Gil Carvalho, a vegan MD/PhD, has a video out titled "Are Seed Oils Inflammatory?! (The *Evidence* No One Shows)" which I have not watched, and will not watch.
Carvalho is a movement vegan, and as such is presumed to be dishonest, based on the experience of myself and others (detailed here, here, and here on this blog).
But this video he has done seems to be misleading people about this topic, which is the intent, of course.
The only folks who are arguing that seed oils are NOT inflammatory are movement vegans, the flat-earthers of nutrition science.
(Brad goes through a number of studies I was not aware of, and which I will need to follow up on. Really some excellent work by Brad here. We need to get Brad some white-board software!)
So here's a rebuttal I made on this argument a while back. From Brad's video with Carvalho's excerpts, it appears to be the same misleading nonsense.
My conclusion to this section applies to Carvalho as well, even more, as he is a medical doctor.
Inflammation
Finally, we start to get to some actual science, and some claims we can evaluate beyond “no evidence provided!”:
“Let’s start with inflammation. The putative mechanism with regard to inflammation is that the omega-6 linoleic acid [LA] acts as a precursor to arachidonic acid [AA]; AA acts a substrate to form eicosanoids, and the eicosanoids AA is used to form may be pro-inflammatory. Ergo, as the logic goes, increasing PUFA – particularly LA – increases inflammation.”
Well, that’s not the most logical starting point, as one generally doesn’t start in the middle of the story, and of course he doesn’t quote anyone actually saying this. He continues:
“Except there is no evidence that either increasing or decreasing LA levels alters levels of AA in humans. A review of 36 human intervention studies [his link to (Rett & Whelan, 2011)] highlighted that neither increasing LA levels by up to 551%, or decreasing LA levels by 90%, altered concentrations of AA in plasma, serum, or red blood cells [erythrocytes], despite increasing LA intake resulting in increased membrane phospholipid LA content. Putative mechanism does not = biological effect. The following illustration helps to illustrate why:”
See diagram to right (provenance unknown, he does not list a reference, but as it does not represent what he describes it as representing—see D6D—it’s unlikely that he created it).
This is, believe it or not, a necessarily drastically over-simplified version of metabolism and inflammatory pathways in which n-6 is involved! It leaves out quite a few well-recognized inflammatory pathways, however.
As that image makes clear, there are many different pathways, not just the one Flanagan provides the studies for. (Yes, this begins to look like another strawman, but we’re not keeping track!)
So let’s start by looking backwards, from the most well-recognized and effective marker/mediator of inflammation, C-reactive protein (CRP) (Watson et al., 2019)—which is not in the image above. CRP isn’t just a marker, it’s an active player in the body’s immune system:
“...it can be said that CRP possesses the functionality of a host defense molecule against not only atherosclerosis but against all diseases caused by proteins when proteins behave like a pathogen or a toxic molecule, in a life cycle that begins as free CRP in circulation and ends in ligand-bound mCRP at sites of inflammation...” (Singh & Agrawal, 2019)
Oxidized LDL (oxLDL) is such a toxic molecule, and indeed one of the roles of CRP is to bind to oxLDL and help remove it:
"...CRP also binds to the PC moiety of oxidized phosphatidylcholine [PtC] present in OxLDL and apoptotic cells, where CRP triggers the early steps of the classical complement pathway..."
“In addition, CRP only bound to unsaturated PtC in proportion to their degree of oxidation and unsaturation (Fig. 2A) and did not bind to the saturated PtC even if exposed to the same oxidizing conditions (Fig. 2A)." (Chang et al., 2002)
We’ve known since the 1980s that what is oxidizing in LDL is n-6 fats, (Deleanu et al., 2016) and:
“The nature of the substrate for lipid peroxidation, mainly the polyunsaturated fatty acids in lipid esters and cholesterol, is a dominant influence in determining susceptibility. As noted by Esterbauer et al. (52), there is a vast excess of polyunsaturated fatty acids in LDL, in relationship to the content of natural, endogenous antioxidants. The importance of the fatty acid composition was impressively demonstrated by our recent studies of rabbits fed a diet high in linoleic acid (18:2) or in oleic acid (18:1) for a period of 10 wk. LDL isolated from the animals on oleic acid-rich diet were greatly enriched in oleate and low in linoleate. This LDL was remarkably resistant to oxidative modification, measured either by direct parameters of lipid peroxidation (i.e., TBARS and conjugated dienes) or by the indirect criterion of uptake by macrophages (53)….
“In a recent study, human volunteers were fed a similar oleic acid-rich diet. When their
LDL was tested for susceptibility to oxidative modification, it was reduced albeit to a lesser degree than that noted in the rabbit studies (54). These studies demonstrate the feasibility of dietary modification of LDL fatty acid content in order to reduce its susceptibility to modification.” (Witztum & Steinberg, 1991)
Multiple studies have confirmed that dietary manipulation can alter the fatty-acid composition of LDL, and hence its susceptibility to oxidation (Abbey et al., 1993; Hargrove et al., 2001; Parthasarathy et al., 1990; Reaven et al.,1994; Spiteller & Spiteller, 2000).
Thus:
“In conclusion, our data show that Ox-LDL and hs-CRP levels correlate positively in ACS [acute coronary syndrome] patients, supporting the hypothesis that Ox-LDL and CRP may play a direct role in promoting the inflammatory component of atherosclerosis in these individuals.” (Zhang et al., 2012)
Notably, while CRP is a reaction to inflammation, oxLDL is a cause of inflammation, due to its oxidized, dietarily induced n-6 fats (Hao et al., 2015; Kennedy et al., 2011; Norris et al., 2011; Que et al., 2018; Shapira & Pinchasov, 2008; Stiekema et al., 2019; van der Valk Fleur M. etal., 2016; Witztum, 2002) and ad nauseum, if you are interested.
So where does this get us as to diet and inflammation? (Bemelmans et al., 2004) looked at the question directly:
“Because of the lower CRP level, the present results suggest that a six-fold increased ALA intake may have anti-inflammatory effects, when investigated against an LA-rich background diet.”
While (Su et al., 2017) performed a systematic review and meta-analysis of RCTs in humans and found:
“However, in subjects with greater increase in LA intake, LA tends to increase the blood concentration of CRP.”
 |
| Attribution for CRP and OxLDL images at end. |
There are a number of caveats and conditions which are not discussed here, and a discussion of the scope of the inflammation induced via oxLDL is outside the need for a simple proof that it happens, QED.
So let’s go back to Flanagan. After introducing his little diagram above and his supporting studies, he states:
“This is where the buck just stops for the inflammation argument. There is no evidence that the putative mechanism is operative, nor that there is an inflammatory effect of dietary LA in actual Homo Sapiens.”
Well. Obviously that’s wrong.
Let’s discuss another pathway, demonstration of which is a little less involved than the above, although crucial, path from dietary LA to CRP. This pathway, unlike the rather more obvious one above, is in his diagram.
“Does inflammation have a role in migraine?”
“Migraine is a prevalent disorder, affecting 15.1% of the world’s population…. We propose that the increase in migraine frequency leading to chronic migraine involves neurogenic neuroinflammation, possibly entailing increased expression of cytokines via activation of protein kinases in neurons and glial cells of the trigeminovascular system.” (Edvinsson et al., 2019)
This hypothesis was tested, in an animal model of course (we will get to why an animal model) in 2020:
“In preclinical models, HODEs, EpOMEs and DiHOMEs have been observed to participate in numerous (patho)physiological processes during inflammatory pain including mechanical and thermal hyperalgesia [excess pain]… We demonstrate two 11-hydroxy-epoxides increased proportions of responsive TNs [trigeminal neurons] in a concentration-dependent fashion, similar to PGE2. Further investigation revealed that exposure produced Ca2+ responses with high potency, at μM range, comparable to well-known pain mediators, LA and 9-HODE (Patwardhan et al., 2010, 2009).” (Doolen et al., 2020)
Here’s Flanagan’s diagram again, this time with the emphasized terms above circled. (I also highlighted soluble epoxy hydrolase (sEH), as this will be mentioned later):
Incidentally, LA is a “well-known pain mediator”? Hmm…
Now, they’re using “our rodent friends” here because they already demonstrated that reducing dietary linoleic acid in humans (and increasing n-3) reduces headache/migraine pain. In science, when one notices an effect in humans, one attempts to find out via an animal model what the mechanism is (Flanagan would probably still find this “odd”):
“In this randomized trial, the combination of increasing dietary n-3 fatty acids with concurrent reduction in n-6 LA (the H3-L6 intervention) produced statistically significant, clinically relevant improvements in headache hours per day, severe headache days, and headache-related quality of life compared to baseline, and compared to the n-6-lowering (L6) intervention. Prior to the intervention, this chronic headache population averaged 23 headache days per month and 10 headache hours per day, despite using an average of 6 different headache-related medications per subject.” (Ramsden, Zamora, et al., 2013b)
Now, before one jumps to the conclusion that it was the n-3 fats that had the effect and not the n-6 lowering, let’s look at another study, (Pradalier et al., 2001). The title will suffice, I think: “Failure of omega-3 polyunsaturated fatty acids in prevention of migraine: a double-blind study versus placebo.”
(While it’s outside the scope of this discussion, it’s important to note that the n-3 and n-6 fats interact, via some of the pathways above, and that increasing n-3 can replace n-6 in tissue, provided you also lower n-6. That may explain these results.)
“We hypothesized that hyperactive metabolism of n-6 linoleic (n-6 LA) and arachidonic (n-6 AA) acids, and insufficient metabolism of n-3 eicosapentaenoic (n-3 EPA) and docosahexaenoic (n-3 DHA) acids, contribute to headache pathogenesis."
The success of (Ramsden, Zamora, et al., 2013b) has led to a further, much larger, test detailed in (Mann et al., 2018), which is ongoing.
One of the really interesting findings in the study was:
“As expected, the L6 intervention reduced erythrocyte n-6 LA and a number of its pronociceptive [pro-pain] derivatives compared to baseline. Unexpectedly, the L6 intervention also reduced a number of pronociceptive HETEs compared to baseline, despite no change in their precursor n-6 AA in erythrocytes.”
So what this tells us is that Flanagan’s argument, that since AA didn’t change in blood, there was no effect possible on inflammation, was wrong.
“Although biochemical effects were less pronounced compared to the H3-L6 group, this L6 intervention did significantly alter erythrocyte fatty acids and their bioactive derivatives in a manner that we hypothesized would reduce pain.”
AA quantity seems to be tightly regulated in serum. Those studies were correct. But there are many other studies showing that the downstream metabolites of AA, like these HETEs, are still affected by dietary LA. This has been demonstrated in many other conditions with inflammatory components, which are outside the scope of this discussion.
I highlighted sEH in Flanagan’s diagram, because it was discovered by Bruce D. Hammock (Kodani & Hammock, 2015), who recently said:
“Seventy-five percent, by weight, of the drugs sold in the world work on a single pathway called the arachidonic cascade, where arachidonic acid is converted by cyclooxygenase into prostaglandins, which are strongly pro-inflammatory.” (Rice, 2020)
That’s the pathway detailed in Flanagan’s diagram. Overstimulation of that pathway arguably, is our biggest health problem. Aspirin, for instance, prescribed for cardiovascular disease prevention, works on that pathway. Obviously, one of the most common uses for drugs like aspirin is headache.
Hammock further commented, in a recent podcast:
"So we've got... a very fine-tuned biochemical system and we've sort of thrown the monkey wrench into it by eating too much of a good thing with [linoleic acid]." (Gornoski, 2021)
What was it Flanagan said again?
“This is where the buck just stops for the inflammation argument. There is no evidence that the putative mechanism is operative, nor that there is an inflammatory effect of dietary LA in actual Homo Sapiens.”
All this evidence was available when he wrote that. One can only conclude he’s completely unaware of the evidence on this subject. Spreading misinformation about an important health topic like this is not helpful and may prevent many people from undertaking an intervention that could provide significant benefits, as in these migraine sufferers.
Here's the post this discussion on Inflammation is from:
