Does the form of omega-3 make a difference when it comes to bioavailability-and will more science be dedicated to elucidating the differences?
Evidence-based human studies have shown that obtaining the desired health benefits of DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) omega-3 fatty acids-including brain and visual support, cardio care, blood triglyceride lowering, and others-requires sufficient daily intake and duration (weeks to several months). (For more information, visit www.dhaomega3.org.) Of course, the relative bioavailability of omega-3 fatty acids from different sources (e.g., fish versus supplements versus functional foods) and when consumed from different structural forms (triglyceride, ethyl ester, free fatty acid, and phospholipid) is of considerable importance as well.
While the amounts of DHA/EPA in a product are often known to the consumer, no information on the relative bioavailability of the omega-3 fatty acids present is generally provided. However, both the DHA/EPA amounts in the product, and the bioavailability of the DHA/EPA, are of utmost importance to ensure appropriate delivery of the omega-3 fatty acids to the bloodstream following their digestion and passage across the intestinal wall and eventual assimilation to target tissues.
Most fish-derived DHA/EPA omega-3 is present in the “natural” triglyceride form, with a much lesser amount present in the phospholipid form. From fish, fish oil is derived, processed, and sold in encapsulated supplements (or bottled oils) as a source of DHA/EPA in the triglyceride form.
Further, the omega-3 fatty acids therein can be industrially converted to the ethyl ester forms of DHA/EPA, which allows for their concentration via procedures such as molecular distillation. Such oil concentrates of DHA/EPA can be sold as supplements or be converted industrially back to the triglyceride form prior to being incorporated in commercial supplements.
The term bioavailability generally refers to the capability of the orally ingested omega-3 fatty acids to be digested in the gastrointestinal tract and cross the intestinal wall, thereby entering the bloodstream and, subsequently, the various body tissues and organs. The bioavailability of DHA/EPA in humans has been measured via both acute studies (very short-term studies, such as a few hours after consumption) or via chronic studies (long-term daily consumption over weeks or months). The net rise in omega-3 fatty acid levels in blood samples at the end of the study relative to baseline levels is regularly used to assess the relative bioavailability of different sources/forms of omega-3 fatty acids when compared at essentially equal levels of intake.
Because of the wide variability in the results between individual subjects and other factors, acute studies appear not to be as dependable as chronic studies in making conclusions with respect to bioavailability.
There have been a number of short-term acute studies in human subjects which have attempted to determine if the bioavailability/absorption of EPA and DHA, when taken as supplements, is any different when the “natural” triglyceride form versus the ethyl ester form is consumed. The results from such human studies appear to be somewhat influenced by the experimental designs used for such evaluations, including the doses, duration, and timing of the blood measurements for the resulting omega-3 accumulations following supplementation.
The early short-term studies by Lawson and Hughes (1,2) indicated a much better apparent human absorption of both EPA and DHA (at intake levels of 1.00 and 0.67 g, respectively) in the triglyceride form compared to the ethyl ester form. Furthermore, they reported that the marked differences in absorption between the two forms were less pronounced after a high-fat meal compared to a low-fat meal.
Subsequent studies by el Boustani et al. (3) reported a greater incorporation of EPA into circulating blood plasma fat (as triglyceride) when EPA (1 g) was consumed as the triglyceride form relative to the ethyl ester form.
Maximal plasma levels of DHA/EPA were also found to be significantly lower with ethyl ester forms as compared to triglyceride forms in a German study. (4)
In contrast to the previous studies, Luley and colleagues (5) found similar bioavailability for triglyceride versus ethyl ester preparations of EPA/DHA. In support of the latter study, Nordoy et al. (6) provided test meals to human subjects, with very high doses of omega-3 fatty acids (28 g) as triglyceride or ethyl ester forms. Blood sampling and measurements conducted at 24 hours after consumption of the omega-3 meals indicated their concentrations to be similar. The authors concluded that fish oil omega-3 fatty acids given as ethyl ester or triglyceride form were equally well absorbed, and that EPA and DHA were also equally absorbed.
Long-term chronic studies have compared the relative bioavailability of DHA/EPA when ingested as fish or supplements.
The early study by Visioli et al. (7) indicated a greater net rise in human blood plasma levels of DHA after six weeks when DHA from salmon was consumed daily, compared to DHA intakes via supplementation (as the ethyl ester form)-even when the latter DHA intakes were higher than those from fish.
A subsequent study by Harris et al. (8) compared blood levels of omega-3 fatty acids in subjects having similar intakes of DHA and EPA from salmon (mainly triglyceride form) or supplemental ethyl ester form. The EPA level in the red blood cells was found to rise faster in the fish group by four weeks, with no apparent differences in bioavailability of DHA/EPA exhibited by the end of the study at 16 weeks.
Based on a two-week chronic study that measured the rise in blood levels of DHA in subjects consuming equivalent daily intakes of DHA from cooked salmon (mainly triglyceride form) versus supplemental DHA from an algal source (as triglyceride), a bio-equivalence of the two DHA sources was found. (9)
It should be mentioned that a well-controlled, 16-day bioavailability study in piglets showed a significantly greater rise in DHA blood levels when identical amounts were consumed daily in triglyceride rather than phospholipid form. (10) By contrast, Carnielli et al. (11) reported that DHA from a phospholipid form in formula was somewhat better absorbed than that from preterm breast milk (mainly in natural triglyceride form) at 88% and 78% efficiency, respectively, while no difference between the breast milk and a triglyceride form of DHA was found with respect to absorption.
Direct comparison of similar intakes of DHA/EPA (as ethyl ester) over three weeks in a capsule or as a specific type of microencapsulated preparation for food applications indicated no significant difference in human volunteers based on blood measures of serum phospholipids of DHA/EPA from our laboratory. (12)
Two major long-term, well-designed omega-3 bioavailability clinical trials (large numbers of subjects and lengthy durations) have been published.
The study by Dyerberg et al. (13) attempted to compare the bioavailability of the different forms of DHA/EPA. A similar dose (3.1 to 3.6 g/daily) of ingested DHA plus EPA across the different preparations was compared-namely, re-esterified triglyceride, ethyl ester, free fatty acid, fish body oil (natural triglyceride form), and cod liver oil (natural triglyceride form). The omega-3 supplements were each given twice daily at mealtimes for two weeks, and the net rise of the DHA plus EPA, as differences between serum lipid concentrations at the end of the study relative to baseline, was used to compare and assess relative bioavailability.
The bioavailability of DHA/EPA from the re-esterified triglyceride form was found to be significantly better than for the ethyl ester form. By assigning an apparent “bioavailability index” of 100% for the rise in circulating DHA plus EPA found with natural fish oil, the re-esterified triglyceride form was determined to have an index of 124%, as compared to only 73% for the ethyl ester form. An intermediary index of 91% was found for the free fatty acid form.
Interestingly, even though essentially identical intakes of the triglyceride and ethyl ester forms were ingested daily (1.85 and 1.87 g, respectively), the net rise of EPA in the circulating blood serum phospholipid was found to be markedly greater, by 62%, for the re-esterified triglyceride form as compared to the ethyl ester form.
Very recently, Neubronner and colleagues from Germany reported (14) on the largest (150 volunteers) and longest (over a period of six months) study on the comparative bioavailability when supplementing with the triglyceride versus the ethyl ester forms. (Daily dose of EPA and DHA was 1.00 g and 0.67 g, respectively.) The increased levels of EPA and DHA in the red blood cells in the triglyceride group were significantly greater than for the ethyl ester group (197% versus 171% at six months). This latter study indicated a moderately better bioavailability (by approximately 15% overall in relative terms) with long-term intakes of EPA and DHA as the triglyceride form.
In general, it would appear advantageous to bioavailability if consumers ingested their DHA/EPA supplements at or around mealtime rather than on an empty stomach. Our studies have indicated little difference in bioavailability if such supplements are consumed at one mealtime or spread out over all meals. Also, there is no convincing data in the evidence-based literature to date to suggest that the gastric acid–resistant coating of omega-3 capsules can enhance DHA/EPA bioavailability.
The triglyceride forms of DHA/EPA can be expected to give similar bioavailability (if taken with meals) to that of fish sources of DHA/EPA, which are mostly in the natural triglyceride form. However, while recent long-term studies indicate a somewhat better bioavailability for DHA/EPA in triglyceride versus ethyl ester form, the cost of high-omega-3 concentrates is generally much greater for the triglyceride forms versus equal amounts of omega-3 in the concentrated ethyl ester form. Future trials comparing the bioavailability of DHA/EPA from phospholipid and free fatty acid versus other forms in humans would be of interest. Also, the various microencapsulated forms of DHA/EPA now available for food/beverage applications should be clinically tested for bioavailability.
In September, Douglas Laboratories introduced a new product, QÃELL Omega-3 Fish Oil, which the company calls its “newest, most potent form of omega-3 supplementation.” According to the company in press materials: “The QÃELL difference lies in its supercritical CO2 extraction method, providing a highly concentrated triglyceride form of omega-3. Using supercritical CO2 extraction technology, omega-3 fatty acids are extracted without high temperatures, oxygen, or chemical solvents, ensuring that the oil is protected from oxidation, microbial contamination, solvent residue, and isomer formation. This is also the preferred extraction method as it is more environmentally responsible and also purifies and concentrates to a higher degree. Additionally, a growing body of scientific evidence supports the triglyceride (or re-esterified triglyceride) form of the fatty acids as having the greatest absorption (compared to the ethyl ester form), significantly increasing the index of EPA and DHA in the blood.”
By Jennifer Kwok Grebow, Editor-in-Chief
As Dr. Holub’s article emphasizes, research is still progressing-and results still mixed-on which omega-3 forms may be best absorbed or bioavailable. At the recent SupplySide West trade show, I spoke to several omega-3 industry members about the topic.
While triglyceride-form omega-3 fatty acids may be more expensive (it’s costlier to add the extra processing step of taking an ethyl ester product back to its triglyceride state), ingredient suppliers say that some customers have been increasingly asking for the triglyceride form. “We’re seeing increased demand for the triglyceride form because it’s considered more natural,” says Gunilla Trajberg, marketing manager for EPAX Norway AS (Oslo, Norway). “The science is divisive-some claim that the triglyceride form is better absorbed in the body, and some studies show that there is no difference really. We offer both forms, and it’s up to our customers to choose which.”
“It is more expensive to buy a triglyceride product/concentrate than an ethyl ester, so you want to be able to justify the cost and whether there is an added benefit. But I think it’s still up for debate. I don’t know if anyone has really conclusive science on that yet,” adds Katherine Bond, director of business development for Cyvex Nutrition (Irvine, CA), whose parent company is fish oil omega-3 supplier Omega Protein.
“Animal studies have demonstrated a better uptake of EPA and DHA by giving a phospholipid compared to a triglyceride formulation. Increased uptake may translate into higher tissue concentrations of these fatty acids. However, omega-3 supplements are not a pain-killer type of product, which has to help and give an effect as soon as possible. Rather, a food supplement should be taken over months and years, and so a small difference in uptake is not very essential,” contends Morten Bryhn, MD, PhD, scientific adviser for EPAX Norway AS.
Eric Anderson, vice president of sales and marketing, Aker BioMarine (Oslo, Norway), supplier of the trademarked Superba krill oil, says that as opposed to the bioavailability of omega-3 sources, it’s bioefficiency that matters. “The bioavailability definition is whether they achieve uptake and absorption by the body. The difference is in bioefficiency. How much of the omega-3 fatty acids make it to the cells and tissues?”
According to Anderson, his company has conducted a single-center, open-label, randomized crossover study, with data to be published, showing that the DHA and EPA from phospholipid-bound krill oil is about 60% better compared to triglyceride sources in reaching human tissue. “Whether that’s because the body is burning the triglycerides as energy or if there’s some other mechanism that’s not fully elucidated, we’re not perfectly sure,” he says. The study looked at equal doses (8 g) of Superba krill oil, Superba krill powder, and fish oil (and interestingly found the krill powder to be even more bioavailable than the krill oil, the company says).
Adam Ismail, executive director of the Global Organization for EPA and DHA Omega-3s (GOED), says that we’re still in the early stages in terms of scientific investigation. “Omega-3s aren’t really a commodity ingredient yet. They have a tendency to be looked at as a commodity ingredient, but just between the ratios of EPA and DHA alone, we know that the different fatty acids have different functions but we don’t fully know what they are yet in every case. And the same applies to their forms. If you look at it in terms of life stages of research, we’re still at an early stage just trying to figure out what EPA and DHA do differently, and then from a product-form point of view, we’re at an even earlier stage.”
Still, he says, expect more research to come. “There’s not a ton of research differentiating between these different product forms, but it’s coming. People are working on it and trying to answer these questions. I think we’re going to know a lot more in the next couple of years. One of the issues is that there needs to be more university-led research in this area. Right now, a lot of the companies are investing in it, and I think universities are starting to get excited enough to look at these areas. If we can get universities to really do independent research in these areas, I think we’ll know a lot more.”
1. L Lawson and B Hughes, “Human absorption of fish oil fatty acids as triglycerides, free acids, or ethyl esters,” Biochemical and Biophysical Research Communications, vol. 152, no. 1 (Apr 15, 1988): 328-335.
2. L Lawson and B Hughes, “Absorption of eicosapentaenoic acid and docosahexaenoic acid from fish oil triglycerols or fish oil ethyl esters co-ingested with a high-fat meal,” Biochemical and Biophysical Research Communications, vol. 156, no. 2 (Oct 31, 1988): 960-963.
3. S el Boustani et al., “Eternal absorption in man of eicosapentaenoic acid in different chemical forms,” Lipids, vol. 22, no. 10 (Oct 1987): 711-714.
4. B Beckermann et al., “Comparative bioavailability of eicosapentaenoic acid and docosahexaenoic acid from triglycerides, free fatty acids and ethyl esters in volunteers,” Arzneimittelforschung, vol. 40, no. 6 (June 1990): 700-704.
5. C Luley et al., “Bioavailability of omega-3 fatty acids: ethyl ester preparations are as suitable as triglyceride preparations,” Akt Ernahrungsmed, 15 (1990): 122-125.
6. A Nordoy et al., “Absorption of the n-3 eicosapentaenoic and docosahexaenoic acids as ethyl esters and triglycerides by humans,” American Journal of Clinical Nutrition, vol. 53, no. 5 (May 1991): 1185-1190.
7. F Visioli et al., “Dietary intake of fish vs. formulations leads to higher plasma concentrations of n-3 fatty acids,” Lipids, vol. 38, no. 4 (April 2003): 415-418.
8. WS Harris et al., “Comparison of the effects of fish and fish-oil capsules on the n-3 fatty acid content of blood cells and plasma phospholipids,” American Journal of Clinical Nutrition, vol. 86, no. 6 (Dec 2007): 1621-1625.
9. LM Arterburn et al., “Algal-oil capsules and cooked salmon : nutritionally equivalent sources of docosahexaenoic acid,” Journal of the American Dietetic Association, vol. 108, no. 7 (July 2008): 1204-1209.
10. SA Mathews et al., “Comparison of triglycerides and phospholipids as supplemental sources of dietary long-chain polyunsaturated fatty acids in piglets,” Journal of Nutrition, vol. 132, no. 10 (Oct 2002): 3081-3089.
11. VP Carnielli et al., “Intestinal absorption of long-chain polyunsaturated fatty acids in preterm infants fed breast milk or formula,” American Journal of Clinical Nutrition, vol. 67, no. 1 (Jan 1998): 97-103.
12. CJ Barrow et al., “Bioequivalence of encapsulated and microencapsulated fish-oil supplementation,” Journal of Functional Foods, 1 (2009): 38-43.
13. J Dyerberg et al., “Bioavailability of marine n-3 fatty acid formulations,” Prostaglandins, Leukotrienes, and Essential Fatty Acids, vol. 83, no. 3 (Sept 2010): 137-141.
14. J Neubronner et al., “Enhanced increase of omega-3 index in response to long-term n-3 fatty acid supplementation from triacylglycerides versus ethyl esters,” European Journal of Clinical Nutrition, vol. 65, no. 2 (February 2011): 247-254.