How Can A Pattern Recognition Receptor Affect Gut Inflammation? (NOD2)

Vitamin D is required for the correct function of NOD2, and vitamin D deficiency is potentially harmful to the communication between NOD2, toll-like receptors, and the gut flora. Furthermore, multiple studies have found that people with higher circulating levels of vitamin D in their blood were less likely to develop Crohn’s disease [R].

However, in cell studies, mutations in the NOD2 gene had a stronger effect than vitamin D levels; that is, people with NOD2 mutations are unlikely to be able to correct the function of this gene with vitamin D alone [R, R, R].

Crohn’s disease (and the steroids used to treat it) have been linked to calcium and vitamin D deficiencies and subsequent osteoporosis. The best source of vitamin D is moderate exposure to sun [R, R, R].

Vitamin D is required for NOD2 to function correctly. The best way to get enough vitamin D is through moderate sun exposure.

Resistant Starches

Another nutrient that seems to be required for correct NOD2 function is butyrate, a short-chain fatty acid produced by beneficial bacteria in the gut. One study found that butyrate increased the expression of NOD2 while simultaneously decreasing the inflammatory cytokine NF-κB. Detrimental mutations in NOD2 tend to increase NF-κB, so butyrate is being investigated for its potential to correct this inflammatory pathway [R, R].

So far, butyrate’s potential benefits have been better studied in ulcerative colitis than in Crohn’s disease. However, in one study of 13 people with Crohn’s disease, a type of IBD, butyrate supplements improved 69% of cases, with symptoms completely disappearing in 54% (seven participants) [R, R, R, R, R].

Butyrate is available as a supplement; dietary factors also affect how much butyrate is produced by your gut bacteria. 

For Crohn’s, dietary butyrate supplements are not likely to help that much because it needs to be created in your large intestine, which happens with resistant starches and fibers.

Therefore, the best foods to increase butyrate production are those with plenty of resistant starches—starch that you can’t digest, but that the gut flora can in the large intestine. Baked potatoes that are cooled and green bananas are two good sources of resistant starch [R, R, R].

In general, eating fruits and vegetables, which contain a lot of fiber will help produce butyrate in the large intestine.

Resistant starches from sources like cooled baked potatoes and green bananas feed beneficial gut bacteria, which produce butyrate, a nutrient that appears to support NOD2.

Omega-3 Fatty Acids

Omega-3 fatty acids have been found to reduce the activity of both NOD2 and TLR4 in pigs. It is likely that omega-3s mostly act on TLR4, with the side effect of reducing the requirement for NOD2 in response [R, R].

In a clinical trial of 49 obese pregnant women, supplementation with omega-3 fatty acids (DHA and EPA) reduced the expression of TLR4 in body fat and the placenta. These fatty acids also lowered TLR4 levels in cells [R].

Omega-3 fatty acid intake, including from fish, has been inversely linked to the development of Crohn’s disease; that is, people who eat more fish (and omega-3s) appear less likely to get Crohn’s [R].

It is unclear whether omega-3 supplementation can help Crohn’s disease that has already developed and progressed. However, multiple studies have suggested that omega-3s may help keep Crohn’s disease in remission [R, R].

The balance between omega-3 and omega-6 fatty acids may be more important than omega-3 intake alone. People who eat more omega-6 fats and less omega-3 fats appear to be more susceptible to IBD [R].

Seafood is the richest sources of omega-3 fatty acids; sunflower, corn, soybean, and cottonseed oils are among the richest sources of omega-6 fatty acids and should be avoided [R].

Omega-3 fatty acids are anti-inflammatory and reduce TLR4, which reduces the need for NOD2 to activate and regulate it.

Probiotics

Because of NOD2’s close relationship with the gut flora, researchers are investigating whether probiotic supplements could be beneficial for people with harmful NOD2 mutations [R].

Some species of beneficial bacteria produce proteins called peptidoglycans in their cell walls. NOD2 senses these proteins, recognizes the presence of beneficial bacteria, and suppresses the inflammatory response [R].

Certain probiotic strains have been studied in people with Crohn’s disease, including Lactobacillus rhamnosus, Lactobacillus casei, Bifidobacterium breve, Bifidobacterium longum, and Saccharomyces boulardii. Of these, the first four showed some promise for people with active Crohn’s disease, while S. boulardii and L. rhamnosus may be helpful for keeping the disease at bay in patients in remission [R].

Some probiotic species suppress the inflammatory response by signalling to NOD2 that they are safe. These species may also be helpful in controlling Crohn’s disease.

Curcumin

Some studies have found that curcumin reduced NOD2, TLR4, and NF-κB activation. As with omega-3 fatty acids, however, the reduction in NOD2 may well be a result and not a cause of the reduction in other inflammatory signals; that is, when TLR4 and NF-κB are low, NOD2 is not required to regulate them [R].

Curcumin is a natural anti-inflammatory compound extracted from turmeric. Multiple clinical trials have produced promising results for curcumin in IBD (including Crohn’s), and further research is currently underway. Remember to never combine supplements with medications without first discussing these combinations with your doctor [R, R, R].

Curcumin is an anti-inflammatory supplement that reduces TLR4 activation, which may reduce the need for NOD2.