, a recap of Genetics 101: You have 23 pairs of chromosomes in your body; you inherit half from your mom and half from your dad. These chromosomes house hundreds to thousands of genes that code the instructions for making various proteins in your body.
Everyone has the NOD2 gene in their DNA, and in most people it works just fine, producing a protein called, surprise, NOD2, says Dr. Núñez. This protein lives in the cells that line your intestinal tract, adds Andrew Hurtado-Lorenzo, Ph.D., vice president of translational research programs at the Crohn’s and Colitis Foundation in New York City. The intestinal tract just happens to be the largest immune organ in your body, so if NOD2 detects the presence of invasive microbes, it kickstarts the production of molecules that fight the infection. When all works as it should, those germs are vanquished before you even know they're there.
So, What Does a Mutant NOD2 Gene Have to Do With Crohn’s?
When you inherit a mutation of the NOD2 gene, which was the first one to be connected with an increased risk for Crohn's, things in your gut can go awry. “These mutations alter the size and shape of the NOD2 protein, thereby impairing its biological function inside cells,” Dr. Hurtado-Lorenzo explains.
Since it was first discovered in 2001, several mutations of the NOD2 gene have been specifically linked to Crohn’s disease risk, Dr. Hurtado-Lorenzo says. “In people that carry one copy of mutant NOD2, the risk of developing Crohn’s disease increases two-to-four fold. In contrast, in people with two copies of the mutant NOD2, the risk of developing Crohn’s increases by 17 to-20 fold,” he explains.
While not everyone with a Crohn’s diagnosis has an NOD2 mutation, between a third and a half of them do possess at least one (while only about 11% of people in the general population carry one). What's more, research also shows that NOD2 mutations are mainly found in Caucasians, and less so in other groups, such as those living in Asia and sub-Saharan countries, according to Dr. Núñez.
How Does the Gut's Microbiome Impact NOD2?
One of the sneaky things about genes is that they don't always act alone. That's why scientists suspect some people with a certain mutation develop symptoms and others don't. In the case of Crohn's and NOD2 mutations, researchers think the missing link may lie among the trillions of microorganisms (including bacteria, viruses, and fungi) that normally live in the gut, says Dr. Núñez.
Because mutational changes to the NOD2 protein can result in compromised immune function, abnormal levels of bacteria can accumulate in the GI tract. As a result, the body's immune system goes into overdrive to get rid of them, ultimately triggering the inflammatory response that damages your gut tissue and leads to those all-too-familiar Crohn's symptoms: pain, cramping, diarrhea, vomiting, ulcers, and more.
Which Bacteria Are the Bad Guys?
“We do not know the bacteria that cause Crohn’s disease or IBD in humans," says Dr. Núñez. "But our recent studies on mice suggest that rare bacteria can accumulate and invade the gut tissue, leading to colitis that resembles human Crohn’s disease when the NOD2 gene is deleted.”
The majority of bacteria in the gut microbiota are good guys, Dr. Núñez clarifies. But rare bacteria that normally would be controlled by a healthy immune system, including NOD2, could potentially invade the intestinal tissue and create the intestinal inflammation seen with Crohn’s.
One 2019 review of research cited three main factors that can affect the types of bacteria found in your gut:
Your birth. Your gut microbiota develops early in life based on the microbiota that hangs out with you in your mother’s uterus, the study says. Whether you’re delivered vaginally or by C-section also makes an impact. That said, your microbiota isn’t set in stone after birth—other factors can change it later.
Your diet. Your diet as a baby also contributes to how your gut microbiota develop—research shows that breastfed infants have more stable microbiota and a good immune response. While much of what determines the composition of your gut microbiota happens when you are a baby, your diet throughout life also has an impact, the study says. For example, vegetarian diets are linked with a healthy, diverse gut microbiota that are good at breaking down insoluble carbs, while a Western, non-vegetarian diet may produce more harmful compounds.
Antibiotic use. While there are obvious benefits to taking antibiotics if you have a bacterial infection, it comes with a downside: They can destroy some of the beneficial parts of your gut microbiota, too. This can lead to the growth of unwanted bacteria, the study says. Similarly, probiotics can positively impact your gut microbiota. That said, research is mixed on whether probiotics are beneficial to people who have intestinal diseases.
More research is needed to fully understand the implications of these potential different factors, says Dr. Nunez. But it’s clear that NOD2 mutations affect how gut bacteria behaves.
Should You Be Tested for This Genetic Mutation?
If you have Crohn’s disease or if it runs in your family—and about 1 in 5 people with Crohn’s have a blood relative with some form of IBD, according the National Human Genome Research Institute—you're probably wondering if you should get tested for an NOD2 mutation.
The lowdown? It may be worthwhile, especially if you're already diagnosed. That’s because the test could help predict the course of your disease and help guide future treatment decisions. There's some evidence that the mutation corresponds with more complicated forms of Crohn's, including the development of intestinal obstructions that require surgery, Dr. Hurtado-Lorenzo explains.
While more research is definitely needed, a positive test for the NOD2 mutation, along with other clinical info—such as having certain antibodies—could actually help predict your Crohn’s prognosis, Dr. Hurtado-Lorenzo suggests.
Knowing your genetic status is also valuable because it can help doctors guide your Crohn’s treatments more effectively, he explains. They may suggest a more aggressive treatment plan from the get-go, for example.
What if you don’t already have a Crohn’s diagnosis? In that case, getting tested just isn’t that useful. That’s because, again, predicting whether someone will develop Crohn’s isn’t as simple as finding out whether they have the mutant NOD2 gene, Dr. Hurtado Lorenzo warns. The mutation still isn’t a guarantee of Crohn’s development. Even if you do test positive, it’s not beneficial, since (at this point, anyway) there is nothing you can do to prevent Crohn’s disease.
“Because there are currently no preventive treatment options for IBD, this information [gained from the test] may rather create a psychological burden for carriers, as opposed to instructing doctors on how to prevent disease onset in NOD2 carriers,” Dr. Hurtado Lorenzo explains.
The Future of IBD Research
In other current IBD research, genetics remain a huge focus. For example, the first-ever genetic prognosis test for IBD was just launched in the U.K. and Ireland in April 2019, Dr. Hurtado-Lorenzo says—although NOD2 isn’t part of it. The test may be helpful for doctors looking to better personalize treatments for people with Crohn’s disease, he adds.
The test, called PredictSure IBD, measures the expression of 17 other genes that may be present in the blood of people with IBD—Crohn’s or ulcerative colitis—at diagnosis. “High levels and low levels of these 17 genes can prognosticate high risk or low risk of developing aggressive IBD disease course, respectively,” Dr. Hurtado-Lorenzo says.
In the U.K., a 2019 study in Gut that followed up after four years showed that the test was successful in classifying IBD patients into categories of either high-risk or low-risk of aggressive disease, which then helped guide treatment decisions.
And, in the U.S., a study is currently evaluating the effectiveness of this test to predict IBD prognosis in American patients. If this test is approved, it will become the first-ever IBD prognosis test approved in the U.S.—a real milestone. The study is still in the recruiting stage, so stay tuned—but the Crohn’s and Colitis Foundation is hopeful that results will show it to be as successful as it was in the U.K. study.
Finally, in Dr. Núñez's lab, he and his team are focusing on gut bacteria and diet in animal models. “For example, [our research is looking at] the link between NOD2 mutations and specific bacteria that trigger Crohn’s,” he says.
Bottom line? The interplay of gut microbiota and genetics, aided by environmental factors, is driving innovative Crohn's research right now. Does that mean real answers about the causes of this IBD are finally within reach? Watch this space.