Can this Gene Contribute to Inflammatory Bowel Disease? (JAK2)

Low-FODMAP Diet

FODMAPs are a group of carbohydrates identified as some of the prime irritants in IBD. FODMAPs is a catchy acronym that stands for Fermentable Oligosaccharides, Disaccharides, Monosaccharides, And Polyols, such as [R, R, R]:

• Fructose
• Lactose
• Fructans and galactans
• Galacto-oligosaccharides
• Polyols (sugar alcohols)

Some experts recommend a low-FODMAP diet to help control the symptoms of ulcerative colitis and Crohn’s disease. 

Specific oligosaccharides can increase the expression of IL-23 in the gut and thus worsen the impact of your variants [R].

In rats, eating a high-fructose diet causes inflammation and tissue scarring in the liver in part by activating the JAK2/STAT3 pathway [R, R].

For more about the low-FODMAP diet, check out this post on how it works and this post on which foods are included.

Omega-3 Fatty Acids

High intake of omega-3s from fish (EPA and DHA) may be protective against the development of IBD, especially ulcerative colitis. In the case of Crohn’s disease, they seem to help prevent it and keep it in remission, but it’s unclear whether they can improve the symptoms once the condition has developed and progressed [R, R, R].

However, meta-analyses concluded that further, higher-quality research is needed before omega-3s can be recommended as a complementary strategy to manage IBD [R, R].

In rats, supplementation with omega-3s blocked the activation of JAK2/STAT3 and other inflammatory pathways [R].

Foods rich in omega-3 fatty acids especially include fatty fish such as salmon, mackerel, sardines, herrings, and tuna.

Green Tea

In a small clinical trial on 20 people with ulcerative colitis, a commercial extract with the green tea polyphenol epigallocatechin gallate (Polyphenon E) helped improve the symptoms and maintain remission. Green tea and its polyphenols were similarly effective in multiple studies of animals with colitis [R, R].

In two mice studies, green tea polyphenols reduced inflammation by specifically blocking the JAK2/STAT3 pathway [R, R].

Epigallocatechin gallate also improved pouchitis, a complication that may occur in ulcerative colitis patients after the surgical removal of the colon, in a pilot trial on 9 people [R].

Avoiding FODMAPs, eating fish rich in omega-3 fatty acids, and drinking green tea may help control IBD and reduce JAK2 activity.

Managing Stress

Psychological stress has well-known detrimental effects on gut health and inflammation. It raises gut permeability and the levels of different inflammatory cytokines [R, R].

In mice with IBD, stress worsened gut inflammation by increasing the production of cytokines and chemokines. Interestingly, a JAK2 inhibitor suppressed the production of chemokines, suggesting it helps prevent neutrophils from building up in the gut [R, R]. 

Many people with IBD develop anxiety and depression associated with their debilitating gastrointestinal symptoms. Furthermore, psychological stress may worsen the symptoms of IBD. Because of this potential feedback loop, many doctors emphasize the importance of managing the mental health of IBD patients [R, R, R, R].

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].

In a cell-based study, cigarette smoke increased the production of both JAK2 and STAT3 [R].

Properly managing stress and giving up smoking helps with gut inflammation and may reduce JAK2 activity.

Probiotics

People with IBD often have impaired gut microbiome, which may worsen their disease. In a meta-analysis, a blended probiotic containing Lactobacillus and Bifidobacterium strains increased remission rates by 1.7x in ulcerative colitis patients [R].

These two strains were beneficial in different trials with ulcerative colitis patients [R, R, R, R].

In cells, pretreatment with different Lactobacillus probiotics (L. plantarum, L. rhamnosus, and L. acidophilus) blocked JAK2 activation [R].

People with IBD may have alterations in their gut bacteria that result in lower production of butyrate, a short-chain fatty acid that preserves the ability of the gut lining to take up nutrients while blocking the absorption of microbes and their toxic products [R, R].

Butyrate blocked different JAK2 signaling pathways in cells. In mice with ulcerative colitis, butyrate reduced tissue damage and the production of JAK2 and STAT3 in the colon [R, R]. 

The potential benefits of butyrate can be obtained by taking probiotics that restore the gut microbiota or supplementing with sodium butyrate.

Resveratrol

Resveratrol is an antioxidant polyphenol very abundant in red wine and claimed to be responsible for its purported benefits [R].

Supplementation with 500 mg/day resveratrol for 6 weeks improved disease severity and quality of life by reducing inflammation and oxidative damage in 2 clinical trials on 106 people with ulcerative colitis [R, R].

A study of over 400,000 men associated a high dietary intake of polyphenols, including resveratrol, with a lower incidence of Crohn’s disease [R].

Resveratrol reduced intestinal inflammation and tissue damage while restoring the barrier function and microbiota of the gut in multiple studies of animals with IBD [R, R, R, R, R, R, R].

This compound specifically blocked JAK2 in obese mice with osteoarthritis and white blood cells (macrophages). A synthetic resveratrol derivative improved IBD and other inflammatory conditions by targeting JAK2 [R, R, R].

Curcumin

Curcumin is the active ingredient of turmeric with potent anti-inflammatory effects [R].

Multiple clinical trials have produced promising results for curcumin in IBD, and further research is currently underway. Similarly, a supplement with curcumin, green tea, and selenium improved mild-to-moderate ulcerative colitis in a trial on 20 people [R, R, R, R].

In mice with IBD, dietary curcumin improved injuries and reduced the activation of JAK2 and STAT3 [R].

Curcumin also blocked the JAK2/STAT3 pathway in animals with other conditions that cause inflammatory and oxidative damage [R, R, R].

Andrographis

Andrographis paniculata, known as the “King of Bitters”, is traditionally used in Ayurveda and Chinese medicine. It may improve the symptoms of ulcerative colitis [R].

In two clinical trials, andrographolide, the active ingredient in andrographis, improved ulcerative colitis by suppressing the IL-23/IL-17 axis [R, R]. 

Taking 1,200 – 1,800 mg andrographis daily for 8 weeks reduced the symptoms of mild-to-moderate colitis in adults, with the 1,800 mg dose being more effective. However, it did not affect remission rates any more than placebo [R].

Berberine

Berberine is a compound found in several different plants, including barberry (Berberis vulgaris), oregon grape (Mahonia aquifolium), goldenseal (Hydrastis canadensis), and Chinese goldthread (Coptis chinensis). It has a 3000-year history of use in traditional Chinese and Indian medicine [R].

In a phase I trial on 16 people with ulcerative colitis, berberine (900 mg/day as an add-on to mesalamine) reduced gut tissue damage [R].

Berberine also improved IBD and prevented it from developing into cancer in animal studies by reducing inflammation and oxidative damage, restoring gut barrier function and microbiota, and regulating the development of T cells [R, R, R, R, R, R].

In addition, berberine reduced JAK2 activity in mice with colitis and diabetic rats [R, R].

Rhodiola

Rhodiola is a flowering plant from very cold regions whose root is mainly used for its potential cognitive and physical benefits [R].

Its component salidroside decreased inflammation by preventing the activation of the JAK2/STAT3 pathway in animal studies [R, R].

This compound also reduced gut inflammation in mice with IBD [R, R].

Licorice

Licorice has many components with promising health benefits. It has been used in herbal and folk medicine for its anti-inflammatory properties.

Licorice extract and two active compounds from this herb reduced gut inflammation and prevented its development into cancer in mice and rats with IBD. In one of the studies, licorice flavonoids reduced the levels of both JAK2 and STAT3 [R, R, R].

Preliminary research suggests that probiotics, resveratrol, curcumin, andrographis, berberine, rhodiola, and licorice may help with IBD in part by reducing JAK2 activity.

JAK Inhibitors

Given the role of JAK proteins in several diseases such as bone marrow cancer (myelofibrosis, polycythemia vera, thrombocythemia), lymph node cancer (Hodgkin lymphoma), psoriasis, rheumatoid arthritis, diabetic kidney disease, and lupus, the development of drugs that block their activity is a promising therapeutic strategy [R, R, R, R, R, R, R].

Tofacitinib is the only JAK inhibitor approved for moderate-to-severe ulcerative colitis, with proven effectiveness at helping reduce the symptoms and maintain remission. Although it targets mainly JAK1 and JAK3, tofacitinib can also inhibit JAK2 [R, R, R, R].

Because its effects in trials on people with Crohn’s disease were modest, tofacitinib is not approved for this condition [R, R, R].

The JAK2 inhibitors cibinetide and ruxolitinib have only been tested against IBD in animals, showing good anti-inflammatory results in both cases [R, R].

A drug that preferentially targets JAK1 and JAK3 (tofacitinib) is approved for ulcerative colitis. JAK2 inhibitors are currently being investigated against IBD.