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).
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.
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.
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.
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).
References:

• 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).