Scientists have discovered that nitric oxide plays a dual role in intestinal inflammation: nitric oxide produced by intestinal cells exerts anti-inflammatory effects, while that generated by immune cells (especially macrophages) exacerbates inflammation. The combined use of natural supplements fisetin and citrulline can precisely increase nitric oxide levels in intestinal cells, effectively alleviating colitis and inhibiting the development of colon cancer in mouse experiments.
The Dual Role of Nitric Oxide in Gut Inflammation
Imagine a battle raging within your gut: on one side, the “guard” cells defending the intestinal wall, and on the other, the rogue immune cells (especially macrophages) that stir up inflammation. Scientists have long tried to send nitric oxide (NO) as reinforcements to aid the “guard” cells, but they discovered that sometimes, NO ends up “switching sides,” exacerbating the conflict. How is that possible? Could nitric oxide be a “double agent” in the body?
In recent years, researchers have been exploring the complex role of nitric oxide in inflammatory bowel diseases (IBD), where both genetics, gut microbiota, and immune system dysfunctions play a significant part. A recent study published in Cell Reports by scientists from the Weizmann Institute has uncovered a potential breakthrough in treating gut inflammation, offering hope for both colitis and colon cancer.
The Contradictory Role of Nitric Oxide in Gut Cells
Nitric oxide (NO) is a signaling molecule that plays a key role in a wide range of biological processes in the body. Scientists have long been interested in understanding its role in inflammatory diseases such as Crohn's disease and ulcerative colitis. However, the research shows that, in certain contexts, NO might not alleviate gut inflammation, and can even worsen it.
Image from https://www.researchgate.net/publication/325203787_Induction_of_Nitric-Oxide_Metabolism_in_Enterocytes_Alleviates_Colitis_and_Inflammation-Associated_Colon_Cancer
The researchers hypothesized that this contradiction arises because NO has different effects depending on the type of cell producing it. They conducted a study using genetically modified mice to block NO production in specific cells—either in the gut epithelial cells that line the intestinal wall, or in immune cells. The results showed that when NO production in the gut epithelial cells was blocked, the mice’s colitis-like symptoms worsened. However, when NO production was blocked in immune cells, particularly macrophages, the inflammatory symptoms improved.
Graphical Abstract
Thus, the researchers concluded that boosting NO levels might help treat inflammatory bowel diseases, but only if the NO is selectively targeted to the gut epithelial cells.
Natural Supplements to Selectively Boost Nitric Oxide in Gut Cells
In their quest to target the “guard” cells without causing harm, the researchers turned their attention to two natural compounds: quercetin and citrulline. Quercetin, a flavonoid found in apples, persimmons, and strawberries, has been shown to increase the activity of an enzyme called ASL, which produces arginine—the precursor needed to make NO. Citrulline, found in watermelon, beets, and spinach, also enhances ASL activity.
Figure 3. Reduced Colitis Severity in ASL CKO lmmune Cells
When quercetin and citrulline were combined in the mice, they effectively boosted NO production specifically in the gut epithelial cells. This selective enhancement of NO production helped to alleviate the symptoms of colitis. More remarkably, the treatment also had beneficial effects in preventing colon cancer, a disease often linked to chronic gut inflammation. After treatment with quercetin and citrulline, the mice’s intestinal inflammation and colon tumors were reduced, with a notable decrease in tumor number and size.
Conclusion: A Potential Breakthrough in Treating Gut Inflammation and Colon Cancer
This study presents a promising new direction for treating inflammatory bowel diseases (IBD). Its key findings can be summarized as follows:
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The role of NO in gut inflammation is not straightforward—it depends on the type of cell producing it. While NO produced by gut epithelial cells acts as a “defender” against inflammation, NO produced by immune cells, especially macrophages, exacerbates the disease.
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The researchers identified a novel therapeutic approach by selectively increasing NO production in gut epithelial cells using natural supplements—quercetin (from apples, persimmons, etc.) and citrulline (from watermelon, spinach, etc.). This strategy helped to alleviate colitis symptoms in mice without causing side effects.
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In addition to treating IBD, this approach showed promise in preventing colon cancer, a condition often driven by chronic inflammation in the gut.
If these results can be replicated in humans, this natural supplementation strategy could offer a new way to manage gut inflammation and reduce the risk of colon cancer. Since quercetin and citrulline are available as over-the-counter nutritional supplements, their practical application could bring significant benefits to those suffering from inflammatory bowel diseases.