Can This Gene Worsen Gut Inflammation? (NOS2)

Giving Up Smoking

Smoking is clearly associated with an increased incidence of Crohn’s disease, while its effects on ulcerative colitis are less evident — this condition seems to be more common among former smokers but less among people who currently smoke [R].

Smoking is also associated with an increased incidence and severity of stomach and colorectal cancer [R, R].

While avoiding smoking is a good idea for everyone, this may be even more beneficial to people with overactive NOS2 variants, since cigarette smoke increases NOS2 production (as seen in isolated lungs and blood vessels). Importantly, the ‘A’ variant of rs2297518 was associated with an even higher risk of stomach and colon cancer in smokers [R, R, R, R, R].

Avoiding Excess Alcohol

Some studies in rats have reported that chronic alcohol intake may increase NOS2 production [R, R].

In people already diagnosed with IBD, alcohol may worsen the symptoms and increase the risk of infections [R]. 

Similar to the case of smoking, alcohol further increased the risk of stomach cancer in carriers of the overactive NOS2 variant of rs2297518 [R].

Everyone has a different threshold of alcohol that is healthy for them. If you’re experiencing gut inflammation, we recommend cutting alcohol out if you have negative NOS2 genetic variants. 

Giving up smoking and drinking less alcohol may lower NOS2 activity and contribute to reducing gut inflammation.

Healthy Fats

Omega-3 fatty acids (such as EPA and DHA) have been reported to reduce the expression of NOS2 and other inflammatory markers in white blood cells [R, R].

Similarly, a compound from high-quality olive oil (oleocanthal) has also reduced NOS2 and NO production in response to inflammation in cartilage cells [R, R, R].

Although their quality was often insufficient, several studies have associated dietary omega-3 fatty acids and olive oil with a reduced incidence of IBD, as well as improvements in its symptoms [R, R].

Antioxidant Vitamins

Across a large number of studies, many different researchers have concluded that the negative effects of high NO levels may stem from its ability to produce free radicals. Therefore, eating sufficient amounts of antioxidant vitamins may prevent the harmful effects of NO-overproducing NOS2 variants [R]. 

For instance, one study concluded that a diet rich in vitamin A was associated with lower rates of colorectal cancer in people with the ‘A’ allele of rs2297518 [R].

In another study on 10 people infected with the ulcer-causing microbe Helicobacter pylori and taking aspirin, supplementation with vitamin C reduced NOS2 levels and prevented damage to the stomach lining [R].

In rats given toxic doses of a drug (methotrexate), pretreatment with vitamin E blocked NOS2 activation in the bowel and prevented oxidative stress [R].

Dietary Polyphenols

People with overactive NOS2 variants may also benefit from incorporating more polyphenol-containing foods into their diet. For example, one study reported that, for people with the ‘A’ allele of rs2297518, eating sufficient lutein (mainly found in green leafy vegetables) was associated with lower rates of colorectal cancer [R].

Other food polyphenols that may reduce NOS2 activity and inflammatory or oxidative damage to the gut include:

• Resveratrol (in grapes, blueberries, peanuts, pistachios, and dark chocolate) [R, R]
• Epigallocatechin gallate (mainly in green tea) [R]
• Quercetin (in leafy vegetables, broccoli, apples, peppers, tea, and fruit juices) [R, R]
• Rutin (in oranges, buckwheat, apricots, cherries, grapes, and plums) [R]

These polyphenols are also available as supplements. If you don’t like their food sources or are intolerant to them, you can consider taking them this way. 

However, keep in mind that their effects on NOS2 function have only been tested in animals and cells — and more research will be needed to know for sure if they have similar effects in humans as well.

A number of promising studies suggest that diets rich in healthy fats, antioxidant vitamins, and polyphenols may help reduce gut inflammation in people with overactive NOS2 variants. However, most studies were done in animals and cells. Further clinical research is required.

Probiotics

Probiotics with different species of Lactobacillus (L. plantarum, L. acidophilus, L. casei, and L. delbrueckii) and Bifidobacterium (B. longum, B. animalis, and B. breve) improved gut inflammation and reduced NOS2 activity in multiple animal studies [R, R, R, R, R, R].

In clinical trials, these probiotics restored the gut flora and improved digestive conditions such as diarrhea, constipation, H. pylori infection, IBS, ulcerative colitis, and gut discomfort [R, R, R, R, R, R, R, R, R, R, R, R].

Alternatively, some scientists have hypothesized that people with IBD may have alterations in their gut bacteria that result in lower production of butyrate. Butyrate is a short-chain fatty acid shown to lower NOS2 activity and oxidative stress in rats and cells. However, no clinical evidence supports its use in humans with IBD [R, R, R, R].

Whey Protein

In mice and rats with IBD, whey protein reduced intestinal inflammation by reducing the levels of NOS2-derived NO and several inflammatory cytokines [R, R].

Whey protein also reduced gut inflammation and damage to the intestinal lining by increasing both antioxidant defenses and good bacteria in 30 patients with Crohn’s disease [R].

Curcumin

Curcumin is an antioxidant compound naturally found in turmeric. Dietary curcumin reduced gut inflammation and NOS2 production in mice with IBD and inflammation-induced colorectal cancer [R, R].

In a small trial on 14 people with mild to moderate ulcerative colitis, curcumin enhanced the effectiveness of the anti-inflammatory drug mesalamine [R].

Different probiotics may improve gut inflammation in part by reducing NOS2 activity. Among them, probiotics are most promising. Preliminary research suggests that whey protein and curcumin may help too, but more clinical research is needed.