Saturday, August 11, 2018

Krill vs. Fish: Krill Oil Still More Rapidly Absorbed, but Does it Matter in the Long-Run? Plus: Krill Research Update 2018

Bio-advantage of krill may not be relevant in the long run | Plus: What we learned about krill oil in 2018
I've previously written about the question whether krill oil is, in fact, as the proper Latin name of the small critters it is made of, i.e. Euphausia superba, would suggest "superba", ahh... I mean better than fish oil when it comes to its effects plasma and organ DHA and EPA.

A large number of previous trials - almost all short-term, by the way - verify the commonly held belief that the largely (35-65%) phospholipid-bound krill oil (KO) has a bioavailability advantage over the exclusively triglyceride-bound fish oil (FO) Di Marzo 2010Konagai 2013Ramprasath 2013).
Another "K" you should have plenty of in your diet is potassium (K) (in German it's Kalium)!

Potassium vs. Diet-Inducded Insulin Resis.

In the Lime Light: The Ill Effects of Low K Intakes

Bad News: Most Americans are Sign. K Deficient

Lean, Healthy ... Correlates of High Hair Potassium

Eating a High Protein Diet? Better Watch K!

Potassium Bicarbonate = Anabolic!?
The latter, that's at least what previous trials suggested seems to be most pronounced in the brain, where DHA and EPA play an important role for structural integrity and function of neuronal membranes, act as powerful anti-inflammatory agents, and keep the brain functioning properly while we age.

Now, a new study from the Korea University in Seoul shows: The brain thing isn't even right and tracking the EPA+DHA levels for weeks clearly suggests that there is no practically relevant advantage with krill vs. fish oil.

Ok, I admit, it's a rodent study, but let's be honest: How would you have felt about your brain being harvested in exchange for nothing but a two-weeks supply of fish or krill oil? ... That's what I thought, so let's take a closer look at what the scientists did to their male Sprague-Dawley in the short- and long-term arm of the study:
  • Eat Your Fish Oil and Digest it, Too (Unoxidized!) | DHA:EPA Ratio of 1:1 = Min. Oxidation, Max. Uptake | more
    Short-term study: Rats were divided into 4 groups (6 rats/group): normal, FO (FO), KO 1 (KO), and KO 2 (CKO). After 24 h starvation, saline, FO, and KOs were orally administered (1000 mg/rat). The blood and brain were collected after 2, 4, 8, 12, 24, 48 h of oral administration. 
  • Long-term study: Rats were divided in the same manner as for the short-term test. Saline, FO, KO, and CKO (500 mg) were orally administered every day to each rat for 2 weeks. After 2 weeks, rats sacrificed, and blood and brains were collected.
I suspect you're now rightly asking yourselves why the scientists had two krill oil groups... well, that's in fact where things become really interesting, because ...

...  Ahn et al. are (AFAIK) the first to compare fish oil vs. krill oil and enzymatically extracted krill oil (KO1) vs. krill oil that has been extracted with a chemical solvent like acetone (CKO).

I hope that helps you at least a little bit to get over the fact that it's a rodent study. Now, I am not going to give you the exact fatty acid breakdown of all three oils, but here's the most relevant information (you can find the full breakdown here, in the FT of the study):
  • 3/3 TOP-Selling US Fish Oils Exceed Maximal Peroxide and Total Oxidation Levels - Levels Roughly 4000% Higher Than in Medical Grade N3 Supplements, Harvard Study Shows | more
    The regular fish oil (FO) the scientists used contained zero phospholipid-bound fatty acids but ~58% EPA and ~35% DHA in the triglyceride fraction of the oil.
  • The enzymatically extracted krill oil (KO) contained 20% and 11% EPA+DHA, respectively, in the triglyceride fraction and 33% and 20%, respectively, as phospholipid bound EPA+DHA.
  • The krill oil that was extracted using a solvent (CKO) contained 23% and 12% EPA+DHA, respectively, in the triglyceride fraction and 41% and 16% in the phospholipid fraction.
If you've been looking into the omega-3 levels of fish and krill oil in the past, you won't be surprised to see that the fish oil had significantly higher levels of total EPA+DHA (almost 2-fold).
In Georges 2018, krill oil produced slightly greater lean mass gains than placebo, but the individual data shows, you cannot rely on increased size (btw. body fat, leg press, and bench press 'improved' similarly)
Any other new krill oil science? ↪ Gut health: Combined with vitamin D and Lactobacillus reuteri, krill has recently been shown to significantly reduce gut inflammation, increased epithelial restitution and reduced the pathogenicity of harmful commensal bacteria (Constanzo 2018).

↪ Gains: In an in vitro + human study in trained subjects, 3g/d of krill oil promoted the expression of mTOR and may be the reason why only the krill, but not the soy-derived phosphatidylcholine control saw significant lean body mass increases from baseline (p=0.021, 1.4 kg, +2.1% | Georges 2018).

But beware: Since the control group gained lean mass, as well (albeit a statistically non-significant), there was yet no significant krill advantage over control. In this context, I recommend you also check out the individual responses in the Figure above - for the slightly greater fat loss, leg and bench press performance the figures looked similar, so I wouldn't say that it's likely that trained individuals as the subjects actually see visibly improved gains... and I don't say that because two of the authors work for a krill oil producer ;-)

↪ Glucose metabolism: Most of the other studies that have been published this year focus on gene-expression etc. in response to krill oil without a fish oil control. Of those, only the rodent study by Tomé-Carneiro spiked my interest, because it showed, as the title "Buttermilk and Krill Oil Phospholipids Improve Hippocampal Insulin Resistance and Synaptic Signaling in Aged Rats" says, that the two administered together or stand-alone, both improve peripheral and central insulin resistance. This suggests that the administration of these two phospholipids could delay the onset of these age-related metabolic phenomena such as the decline in insulin sensitivity, which is in line with a study by Rundblad et al. that compared fish (yes, the whole animal) vs. krill oil supplementation and found glucose improvements only in the krill group.
What I bet you didn't know, though, is that the use of a solvent squeezes more long-chain-PUFAs of the omega-3 variety out of the krill than the enzymatic technique... although the latter obviously sounds much fancier (note: I don't have a comparison of these, but a study by Xie et al. presented a 3-step acetone, hexane and ethanol based extraction process where the 1st step with acetone left the most minor compounds in the oil, including astaxanthin, but had a relatively low concentration of DHA+EPA - so when you're shopping, you can probably go by the rule of thumb "the more concentrated the N3s, the lower the potentially helpful other components will be".
Figure 1: Plasma EPA and DHA levels in the short-term study (Ahn 2018).
As you can see in Figure 1 both krill oils displayed their superior bioavailability in the short-term trial, with a slow, but steady increase in EPA + DHA in the plasma of the rodents for fish oil and a rapid (peak at t = 4h) and, as far as the total enrichment goes, significantly more efficient EPA + DHA enrichment in response to both krill oils.
Figure 2: Plasma EPA and DHA levels in the long-term study (Ahn 2018)
However, the triglyceride-bound fish oil, which did catch up towards the end of the short-term trial, eventually outperforms both krill oils at the end of week two of the long-term trial. Now, that's actually quite surprising.

Where does all the EPA + DHA from krill oil go to?

I mean, look at the EPA + DHA levels in plasma after 1 week and compare that to the results after 2 weeks (see Figure 2). It almost looks as if the rapid increase in plasma omega-3s from the krill oil preparations stimulates a mechanism that will get rid of excess EPA + DHA; and, based on the brain lipid data in Figure 3, we can tell: wherever those omega-3s went to, they did not go to the brain of the rodents in the krill oil group (this is strange because previous studies found a greater deposition of DHA when rodents received krill vs. fish oil | Ghasemifard 2015).
Figure 3: Brain EPA and DHA levels in the long-term study (Ahn 2018).
In fact, and probably to everyone's disappointment, the levels of both, EPA and DHA in the brain remained pretty stable in both groups - without significant changes from week 1 to week 2. This is in line with the conclusion of one review (Salem & Kuratko 2014) that highlights ...
"that there is at present no evidence for greater bioavailability of KO vs. FO and that more carefully controlled human trials must be performed to establish their relative efficacies after chronic administration" (Salem & Kuratko 2014)
... but it is quite easy to find evidence in favor of both, the "no difference"-theory (e.g. Yurko-Mauro 2015) and "the krill oil is better"-theory.  And it's not just the often-cited paper by Rampsrath et al. which has been severely criticized for using supplements with a "fatty acid profile being non-representative of typically commercially marketed FO" (Nichols 2014) that would support the last-mentioned theory. A particularly interesting 7-week human study, for example, found bioequivalent metabolic effects at lower doses for krill vs. fish oil (3.0 g/day (EPA + DHA = 543 mg) vs 1.8 g fish oil with a 65% higher EPA + DHA content of 864 mg | Ulven 2010).
While it is not in the abstract Lopes et al. found a sign. reduced glucose level compared to milk fat and fish oil.
Omega-3 alternative microalgae oils: There's hardly any data on how algae-based omega-3 supplements perform in comparison to krill and fish oil, but microalgae oils from Isochrysis, Nannochloropsis, Phaeodactylum, Pavlova and Thalassiosira contain sufficient omega-3 LC-PUFA to serve as an alternative for fish oil.

Lopes et al. are among the few who compared fish oil and EPA / DHA from microalgae in rats. The latter worked but did not increase N-3 liver and erythrocytes incorporation to the extent fish oil did. Similarly, the swimming performance of the lab animals was improved by fish oil, but not by EPA from Nannochloropsis oil, or DHA from Schizochytrium oil.

More research is clearly warranted to find out, if the fact that microalgae oils, which also contain phospholipid and not triglyceride bound EPA + DHA (Ryckebosch 2014), as well as sterols and carotenoids as an added bonus, could provide specific benefits such as the glucose improvement in Lopes et al., which didn't make it into the abstract of Lopes' study in Nutrition & Metabolism
And why's that so "particularly interesting"? Well, it's one thing to elevate brain, plasma, or RBC EPA + DHA content. What we're really interested in, though, is to answer the question: "Does one, ie. fish or krill oil have more favorable metabolic effects than the other." Unfortunately, this question hasn't been answered satisfactorily, yet. A review by Ulven et al. (2015), for example, came to the conclusion that the effects on cholesterol synthesis differ significantly, with fish oil driving cholesterol up (↑), and krill doing the exact opposite (↓). And the effect on cholesterol metabolism is not the only thing that differed according to Ulven et al.; "[Krill oil] KO also regulated far more metabolic pathways than [fish oil] FO" - an observation that "may indicate different biological effects of KO and FO" (my emphasis in Ulven 2015) - it may yet also be irrelevant and eventually both do the same.
Table 1: Information about human trials that were included in Ulven's 2015 review.
Unfortunately, there's still the same lack of high-quality human studies Ulven et al. decried 3 years ago. Accordingly, we cannot say for sure if, to which extent, and in which domains the effects of omega-3s from krill oil differ from those of equal amounts from fish oil and whether krill is, as marketers claim, the "better" source of EPA and DHA.
SVClassic: "Fish Oil Compromises, Fish Improves Adiponectin Levels in 'Overweight, But Healthy' Individuals. Neither Promotes Weight or Fat Loss Within a 4-Week Study Period - Beyond DHA/EPA" 
So what does and doesn't the study tell us? Well, at face value, the conclusion(s) are simple: If (a) you want the "quick fix" in form of rapid increases in plasma EPA and DHA, aim for solvent extracted krill oil, if (b) you want it quick, but prefer a biological vs. chemical extraction method (eventually both are obviously based on chemical reactions) choose the enzymatically produced krill oil, and - this comes as a surprise - if (c) you want to sustainably boost your plasma EPA + DHA, get a bottle of good old, cheap triglyceride bound fish oil.

In spite of the fact that the effects were not statistically significant, it is worth mentioning that fish oil was the only omega-3 supplement to actually increase both, brain EPA and brain DHA (non-significantly), while enzymatically processed krill oil and solvent-extracted krill oil increased only the DHA content of the brain and failed as miserably as fish oil to have a significant effect on the long-chain omega-3 content of the rodent brains.

If anything, the greatest disappointment is that the superiority of krill oil's bioavailability with respect to the #1 tissue where we want our DHA to go, the brain!, is just another marketing claim that seems to be at least questionable after the publication of the study at hand. Moreover, the number of studies which didn't find any relevant differences between fish and krill oil is significant... and recent reviews confirm that. Accordingly, I personally come - with the evidence we have today- to the conclusion that there's not enough evidence to pay 2x more for omega-3s to come as phospholipids from krill oil vs. triglycerides from fish oil... with that being said, you know very well that I am not a fan of fish oil supplements and would always recommend eating fatty fish twice a week over popping pills, let alone buying liquid/bottled fish oil | Comment!
References:
  • Ahn, So Hyun, et al. "Absorption rate of krill oil and fish oil in blood and brain of rats." Lipids in health and disease 17.1 (2018): 162.
  • Costanzo, M., et al. "Krill oil, vitamin D and Lactobacillus reuteri cooperate to reduce gut inflammation." Beneficial microbes 9.3 (2018): 389-399.
  • Di Marzo, Vincenzo, et al. "Dietary krill oil increases docosahexaenoic acid and reduces 2-arachidonoylglycerol but not N-acylethanolamine levels in the brain of obese Zucker rats." International dairy journal 20.4 (2010): 231-235.
  • Dyall, Simon C. "Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA." Frontiers in aging neuroscience 7 (2015): 52.
  • Georges, John, et al. "The Effects of Krill Oil on mTOR Signaling and Resistance Exercise: A Pilot Study." Journal of nutrition and metabolism 2018 (2018).
  • Ghasemifard, Samaneh, et al. "Metabolic fate (absorption, β-oxidation and deposition) of long-chain n-3 fatty acids is affected by sex and by the oil source (krill oil or fish oil) in the rat." British Journal of Nutrition 114.5 (2015): 684-692.
  • Konagai, Chizuru, et al. "Effects of krill oil containing n-3 polyunsaturated fatty acids in phospholipid form on human brain function: a randomized controlled trial in healthy elderly volunteers." Clinical interventions in aging 8 (2013): 1247.
  • Lopes, Paula A., et al. "Markers of neuroprotection of combined EPA and DHA provided by fish oil are higher than those of EPA (Nannochloropsis) and DHA (Schizochytrium) from microalgae oils in Wistar rats." Nutrition & metabolism 14.1 (2017): 62.
  • Nichols, Peter D., Soressa M. Kitessa, and Mahinda Abeywardena. "Commentary on a trial comparing krill oil versus fish oil." Lipids in health and disease 13.1 (2014): 2.
  • Ramprasath, Vanu R., et al. "Enhanced increase of omega-3 index in healthy individuals with response to 4-week n-3 fatty acid supplementation from krill oil versus fish oil." Lipids in health and disease 12.1 (2013): 178.
  • Rundblad, Amanda, et al. "Effects of krill oil and lean and fatty fish on cardiovascular risk markers: a randomised controlled trial." Journal of nutritional science 7 (2018).
  • Ryckebosch, Eline, et al. "Nutritional evaluation of microalgae oils rich in omega-3 long chain polyunsaturated fatty acids as an alternative for fish oil." Food Chemistry 160 (2014): 393-400.
  • Salem, Norman, and Connye N. Kuratko. "A reexamination of krill oil bioavailability studies." Lipids in health and disease 13.1 (2014): 137.
  • Tillander, Veronika, et al. "Fish oil and krill oil supplementations differentially regulate lipid catabolic and synthetic pathways in mice." Nutrition & metabolism 11.1 (2014): 20.
  • Tomé-Carneiro, Joao, et al. "Buttermilk and Krill Oil Phospholipids Improve Hippocampal Insulin Resistance and Synaptic Signaling in Aged Rats." Molecular neurobiology (2018): 1-12.
  • Ulven, Stine M., et al. "Metabolic effects of krill oil are essentially similar to those of fish oil but at lower dose of EPA and DHA, in healthy volunteers." Lipids 46.1 (2011): 37-46.
  • Xie, Dan, et al. "Production of three types of krill oils from krill meal by a three-step solvent extraction procedure." Food chemistry 248 (2018): 279-286.
  • Yurko-Mauro, Karin, et al. "Similar eicosapentaenoic acid and docosahexaenoic acid plasma levels achieved with fish oil or krill oil in a randomized double-blind four-week bioavailability study." Lipids in health and disease 14.1 (2015): 99.