Gene flaw may explain omega-3s’ mixed record; new supplements may help. 03/02/2020
About three million people in the U.S. suffer from inflammatory bowel diseases or IBDs.
Although IBDs only affect one in 100 Americans, the experience is often painful, disruptive, embarrassing, or even life-changing.
Symptoms usually appear before age 30, but some patients don't develop signs of these diseases until they’re in their 50s or 60s.
The frequency of video ads for IBD drugs — mostly immunosuppressants like Entyvio (vedolizumab) and Humira (adalimumab) — indicate the extreme distress and desperation that IBDs can cause.
Omega-3 fatty acids from seafood have been viewed as promising IBD therapeutic allies, because they're essential to the body's inflammation control system — but clinical trials haven't found omega-3 fish oil substantially or consistently helpful for IBD patients.
Emerging evidence suggests that the mixed clinical record of omega-3s in IBD patients may stem from a genetic flaw — one linked to their vulnerability to these diseases — that impairs their bodies' ability to convert dietary omega-3s into the critical inflammation-ending compounds called specialized pro-resolving mediators or SPMs.
Positive results from animal studies suggest that supplemental SPMs may offer a way to get past that roadblock and help halt the damaging inflammation caused by IBDs — but before we get into that possibility, let's review what's known about IBDs and diet.
What are inflammatory bowel diseases (IBDs)?
This umbrella term IBD covers two conditions — Crohn’s disease and ulcerative colitis — that inflame the gastrointestinal (GI) tract and can lead to permanent damage.
IBDs are autoimmune disorders in which the body mounts misguided immune attacks on harmless substances in the GI tract. The persistent inflammation produced as part of the body’s erroneous immune response can permanently damage tissues and impair patients’ ability to digest food and live normally.
Crohn’s disease (CD) mostly afflicts the digestive tract and surrounding tissues, while — as its name implies — ulcerative colitis (UC) causes sores and ulcers in the colon and rectal area. The symptoms range from diarrhea, stomach pain, and weight loss to malnutrition, rectal bleeding, and frequent, urgent bathroom trips.
IBDs also raise the risk for colorectal cancer and can lead to complications including bowel obstructions, perforated colon, dehydration, fistulas, blood clots, ulcers, and anal fissures.
Although its symptoms can be similar, irritable bowel syndrome or IBS is distinctly different from IBDs. Irritable bowel syndrome is linked to stress, doesn’t damage the colon or intestines, involve autoimmunity and chronic inflammation, or raise the risk of colon cancer.
Drug treatments for IBDs
To dampen inflammation in the GI tract, doctors typically prescribe drugs of two kinds:
- Anti-inflammatory agents such as mesalamine, balsalazide, and olsalazineor.
- Immune-suppressive/anti-inflammatory drugs such as methotrexate, adalimumab (Humira), and vedolizumab (Entyvio).
Unfortunately, IBD drugs have mixed records of efficacy and can cause adverse side effects. And IBDs can be triggered or aggravated by chronic use of non-prescription anti-inflammatory drugs like ibuprofen (e.g., Advil and Motrin IB) and naproxen sodium (e.g., Aleve). That’s probably because chronic use of such drugs loosens the barrier between the gut and bloodstream, leading to so-called “leaky gut” syndrome.
Dietary allies and risks
Eating patterns like the standard American diet are considered a risk factor for developing IBDs.
Accordingly, IBD patients are typically advised to avoid pro-inflammatory foods characteristic of the standard American diet, including cheap, omega-6-laden vegetable oils (see "The role of America’s 'omega imbalance' in IBDs", below), sugars, refined carbohydrates, soda, and fried foods.
Earlier this year, an international scientific team published their guidance on foods that can help or harm IBD patients — and possibly raise or lower the risk for IBDs. These were their conclusions, to which we’ve added some bracketed comments based on our review of the evidence (Levine A et al. 2020):
- Safe/helpful foods: Fruits and vegetables (especially in CD); Seafood and its omega-3 fatty acids (especially in UC).
- Foods uncertain to help or harm: Complex carbohydrates, sugars, fructose, wheat, and gluten. [The team’s uncertain opinion about sugars seems odd, given the significant evidence linking diets high in sugars — and sugar-like refined carbohydrates — to heightened risk for both types of IBD and worse symptoms in each.]
- Crohn’s disease: Minimize saturated fats and avoid trans fats; No restrictions for red meat (unprocessed), lean chicken meat, or eggs. [The advice to minimize saturated fats seems at odds with the lack of red-meat restrictions, since red meats contain substantial amounts.]
- Ulcerative colitis: Minimize red and processed meats and saturated myristic fatty acid.
The international team found insufficient evidence to advise against low-level alcohol consumption.
Can anti-inflammatory foods or pills help?
There's good evidence that certain foods help reduce chronic inflammation.
Most importantly, the body needs the omega-3 fats (DHA and EPA) found in most human cells and in seafood — especially fatty fish like salmon or sardines — to make critical immune system compounds called “specialized pro-resolving mediators” or SPMs, which include resolvins, protectins, and maresins.
As the term “pro-resolving” in their name implies, the body uses SPMs to end or “resolve” inflammation after it’s no longer needed to deal with a wound or infection — and IBDs cause chronic inflammation in the GI tract.
Small amounts of the only plant-source omega-3, called ALA, occur in certain plant foods, but the body can’t use ALA to make the SPMs needed to end inappropriate inflammation.
As needed — when someone’s diet doesn’t provide enough (or any) EPA and DHA from seafood or fish oil — the body can convert a very small percentage of dietary omega-3 ALA into small amounts of EPA and DHA, from which it can make SPMs. (For more information about plant- and seafood-source omega-3s, see our Omega-3 Facts & Sources page.)
But given the importance of EPA and DHA to critical body functions, and of the SPMs made from them to inflammation control, it makes sense to include ample amounts of omega-3-rich fatty fish and/or fish oil in your diet.
In addition to omega-3 DHA and EPA from seafood and fish oil, the body gets anti-inflammatory benefits from the antioxidants that abound in many fruits and vegetables — especially colorful varieties — and in extra-virgin grade olive oil.
The abundance of omega-3s and antioxidants in Mediterranean-style diets — ones rich in vegetables, fruits, fish, extra-virgin olive oil, and nuts — explains the ample evidence that they tend to lower inflammation levels in the body. (See Big Gut-Health Boost from Fish and Plant Foods.) Accordingly, the Crohn’s & Colitis Foundation says that the Mediterranean Diet may help some people with IBDs.
There’s also some evidence that supplemental curcumin — the antioxidant fraction in turmeric root — helps ease ulcerative colitis and prevent relapses, but only special, highly-absorbed curcumin supplements are likely to exert significant anti-inflammatory effects.
In addition, supplemental vitamin D appears to alleviate the symptoms of Crohn’s disease in patients with low levels. The best-absorbed, most efficacious form is vitamin D3.
Seafood-source omega-3s: A mixed clinical record
There’s some evidence that the omega-3s in seafood and fish oil (DHA and EPA) can reduce the damaging inflammation characteristic of IBDs and thereby alleviate the symptoms.
However — despite their essential role in “resolving” inflammation — tests of fish oil in clinical trials haven’t consistently produced substantial benefits for IBD patients.
For example, a pair of clinical trials — the Epanova Program in Crohn's Study (EPIC-1 and EPIC-2) — didn’t find omega-3 supplements very effective for treating symptoms in Crohn’s disease patients. But, given the essential role of omega-3 is in ending inflation, the authors of those trials think it’s a possibility that’s still worth pursuing (Feagan BG et al. 2008).
As the authors of an evidence review wrote four years ago, “There are numerous controversies in the literature on the effects of (omega-3 fatty acids) in the prevention or treatment of IBD, but their effects in reducing inflammation is incontestable. Therefore, more studies are warranted ...”. (Barbalho SM et al. 2016)
Does an omega-3-related gene flaw explain IBDs and suggest a solution?
In a study published last year, a team of scientists from Tennessee's Vanderbilt University took a deeper look at the role of fatty acids in Crohn’s disease patients (Scoville EA et al. 2019).
Elizabeth Scoville, MD
of Vanderbilt Unviversity
A Vanderbilt team led by Elizabeth Scoville, M.D. collected blood from 116 people with Crohn’s disease and 27 healthy people, and was surprised to find that the Crohn's patients had fairly high levels of omega-3s. And higher blood levels of omega-3s were linked to higher levels of pro-inflammatory messenger compounds — a finding at odds with the known anti-inflammatory effects of omega-3s.
These findings were surprising because studies have generally found low levels of omega-3s — and high, pro-inflammatory levels of omega-6 fatty acids — in IBD patients.
The Vanderbilt team suspects that people genetically predisposed to get Crohn’s disease may also have a genetic variation that impairs conversion of omega-3 DHA and EPA into the critically important anti-inflammatory compounds discussed above, called specialized pro-resolving mediators or SPMs.
And they suspect that the same genetic variation may direct more omega-6 fatty acids toward conversion into pro-inflammatory compounds: findings that could help explain why fish oil supplements haven’t consistently alleviated IBD symptoms in clinical trials.
The Vanderbilt researchers believe there may be a way to get around the suspected genetic flaw that prevents conversion of omega-3s into SPMs: “The discovery of omega-3-derived anti-inflammatory molecules coined SPMs … may offer a fascinating new complementary approach to IBD treatment.”
As the Vanderbilt team said, omega-3-derived SPMs counterbalance the pro-inflammatory effects of the extremely excessive amounts of omega-6 fatty acid in the standard American diet, which mostly comes from cheap vegetable oils.
They noted that SPMs boost production of anti-inflammatory proteins (i.e., cytokines), and can help stimulate healing of digestive tract tissues damaged by the chronic inflammation characteristic of IBDs.
The idea that supplements containing SPMs might help ease the symptoms of IBDs — and reduce intestinal damage — is strongly supported by the results of relevant animal studies, as described last year in a research paper published by Spanish scientists (Irún P et al. 2019).
And in a paper published earlier this year, Brazilian researchers agreed that the effects of SPMs in animal studies suggest that these omega-3-derived compounds might be able to safely suppress the inappropriate autoimmune response and resulting inflammation seen in IBDs: "A growing body of evidence demonstrates that isolated SPMs show efficacy at very low doses ... SPMs block pain, infection and neuro-immune interactions and, therefore, emerge as a new class of non-immunosuppressive and non-opioid analgesic drugs." (Fattori V et al. 2020)
Supplemental SPMs are readily available through online outlets, but we can't vouch for the absorbability or efficacy of any particular brands.
The role of America’s “omega imbalance” in IBDs
In addition to omega-3s, we also need essential fatty acids belonging to the omega-6 family.
Americans consume far too many omega-6 fats, mostly from an overabundance of cheap, commonly used vegetable oils like soybean, corn, cottonseed, safflower, and sunflower. These omega-6-laden oils also predominate in most processed/packaged foods — like chips — and are used to fry and cook most foods in most takeout chains and restaurants.
Although omega-6s play pivotal roles in our cells, the hugely excessive amounts in the standard American diet are persuasively linked to higher risks for inflammation-related conditions ranging from obesity, metabolic syndrome, and cardiovascular disease to dementia, cancer and autoimmune disorders — including inflammatory bowel diseases.
The average American’s gross “omega imbalance” — very low intakes of omega-3s and very high intakes of omega-6 fats — disrupts the immune system’s ability to control inflammation, while impairing optimal brain function and vascular health.
The diets of IBD patients typically include high intakes of omega-6 fatty acids and very large amounts of saturated animal fats. Saturated fats don’t pose inherent health risks, but large amounts appear to aggravate IBD symptoms.
Accordingly, the Vanderbilt team also suggested that doctors and patients should focus on optimizing the omega balance in patients’ diets and limiting intake of animal foods high in saturated fats, which abound in the standard American diet.
An Italian scientific team echoed those sentiments in a study published two years ago, citing studies that linked higher-than-average intakes of omega-3s versus omega-6s — mostly achieved by increasing omega-3 intakes — to reduced risk of IBDs and higher rates of disease remission: “Fat-containing diets rich in olive oil, dairy products and fish … should be consumed while avoiding large intakes of vegetable oils rich in omega-6 polyunsaturated fatty acids.” (Reddavide R et al. 2018)
Indeed, a large study of ulcerative colitis found that the disease is fueled by eating too many omega-6 fats, and linked diets high in olive oil to a 90% drop in people’s risk for that particular IBD: see Colitis Curbed by Olive Oil but Fueled by Omega-6 Fats.
Those sentiments were echoed in an evidence review from researchers at the Cleveland Clinic: “… omega-6 fatty acids, long chain fatty acids, protein, and digestible carbohydrates [i.e., starches and sugars versus fibers], may contribute to IBD pathogenesis through altering intestinal microbiota, increasing intestinal permeability [i.e., leaky gut], and promoting inflammation; whereas omega-3 fatty acids, medium chain triglycerides [such as in coconut oil], and non-digestible carbohydrates [i.e., fibers] improve these parameters and intestinal health.” (Dixon LJ et al. 2015)
Last year, the Brazil-based authors of an evidence review agreed that diets high in omega-6 fats promote IBDs by causing chronic inflammation, altering the composition of people’s gut microbiome’s, and by making people's intestines more permeable and less able to keep substances that can trigger autoimmune reactions out of the bloodstream. They noted that, in contrast, omega-3s generally reduce those risk factors for IBDs and other autoimmune conditions.
However, the Brazilian group concluded that the evidence available at the time was too scarce and conflicting to draw clear conclusions: “There is still much controversy about the effects of these [omega-3 and omega-6 fatty] acids both on (Crohn’s disease) or (ulcerative colitis), possibly due to the variability in the doses and way of delivery, in the size of the samples, and the biases found in different clinical trials.” (Marton LT et al. 2019)
And the Italy-based authors of a recent evidence review agreed: “… there remains a lack of well-designed clinical trials that include IBD patients … to confirm the … possibility not only of preventing the recurrence of IBD but also of delaying or blocking its onset with the aid of a diet containing a balanced ratio of n-6/n-3 PUFAs [i.e., omega-6/omega-3 polyunsaturated fatty acids].” (Scaioli E et al. 2017)
So, we clearly need more study on this score — research that can't come too soon for people suffering from the truly awful symptoms and consequences of IBDs.
- Barbalho SM, Goulart Rde A, Quesada K, Bechara MD, de Carvalho Ade C. Inflammatory bowel disease: can omega-3 fatty acids really help? Ann Gastroenterol. 2016 Jan-Mar;29(1):37-43. Review.
- Cabré E, Mañosa M, Gassull MA. Omega-3 fatty acids and inflammatory bowel diseases - a systematic review. Br J Nutr. 2012 Jun;107 Suppl 2:S240-52. doi: 10.1017/S0007114512001626. Review.
- Centers for Disease Control and Prevention (CDC). IBD Statistics. Accessed at https://www.cdc.gov/ibd/data-statistics.htm
- Dixon LJ, Kabi A, Nickerson KP, McDonald C. Combinatorial effects of diet and genetics on inflammatory bowel disease pathogenesis. Inflamm Bowel Dis. 2015 Apr;21(4):912-22. doi: 10.1097/MIB.0000000000000289. Review.
- Fattori V, Zaninelli TH, Rasquel-Oliveira FS, Casagrande R, Verri WA Jr. Specialized pro-resolving lipid mediators: A new class of non-immunosuppressive and non-opioid analgesic drugs. Pharmacol Res. 2020 Jan;151:104549. doi: 10.1016/j.phrs.2019.104549. Epub 2019 Nov 17. Review.
- Feagan BG, Sandborn WJ, Mittmann U, et al. Omega-3 Free Fatty Acids for the Maintenance of Remission in Crohn Disease: The EPIC Randomized Controlled Trials. JAMA. 2008;299(14):1690–1697.
- Geerling B.J, Dagnelie P.C, Badart-Smook A, Russel M.G, Stockbrugger R.W, Brummer R.J. Diet as a risk factor for the development of ulcerative colitis. Am. J. Gastroenterol. 2000;95:1008–1013.
- International Society for the Study of Fatty Acids and Lipids (ISSFAL). Omega-3 Fats May Reduce Risk of Gastrointestinal Diseases. July 2, 2014. Accessed at http://www.issfal.org/news/articles/2014/07/02/omega-3-fats-may-reduce-risk-of-gastrointestinal-diseases
- Irún P, Lanas A, Piazuelo E. Omega-3 Polyunsaturated Fatty Acids and Their Bioactive Metabolites in Gastrointestinal Malignancies Related to Unresolved Inflammation. A Review. Front Pharmacol. 2019 Aug 2;10:852. doi: 10.3389/fphar.2019.00852. eCollection 2019. Review.
- Levine A et al. Dietary Guidance for Patients with Inflammatory Bowel Disease from the International Organization for the Study of Inflammatory Bowel Disease. Clin Gastroenterol Hepatol. 2020 Feb 14. pii: S1542-3565(20)30185-3. doi: 10.1016/j.cgh.2020.01.046. [Epub ahead of print] Review.
- Limdi JK. Dietary practices and inflammatory bowel disease. Indian J Gastroenterol. 2018 Jul;37(4):284-292. doi: 10.1007/s12664-018-0890-5. Epub 2018 Sep 12. Review.
- Marton LT, Goulart RA, Carvalho ACA, Barbalho SM. Omega Fatty Acids and Inflammatory Bowel Diseases: An Overview. Int J Mol Sci. 2019 Sep 30;20(19). pii: E4851. doi: 10.3390/ijms20194851. Review.
- Reddavide R, Rotolo O, Caruso MG, Stasi E, Notarnicola M, Miraglia C, Nouvenne A, Meschi T, De' Angelis GL, Di Mario F, Leandro G. The role of diet in the prevention and treatment of Inflammatory Bowel Diseases. Acta Biomed. 2018 Dec 17;89(9-S):60-75. doi: 10.23750/abm.v89i9-S.7952. Review.
- Sakamoto N, Kono S, Wakai K, Fukuda Y, Satomi M, Shimoyama T, Kobashi G. Dietary risk factors for inflammatory bowel disease: A multicenter case-control study in Japan. Inflamm. Bowel Dis. 2005;11:154–163.
- Scaioli E, Liverani E, Belluzzi A. The Imbalance between n-6/n-3 Polyunsaturated Fatty Acids and Inflammatory Bowel Disease: A Comprehensive Review and Future Therapeutic Perspectives. Int J Mol Sci. 2017 Dec 5;18(12). pii: E2619. doi: 10.3390/ijms18122619. Review.
- Scoville EA, Allaman MM, Adams DW, Motley AK, Peyton SC, Ferguson SL, Horst SN, Williams CS, Beaulieu DB, Schwartz DA, Wilson KT, Coburn LA. Serum Polyunsaturated Fatty Acids Correlate with Serum Cytokines and Clinical Disease Activity in Crohn's Disease. Sci Rep. 2019 Feb 27;9(1):2882. doi: 10.1038/s41598-019-39232-z.