Eat Your Fish Oil and Digest it, Too (Unoxidized!) | DHA:EPA Ratio of 1:1 Minimizes Oxidation, Maximizes Uptake | Plus: Fishes that Come Close are Sardines, Rainbow Trout, ...

The often-heard "the more DHA, the better"-rule is - like so much you'll read about fish oil online - not the evidence-based truth it seems to be. Some extra EPA may keep the oil from getting oxidized before you even absorb it.
No, I am not a fish oil fanboy, that's for sure. But how can you be if your chances to get already oxidized fish oil are 100% if you buy any of the US TOP-sellers (and assume that it's not different in Europe). Speaking of which: There's new research allowing us to add two new and potentially important criteria to the inofficial SuppVersity-"How to buy and use your fish oil" guide.

The corresponding research comes from an international team of researchers and was first published in 2017. It is thus not exactly revolutionarily new but in view of the fact that I haven't seen the results being addressed anywhere before still SuppVersity newsworthy (Dasilva 2017).
You can learn more about omega-3 & co. at the SuppVersity

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In the paper, the authors followed up on their own research showing that increasing the proportion of DHA in marine lipid supplements significantly reduces associated health benefits (in terms of lipidomic biomarkers of oxidative stress and inflammation) compared with balanced EPA:DHA supplementation (Dasilva 2015). In conjunction with evidence suggesting that these difference may be brought about during the digestive process, where the rate of oxidation and subsequently impaired uptake may be a function of the ratio of DHA:EPA.

The scientists starting hypothesis was thus that EPA and DHA molecules "might have differential resistance to oxidation during gastric digestion, and the oxidation level achieved could be inversely correlated with intestinal absorption and, hence, with the resultant health benefits" (Dasilva 2017).
Figure 1: TIM system, simulating the upper gastrointestinal tract for fat digestion studies (Domoto 2013). In the study I grabbed this illustration from, it was used to demonstrate and quantify the improved absorption of phospholipid- vs. triglyceride bound omega-3s I wrote about as early as in 2012 (read the #SVClassic)
To really get to the bottom of the underlying mechanisms, the scientists decided to test their hypothesis by investigating the degree of oxidation in the stomach, and the levels of bioaccessible lipids, of varying molar proportions of DHA and EPA (2:1, 1:1, and 1:2) using the well-established dynamic gastrointestinal tract model TIM-1.
Tumor-free status according to age. Description of the results in the text.
Less surprising but noteworthy: Fish oil is more potent than plant sources of omega-3s when it comes to the prevention of breast cancer, a recent study from the University of Guelph and the McGill University shows. While we are dealing with rodent data, it is newsworthy that the scientists were able to assess the potency of ALA (plant omega-3) vs. DHA+EPA (as in fish oil) for the first time. Their estimates show "that ALA was 1/8 as potent as EPA+DHA" (Liu 2018).

As usual, though, it makes sense to look beyond the abstract and at the data in the Figure on the left!

The mice receiving 7% safflower + 3% fish oil (FO) developed the virally programmed tumor significantly later than those on either 7% safflower + 3% flax (3%FS) or the control diet with 10% safflower, but the higher dosed (more omega-3, but in form of ALA vs. DHA/EPA) 10% flaxseed diet (10%FS) outperformed them all. That doesn't change the overall conclusion that - gram by gram - fish oil is more important, but it highlights that ALA, the plant form of omega-3s, is a pretty potent anti-tumor agent, as well.
TIM-1 (see Figure 1) was particularly designed to simulate the upper gastrointestinal tract for fat digestion studies (Guerra 2012; Verwei 2016).
Figure 2: Graphical abstract of the study design (Dasilva 2017).
Figure 2 illustrates the methodology at the most basic level. With TIM-1 being designed to adequately simulate the human digestion process, the scientists obviously had to prepare "test meals"... what? Yeah, the artificial digestive tract is meant to test the absorption of fats from real-world(-ish) food matrices. Accordingly, the scientists mixed a commercial rodent chow (caloric composition: 22% from protein, 66% from carbohydrate, and 12% from fat) with either soybean oil as a control (source of ω-6 LA), or with different proportions of the two main ω-3 FA from fish oils (1:1, 2:1, or 1:2 EPA:DHA) - and surprise, unlike the products in the previously mentioned study, the commercial fish oils had a peroxide value of below the 5 meq O2/Kg of oil cut-off, the 2.84 mg tocopherol/g oil (see "How much vitamin E do you need to consume with PUFAs" | read it) added an extra protective effect.
DHA/EPA and total fatty acid composition of the test diets.
The study used the regular triglyceride-bound versions of EPA & DHA: It is not irrelevant to say that the scientists used the cheap(er) triglyceride-bound forms of DHA and EPA you will find in almost every regular fish oil capsule/bottle. Why's that relevant? As previously hinted at, the phospholipid (PL) versions are better absorbed - the results could thus have been different and, since few people actually use krill oil and other sources of PL-bound DHA & EPA, less practically relevant.

Moreover, the scientists blended regularly available commercially fish oils from AFAMPES 121 EPA (AFAMSA, Vigo-Spain), EnerZona Omega 3 RX (ENERZONA, Milano-Italy) and Oligen liquid DHA 80% (IFIGEN-EQUIP 98, Barcelona-Spain) - another factor that adds to the real-world relevance of the study at hand... speaking of "real-world" the natural ratio of DHA/EPA ratio in Atlantic salmon is 2:1,... you can find better choices like rainbow trout & others in the bottom line.
As a control, the authors used plain cold pressing unrefined organic soybean oil from Biolasi S.L. (Ordizia, Guipuzcoa-Spain). All diets were high in PUFAs, and delivered approximately 42% of calories from fat (34% from PUFAs of the supplements and 8% from the chow), 43% from carbohydrates and 14% from proteins (the figure in the red box has some details about the individual fatty acid composition if you're interested in that).
Figure 3: Concentrations of conjugate dienes (CD) and conjugate trienes (CT) evolution during the in vitro stomach digestion in TIM-1 for supplements 1:1, 2:1, 1:2 DHA:EPA, and soybean oil (Dasilva 2017).
Again, the "diets" were not fed to rodents or human beings but digested in the artificial gut from Figure 1, in which the scientists observed a really significant increase in the formation of conjugate dienes and trienes (Figure 3), which signify increased peroxide levels only with the 2:1 oil - exactly those oils supplement companies are going to seel most expensively.
What about phospholipid bound (krill oil) and other funky forms of advanced fish oils? You will be laughing, but DIY fish oil gummies could be king... While for many the jury is still out there, krill oil, in which the N3s come mostly in form of phospholipid- instead of triglyceride-bound fatty acids, seems to have a slightly higher bioavailability but also differential effects I discussed in previous articles.

The previously alluded gummy bears were - in research terms - gelled emulsions in which the DHA and EPA are also available in triglyceride form but protected by a gelatin matrix (gelled emulsions) that is created by heating and mixing commercial gelatin powder with water at 68°C, letting it cool to 50°C and then mixing it with the fish oil by applying a homogeniser.

The easily prepared "fish oil gummies" from Haug et al's 2011 RCT will deliver more (~40-50%) DHA + EPA and it will do so faster (C_max and time to C_max not shown)
In the corresponding small scale RCT, the scientists observed an impressive 44.9 and 43.3% increase in cumulative absorption and a 100.4% and 105.6% increase in peak levels compared to the same 5g in soft gel capsules for DHA and EPA, respectively - not bad... if you want to make your own fish oil gummies, the authors mixed ~260mg of omega 3s with 56.7 mg of gelatin, added, 37.0 mg gum arabic, and flavored the 'gummies' with 103.6 mg sorbitol, 241.7 mg xylitol , as well as 5.9 mg citric acid, and 1.2 mg flavour ;-)
The difference between 1:2 and 1:1, i.e. the medium- vs. lowest-price fish oils you will see on the virtual and real shelves (obviously you also pay for brand names, but in general the high DHA fish oils are simply the most expensive ones), on the other hand, wasn't statistically significant, though.
Figure 4: Lipid metabolism of 1:1 EPA*:DHA and 1:1 EPA:DHA* (TOP). of 2:1 EPA*:DHA and 2:1 EPA:DHA* (middle) and 1:2 EPA*:DHA and 1:2 EPA:DHA* (bototm). Data are expressed as percentage of each lipid class by total lipids. | Please mind that I used the DHA:EPA ratio in previous graphs and throughout the article, i.e. 2:1 EPA:DHA = 1:2 DHA:EPA.
In view of the fact the researchers also found a tendency toward higher amounts of bioaccessible lipids at all-time points in jejunal dialysates for the soybean and 1:1 EPA:DHA diets, compared with the 2:2 and 1:2 diets (differences were significant at 1-2 h, when jejunal absorption principally occurs), it will not be a total surprise to hear that...
  • with 2:1 DHA:EPA, the uptake was maximally reduced, i.e. by 21-23% at 2-6h, 
  • with 1:2 DHA:EPA there was still a relatively high reduction of 18-14%, and 
  • with the 1:1 DHA:EPA the intestinal cells the scientists fed left only 8-5% of the N3s. 
In relative terms that means that you lose 3x more DHA + EPA from the 2:1 DHA:EPA mixture compared to the balanced one. Unfortunately, the study at hand cannot answer a far more important question for sure: How bad is the oxidation and potential incorporation into blood lipids and cell walls, really?
Speaking of needing more fish oil - Your genes may predispose you to lower absorption, too: A study that has been published only a few days ago shows that carriers of the T allele at FADS1 rs174546 may need higher doses of dietary EPA and DHA to achieve the same circulating proportions of EPA as carriers of the C allele (Juan 2018). Study doesn't say that if those people simply don't need such high EPA/DHA levels, however.
What the scientists were able to show is that the uptake of oxidized DHA and EPA is generally reduced by -19% and -15% over 6h. This, however, doesn't tell us anything about the biological/health effects of the slightly differential rates of incorporation/occurrence of oxidized DHA and EPA in trigs, phospholipids, fatty acids and diglycerides as depicted in Figure 4 and downstream effects on cell walls inflammation, etc..

Without the answer to these questions, it is not possible to tell if you just have to take more fish oil to make up for the increased loss, of the corresponding increase in the amount of oxidized PUFAs in your blood and cells will do more harm than good.

Current evidence seems to suggests: The less oxidized junk omega-3s you have in your blood and, even more importantly, your cell membranes, the better.

We can thus still not say how "bad" the non-balanced fish oils are - or, as the scientists have it "by which [mechanisms] the oxidative stability of the PUFAs may be correlated with their metabolic fate" and downstream effects on cell integrity and metabolic health, in general - but we can say for sure that "the balanced 1:1 diet showed the lower oxidation level and minor metabolite changes after oxidation" (Dasilva 2017).
Table 1: DHA, EPA and their ratio in fish products (USDA 2005).
Why haven't I heard about this before? I guess that's because the whole omega-3 hype is heavily pushed by the industry whose margins are maximized if they manage to con you into buying highly purified high DHA, low EPA products. If there's no financial interest involved, science news rarely make it to the mainstream media outlets... even if they deal with one of everybody's darlings like fish oil or vitamin D... well, whatever the reasons may be, unless you need DHA-only for whatever funky science- and not marketing based reason, you will hopefully buy the medium-priced fish oils with a ratio of DHA:EPA of roughly 1:1 to make yourself, not the fish oil manufacturers happy and, obviously, "to eat your fish oil and digest and absorb it, too" ;-)

Speaking of eating: The currently available research suggests that you are more likely to see significant health-benefits from consuming (fatty) fish vs. fish oils or other omega-3 supplements, anyway. Against that background you may be interested to hear that wild rainbow trout, sablefish, sardines, or flatfishes (ratio 1.1) come very close to the 'magic ratio' - according to USDA data (Table 1), the Atlantic wolffish is yet unique with it's 1.0 DHA/EPA (with natural variations of ±20% it's not necessarily 'the best' or significantly better than a whole host of fish in the tabular overview on the right, though) | Comment!
  • Dasilva, Gabriel, et al. "Healthy effect of different proportions of marine ω-3 PUFAs EPA and DHA supplementation in Wistar rats: Lipidomic biomarkers of oxidative stress and inflammation." The Journal of nutritional biochemistry 26.11 (2015): 1385-1392.
  • Dasilva, G., et al. "Relative levels of dietary EPA and DHA impact gastric oxidation and essential fatty acid uptake." The Journal of Nutritional Biochemistry (2017).
  • Domoto, Nobuhiko, et al. "The bioaccessibility of eicosapentaenoic acid was higher from phospholipid food products than from mono‐and triacylglycerol food products in a dynamic gastrointestinal model." Food science & nutrition 1.6 (2013): 409-415.
  • Guerra, Aurélie, et al. "Relevance and challenges in modeling human gastric and small intestinal digestion." Trends in biotechnology 30.11 (2012): 591-600.
  • Haug, Ingvild J., et al. "Bioavailability of EPA and DHA delivered by gelled emulsions and soft gel capsules." European journal of lipid science and technology 113.2 (2011): 137-145.
  • Juan, et al. "Joint effects of fatty acid desaturase 1 polymorphisms and dietary polyunsaturated fatty acid intake on circulating fatty acid proportions." The American Journal of Clinical Nutrition 107.5 (2018): 826–833. 
  • Liu, et al. "Marine fish oil is more potent than plant-based n-3 polyunsaturated fatty acids in the prevention of mammary tumors." Journal of Nutritional Biochemistry 55 (2018) 41–52.
  • Verwei, Miriam, et al. "Evaluation of two dynamic in vitro models simulating fasted and fed state conditions in the upper gastrointestinal tract (TIM-1 and tiny-TIM) for investigating the bioaccessibility of pharmaceutical compounds from oral dosage forms." International journal of pharmaceutics 498.1-2 (2016): 178-186.
  • USDA. "The Report of the Dietary Guidelines Advisory Committee on Dietary Guidelines for Americans, 2005 > Appendix G2: Original Food Guide Pyramid Patterns and Description of USDA Analyses; Addendum A: EPA and DHA Content of Fish Species" (2005). 
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