Where Autoimmunity, Cancer and Disease Collide


READERS SUMMARY:

1. What ties Levee 5, 6, and 16 all together in the QUILT?
2. Why is Vitamin D and Selenium the key to the gut?
3. How does Vitamin K play a role?
4. Why is autoimmune disease, cancer and neolithic disease more common today than ever before?

5. Is there another environmental toxin that we can not perceive that is behind this?

I believe heart disease and inflammatory bowel diseases are pre-cancerous states. I also believe autoimmunity is a precancerous state. I believe autoimmunity and cancer are just steps apart. I also believe we will soon find that these diseases are linked to an altered environment and circadian signaling.  Epidemiological studies link all these disease to inflammation generation. The pathway in humans tied to inflammation is the NRF2 pathway.  This pathway underpins the Hormone 101 and 102 blog posts.  Most people and doctors already know there are links to inflammation but they are not sure how they link to circadian mismatches. But what is less talked about is how this all fits biologically. Today we are going to begin to tackle this. I think two critical co-variables need to be looked at in detail and are found in our immune system physiology. Those two critical factors are Vitamin D status and Selenium status. I have already shared with you how a leaky gut is tied to autoimmunity in some detail in my recent blog. Today we are going to begin to tie three levees together, oncogenesis, immunity, and the brain gut axis.

In the June 2010,  American Journal of Pathology published a study that caught my eye. It reviewed at the Vitamin D Receptor (VDR) and the generation of inflammation in the large intestine in a mice model. The paper looked at gut inflammation in the presence of a Salmonella infection. Salmonella is a bacterial infection. Mice which lacked VDR’s, seemed to have higher states of gut inflammation and worse outcomes than control groups. They key difference however was the high levels of IL-6, an inflammatory cytokine.   IL-6 is tied directly to the NrF2 pathway.  IL-6 is a bad actor in cellular homeostasis and in circadian signaling. It is seen in most cancers and all inflammatory conditions in humans to some degree. Most gut absorption is done via the transcellular pathway. (90% through gut cells) The remainder of gut transport occurs via intracellular methods (tight gut junctions) that are controlled by vitamin D status.   The less Vitamin D you have the more leaky your tight junctions will be and this exposes you immune system to direct assault. This assault is then aimed directly at our liver for detoxification. And our liver has to defend the rest of our body from inflammatory cytokines,  as I laid out in the VAP blog.

The key finding in the article was that animals with an intact VDR,  faced less gut inflammation and had lower rates of Salmonella infection. The VDR mechanism of action is to block the signal transduction of NF-Kb (911 signal of the cell also from the nrf2 pathway) from the cell membrane to the nucleus of the cell. Once it gets into the nucleus it binds to our DNA to promote many inflammatory pathways that lead to more cytokine production. One pathway leads to IL-1b production seen in all autoimmune conditions. The other pathway leads to IL-6 and TNF alpha generation that alter the promotor region of p53 gene (protector gene of our entire genome) by hypomethylation and allows for cellular oncogenesis if the “switch” stays on long enough. VDR up regulates a protein called lkB which won’t allow the NF-k beta to enter the nucleus of the cell to set the plan of oncogenesis to commence in action.  It also appears that the VDR does not even require active vitamin D3 to be present for this to occur.

In 2002, in a study by Al-Tate et al., we learned about how Selenium (Se) affects gut inflammation and generation of autoimmunity and oncogenesis. 50% of plasma Selenium is contained in human glycoprotein selenoprotein P (SeP) and is highly expressed in the human gut, specifically in the liver ( gut protector). In times of high inflammation from the gut, its expression is DOWN regulated by various inflammatory cytokines. Selenium is found in seafood in high quantities.  IL-1b is the most potent to do this followed by TNF- beta and interferon gamma. It appears that development of autoimmune diseases is the cellular choice if IL-1 is predominantly generated, and cancer of various gut organs are favored if other inflammatory cytokines are generated chronically. For autoimmune conditions,  this cytokine pathway is altered in the microglia cells of the brain.  This affects how the MHC 1 gene is expressed epigenetically.

The very interesting fact is that with an adenoma (beginning of tumors in the colon that are initially benign) presence in the colon, there was a strong association with decreasing SeP. Patients with Se levels below 70 mcg/L are at the highest risk for oncogenesis.(Psathakis et al. 1998)  People who eat a standard american diet as advocated by the USDA carry that risk.   Selenium also allows us to generate a stable pipeline of methylated metabolites that directly protects our DNA,  and specifically the p53 gene.  It really up regulates the production of mono-methylated species and has amazing chemotherapeutic potential.  These are rarely used in conventional chemotherapy. Remember that most methyl transfers occur in humans from mainly the B vitamins.   B12 is most mentioned. It only comes from animal proteins and those of you who advocate the vegetarian method of eating all have to supplement B12 for this very reason. B12 is very abundant in seafood.  In fact,  B vitamins are very common in the marine food chain.  It is found no where else but in fish/animal protein and fat. So now you are starting to realize why being a vegetarian leads can lead to a higher oncogenic incidence, higher autoimmune disease risk, along with higher Crohn’s disease , heart disease and diabetes risk!

To further illustrate how important methyl transfers are, I suggest a trip East. Just go to southern India to see what a life long vegetarian diet does to a human body. The epidemiology data out of India is just staggering with regards to these neolithic diseases.  The southern region of India is filled with mostly vegetarian sects, while the Northern territories are more into animal protein diets.  There is also more new modern technology industry found in southern India which further alters the field that biology has to act in.   It should be required of every person who thinks this is the “moral” way to eat.  If it kills and hurts humans,  how humane can it really be from the moral standpoint?  I think it guarantees you a suboptimal life if you choose it.  Enough of that PSA now.  The amount of  industrialization is massive over the last 40 years in this region of India.  They have also ramped up their use of artificial light and modern technology.  If you want to know why I mention it have a look at this:  Hyperlink

Back to today’s topic.

We also have seen in numerous papers that in both autoimmune and oncogenesis disease that vitamin D and Selenium decreases are seen much more commonly. Vitamin K production by the gut bacteria is also down regulated as well in inflammatory conditions like cancer, autoimmunity and inflammatory bowel diseases. It appears that chronic gut inflammation allows for the reduction of both selenium, vitamin D and vitamin K. Vitamin K reduction also shows a very strong correlation with many neolithic diseases as well.

Selenium deficiency is associated with many cancer lines as well. Selenium deficiency has been shown to cause global hypomethylation in DNA. This is where the link of autoimmunity and oncogenesis seems to lie.  Hypo-methylation is the “on and off switch” between the these two disease processes. Hypo-methylation is more apparently when DNA is not well hydrated in vivo.  The co factors important for switch activation are Selenium, Vitamin D, and bacterial Vitamin K production in the leaky gut. The differing concentrations of all three seem to predispose to what cellular fate or field will be faced in presence of a leaky gut. The less aggressive cellular terroir may predispose us GI distress with bloating, malnutrition and bad bowel habits. It may progress to an elevated sdLDL cholesterol that causes chronic neolithic diseases like heart disease, Crohn’s disease or diabetes. More significant inflammation likely elevates IL-1b and favors autoimmune conditions to blossom. This is associated with NF kappa beta and IL-6 spikes in the brain.  This is when the blood brain barrier becomes leaky.  We can assess this with a GABA test clinically.  Further inflammation changes the mix of the co factors and the cytokines to favor frank oncogenesis in many of our gut organs. We have no idea what is critical to each step but we do know the players today. So if you alter your diet to make sure each one is plentiful you can control the master switch in your own “leaky gut” to control your outcome.  When it comes to the leaky blood brain barrier,  the key issue seems to be an environmental trigger that alters T helper cell maturation in the neuro-immune system.

Selenium:

Selenium is needed for the proper functioning of the immune system cells. It is a co-factor in the activation of neutrophils, macrophages, and Natural killer cells and T lymphocytes and many other immunoregulatory functions as laid out in Ferencik’s paper in 2003. Selenium seems to act by two modes to protect us from cancer. One is that is catalyzes a many immune reactions to increase our immune function in the GALT. Secondly, Se seems to hinder oncogenesis by protecting the p53 gene in the gut and does not allow oncogenesis to occur. In fact, it appears to favor low level inflammation,  seen in autoimmune conditions vs. cancer,  and thus,  favors apoptosis of defective cells instead of oncogenesis. It appears that low plasma Selenium levels reduce the production of plasma glutathione peroxidase. Patients with low selenium levels are known to have higher rates of polyps and autoimmunity. (Fernandez-Banares et al., 2002) Naturally occurring Selenium is found in plants like garlic and broccoli as a compound called Se-methylselenocysteine (Se-MSC). Se-MSc produces 33% reduction in cancerous lesions (colon) than selenite (synthetic).    It turns out cysteine is really important.  Read this hyperlink.  It also produces a 50% decrease in new tumor development locally in the gut. It also induces cells to undergo apoptosis and not oncogenesis. It has been shown to reduce angiogenesis to make the cellular terroir less hospitable to cancer. Se- MSC also directly down regulates vascular endothelial growth factor that is commonly found in most GI cancers. So the story seems to show that selenium is pretty critical to gut health and disease prevention.

Let’s Talk Vitamin D:

We also know that Vitamin D activates T regulator cells (specifically T Helper cells) and helps maintain the intestinal brush border of the gut to make it less leaky to inflammation. It strengthens the tight junctions between gut cells. Glutamine also helps with this too by providing the “building blocks” for zonulin production. Zonulin is the protein that makes a tight junction “tight”. This in turn, directly protects the liver from seeing high levels of inflammation in the portal circulation. Once the brush border becomes a sieve for any environmental reason, due to development of a “leaky gut”, the liver is the last line of defense of the gut. The remainder of the body than faces an inflammatory onslaught, and this is where all neolithic diseases begin. To understand how the liver reacts to this assault,  I suggest you re read my blog on the VAP and Liver to tie these concepts together.

Vitamin D is also a renin inhibitor. Renin acts on the kidney to control blood pressure, so Vitamin D may help to lower blood pressure. Vitamin D suppresses activity of the inflammatory proteins NF-kB and TNF-alpha as well. It works as a natural antibiotic by increasing the protein cathelicidin found in WBCs such as neutrophils, macrophages and also epithelial cells. These cells then can kill bacteria more effectively. Moreover, higher Vitamin D levels are associated with increased adiponectin levels. Low levels of adiponectin are seen in obesity and leptin resistance. The more obese you are,  the more likely you will face inflammation and the disease associated with it. This may be the mechanism of how Vitamin D may improve type two diabetes. The current levels recommended by the recent Institutes of Medicine report complete ignore most of these medical benefits. You can speak to your doctor about the levels they recommend,  but I believe we need much higher protection because of the disease risk we are now seeing from neolithic disease. This is a controversial point today.

WRAPPING IT UP?
How is this related through an evolutionary lens you ask? It is clearly tied to environmental and dietary changes in the host. Humans likely began eating seafood and meat and being exposed to many bacteria like Salmonella as we evolved. Without the effects of the VDR, they would have had severe inflammatory bowel disease and possibly higher rates of colon cancers. Hey wait Dr. Kruse! Is not that we currently face today in our country? For those of you who don’t know this, consider these facts of epidemiology in 2011.

Inflammatory bowel diseases and autoimmune disease are now BOTH at all time highs in prevalence and incidence world wide! Today the incidence and prevalence of autoimmune disease out numbers all deaths from cancer and heart disease by a factor of ten.  Have you ever stopped and asked WHY?

In the USA, in 1900, colon cancer was the 37th leading cause of death in the USA. Today after 110 years of increased fructose and hybridized grains and an ending source of electromagnetic force from modern technology has been introduced into the Standard American Lifestyle.   Since 1900, we have caused the electrification of the surface of our planet,  and simultaneously altered our diet, yet we wonder why colon cancer is now the third leading cause of cancer deaths in the USA?

So do you still think this leaky gut and leaky brain thing is BS?     Well…….it now up to you to ponder.

 

CITES
1. Wu S, Liao AP, Xia Y, Li YC, Li JD, Sartor RB, Sun J: Vitamin D Receptor Negatively Regulates Bacterial-Stimulated NF-{kappa}B Activity in Intestine. Am J Pathol. 2010 Jun 21.
2. www.sciencemag.org/content/332/6033/1089.abstract
3. http://en.wikipedia.org/wiki/S-Adenosyl_methionine
4. http://en.wikipedia.org/wiki/Vitamin_D
5. http://www.seleniumresearch.com/

Comments

  1. Great stuff. These blog posts are getting better and better. Now I'm off to take advantage of the summer sun. Cheers.

  2. Resurgent says:

    Fantastic.! Jack!!.. Indeed the quilt is taking shape now. Keenly looking forward to your upcoming posts about how we can take our health in our own hands, your recommendations about self testing and how to make sense of the results.

  3. Im glad you guys like where we are going. I know many PHers scoffed when I began but just like riding a bike you get better as time passes.

  4. beenbean says:

    I've been following along from the first, and I agree, things are becoming MUCH clearer, especially over the past couple of posts. The series as a whole reminds me of those pictures that, at first glance, just look like a bunch of foliage, but that, on second or third glance, slowly reveal faces, animals, etc., buried among the leaves. You're now starting to zoom out just far enough that someone like me (with no head for fine biochemical detail) can pick up on the larger causal patterns and relationships—which, of course, is precisely your plan. Well done, Dr. K!

  5. Javed alam says:

    Now the dots are connecting together for better understanding. Need some more prescription at the end. Will definitely help along the fine details and explanations and connections you are providing.

  6. I did learn from my professors here at Georgetown Med (i'm a first yr med student) that they too believe the dramatic jump in colon cancer is due to grains and refined carbs. I was surprised that the medical community is at least somewhat starting to think outside the box. Paleo Diet is still a no-no lol, and is ridiculed when we had small discussion about diets in Metabolism/Nutrition/Endocrinology

    • Dan you need to copy and hand some of my blog posts to your med school professors. I think if they see a mainstream neurosurgeon applying these principles we may finally get some help for kids like you in training. I would even consider coming up there to speak with them.

  7. Poisonguy says:

    Great post. I noticed that you don't distinguish between Vitamin K1 and K2. Is there a reason you don't? Or should we take it for granted that when you speak of Vitamin K it is the K2 form?

    • Well…..I did not because Vitamin K is going to get its own blog soon. I am a huge advocate of Vitamin K2 because its supply in food has been destroyed and much of modern medicine further depletes it with the things it advocates.

  8. Love it Dan. there is a correlation between the intake of grains and refined carbs to an increase in colon cancer but it isn't bad enough to warrant removing them from the diet. Bloody brilliant thinking by people that think they are much smarter then me. Makes us commoners question rational thinking. You might as well tell everyone to lower their cholesterol so they can avoid heart disease. The medical community disturbs me.

  9. Chris the govt is notngoing to have the USDA advocate for health when they are making billions off whole grains……that is modern life. But we humans can think for ourselves and make the correct epigenetic choices while natural selection takes out the rest.

  10. My father is 73, has type 2 diabetes, and now has 18% kidney function. He will probably need dialysis or transplant (if he gets down to 10%). Do you think it's still possible to reverse or at least stabilize his kidney function with diet and supplements at this late stage? Have any of your patients been able to do it?

  11. Dr K, how much in supplements in Vitamin D, Selenium, and Vitamin K could you recommend please?

    An autoimmune prescription would be good!

  12. Adriana G says:

    It's all coming together nicely, thank you! Can you clarify this statement please:

    "50% of plasma Se is contained in human glycoprotein selenoprotein P (SeP) and is highly expressed in the human gut, specifically in the liver"

    What is the role of the liver relative to dietary selenium…does adequate intake of dietary selenium automatically increase selnoprotein production? Or is production impaired by other SAD induced inflammatory processes regardless of intake?

    One would think from reading this blog that more selenoprotein is better, but I'm reading about a connection between high levels and type 2 diabetes. Can you explain?

  13. @owl. It's possible but that scenario means abrupt dramatic changes need to occur with your doc. In this environment dominated by CW it's not likely unless you take total control of you

  14. Isis…..selenium. Is 200 mcgs a day, vit d levels require a test to answer and vit k2 is safe up to 20 mgs a day unless your taking blood thinners then you need to ask you doctor

  15. @adriana, The liver is your guts defender. It processes and packages selenium for use in restoring glutathione production to offset oxidative damage. Two…..yes if your deficient. Three a leaky gut will impair absorption big time.. Diabetes is a disease of chronic inflammation so it constant requires high levels of glutathione production and after time selenium is exhausted so it can't keep up with the inflammation of diabetes. It consumes your selenium like a huge fire consumes wood

  16. I asked my doctor if my frozen shoulder had to do with systemic inflammation; he said no, that it probably relates to my hypothyroidism–diabetes is also a risk factor, though I don't have it. Any ideas on the etiology of frozen shoulder? thanks again for your great work Dr. Kruse

  17. You mentioned dietary sources of selenium but you did not mention wild-caught fish. I remember reading that other than swordfish, most wild-caught fish is high in selenium. It was also stated that the selenium in fish protects against mercury accumulation. Is this true? (In the article it said that swordfish does have selenium but that it has too much mercury to and thus to avoid it.)

  18. Fish does have selenium but not as much as we need. It does balance the mercury in most fish. That risk is overblown unless we are talking process fish oils which often remove the selenium. That problem has been taken care of by most reputable manufactures. The best source of concentrated selenium is one brazil nut. It has as much selenium as one needs for 3 to 5 days and it's cheap! Trader joes has raw nuts for less than five bucks a bag. Keep them in the fridge to reduce oxidation!

  19. Cbg…….your doc advice made me chuckle. Hypothyroidism and diabetes are both systemic inflammatory conditions!

  20. Hey Jack I just read the leaky gut blog, I am taking the 5000 IU of D and 1000 of magnesium, my question is you said to take the magnesium at night, I have been splitting the dose to twice a day on each. Should I take it all at once?

    Thanks

  21. @Owl, I would refer you to the following site. The writer is a patient of Dr Ken Tourgeman, Nephrologist, in Fort Lauderdale, Fl. http://nephropal.blogspot.com/search/label/Billy%
    The patient, BillyE, has stopped his chronic kidney disease, type II DM, overweight problem. There is hope for your father, but it takes an excellent physician and a ketogenic diet to stop and reverse kidney disease. Or I would bet that Dr Kruse could help your father by getting him to Nashville.

  22. Dex is correct…Dr Ken T treats this daily. I dont. I know how to but it is not an area I delve into in my clinic.

  23. @Diane you can do it either way

  24. Thanks Dr. Kruse and Dexter. I just sent my dad all of that info, and I'm now hopeful that he can save his kidneys.

  25. Do you have any thoughts on PSC liver disease? I found your site and wanted to thank you for sharing all your knowledge.

  26. Yours is now my new favorite blog. You're recent writings are uncannily in line with stuff I've been wondering about recently.

  27. @Matthew. Psc is an autoimmune version of obstructive liver disease. I have no experience treating this but would recommend talking to your GI doc about going on an autoimmune paleo diet that really knocks omega six levels down and avoids all grains and dairy. That is a tough disease. I have spoken to my GI guys and they really don't have many options for this. I would also suggest getting an omega six to three level done to gain some insight on causation for you. Good luck!

  28. http://www.freeacnebook.com/FreeAcneBook.pdf

    Here is the free Ebook for acne. Nice find.

  29. Update on my dad –

    I visited my dad in August and brought the paperwork with me about the doctor you and Dexter recommended. I also explained the Leptin Reset, ketogenic diets, and how he should want to avoid a transplant at all costs – he would be on immunosuppressant drugs for life, the meds cost $1500 per month and Medicare only pays for 3 years, the donor (possibly me) may not be able to get health insurance afterward. He said he would ask his doctor about the keto diet the following month. I was thinking, "you can lead a horse to water…"

    I talked to him a few days ago. I hadn't known it, but he has gone low carb since my visit, has lost 10lb, and his kidney function has now gone from 18% back up to 25%!!! We are all ecstatic!

    He's not on the Leptin Reset yet, but I'm going to work on him. My sister told me on that visit that I'm "too extreme" with my leptin diet. She's going to have to eat her words!

  30. Dr Kruse, I am new to your website, and was not sure where to put this question. What is your opinion on antineoplastons in cancer tx? (Burzynski clinic in Houston). I am GP DVM and no expert in oncol but seems to me he may be on to something that the industrial machine doesn't want out. What we need is honesty and transparency in science, and it's gotten to who to believe?? Thank you for all your wonderful work and effort you have put into this website, which a colleague turned me on to this weekend. As you state, thinking for yourself is key, an a crucial step in being a survivor in the world unfolding.

    • @Dr DVM I am very interested in Burzynski's work……and especially the effects of phenylbutyrate as an antineoplaston. I have zero clinical experience with them but if I had a cancer that had a poor treatment response I think genetic targeted therapy makes a ton of sense. Dr. B appears way ahead of clinical oncology in this area.

  31. If you test cytokines, is it possible to infer what issues are causing specific cytokines to elevate?

  32. Dr. Kruse, My best friend has a blog, Pretty in Primal, and she suggested I contact you. I have been gluten free for 2 years and primal for 1 year but unfortunately I have been diagnosed with breast cancer. I am ER+PR+Her2- Stage IIA Grade 3. I had a partial mast. w/ reconstruction. In 2 weeks I start Chemo. TCx4 plus radiation and then they want me on Tamoxifen for 5 years. I live in Nashville and would love a consultation. My interest is in preventative care. Especially hormones, bone health (so it can't metastasize) and of course inflammation. I have added cold showers. Please email me if we can meet. I have been taking all my vitamins plus I am doing Chi Gong, jumping on mini trampoline for lymph drainage, hypnosis and Chinese acupuncture. I am very proactive. Also, I've mentioned you to my dentist and oncologist.

    • @Sophia We can meet……tell Erin to send me your Cell via FB and we can meet up. I am going to be free this weekend. Maybe we can meet and talk

  33. Lauren Porter says:

    Hi Dr K. Just re-reading this after my hsCRP came in at 1.2 and working to decrease inflammation (I had breast ca in 2010). My vitamin D now tests above the range (I have 162nmol/L with a range of 50-150) so I’m thinking that’s a good sign. And I eat a Brazil nut daily and offal 3-5x per week (as well as lots of pastured organic beef and eggs, seafood, CO, ghee, greens, etc). In addition to CT and diet and sleep/circadian fidelity, are there other things I should be doing? Thanks (and hope you had a happy bday – loved those family CT photos!)

    • @Lauren Porter…….if that is the case I would strongly suggest you “CT the girls” and trend your HS CRP………add turmeric to your regimen and resveratrol too. Also 99% dark chocolate.

  34. Lauren Porter says:

    Thanks! Definitely been ‘CTing the girls’ (ice directly on them while in the bath) and eating spoonfuls of tumeric daily. Can’t get 99% dark chocolate here, so have been eating massive amounts of 100%. Thanks again.

  35. Dr. Kruse,

    What is your opinion on liver flush? Epsom salts and grapefruit juice. Do they actually help the liver clear out stones, and are they safe to do?

    The Best

    • @Conan like epsom salts….hate grapefruit juice……that is neolithic to the max. Silly marin or NAC for the liver are go to’s Plus IV glutathione is great……If you can find grass fed sourced Whey to make glutathione in the liver…..great but lots of luck finding it. It is as hard as finding a paleo radiologist blogger these days.

  36. Thanks Jack,

    You are supremely helpful. You are a rare individual indeed.

    The Best

Trackbacks

  1. [...] For the thyroid gland to produce the most active form of the thyroid hormone T3, selenium is essential but also helps regulate the amount of hormone that is produced. Remember T3 is a co factor in steroid cascades and also in reversing muscle leptin resistance at UCP3. We need 200 mcgs a day. Most don’t eat it. One brazil nut a day can do the trick. If you don’t eat them then I recommend a supplement every other day of 200 mcgs. Its dirt cheap and easy to find. Selenium is also critical in many stress related processes. Selenium is active in prevention of oxidative stress. Selenium works with a group of nutrients that include vitamin E, vitamin C, glutathione, and vitamin B3, to prevent oxidative stress. I wrote about selenium here in more detail. [...]

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