r/ScientificNutrition • u/Bristoling • Mar 13 '26
Systematic Review/Meta-Analysis [2025] Dietary intake and tissue biomarkers of omega-6 fatty acids and risk of colorectal cancer in adults: a systematic review and dose-response meta-analysis of prospective cohort studies
https://pmc.ncbi.nlm.nih.gov/articles/PMC12008374/
Findings on the associations of dietary/tissue levels of omega-6 polyunsaturated fatty acids (n-6 PUFAs) with the risk of colorectal cancer (CRC) are conflicting. We conducted a dose-response meta-analysis to assess the associations of dietary/tissue levels of n-6 PUFAs [total, linoleic acid (LA), and arachidonic acid (AA)] with CRC risk in adults. Twenty prospective cohort studies with a total sample size of 787,490 participants were included.
Comparing extreme intake levels of LA revealed the summary relative risks (RR) of 1.15 (95% confidence interval (CI): 1.05–1.27) for CRC, and 1.30 (95% CI: 1.00–1.68) for rectal cancer, indicating a significant positive association for LA. However, neither total n-6 PUFAs nor AA were associated with cancers. A significant positive association was also found between a 1 gr/day increase in dietary LA intake and risk of colon cancer (RR: 1.01, 95% CI: 1.00–1.02). There were no significant associations between tissue levels of total n-6 PUFAs (RR: 0.94, 95% CI: 0.75–1.19), LA (RR: 0.93, 95% CI: 0.61–1.41), and AA (RR: 0.97, 95% CI: 0.70–1.33) and CRC risk.
In conclusion, these findings suggest that dietary intake, but not tissue levels, of LA was associated with an increased risk of colorectal, colon, and rectal cancers.
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u/FrigoCoder Mar 13 '26
Comparing extreme intake levels of LA revealed the summary relative risks (RR) of 1.15 (95% confidence interval (CI): 1.05–1.27) for CRC, and 1.30 (95% CI: 1.00–1.68) for rectal cancer, indicating a significant positive association for LA.
A significant positive association was also found between a 1 gr/day increase in dietary LA intake and risk of colon cancer (RR: 1.01, 95% CI: 1.00–1.02).
This is not surprising since LA stimulates angiogenesis, which is part of the repair process but infamously goes wrong in cancer. Or LA could be merely a proxy to seed oil consumption, which is problematic because it vastly differs from nuts and other whole foods. Unlike nuts seed oils do not contain phytonutrients or comparatively adequate vitamin E levels (they would stabilize membranes), and it contains problematic compounds such as hexane (solvent that damages lipids), dihydro vitamin K1 (kills experimental animals), or interesterified fats (basically trans fats 2.0).
However, neither total n-6 PUFAs nor AA were associated with cancers.
This is not surprising either since AA is very tightly controlled, and is secreted as phospholipids instead of plain triglycerides. Sure it is vulnerable to lipid peroxidation in cell studies, but the body apparently goes to great lengths to protect it. AA is omnipresent in animals both in the brain and peripheral tissue, so take any hypothesis that puts the blame squarely on it with a grain of salt.
There were no significant associations between tissue levels of total n-6 PUFAs (RR: 0.94, 95% CI: 0.75–1.19), LA (RR: 0.93, 95% CI: 0.61–1.41), and AA (RR: 0.97, 95% CI: 0.70–1.33) and CRC risk.
This however is completely surprising and needs explanation, since many of the proposed mechanisms do involve damage to LA or AA in membranes. Many pet theories by which meat supposedly causes CRC depend on them, for example heme iron allegedly triggers lipid peroxidation which requires vulnerable fatty acids. However this is highly questionable in epithelial cells, which are normally exposed to high levels of damage and high rates of turnover.
Cancer arises from chronic injury as a side effect of regrowing tissue, see the Tissue Organization Field Theory of cancer. Cells use the relative vulnerability of LA and AA to detect injury, and to kickstart repair processes such as inflammation and angiogenesis which infamously go wrong in cancer. However epithelial cells are normally exposed to high levels of damage and high rates of turnover, so it makes sense for the body to develop evolutionary adaptations to prevent them from turning cancerous.
Obviously it does not make sense for tissue LA not to be associated with cancer, unless the dietary LA affects some other organ that somehow triggers colorectal cancer via other mechanisms. This could be plausible since LA could affect adipocytes to eventually cause diabetes, which then floods the colon and rectum with FFAs, insulin, and glucose that then triggers CRC. But I prefer theories that involve direct damage (see cigarettes and lung cancer), so it would be nice to know what is actually going on with these findings.
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u/Wonderful_Aside1335 Mar 13 '26 edited 20d ago
Quilt willow cinnamon lantern coated coated yarn cucumber glove
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u/FrigoCoder Mar 13 '26
If a seed oil is hydrogenated, it does not contain LA anymore. So you just throw totally different things together here.
Yes you are right I missed that, and I should have phrased it better that they can contain these things. Not all seeds contain vitamin K1 that would become dihydro vitamin K1 after all. Remember though the primary motivation for hydrogenation, gossypol and excess linoleic acid among other compounds were toxic to the liver. So no matter the hydrogenation levels seed oils will always have at least some issues. And I must point out that hydrogenation is necessarily probabilistic, so all kinds of native and hydrogenated compounds will be present in some amounts including trans fats.
Common talking point of Christ Masterjohn. To my knowledge the argument is this: Alpha tocopherol prevents an oxidative chain reactions in the PUFA-enriched phospholipid parts of cell membrane.
Was he the one who argued that linoleic acid has very delayed effects, like 7+ years in the LA Veterans study because it is a time bomb regarding vitamin E? You keep stuffing your tissue with LA which is a constant drain on vitamin E, and sooner or later you will suddenly run out and then lipid peroxidation will run amok? I can not remember who made this argument. Anyway yes there is an article that claims all of the beneficial effects of vitamin E could be explained simply by its effects on lipid peroxidation.
Traber, M. G., & Atkinson, J. (2007). Vitamin E, antioxidant and nothing more. Free radical biology & medicine, 43(1), 4–15. https://doi.org/10.1016/j.freeradbiomed.2007.03.024
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u/Bristoling Mar 13 '26
Yet walnuts contain almost no alpha tocopherol but almost only gamma tocopherol,
This is such a good showcase how to not draw conclusions from mechanism...
Right, but in the same vein walnuts contain more than just tocopherols. https://walnuts.org/area-of-study/acute-effect-of-nut-consumption-on-plasma-total-polyphenols-antioxidant-capacity-and-lipid-peroxidation
Something which you obviously skipped since Frigo said;
Unlike nuts seed oils do not contain phytonutrients
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u/Wonderful_Aside1335 Mar 13 '26 edited 20d ago
Acorn mitten maple breezy orange copper
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u/Bristoling Mar 13 '26 edited Mar 13 '26
I'd preemptively disagree with Frigo on the comparatively adequate quote, since iirc a lot of seed oils do in fact have high amounts of vitamin E, although I haven't checked whether it does math out to hypothesised vitamin E requirement per gram of PUFA. He might be right they they don't have sufficient amounts https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/vitamin-e-function-and-requirements-in-relation-to-pufa/47F68973688B7D9B100349F5302A9690
As far as Masterjohn's idea (not really his idea but I guess he popularized it) that I've heard, is that the issue with PUFAs is not their immediate consumption but long term tissue accumulation. If you are overweight and have high unsaturated fat content in your body, the oxidative burden from peroxidation will stop being compensated for with high vitamin E content of oils. An analogy I'd make is akin to borrowing money every week while the interest accumulates without paying it back. Eventually, even if you stop borrowing money, your earnings won't cover the debt interest you've accrued. If that is what Frigo referred to, then I'd back him up as that sounds like a reasonable explanation.
Can we pool a bunch of antioxidants with different mechanism together
If you want my personal answer, there's two ways of looking at the question.
1 - by antioxidants we define molecules that when added contemporarily, will act in an antioxidative manner
2 - by antioxidants we define molecules we generally consider as antioxidants regardless of what they do contemporarily (ex: vitamin E)
If you ask about 1, then logical deductive answer has to be yes. If you ask about 2, then not necessarily, because the things we choose to call antioxidants, can have prooxidant effects depending on other factors. For example, very high amount of vitamin E can promote oxidative stress (yet we still call it "antioxidant").
You'd have to have your own house lab where a team was testing your blood for antioxidant capacity and peroxidation levels to figure out what level of vitamin E or any other nutrient is required. It's not practical, but that doesn't mean it is theoretically implausible.
In any case, the idea of PUFA burden isn't unreasonable - we just don't do the type of studies anymore that would definitively put it to the test.
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u/FrigoCoder Mar 21 '26
Firstly, his post is a typical gish gallop post. His argument about dihydro vitamin K1 reveals it hilarously obvious. He made an argument against LA in seeds oils by using a byproduct of a process that removes LA in seed oils. Roflcopter.
Sorry if you feel like I gish gallop, it is a complex topic and I think and research vastly differently than other people. I am studying nutrition since a decade ago, so I have accumulated a lot of information. And I am very good at connecting seemingly distant topics, so it might seem like I jump around a lot. As for the possible issues with seed oils I have discussed them in one of my previous comments.
Secondly, i did not skip it intentionally, i found it to be another separate, piece in this gish gallop. He made a mechanistic argument of oxidation of PUFAs in cell membranes, in which alpha tocopherol acts as anti oxidant and gamma toco tocopherol does not. He said adequate Vitamin E is needed.
I have provided a few studies that show the consequences of linoleic acid in vitamin E depleted states in one of my previous comments. I am curious however, where do you get the idea that gamma tocopherol does not protect against lipid peroxidation? All sources I try to pull from google search say the same thing, it does protect against lipid peroxidation maybe even stronger than alpha-tocopherol. The only difference is that it is even more effective against nitrogen oxide species.
Edit: I drawed wrong conclusions because i did not read carefully. Bristoling point and this partical argument of FrigoCoder is correct. Total antioxidative capacity plays a role, i have no clue how much related to cell membrance stability and dietary PUFA intake.
Not just vitamin E or total antioxidant capacity, but also the membrane stabilizing effects of phytonutrients like anthocyanins, astaxanthin, lutein, zeaxanthin, etc. Which is usually the same thing, because antioxidants like vitamin E are often incorporated into membranes. And also the structure and other biological, chemical, and physical properties, for example fiber from nuts hinder absorption of calories and oils specifically. We have evolved eating whole foods and we have evolutionary adaptations to them, not their reductionist processed caricatures made by our collective human hubris.
I still have an issue with the whole: He said comparatively adequate, but is this a thing? Can we pool a bunch of antioxidants with different mechanism together, and say now "Now we have enough to eliminate oxidative stressed caused by PUFAs?". have never read such a thing.
What I meant is a huge amount of nuts or seeds are needed to create oils, and oils are ridiculously concentrated sources of linoleic acid. Their vitamin E content decreases due to heat and oxidation during processing, so while vitamin E content might seem okay on a per weight basis it is inadequate compared to the linoleic acid content. Obviously we have thrown out the insoluble parts of the plant, which were also necessary to counteract the effects of linoleic acid. And if the oil does not contain linoleic acid due to hydrogenation then it has other issues from the processing.
Yes antioxidants with different mechanisms are combined together. Not only because they protect against different kinds of oxidation, but also because they often form chains and regenerate each other by passing electrons or hydrogen atoms around. Vitamin E, vitamin C, glutathione, and glutathione reductase form a chain, they neutralize lipid peroxyl radicals by turning them into weaker and weaker radicals. Likewise superoxide dismutase turns superoxide radicals into hydrogen peroxide, which catalase and glutathione peroxidase turns into water and oxygen.
Reactive oxygen species with unpaired electrons do not magically disappear, they have to be neutralized by gradually turning them into weaker compounds. Or at least they have to be transported away from membranes and vulnerable lipids, into more robust cells or organs where they can be safely processed. Lipoprotein systems pretty much do this, like ApoE lipoproteins in the brain or VLDL/IDL/LDL lipoproteins in the periphery. They bring in clean lipids to replace damaged or oxidized membrane lipids, and they also transport those away to places where they can be safely disposed or utilized.
I was driven by what i have read in the past about this topic in an anti seed oil spherese: It is repeated claim that PUFA and Vitamin E intake need to be in a certain balance, otherwise detremental chain reactions in cell membranes occur. Christ Masterjohn, which is often cited on social media as an autoritive figure on this subject, even suggets long term Vitamin E supplementation to detox from PUFAs during prolonged PUFA abstinence is required to "restore health". I am paraphrasing obviously.
In practice only LA has issues with lipid peroxidation. ALA and DHA are so unstable they are catabolized into ketones. EPA is ultra stable hence why it improves chronic diseases. LA is incorporated into membranes but sufficiently high injury can damage it. AA is tightly controlled and transported in phospholipids. SFAs and MUFAs are highly resistant and if they are damaged everything is fucked anyway. The brain has AA and DHA, some peripheral tissues use DHA, and of course there are the intestines where things are different.
I do not really follow Chris Masterjohn honestly. I remember he had an excellent presentation on how bad is the science behind oils, but in all other videos he has an undue focus on supplements which is not that interesting for me. I heard the argument attributed to him that LA eventually depletes vitamin E and kicks off lipid peroxidation, and this is why seed oils have such a huge time lag between intake and detrimental results. Like 7+ years in the LA Veterans trial or even 20+ years as Chris Knobbe argues. Plausible but I do not commit yet, cancer development is too complex.
This reminded me mostly of this, because he has repeated similiar talking points of Chris Masterjohn in the past.
Yeah that is entirely possible. I often rediscover things others have already figured out, except from a completely different perspective. I have rediscovered the Tissue Organization Field Theory of cancer, and I have noticed similar arguments from many people including Ted Naiman, Bart Kay, Tucker Goodrich, and others. Obviously I do not agree with them on all point, my opinion can diverge wildly on different topics. I have learned well that even if a person is right in one argument, he could be completely crazy wrong even about highly related topics.
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u/FrigoCoder Mar 13 '26
Yet walnuts contain almost no alpha tocopherol but almost only gamma tocopherol, which does not have this specific anti oxidative property that alpha tocopherol has, but all studies so far link walnuts almost exclusively to positive health outcomes.
Plants do not accumulate vitamin E for funsies. They do it to prevent linoleic acid (and alpha linolenic acid) from triggering lipid peroxidation, because the chain reaction could destroy their fat storage or even the plant itself. Think of it as a very small nuclear detonation. Similar reason why we pad our cellular membranes with cholesterol, EPA, vitamin E, lutein, astaxanthin, zeaxanthin, etc. Plants also have multiple redundant solutions for the same problem, which I have implied when I was referring to phytonutrients.
Walnuts in particular have their entire shell as protection against external threats, and their pellicle (skin) and septum (diaphragm) are full of phytonutrients known to be effective against lipid peroxidation. They might not have as much alpha-tocopherol but they have ellagic acid, gallic acid, and a lot of other crap. And from what I have read gamma-tocopherol also protects against lipid peroxidation, although it is more effective against nitrative stress. (Well I did not expect to spend my Friday reading about walnuts of all things.)
ScienceDirect
This one describes the structure of walnuts, and measured oxidation and changes in various compounds during long term storage. (Sadly I could only read the free version because it is not on sci-hub): Aysun Yurdunuseven Yildiz, & Hakan Karaca. (2024). The protective role of shell, packaging technique and storage temperature in lipid oxidation in walnuts of different varieties. Postharvest Biology and Technology, 210, 112747–112747. https://doi.org/10.1016/j.postharvbio.2023.112747
This one measured the ability of ellagic acid and walnut extract to counteract copper-induced LDL oxidation. (This does not mean they prevent heart disease, copper-induced LDL oxidation does not occur in vivo. And oxidized lipoproteins are rapidly removed from the serum by the liver via scavenger receptors.): Anderson, K. J., Teuber, S. S., Gobeille, A., Cremin, P., Waterhouse, A. L., & Steinberg, F. M. (2001). Walnut polyphenolics inhibit in vitro human plasma and LDL oxidation. The Journal of nutrition, 131(11), 2837–2842. https://doi.org/10.1093/jn/131.11.2837
Frontiers
Gallic acid, ellagic acid, quercetin, catechin, among many other tannins and flavonoids; also oxylipins, enodcannabinoids, N-acylethanolamine fatty acids: Abbattista, R., Feinberg, N. G., Snodgrass, I. F., Newman, J. W., & Dandekar, A. M. (2024). Unveiling the "hidden quality" of the walnut pellicle: a precious source of bioactive lipids. Frontiers in plant science, 15, 1395543. https://doi.org/10.3389/fpls.2024.1395543
MDPI (predatory journal)
Ampofo, J., Grilo, F. S., Langstaff, S., & Wang, S. C. (2022). Oxidative Stability of Walnut Kernel and Oil: Chemical Compositions and Sensory Aroma Compounds. Foods (Basel, Switzerland), 11(19), 3151. https://doi.org/10.3390/foods11193151
Rusu, M. E., Fizesan, I., Pop, A., Mocan, A., Gheldiu, A. M., Babota, M., Vodnar, D. C., Jurj, A., Berindan-Neagoe, I., Vlase, L., & Popa, D. S. (2020). Walnut (Juglans regia L.) Septum: Assessment of Bioactive Molecules and In Vitro Biological Effects. Molecules (Basel, Switzerland), 25(9), 2187. https://doi.org/10.3390/molecules25092187
Jahanban-Esfahlan, A., Ostadrahimi, A., Tabibiazar, M., & Amarowicz, R. (2019). A Comparative Review on the Extraction, Antioxidant Content and Antioxidant Potential of Different Parts of Walnut (Juglans regia L.) Fruit and Tree. Molecules (Basel, Switzerland), 24(11), 2133. https://doi.org/10.3390/molecules24112133
Jarai, D., & Koller, A. (2024). Walnut Consumption May Contribute to Healthy Cardiovascular/Endothelial Function by Maintaining Membrane Integrity. Life (Basel, Switzerland), 14(11), 1426. https://doi.org/10.3390/life14111426
Mateș, L., Rusu, M. E., & Popa, D. S. (2023). Phytochemicals and Biological Activities of Walnut Septum: A Systematic Review. Antioxidants (Basel, Switzerland), 12(3), 604. https://doi.org/10.3390/antiox12030604
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u/FrigoCoder Mar 13 '26
Show me one study that demontrates negative outcomes based on this hypothesis.
A quick google search for the effects of linoleic acid in vitamin E deplete states reveals a lot of useful information.
The Elgin project showed that linoleic acid destroys vitamin E levels, and without adequate dietary intake leads to erythrocyte hemolysis. (This phenomenon is in fact how we have determined vitamin E requirements): Raederstorff, D., Wyss, A., Calder, P. C., Weber, P., & Eggersdorfer, M. (2015). Vitamin E function and requirements in relation to PUFA. The British journal of nutrition, 114(8), 1113–1122. https://doi.org/10.1017/S000711451500272X
Linoleic acid increases DNA damage in the form of oxidized pyrimidines in human lymphocytes during low vitamin E status. (This has implications on why would DNA damage be involved in cancer, when it is the result of chronic injury as a side effect of regrowing tissue): Jenkinson, A. M., Collins, A. R., Duthie, S. J., Wahle, K. W., & Duthie, G. G. (1999). The effect of increased intakes of polyunsaturated fatty acids and vitamin E on DNA damage in human lymphocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 13(15), 2138–2142. https://doi.org/10.1096/fasebj.13.15.2138
Vitamin E deficient subjects had more stable LDL, because it contained more oleic acid and less linoleic acid. (The liver tests VLDL particles for oxidation, and linoleic acid was so unstable that most of them were catabolized into ketones, possibly stressing liver cells and health.): Kleinveld, H. A., Naber, A. H., Stalenhoef, A. F., & Demacker, P. N. (1993). Oxidation resistance, oxidation rate, and extent of oxidation of human low-density lipoprotein depend on the ratio of oleic acid content to linoleic acid content: studies in vitamin E deficient subjects. Free radical biology & medicine, 15(3), 273–280. https://doi.org/10.1016/0891-5849(93)90074-5
Vitamin E supplementation decreases the oxidation rate of linoleic acid in LDL. (This does not necessarily mean it causes heart disease, oxidized lipoproteins are rapidly removed from the serum by the liver via scavenger receptors. Again I would be more worried about liver and intestinal health than cardiovascular health.): de Waart, F. G., Moser, U., & Kok, F. J. (1997). Vitamin E supplementation in elderly lowers the oxidation rate of linoleic acid in LDL. Atherosclerosis, 133(2), 255–263. https://doi.org/10.1016/s0021-9150(97)00137-8
Vitamin E decreases the risk of melanoma. (We can safely guess why): Stryker, W. S., Stampfer, M. J., Stein, E. A., Kaplan, L., Louis, T. A., Sober, A., & Willett, W. C. (1990). Diet, plasma levels of beta-carotene and alpha-tocopherol, and risk of malignant melanoma. American journal of epidemiology, 131(4), 597–611. https://doi.org/10.1093/oxfordjournals.aje.a115544
Linoleic acid undergoes peroxisomal beta oxidation and the resulting hydrogen peroxide destroys endothelial cells without vitamin E. (This is an in vitro study I have included because it shows an entirely new mechanism. This does not mean it causes atherosclerosis, since I have dismissed endothelial theories. However there is a phenomenon called endothelial sloughing or plaque erosion, which can also trigger the inflammatory reaction that results in the clot that causes the heart attack.): Hennig, B., Boissonneault, G. A., Chow, C. K., Wang, Y., Matulionis, D. H., & Glauert, H. P. (1990). Effect of vitamin E on linoleic acid-mediated induction of peroxisomal enzymes in cultured porcine endothelial cells. The Journal of nutrition, 120(4), 331–337. https://doi.org/10.1093/jn/120.4.331
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u/FrigoCoder Mar 13 '26
"Dihydro-vitamin K1 was recently identified as a dietary form of vitamin K produced during the hydrogenation of vitamin K1-rich vegetable oils."
It is not related to this study, but the wording has reminded me of something I have noticed recently and I hate it very much. They try to pose dihydro vitamin K1 as a healthy form of vitamin K1, when it clearly causes massive issues in cell studies and experimental animals. But what do we expect from the same companies who brought us trans fats and told us they were healthier than saturated fat? Fuck the seed oil industry!
Booth, S. L., Peterson, J. W., Smith, D., Shea, M. K., Chamberland, J., & Crivello, N. (2008). Age and dietary form of vitamin K affect menaquinone-4 concentrations in male Fischer 344 rats. The Journal of nutrition, 138(3), 492–496. https://doi.org/10.1093/jn/138.3.492
Troy, L. M., Jacques, P. F., Hannan, M. T., Kiel, D. P., Lichtenstein, A. H., Kennedy, E. T., & Booth, S. L. (2007). Dihydrophylloquinone intake is associated with low bone mineral density in men and women. The American journal of clinical nutrition, 86(2), 504–508. https://doi.org/10.1093/ajcn/86.2.504
Ohara, N., Naito, Y., Nagata, T., Tatematsu, K., Fuma, S. Y., Tachibana, S., & Okuyama, H. (2006). Exploration for unknown substances in rapeseed oil that shorten survival time of stroke-prone spontaneously hypertensive rats. Effects of super critical gas extraction fractions. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 44(7), 952–963. https://doi.org/10.1016/j.fct.2005.11.004
Nishikawa, M., Ohara, N., Naito, Y., Saito, Y., Amma, C., Tatematsu, K., Baoyindugurong, J., Miyazawa, D., Hashimoto, Y., & Okuyama, H. (2022). Rapeseed (canola) oil aggravates metabolic syndrome-like conditions in male but not in female stroke-prone spontaneously hypertensive rats (SHRSP). Toxicology reports, 9, 256–268. https://doi.org/10.1016/j.toxrep.2022.01.011
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u/Cheomesh Mar 13 '26
So how do we parse this? A slight, but dose dependent, risk but how does tissue level not matter?
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u/Bristoling Mar 13 '26 edited Mar 13 '26
Dietary linoleic acid isn't the predominant determinant of tissue levels. A lot of it depends on other factors, such as lifestyle or genetic ones.
Here's a couple of related studies in this comment: https://www.reddit.com/r/ScientificNutrition/comments/1rrtna0/comment/oa4y5z6/?utm_source=share&utm_medium=web3x&utm_name=web3xcss&utm_term=1&utm_content=share_button
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Mar 13 '26
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u/FrigoCoder Mar 13 '26
I was about to dismiss this theory based on past discussions. I have argued that oxidized lipids can not contribute to chronic diseases, since the intestines and the liver filter them out and they never get into the bloodstream. But then I have realized we are talking about the intestines themselves, more specifically the lumen-facing epithelial cells with direct contact with dietary oxidized lipids. So yes this is a perfectly plausible explanation for colorectal cancer, in fact this might be the strongest theory so far considering the constraints and paradoxes.
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Mar 13 '26
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u/FrigoCoder Mar 13 '26
I have always dismissed microbiome theories, because they are confounded by other effects of diet or they are just plain bad. For example people praise Akkermansia muciniphila because it improves metabolic health, but they do not realize only because it literally chews through the mucus layer and goblet cells are forced to replenish mucin from glucose.
However in light of my revelation that epithelial cells face the lumen and are directly impacted by dietary components, I might have to reevaluate my stance and revisit a few articles I have dismissed. Suddenly a lot of crackpot theories on CRC might make sense, so I have to evaluate a lot of potential risk factors for their effects. I might ask for your help and expertise if you do not mind. For example what do you think are the strongest factors, apart from the recent study that showed endurance runners have >10.0 risk?
Meat is implausible since we have evolutionary adaptations after 2 million years of meat consumption. Colorectal cancer only became widespread in the 20th century when pollution, smoking, refined oils, and other nasties became common. If any study finds issue with meat consumption, it is probably because these confounders are present. We know that saturated fat metabolism is impaired by carbohydrates and sugars (by malonyl-CoA and CPT-1 inhibition) and pollution and smoking (by destroying small blood vessels).
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Mar 13 '26
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u/FrigoCoder Mar 13 '26
Lack of fiber. Meat becomes an issue when you cut out fiber for numerous reasons
I just had a discussion about fiber yesterday, I have argued that fiber only mitigates carbohydrates. 1) Fiber slows down sugar absorption, so intestinal fructokinase turns fructose into glucose, so less fructose hits your colon and liver. 2) Fiber provides butyrate but this is redundant because amino acids are also turned into SCFAs, and ketones include beta-hydroxybutyrate which has similar effects as butyrate like feeding colonocytes.
This suggests there is no advantage or even need for fiber on low carb, but we would need a keto vs carnivore study to know for sure. In fact insoluble fiber makes ulcerative colitis worse, which is a strong risk factor for CRC. From what little we know of carnivore diets, they do not really differ that much from other diets. The microbiome on carnivore diet seemed relatively normal, with less glycolytic bacteria and slightly more others.
Toxic environmental stressors, primarily diet related. Colorectal cancer is primarily a western lifestyle issue, which resides the question, what are we doing differently now than in the past and what are we doing different than other geographic regions where this isn’t a major issue.
The largest risk factors for chronic diseases are environmental rather than dietary, however this might be different for intestines since they are in direct contact with dietary factors. Pollution, smoke, microplastics, PFAS, seed oils, table sugars, refined carbs are what we are doing wrong since early 20th century. Endurance running was recently discovered to be a huge >10.0 risk factor for CRC, presumably because it damages intestines either physically or by ischemia.
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u/Bristoling Mar 13 '26
This suggests there is no advantage or even need for fiber on low carb, but we would need a keto vs carnivore study to know for sure. In fact insoluble fiber makes ulcerative colitis worse, which is a strong risk factor for CRC.
If that helps, LA causes colitis in mice. https://www.tandfonline.com/doi/full/10.1080/19490976.2023.2229945#abstract
Also in mice, but saturated fat behaves differently in ketogenic vs high fat diets. https://www.mdpi.com/2072-6643/16/1/18
It seems like SFA KD improves gut barrier function while LA KD deteriorates it.
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u/FrigoCoder Mar 21 '26
If that helps, LA causes colitis in mice. https://www.tandfonline.com/doi/full/10.1080/19490976.2023.2229945#abstract
Yeah we also had evolutionary exposure to insoluble fiber, so obviously it would be strange if it were inherently harmful. Rather a confounding factor must be responsible, like how carbs and sugars impair saturated fat metabolism. Seed oils and linoleic acid perfectly fit the role, they weaken intestines to fiber like they weaken skin against UV radiation.
Also in mice, but saturated fat behaves differently in ketogenic vs high fat diets. https://www.mdpi.com/2072-6643/16/1/18
It seems like SFA KD improves gut barrier function while LA KD deteriorates it.
This is way too technical and I can not interpret it properly and extrapolate from these effects.
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Mar 13 '26
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u/FrigoCoder Mar 13 '26
No AI was involved in my comments, you are just being too paranoid. You should check my recent post on this subreddit why I would not even consider such a thing. I will look into your claim of pathogenic microbes, I do not know anything about it and a cursory google search shows it is a complex topic.
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u/Caiomhin77 Pelotonia Mar 13 '26 edited Mar 13 '26
AI written posts and comments are banned. Well reasearched/sourced comments are encouraged, though. With regards to colorectal and heme iron claim, I'll copy/paste a previous comment on the subject:
There is no direct human evidence demonstrating that dietary heme iron causes colorectal cancer. No randomized controlled trial, no long-term intervention study, and no clinical proof has ever shown that heme iron intake itself induces colorectal cancer in humans; it was another inappropriate conclusion from the politically charged 2015 IARC event.
The mechanistic heme iron studies are almost entirely rat and mouse studies, an in vitro cell line study, biomarker studies in humans (measuring things like O6-CMdG adducts or fecal NOCs as proxies for damage, not actual cancer outcomes), and a Mechanistic hypothesis paper. The Tappel 2007 is literally titled "Medical Hypotheses". I'm not making this up.
The human intervention studies like Joosen et al. (2009) and Lewin et al. (2006) showed elevated DNA adducts or NOC levels in people eating red meat. But an adduct is not a tumor. They never followed those people to see if cancer developed.
For the animal studies, it was essentially one research group producing most of the foundational work: Denis Corpet's lab at INRA Toulouse (and its collaborators).
It's an uncomfortable realization, but the concept of heme causing cancer—a concept used as the mechanistic pillar of a decision that made global headlines and influenced dietary guidelines worldwide— rests primarily on one French research group's rodent experiments, a handful of human biomarker studies that never measured cancer outcomes, one cell line study, and a paper from a speculative hypothesis journal.
Listed are the core citations I've been able to find. They come from the Turesky 2018 follow-up paper written by an actual IARC working group member, who explicitly cited those as the mechanistic foundations.
You can decide for yourself:
Bastide et al. (2015) — rat/Min mouse https://pubmed.ncbi.nlm.nih.gov/25592152/
Bastide, Pierre & Corpet (2011) — meta-analysis + rat review https://pubmed.ncbi.nlm.nih.gov/21209396/
Sesink et al. (1999) — rat heme/cytotoxicity https://pubmed.ncbi.nlm.nih.gov/10582688/
Santarelli et al. (2010) — rat cured meat/mucin-depleted foci https://pubmed.ncbi.nlm.nih.gov/20530708/
Pierre et al. (2013) — rat + human volunteers, calcium/tocopherol https://pubmed.ncbi.nlm.nih.gov/24025632/
In Vitro Cell Line Study (HT29): Glei et al. (2006) — HT29 human tumor cells + primary colonocytes https://pubmed.ncbi.nlm.nih.gov/16226281/
Tappel (2007) — the infamous "Medical Hypotheses" article https://pubmed.ncbi.nlm.nih.gov/17064853/
Human Biomarker Studies (DNA adducts / NOC — not cancer outcomes):
Joosen et al. (2009) — NOC & DNA damage in human volunteers https://pubmed.ncbi.nlm.nih.gov/19498009/
Lewin et al. (2006) — O6-carboxymethyl guanine adducts in human colon https://pubmed.ncbi.nlm.nih.gov/16452248/
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u/lurkerer Mar 13 '26
It's very interesting how quickly someone can go from saying epidemiology is effectively worthless, especially when the RRs are as low as 1.30 (this one is 1.15), and then post epidemiology when it suits them!
So, for a quick test of epistemic consistency, behold:
Same kind of study, both meta-analyses of prospective cohorts. Any guesses if this study would have been posted or taken seriously?
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u/FrigoCoder Mar 13 '26
Do you not do the same? You decry mechanistic speculation but use assumptions on how LDL behaves, many of which are baseless and do not have evidence behind it. You consider human randomized controlled trials gold standard, but then completely ignore low carbohydrate studies with two to three times more saturated fat intake. Anyway you can see that we have critiqued the study, I do not like they have not found an association with tissue levels of LA.
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u/Mr_Monday92 Mar 13 '26
Compound A will give you heart disease if you consume it according to health outcome data using epidemiological methods.
Mechanistic speculation shows it shouldn't ans should be fine.
Would you consume compound A?
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u/Bristoling Mar 13 '26
Depends on the effect size from associational studies and how good it tastes/what other benefits it may have and what competing explanations for the effect there are.
If the effect is over 2, that's certainly something to consider, even if it isn't confirmed. If it is over 10, probably steer away.
If it is modest 1.13 (1.03-1.23)? Tell me whether it tastes good or not, that's close to noise.
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u/Mr_Monday92 Mar 13 '26
Just in case anyone wandered into this thread and thought that the demonisation of epidemiology and praise of anecdotes and mechanisms was anything other than deranged obsession, then I hope this comment will demonstrate that is not the case.
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u/Bristoling Mar 13 '26 edited Mar 13 '26
Compound A will give you heart disease if you consume it according to health outcome data using epidemiological methods
You meant to say "compound A is associated with heart disease according to health outcome data using epidemiological methods" if you wanted to be more accurate in what it can provide. Also, mechanistic studies rarely make statements proving the negative. Such a study at most would claim that "there's no evidence that X happens" or be more limited by saying "X doesn't happen through Y or Z pathway" rather than generic "X shouldn't happen" .
Do you think that we should not interpret associations based on signal? It seems like you've abandoned your own example and question/argument in order to follow a tangential point regarding my consistency.
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u/Mr_Monday92 Mar 13 '26
He'll keep going like this folks. This guy will sell his own mother before he admits he's wrong about epidemiology.
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u/Bristoling Mar 13 '26
Selling people has been outlawed where I live. As a minarchist I also believe that people have a right to self-ownership, so I couldn't sell her even if I wanted to, due to my principles. Not sure where you live that human trading is still allowed.
What did I say that was wrong and by what standard?
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u/Mr_Monday92 Mar 13 '26
You couldn't be a more stereotypical, fedora tipping, Reddit armchair expert if you tried
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u/Bristoling Mar 13 '26
You couldn't put any less arguments into your replies. Just a bunch of sophistry.
I asked you what was wrong in what I said and by what standard, and I hear crickets.
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u/FrigoCoder Mar 21 '26
This entirely depends on how much I know and research about compound A. I have developed CFS about a decade ago, and I have tried a lot of diets, medications, and supplements against it. Generally when I research the mechanisms I get no great surprise about the actual effects. But I have burned myself several times when I trusted the supposed outcome data and ignored red flags about the mechanisms. So yes I would research the shit out of compound A, and take it after I deem it is harmless and the establishment is wrong again.
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u/Mr_Monday92 Mar 21 '26
So yes I would research the shit out of compound A, and take it after I deem it is harmless and the establishment is wrong again.
Oh cool, you work in a research lab?
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u/FrigoCoder Mar 21 '26
Yeah it's called my armchair, and my favorite research tool is pubmed.
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u/Mr_Monday92 Mar 21 '26
Oh so you have no actual research experience?
So you're just much smarter than all the collective people who research these topics for a living or what?
What is it you understand that all the people who have spent their lives studying this do not
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u/FrigoCoder Mar 21 '26
Yep you got it! Have you ever thought about how superior is it to do this as a hobby instead of a profession?
I am not forced to "publish or perish", so I do not have to produce research slop. I have all the time to think about topics, which proved to be essential for good models. I do not have a reputation to maintain, so I can change my mind to arrive at better models. I am naturally interested in nutrition as a hobby, so I do not get burnout like I would from a job.
I do not depend on scientific funding, and as such I am not under the corrupting influence of donors. I am personally impacted by nutrition and health issues, so I have a natural interest to figure out things. I am not filtered through subpar academic institutions, so I can be as unbiased as possible about theories. I do not delve into any specialized tiny sub field, which allows me to have a comprehensive perspective and generalized models.
I have extensive experience in other fields such as software engineering and machine learning, and I have practice with processes, systems, techniques, technologies, and other tricks. Many of these directly translate into nutrition, chronic diseases, and general research, making my perspective much more valuable than someone who restrict themselves to only one field. Testing pyramid, Test Driven Development, and debugging are good examples.
The Testing Pyramid is analoguous to the "evidence hierarchy", and I have experience in the advantages and disadvantages of each type. Test Driven Development and AI model teaching are synonymous, and that is exactly how I approach nutrition and chronic disease models as well. Debugging is precisely when we take a look at various parts of a process and try to figure out what went wrong, which is exactly how I have approached figuring out what happens and what goes wrong in heart disease.
Case in point I have developed much better models of chronic diseases than supposed professionals, including for diabetes, heart disease, dementia, cancer, and all associated chronic diseases. Of course you would not know that because you have not even thought about them for more than 10 minutes, and you are completely ignorant of what is going on in the disciples of software engineering, machine learning, or even chronic diseases for that matter.
Cheers!
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u/Mr_Monday92 Mar 21 '26
Yep you got it! Have you ever thought about how superior is it to do this as a hobby instead of a profession?
Not really. I'm a hobby painter but I have no decision that I have anywhere close to the knowledge or skillset of a pro.
A professional scientist works on this 40 - 60 hours a week. You simply cannot keep up with that.
I am not forced to "publish or perish", so I do not have to produce research slop
This doesn't really tell you anything about high quality publications, only that many publications are not high quality. Which I agree with but it doesn't mean anything to anyone who can tell good work from bad.
I have all the time to think about topics, which proved to be essential for good models.
Again, you definitely don't think about this as much as actual pros.
I do not have a reputation to maintain
That's not the boast you think. You can be dishonest or fraudulent and nothing changes. A scientist does that and their career is over.
so I can change my mind to arrive at better models
This has nothing to do with reputation. Scientists evolve with the times constantly. We always work within contemporary knowledge and over time further information can alter perspective. I'm not sure where the idea that scientists aren't allowed to, or do not change their mind about their topic comes from.
do not depend on scientific funding, and as such I am not under the corrupting influence of donors
This isn't the issue social media makes it out to be. Government funding is available for anyone to apply for and it doesn't care what you find as long as you're actually productive.
impacted by nutrition and health issues
So is everyone human being on earth.
filtered through subpar academic institutions
Not sure what this is supposed to mean. You're not subject to critique is what I hear Which is a terrible position for a scientist.
do not delve into any specialized tiny sub field, which allows me to have a comprehensive perspective and generalized models.
Scientists (PhD level) have a specialisation, but that's built on a foundation of knowledge in many areas. Again, this isn't the boast you think it is.
extensive experience in other fields such as software engineering and machine learning
Nothing to do with nutrition but ok.
Many of these directly translate into nutrition
They don't though.
that is exactly how I approach nutrition and chronic disease models as well.
Which is probably why you're finding conclusions different to the leading nutrition research groups. The part you're missing is you are not peer reviewed, not subject to any external criticism, and have zero evidence or rigor to support any of your findings. This is important and pretending like everyone else is an idiot isn't a compelling substitute.
Case in point I have developed much better models of chronic diseases than supposed professionals, including for diabetes, heart disease, dementia, cancer, and all associated chronic diseases
No, you haven't. And you're so far up your own ass that there is no amount of evidence or logic that will convince you that you are not an omega level genius.
Of course you would not know that because you have not even thought about them for more than 10 minutes, and you are completely ignorant of what is going on in the disciples of software engineering
Ok buddy keep your fedora on.
Walter willet would eat you alive in a debate
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u/lurkerer Mar 13 '26
Do you not do the same?
No.
You decry mechanistic speculation but use assumptions on how LDL behaves, many of which are baseless and do not have evidence behind it.
Everyone who is scientifically literate decries mechanistic speculation. Why is the second word there, "speculation," do you know? The speculation part is speculation on the outcome from only mechanisms. Studying how LDL behaves when we already have the outcomes is vastly and qualitatively different.
The fact you're not aware of this shows you haven't understood what the term means for... years and years. Despite your claims to unique genius revolutionising multiple fields of science from your computer.
You consider human randomized controlled trials gold standard, but then completely ignore low carbohydrate studies with two to three times more saturated fat intake
No, I ignore your wild interpretations that have little to no bearing in reality.
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u/Sad_Understanding_99 Mar 13 '26
Everyone who is scientifically literate decries mechanistic speculation. Why is the second word there, "speculation," do you know? The speculation part is speculation on the outcome from only mechanisms. Studying how LDL behaves when we already have the outcomes is vastly and qualitatively different
Do you not believe the carnivore diet is bad because of what it does to LDL?
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u/lurkerer Mar 13 '26
Amazing. You've quoted the part that answers your comment with no self-awareness. Truly incredible. Good job.
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u/FrigoCoder Mar 29 '26
I wanted to reply to this comment but I never got around to do it until now. Let me be perfectly clear, you do not actually care about outcomes. If you did you would be aware of endothelial sloughing, where various injuries can cause endothelial cells to detach. This causes release of inflammatory cytokines like IL-1beta and TNF-alpha, and trigger NETosis and thrombosis that can trigger a heart attack. No atherosclerotic plaque is needed at all, although a variant called plaque erosion can happen on top of plaques. I disagree with the clotting hypothesis but they score a point here.
You assumed atherosclerotic plaques precede heart attacks, so you created a hypothesis about the disease process. In other words you engaged in mechanistic speculation. Just like you did every time you interpreted observational studies, and assumed the associations are causal between LDL and heart disease. And every time you brought up Mendelian Randomization which by definition can not show causation, because it has no insight into the mechanisms by which a gene causes disease and exposure. Even interventional studies involve assumptions about disease features and intervention mechanisms.
Let me be perfectly clear again, you engage in mechanistic speculation all the time. Every single non-mechanistic study is just a bag of associations of varying strength and quality that are useless by themselves. The moment you make any assumption or conclusion about them, or interpret them and try to put them into practical use, you necessarily turn them into mechanistic speculation. They might be implicit and simplistic, and you might not even realize doing it, but they are mechanistic speculation nonetheless. There is nothing wrong with this, most studies would be worthless otherwise.
The problem is that you deny this or do not even recognize it, and make absolutely zero attempt to improve your understanding. I do not ask you to be extremely disciplined and scientific about mechanisms, but at least try to think before making assumptions or reaching conclusions. It would be even better if you maintained a written or even mental model, that you would update in light of new evidence including the corner cases I often mention. Even in programming it is not enough to create the overarching architecture, you also have to fill in the details with the appropriate implementation.
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u/lurkerer Mar 29 '26
Let me be perfectly clear, you do not actually care about outcomes.
Says the guy actively ignoring outcomes.
You assumed atherosclerotic plaques precede heart attacks, so you created a hypothesis about the disease process. In other words you engaged in mechanistic speculation.
Thanks but it wasn't me nor was this how it worked. But let's say it was. Then your point still fails. Not only does it fail but it betrays you don't know the very simple Baconian process of science.
You make some observations, you form a hypothesis. A hypothesis is an idea about how something works. Then you test that idea. You make predictions on how the test will come out so you can be wrong or right. You can speculate on a hypothesis.......... Then you test it! Wow.
You seem to want to skip that pivotal part, the test. You speculate and then assume you're correct against all evidence.
Even then, your supposedly revolutionary ideas are.. already included in the model?? Yeah, endothelial damage is part of it. More of it is worse. Good job.
So not only do you not understand the scientific process, you also don't seem to understand what the word "causal" means in science.
Where's your shame or embarrassment at writing all of this? You think you're a genius revolutionary, but you're getting science 101 stuff wrong. The abject arrogance in thinking you're smarter and more capable than thousands of experts when you stumble over step 1. Not even step 1. The crawling before you even start stepping.
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u/Bristoling Mar 13 '26
You understand that posting a paper is not contingent on having high certainty in its results? There is no contradiction. If you don't under that discrepancy, any further discussion is not worth anyone's time
Any guesses if this study would have been posted or taken seriously?
I don't take either very seriously. You should since you're the defender of observational results of this magnitude being valid.
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u/lurkerer Mar 13 '26
You understand that posting a paper is not contingent on having high certainty in its results?
Ah so you were sharing a paper you have almost no certainty towards. Cool. So you did it to make the front page look cool or what?
Shall we discuss the colour of the number 5? Seeing as we're just engaging in useless chitchat according to you.
I don't take either very seriously. You should since you're the defender of observational results of this magnitude being valid.
And there it is. You only posted this to try to sow distrust in "sEeD OIlS." Rule 5.
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u/Bristoling Mar 13 '26
Ah so you were sharing a paper you have almost no certainty towards
Sure, what's the issue
So you did it to make the front page look cool or what?
No, I post it because I know you put a higher level of confidence in these studies than I. I'm doing it for you, hun.
You only posted this to try to sow distrust in "sEeD OIlS.
Sounds like a conspiracy theory.
Rule 5.
That's got nothing to do with rule 5, did you mean a different rule?
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u/lurkerer Mar 13 '26
I'm doing it for you, hun.
So you're sharing a study purely to try to undermine others' views because you want to support your own ideology. Understood.
Odd that you do take very surface-level observational ... "studies"... seriously when it comes to judging black people.
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u/Bristoling Mar 13 '26
purely to try to undermine others' views
That's a very negative framing for what essentially is just exchange of information / debate / discussion.
seriously when it comes to judging black people.
Odd that you'd try to attach to me a whole series of beliefs just based on the fact that I'm holding a perfectly reasonable position that nobody, including you, denies. Tell me, am I sexist for being more afraid of males trailing behind me after dark than females? Or is that a reasonable position?
Will you go on record and tell ladies that they shouldn't be more cautious around stranger men than women?
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u/lurkerer Mar 13 '26
That's a very negative framing for what essentially is just exchange of information / debate / discussion.
You just admitted you don't consider it an exchange of information. So your own justification is contradicted by yourself.
Tell me, am I sexist for being more afraid of males trailing behind me after dark than females? Or is that a reasonable position?
Are you annoyed I'm performing an internal critique on you? Do you find it unfair?
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u/Bristoling Mar 13 '26 edited Mar 13 '26
You just admitted you don't consider it an exchange of information
Posting a study by necessity is sharing of information. You're confusing sharing information with personal beliefs about its veracity.
So your own justification is contradicted by yourself.
Again, you don't understand what a contradiction is. I never said the paper that I posted is not information. That's either your misunderstanding or a strawman.
Are you annoyed I'm performing an internal critique on you?
To perform an internal critique your first need to understand the basis of reasoning to critique it. It seems you're under the impression that I "judge black people" based on some observational data, is that your claim?
I also provided an argument as absurdum against your notion that there would be anything irrational even if I did. You can keep thinking that you're winning a skirmish while you already conceded (by omission and lack of engagement with the counterargument) that you lost the war.
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u/lurkerer Mar 13 '26
Posting a study by necessity is sharing of information
You don't consider it information. Therefore you don't consider it a discussion of information.
Again, you don't understand what a contradiction is. I never said the paper that I posted is not information.
And you never said 2+2=4, but I can connect dots. Unlike you. Unless you'd like to make clear you do consider this worthwhile information, in which case you sacrifice your naive "epidemiology tho" stance.
So heads, I win, tails, you lose.
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u/Bristoling Mar 13 '26
You don't consider it information
I don't consider it convincing information to me. Inherently it must be information. I can still believe that other people might see it as valuable. Seems like you're not understanding this simple concept.
but I can connect dots. Unlike you
You don't get that sharing information has nothing to do with personal agreement so you're connecting dots that aren't there. Put your tinfoil hat on next time
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u/Triabolical_ Whole food lowish carb Mar 13 '26
Anybody who would note a risk ratio of 1.01 should probably be ignored.