CLnA, the "Omega-3 Variety" of CLA from Pomegranate & Co, Has Potent Anti-Obesity Effects and the Potential to Become More Than Just Another Anti-Diabetes Drug.

Image 1: Pomegranate - I loved to eat them even before I realized that their seeds are the #1 dietary source (83%) of punic acid.

While more and more people are beginning to grasp the notion that with (naturally occurring) fats - as with everything else in life - there is no simple "good" and "bad", no clearcut "black" and "white" and no definite "beneficial" and "detrimental". The number of different fatty acids and their respective effects on the human metabolism is so vast that it is pretty hard to keep track of all those varieties of saturated and unsaturated carboxylic acids. I would thusly not be surprised if you simply assumed that the "n" in the headline of this blogpost was a type that had slipped in because poor Dr.Andro is chronically stressed from Christmas shopping... well, while the latter is actually correct, the former is not: CLnA is actually the omega-3 variety of the famous conjugated linoic acid (CLA), which in and out of itself is not a single but a group of 28 different trans- and cis-isomers that occur in our diet mainly in the shape of high and full-fat meat and dairy products.

CLnA - Conjugated Linolenic Acid is not a typo ;-)

Within the last couple of years even the medical establishment has come to realize that the chronic omega-6 (n6: linolic acid) overload in our diet is killing us. The "heart-healthy" PUFAs have now become the more and less heart-healthy PUFAs with the totally healthy *rofl* omega-3s and the not just as healthy omega-6s - both, of course, still totally "essential" and WAY better than saturated fats,... (attention: the afore statements are full or irony! Saturated fats are of course NOT the bad guys. Sorry, David if that lead to confusion)... but I am getting derailed, here. So let's get to the point. What every reasonable person appears to agree on, these days, is that we have to lower the ratio of n6:n3 fatty acids in our diets. Now, I am asking you: Has it ever occured to you that CLA essentially is an omega-6 fatty acid? I mean its conjugated linoleic acid - "linoleic" as in omega 6 = linoleic acid! Probably not, right? The reason for that is yet (hopefully ;-) not that you are dump, but simply that the existence of an omega-3 "variety of CLA", namely conjugated linolenic acid, or short, CLnA, is something about which you will only hear, when you read blogs (such as the SuppVersity ;-), which do not stick to copying, pasting and commenting the stuff the authors have read on one of the major news-portals.

Table 1: CLnA isomer content in natural sources (data adapted from Hennesey. 2011)

From a molecular perspective,  CLnA isomers combine the conjugated double bond system of the classic conjugated linolic acid, you know, with the octadecatrienoic fatty acid (C18:3) structure of omega-3s, i.e. linolenic acid. Interestingly, this make-up confers these fatty acids with a high bio-active potential. Now, while this may sound like one of the frankenfood test-tube results of the gene-technology laboratories of Monsanto, we know at least 10 CLnA isomers which occur naturally in foodstuff or as byproduct of fermention processes (cf. table 1).

Adiposity, hyperlipidemia, cancer - CLnAs could help with all!

Image 2: Even if CLnAs would just prevent obesity, this illustration I borrowed from multiplemyelomalifeexpectancy.tk, shows that not being / getting obese alone would prevent a plethora of related maladies. Such as kidney failure, arthritis, gallbladder disease, infertility, asthma, fatty liver disease, sleep apnoea, depression, heart disease, hyperlipidemia, diabetes,... basically every major ailment the increasingly obese convenience society of the Western hemisphere is suffering from.

Due to their anti-adipogenic (meaning preventing the accumulation of body fat) effects CLnA fatty acids have been investigated as potential candidates for the treatment of the obesity epidemic for quite some time, now (Hennesey. 2011). In a 2002 article that was published in the Journal of Applied Biochemistry and Biotechnology, Nishimura et al. report that CLnA isomers exert apoptotic effects on mouse preadipocyte 3T3-L1 cell - or, in plain English, incubation with CLnA did not only hinder the "pubertal" fat cells from becoming mature adipocytes, it actually killed them. In vivo studies with rodents, such as Arao et al. (2004), where the administration of a diet that was enriched with 1% pomegrenate seed oil lead to a 27% reductin in omental white adipose tissue, were able to confirm the "rodent-real world signficance" of these test-tube results.

Other studies showed a normalization of hyperlipidemia in rodent models of the metabolic syndrome and a hand full of studies have explored the usage of CLnA isomers as cytotoxins in the treatment of cancer. In their concise review of the literature, Hennesey, et al. thusly rightly conclude that with their "potent inflammatory and immune modulating properties", their ability to "reduce the risk of obesity, improve cardiovascular health, and mediate strong anti-carcinogenic activity", the use of CLnA isomers or dietary enrichments could offer treatment strategies for pathologies, which "represent some of the greatest mortality risks to humans in the Western world and have been inextricably linked with diet" (Hennesey. 2011).

Adding diabetes to the list of potential targets for CLnA

For today, we are however going to focus on the most recent result from the research front: The effects of CLnAs on diabetes, or, to be precise, the increases in blood glucose, and decreases in anti-oxidant capacity that go hand in hand with the latter. In a recently published study (Saha. 2011), Siddhartha S. Saha and Mahua Ghosh from the Department of Chemical Technology at the University College of Science and Technology of the University of Calcutta (I don't have to tell you that this is in India, do I?) injected male albino lab rats with 60mg/kg streptozotocin (STZ) - this is a common and well-established method to induce a metabolic state that serves as a model of type II diabetes - and fed them diets that contained either no, or 0.5% of the total fat in the form of alpha-eleostearic acid (from bitter gourd, cf. table 1) or punic acid (which was in this case taken from snake gourd oil, but could as well have been extracted from the eponymous pomegrenate, cf. table 1).

Figure 1: Relative blood glucose levels vs. non-STZ injected control in streptozotocin injected rats over the course of the dietary intervention (data calculated based on Saha. 2011)

As you can see in figure 1, this 100% natural "food additive" had a more than pronounced effect on the +300% (vs. non STZ-injected control) elevated blood glucose levels of the "type-2 diabetic" rodents.

Figure 2: Relative level of lipid peroxidation (left) and total antioxidant capacity (right) levels vs. non-STZ injected control in streptozotocin injected rats after the 28-day dietary intervention (data calculated based on Saha. 2011)

And while the glucose levels were still 150% above those of the healthy control levels, the streptozotocin-induced lipid peroxidation in plasma, pancreas and erythrocytes of the lab animals was ameliorated by the snake gourd oil treatment (remember that is the stuff from pomegranate) and even reversed by the bitter gourd diet. Judged by the standardized FRAP assay, the "diabetic animals" that were fed a diet that contained 0.1% alpha-eleostearic acid (of the total diet, which had 20% fat) even exhibited a 10% greater total antioxidant capacity than the totally healthy control!

Figure 3: Relative expression of inflammatory cytokines, TNF-alpha and interleukin 6 in plasma capacity (right) levels vs. non-STZ injected control in streptozotocin injected rats after the 28-day dietary intervention (data calculated based on Saha. 2011)

Snake gourd oil, on the other hand, exhibited more profound effects on the elevated TNF-alpha, interleukin-6 and NF-kappaB levels of the STZ-treated rodents (cf. figure 2) and thus, at least this is my humble opinion, render punic acid the overall more promising agent with respect to the treatment of all sorts of inflammatory (or related diseases). After all, disturbances in the regulation of the nuclear factor kappa-light-chain-enhancer of activated B cells  (NF-kappaB) and the downstream over-expression of TNF-alpha and IL-6 are hallmark features of allmost all the aforementioned ailments of the increasingly obese western convenience society. This is also why I am quite certain that we are going to hear much more about the CLnAs in the month to come... and I guess, I don't have to tell you that right here, at the SuppVersity, is where you will read about respective studies first!

Devil in the Feeding Trough: PGE-Response to "Bad" Red Meat from Grass-Fed Cattle Could Prevent not Cause Cancer, Stroke and a Whole Host of Autoimmune Diseases.

Image 1: You do not need to hunt your red meat like a paleolithic human being, just make sure it comes from grass-fed animals and you will have a "health food" that modulate the your prostaglandin response to inflammatory assaults and thusly reduce your risk of cancer, stroke and autoimmune disesases in a way no fat-free chicken breast will ever do.

I have had this in the news before, in the context of the purported health benefits of CLA, with respect to the modulation of the n3/n6 ratio in your diet and in various other context, you heard me saying, or, I should say, read me writing that rather than popping tons of fish oil caps, you should rather focus on decreasing your overall omega-6 intake by making healthy food choices at the supermarket. In this regard, choosing grass-fed over commercially raised beef (and other meat) products could turn out to be one of the most far-reaching choices you can make. While that alone will help you to concomitantly reduce the n-6 overload, as well as the overall PUFA-burden that is so characteristic of the "Western diet", a recent study shows that eating red meat, even instead of the "healthy" white fat-free chicken breasts, everyone is pounding these days, could actually have profoundly beneficial effects on your (auto-)immune health, protect you from cardivascular disease and (this is important for the ladies) get your menstrual periods and related issues back in order.

How grass-fed beef can help and why it outperforms bison, elk and chicken

In their study, the results of which were published in issue 31 of the journal Nutrition Research, K. Shane Broughton, Daniel C. Rule and Eldon Handrich did what scientists have been doing for decades now. They took mice (your usual carnivorous animal) and put them on one of those grain-based diets that was then enriched with "bad" red meat to make the animals sick. Well, ... while the design was in fact the same, the good news is that the intention was by way of exception not to show "prove" (as if mainstream dietary advice would be interested in "proof", anyway) how bad those nasty red meats are, but to evaluate whether the

[...] consumption of meat from range-fed bison vs range-fed and grain-finished cattle and grain-finished bison would lead to reductions in PGE-2 [prostaglandin E2] release without altering PGI-2 [prostacyclin] release after an infl ammatory stimulus in a mouse model.

Or put simply, the scienists wanted to check whether there was any truth to the superiority of bison compared to the "bad" red meat, when it comes to balancing out the ratio of PGE-2 and PGI-2.

Image 2: Bayer probably won't like it if everyone would start eating grass-fed beef. After all, that would probably reduce the sales of their COX-inhibitor Aspirin protect.

For those of you wondering about a) what those prostaglandins are and / or b) why you would want to modulate their ratio and not eradicate them completely, here is is brief rundown on one of my favorite topics, the Yin&Yang of life and, on a related note, the fallacy of common black-or-white thinking. As with almost everything there are also two sides (in fact there are many more ;-) to the inflammatory coin and PGE-2 and PGI-2, two acronyms that differ by only a single letter, are situated on those opposing sides. If they are expressed at the right ratio, everything is fine. The (relative) over-expression of PGE-2 that is commonly observed in people following the "Western diet", on the other hand, is associated with a host of pathologies, such as elevated risk for color ectal cancer, suppression of ovulation, and increased problems with rheumatoid arthritis and headaches. (Relative) underexperssion of PGI-2, the other hallmark result of the "food" people are poisoning themselves with on a daily basis, in turn, increases the risk of thrombosis and stroke. If any of that does ring a bell, but you do not know which one, you may want to check out the label of your Aspirin tablets - as a cyclooxygenase inhibitor Aspirin also blocks the production of PGE-2... but before you do now pop another of those tabs, I suggest you read on and learn that by paying a few extra bucks for "real meat", you will probably never have to take your daily dose of Aspirin protect.

And while the scientists were right, grass-fed bison is in fact better than grain-fed beef, a closer analysis of their results will show that the often-heard and widely believed statement that "bison is the best form of red meat you can possibly find" is nothing but another of the 1001 dietary fairy-tales of the bloggosphere.

Figure 1: Fatty acid content of the diet (in g per 100g of the whole chow) - saturated, mono- and polyunsaturated fatty acids (n3, n6), left; CLA content, right (data adapted from Broughton. 2011)

But let's first take a look at the experimental diets, the male CD-1 mice were fed for 14 days. What is interesting about these, is that, due to the inclusion of standard rodent chow, the differences in fatty acid composition between the grass-fed vs. corn-fed bison and beef diets and the diets that were based on (wild-type) elk and commercial chicken breast meat were actually not very pronounced (cf. figure 1). And while the inclusion of corn oil in every diet may sound blasphemic in the ears of the hard-core anti-grain croud (I know you are out there ;-), the addition of grass-fed meat to an otherwise standardized (and probably suboptimal) diet is actually a strength of the study. Thusly, the study does reflect pretty well, what could happen, if the average Joe or Jane did nothing else, but replace the corn-fed meat in his/her diet with meat from range-fed animals - and wouldn't you agree that this is a much more realistic scenario than living on nothing but grass-fed beef or bison?

Figure 2: Modulatory effect of 2 weeks on prostaglandin expression of mice after two weeks on diets enriched with range-fed, or feedlot fed meat of different sources (data adapted from adapted from Broughton. 2011)

And, if we focus solely on the PGE-2 to PGI-2 ratio (you can read up on its importance in the red box above), it is obvious that a small dietary change from grain- to grass-fed meets could actually have pretty profound effects on your (auto-)immune health. The data also shows that the "healthy" lean chicken breast your nutritionist has probably told you to eat actually should not be your first choice, when it comes to establishing a healthier prostaglandin milieu - and if you don't believe me, maybe you want to trust Broughton et al.'s judgement:

[...] chicken is promoted for its health benefits, yet in our study, it was no better for possible prevention of PGE 2-associated immune pathophysiology. Furthermore, chicken would not be as beneficial as grain-fed beef and elk consumption in reducing thrombos is and stroke potential.

So, while eating (commercially raised) chicken won't harm you, it will not help you steer your inflammatory response into either the PGE or the PGI direction. Broughton, Rule and Handrich are thusly right, when they conclude that

Based on results of the present study, consumption of any of the range-fed meat sources examined would be better at reducing the possibility of immune-related pathophysiologies than meat from grain-fed cattle. [...] Although range-fed beef and bison consumption would be equivalent for their immune-based role, consumption of range-fed beef would be better for the prevention of thrombosis and stroke.

Now, isn't that surprising? Chicken not the best thing you can eat? The "healthy alternative to beef" that has been pimped in the mass media lately only on par with plain beef and superior as far as reduction in the risk of stroke and thrombosis are concerned? Could it really be possible that the "bad red meat" is not so bad, after all? Is there the remote possibility that it's not red meat per se, but sick meat, or I should say the meat of animals we have been making sick by feeding them the same "healthy whole grains" with which we have been poisoning... ah, I mean nurturing *rofl* ourselves over all these years that is giving us migraines, arthritic joints, cancer, strokes and a whole host of nasty autoimmune diseases? I guess, I will leave it up to you to find and answer to that question ... and I am confident that you are smart to one and one, or rather grain-fed meat and (auto-)immune disease together ;-)

Vitamin A Educates T-Cells, Joins Forces With Vitamin D Against Liver Cancer. Milk Better Than Sugary Electrolyte Solutions for Rehydration? Helicobactor Pylori: Probiotics from Breast Milk & Feces Better Than Amoxicillin!

Lactobacilli are hip, vitamin A is not - at the SuppVersity you still get news on both

1kg! That's the amount of weight you could probably lose if you rid yourself of all the microbes in your gut - from the weight of the bacteria alone, of course. Whether this would be a good idea or not, is however very questionable. On the one hand, we do have the still not fully understood studies on obesity-resistant germ free mice and an accumulating amount of evidence that having the "wrong" bacteria in the gut is at least associated with an increased obesity risk (Blaut. 2012). On the other hand, however, we are seeing new studies on the various benefits of having the "right" gut microbiome being published on an almost daily basis. So what?

Before we take a closer look at a definite benefit of having the "right" gut bacteria, though, let's start out with another likewise gut-related news item on the role of retinoic acid in T-cell education. In a way it's funny, it starts right where the bacteria reside, could have immune-modulatory effects that are way more pronounced and far reaching than probiotics and is still hardly discussed.

Vitamin A is of critical importance to (intestinal) T-cell education

If you have ever asked yourself how the immune cells in your body know what they are supposed to do, Catharine Ross' latest paper that was published in the American Journal of Clinical Nutrition and is based on a short talk the researcher from the Department of Nutritional Sciences at the Pennsylvania State University held at a conference earlier this year may provide at least some additional insides into the role a still way underrated molecule plays in this "T cell education" (Ross. 2012): Vitamin A!

Figure 1: Model of T cell differentiation, from uncommitted naive T cells into different T cell subsets that produce different cytokines and thus promote different functional activities (adapted from Ross. 2012)

As you can see in figure 1, retinoic acid does not simply promote the differentiation of regulatory T cells, which help to suppress inflammatory reactions, it also plays a significant role in normal mucosal immunity (in the gut, the airways and elsewhere) by modulating T cell activation and regulating cell trafficking. Moreover, vitamin A promotes antibody responses to T cell–dependent antigens. Needless to say that

"[...] in a state of vitamin A deficiency, inflammatory T cell reactions may be inadequately opposed and therefore become dominant [...] Although data from human studies are still needed, the framework now developed from studies in mice and rat models suggests that adequate vitamin A status, [...] is  important for maintaining a proper balance of well-regulated T cell functions and for preventing excessive or prolonged inflammatory reactions." (Ross. 2012).

Discovery a beta carotene derived vitamin A receptor blocker is only one of a couple of intriguing findings wrt to vitamin A.

One thing that sticks out from the complex interactions (see figure 1), really is the way by which the interaction of vitamin A with the T-cells in the gut crucially determine the efficiency of the 'fist line defenses' and their downstream effects on the whole organism. It is by no means co-incidental that diarrhea is rampant in areas of the "third world", where a large amount of the population is vitamin A deficient (Beaton. 1994). And in fact studies have shown consitently that

"RA is essential for 'imprinting' gut-homing specificity on T cells activated by intestinal DCs [dendritic cells] and suggested that MLN DCs are a source of RA that drives T cell differentiation toward the gut-homing phenotype" (Ross. 2012)

Moreover, oral tolerance to foreign antigens and thus an allergy free live requires a form of immune suppression, which can be proffered or hampered by sufficient and insufficient vitamin A intakes. In that, the exact effects of vitamin A will depend on the cytokine milieu the T-cells are exposed to. Examples are...

• an exaggerated IL-17 response with vitamin A deficiency, on the one hand, and
  
• an increase of the inflammatory response due to high vitamin A in an IL-15 environment 

Based on these observations, Ross rightly points out that "when RA is used for therapeutic purposes, it should be used cautiously in subjects with various inflammatory bowel conditions and sensitivities to dietary antigens." (Ross. 2012) People with gluten intolerance, celiac and other allergic reactions, for example would probably be better off avoiding the consumption of any form of supplemental vitamin A (on top of what's in their regular diet). Someone with high IL-17 and IL-6 levels as they have been observed in non-celiac inflammatory bowel disease, type 1 diabetes, multiple sclerosis and rheumatoid arthritis, on the other hand, could actually benefit from vitamin A's (especially ATRA) presence during activation of CD4⁺ T cells, because it will - even in the presence of IL-6 - "favor the development of the a Treg lineage at the expense of T cells secreting IL-17" and could thus help reduce chronic inflammation and keep autoimmune reactions at bay (Schambach. 2007; also Ramgolam. 2010).

More news

• 

  Figure 2: Who cares about cell viability, the survival time (in days) matters

  Combination therapy with vitamin A and a vitamin D (not D3, but calcitriol) analog EB1089 kills liver cancer cells. And it does so more effectively than any of the two molecules alone. That's the actually unsurprising result of a study that has been conducted at the Beijing Army General Hospital in China. The researchers injected nude mice with molecules that made them develop hepatocellular cancer. Afterwards, the rodents received either 10 μmol/L retinoic acid (vitamin A), 10 nmol/L EB1089 or both as a combination treatment.
  
  Compared to vitamin A or the calcitriol analog alone, the combination treatmend resulted in a significanlty higher reduction of the viability of hepatocellular cancer cells. Based on TUNEL analysis, Zhang et al. did also establish that individual cancer cells had a higher apoptotic ratio in the combined drug group than in the groups for which the drugs were used separately. Most importantly, however, the tumor weight was decreased and the mice on the combination treatment lived significantly longer (see figure 2; Zhang. 2012)

• 

  In the same publication, Pritchett and Pritchett recommend 1.0-1.5ml / kg body weight per hour of chocolate milk as the optimal post-workout drink to be consumed in the 2 h after a workout.

  Skimmed milk, the ideal post-workout rehydration formula? According to L James' paper in Lamprecht's compendium Acute Topics in Sport Nutrition, milk is a way better choice then the standard sugar + electrolyte rehydration formulas. Interestingly this is not due to the minerals in the milk, or the sugar, but, as James argues, a direct consequence of the milk proteins, which help restore "fluid balance after exercise-induced dehydration to a greater extent than a carbohydrate-electrolyte sports drink." As James points out it will yet have to be elucidated, whether the simple addition of whey protein to a standard sugar + electrolyte formula would exert similar effects (James. 2013).
• Probiotics to kill Helicobacter Pylori? While not every bacteria stands a chance against the nasty gut bug H. Pylori, certain Lactobacillus spp. strains obviously do. At least, if the results of a recent in-vitro + in vivo rodent study by Pei-Shan Hsieh can be replicated in human studies.

  

  Figure 3: Urease activity in H. pylpori after co-incubation with the specific probiotic and resulting bacteriostatic ratio (100% = bacteria free; data adapted from Hsieh. 2012)

  Lactobacillus acidophilus TYCA08, L. acidophilus TYCA15, L. johnsonii MH-68, and L. salivarius subsp. salicinius AP-32 were the most effective strains the researchers from National Chung Hsing University in Taichung, Taiwan, analyzed. And believe it or not, the latter of these, i.e. L. johnsonii MH-68, and L. salivarius subsp. salicinius AP-32, both of which are  by the way found in feces, were even minimally more potent effective than Amoxicillin, a moderate-spectrum, bacteriolytic, β-lactam antibiotic used to treat bacterial infections. L. acidophilus TYCA15, however, steals the show. This probiotic that occurs naturally in breast milk reduced the urease activity of H. Pylori by -97.1% (see figure 3).
  
  In the consecutive rodent study, Hseieh et al. did yet still use 10⁹ CFU/mL of either AP-32 alone, MH-68 alone, or an equal mix of cultures of the two strains and both, "either alone or as a mixture in powder form were effective in reducing H. pylori load in gastric mucosa and help in reducing gastric inflammation and in regulation of gastric acid production." (Hsieh. 2012)

Thats it for today and for this weekend. As mentioned yesterday, there was simply not enough time to do the necessary research for the follow up to the Athlete Triad Series, so that this will have to wait. So don't dig an even deeper whole in the mean time. Maybe you want to do some of the psychomotor tests mentioned in yesterday's news, and check whether you are already overtrained!? How steady are your hands, for example? And whatever the result may be, don't forget to enjoy the rest of the weekend!

References:

• Beaton GH, Martorell R, Aronson KA, Edmonston B. McCabe, G, Ross, AC, Harvey, B. Vitamin A supplementation and child morbidity and mortality in developing countries. Food Nutr Bull 1994;15(4): 282–9.
• Blaut M, Klaus S. Intestinal microbiota and obesity. Handb Exp Pharmacol. 2012;(209):251-73.
• Hsieh PS, Tsai YC, Chen YC, Teh SF, Ou CM, King VA. Eradication of Helicobacter pylori Infection by the Probiotic Strains Lactobacillus johnsonii MH-68 and L. salivarius ssp. salicinius AP-32. Helicobacter. 2012 Dec;17(6):466-77.
• James L. Milk Protein and the Restoration of Fluid Balance after Exercise. In Lamprecht M (ed): Acute Topics in Sport Nutrition. Med Sport Sci. Basel, Karger, 2013, vol 59, pp 120–126. 
• Pritchett K, Pritchett R. Chocolate Milk: A Post-Exercise Recovery Beverage for Endurance Sports. In Lamprecht M (ed): Acute Topics in Sport Nutrition. Med Sport Sci. Basel, Karger, 2013, vol 59, pp 127–134.
• Ramgolam VS, Markovic-Plese S. Interferon-beta inhibits Th17 cell differentiation in patients with multiple sclerosis. Endocr Metab Immune Disord Drug Targets. 2010 Jun;10(2):161-7.
• Ross AC. Vitamin A and retinoic acid in T cell-related immunity. Am J Clin Nutr. 2012 Oct 10.  
• Schambach F, Schupp M, Lazar MA, Reiner SL. Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur J Immunol. 2007 Sep;37(9):2396-9. 
• Zhang J, Zhang H, Zhang X, Yu Z. Synergistic effect of retinoic acid and vitamin D analog EB1089-induced apoptosis of hepatocellular cancer cells. Cytotechnology. 2012 Oct 16.

Gluten Free, But not Suitable For Celiacs: Milk, Chocolate, Corn, Instant Coffee and 20 Other Foods & Food Ingredients That Could Cross-React With Gluten Anti-Bodies

Unless you got the right, i.e. breast milk as a baby and have rendered your gut "gluten proof" - being breast fed, when you are first exposed (or being exposed later in life) has after all been suggested as a protective factor (Farrell. 2005)

This is not going to be a long post; and still, at least for some of you it is going to be an important post. A post that may have the potential to change your life for the better or for the worse depending on whether you actually suffer from gluten-intolerance or have simply been bamboozeled by the "gluten is the devil" messages that are plastered all over the Internet these days.

Actually, I would hope that you belong to neither of the groups and can thus simply ignore this post. For the unfortunate rest, I have prepared a mini-summary of the results of a recent study from the Immunosciences Lab in Los Angeles (Vojdani. 2013)

Milk and cornflakes - a killer combo

A couple of recent studies, as well as reports from patients all of which clearly suggested that "being gluten free" does not equal "being symptom free" had spiked the researchers interest. Was it possible that the persistent symptoms were brought about by cross-reactions between the anti-bodies that would usually attach to the gluten proteins to trigger an immune reaction and other molecules? Molecules from such innocent foods, as dairy, chocolate, and even coffee!?

Suggested read: "Leaky Gut & Gluten Belly: Bacterial Firebugs Translocate from Your Gut to Your Ever-Growing Visceral Fat Depots" | read more

"[W]hen histological response was assessed in celiac patients after 6 months of following a GFD [gluten free diet], complete normalization and reconstruction of villous architecture was observed only in 8% of individuals, while 65% of these patients were in remission and 27% did not respond to GFD and had no observable change in their clinical symptoms (Lanzini. 2009).

The lack of improvement in histopathology and clinical symptomatology in a subgroup of patients on a GFD may be associated with dietary non-ad-herence or cross-reactive epitopes triggering a state of heightened immunological reactivity in gluten-sensitive individuals (Hadjivassiliou. 1997)." (Vojdani. 2013)

The hypothesis certainly isn't totally odd. Kristjansson et al. were for example able to show that 50% of their celiac patients experienced a significant mucosal inflammatory response similar to that elicited by gluten, when they were exposed to cow’s milk protein. Of the 15 healthy controls in their study, however, not a single one showed the slightest signs of auto-immune related inflammatory processes (Kristjansson. 2007).

So is this "real" celiac disease?

It should be obvious though that the corresponding "cross reactive" agents do not induce celiac disease (which is per definition an auto-immune disease that's triggered by the reaction to gliadin). They are however well able to alter the intestinal barrier integrity - a symptom that is also one of the key feature of the early stages of celiac disease.

Figure 1: Reaction of affinity-purified α-gliadin 33-mer polyclonal antibodies to gliadin and different food antigens; data in large figure relative to control, data in small inset relative to a-gliadin (Vodjdan. 2013)

If full remission of celiac disease cannot be achieved even on gluten-free diet, the underlying reason may thus well be the presence of peptides and antigens that (cross-)react with the same anti-bodies the body of celiac patients produces against the α-gliadin 33-mer peptide aka gliadin. Scientists even speculate that the co-exposition to these agents could eventually lead to the establishment of "new" auto-immune diseases and food allergies and some argue that the ever-increasing spectrum of allergies is partly a result of untreated autoimmune reactions which are then "spreading" to other previously well-tolerated foods and food ingredients.

---

Suggested read: "Beyond Celiac: Study Sheds New Light on Obesogenic Effects of Gluten - Are PPARs & Bacteria Both Involved?" | read more

The problem seems real, if you're really gluten intolerant: With milk, all sorts of dairy products (including whey), instant coffee (but not espresso; see small inset), avenin containing oat products (unfortunately, I cannot tell you how you can recognize the "unproblematic" oats at the super market, but if you google "avenin-free oats" you will see a couple of products and stories pop up; Comino. 2011) and corn having a significant potential for cross-reactivity, it appears almost reasonable that some people come back from their visit with a mostly self-proclaimed expert in all things celiac with an endless list of items they are not supposed to eat and a tiny 5-item list of foods they are supposed to live on for the rest of their lives.

What is not reasonable, however, is that this is the case for more and more people who are basically asymptomatic... well, aside from their "inability to lose weight" that is obviously not related to their "inability to exercise" and their "inability to stop watching TV and browsing the Internet for easy quick-fix solutions to obesity problems", but most obviously be brought about by gluten intolerance ;-(

References:

• Comino I, Real A, de Lorenzo L, Cornell H, López-Casado MÁ, Barro F, Lorite P, Torres MI, Cebolla A, Sousa C. Diversity in oat potential immunogenicity: basis for the selection of oat varieties with no toxicity in coeliac disease. Gut. 2011 Jul;60(7):915-22.
• Hadjivassiliou M, Chattopadhyay AK, Davies-Jones GA, Gibson A, Grünewald RA, Lobo AJ. Neuromuscular disorder as a presenting feature of coeliac disease. J Neurol Neurosurg Psychiatry. 1997 Dec;63(6):770-5.
• Kristjánsson G, Venge P, Hällgren R. Mucosal reactivity to cow's milk protein in coeliac disease. Clin Exp Immunol. 2007 Mar;147(3):449-55.
• Lanzini A, Lanzarotto F, Villanacci V, Mora A, Bertolazzi S, Turini D, Carella G, Malagoli A, Ferrante G, Cesana BM, Ricci C. Complete recovery of intestinal mucosa occurs very rarely in adult coeliac patients despite adherence to gluten-free diet. Aliment Pharmacol Ther. 2009 Jun 15;29(12):1299-308. 
• Vojdani A, Tarash I. Cross-reaction between gliadin and different food and tissue antigens. Food and Nutrition. 2013; 4:20-32.

Stevia - More Than Super Sweet: More Scientific Evidence, More Potential Implications for Weight Loss & -Maintenance, Anti-Diabetic & -Autoimmune and Even Pro-Anabolic Effects

Image 1: Stevia is sweeter than sugar, healthier than sugar and could even help reverse some of the damage sugar may already have done to your pancreas.

I know that a few of you were almost furious, when I had the audacity to mention the case-report on the pro-cortisol effects of stevia in the On Short Notice post on Saturday, August 18, 2012; and though I did emphasize that this was most likely something like an allergic reaction and/or an issue with solvents, heavy metals (click here for data on heavy metals in stevia leaves; based on Das. 2012), or whatever else may have been in the specific stevia product the lady used; I suspect that you will like today's blogpost which is basically an update on the beneficial effects stevia could have on your overall and metabolic health, much better.

So what's the latest about stevia, then?

Previous studies have already hinted at the fact that the benefits of the use of stevia go well beyond a mere reduction in energy intake and the overall glucose load the average sweet tooth is exposing her- / himself to. Against that background, the results of a recent publication from the School of Pharmacy in Madhya  Pradesh in India are actually not really surprising.

Figure 1: Blood glucose response (mg/ml) to oral glucose load (left) and superoxide dismutase (SOD) levels in mice treated with 250mg/kg (HED: 20mg/kg; ~1.4-2.0g) stevia extract/day (right; data based on Sharma. 2012)

With most previous studies being conducted on isolated pancreatic islet cells in the petri dish, this is however one of the few studies, which in which the scientists were able to observe a robust in-vivo effect from the administration of no more than 250mg/kg of stevia extract (Herbocal) to alloxan-diabetic (this is a model of type II diabetes that is induced by the injection of the drug Alloxan aka 2,4,5,6-pyrimidinetetrone, an oxygenated pyrimidine derivative) and healthy rodents for 28days - with benefits for both, the sick (normalization of blood glucose and restoration of endogenous antioxidants) and the healthy animals (no drop of blood glucose to hypoglycemic levels and increases in SOD above baseline!)

Could stevia not just ameliorate, but actually "heal" diabetes?

Figure 2: It takes it's time but stevia appears to (fully?) restore pancreatic function!

What's also intriguing are the time-course and general trend of the beneficial effects on blood glucose levels in the diabetic group. If you take a closer look at the data in figure 2 you could even speculate that another four weeks later the blood glucose levels would have totally normalized! And if that were the case, this would mean that the steviosides and rebaudiosides, the active molecules in stevia extracts, could actually have the ability to restore or repair the pancreatic beta cells that have been destroyed by either years of high blood glucose (normal type II diabetics) or the assault of the toxic sugar equivalent alloxan (in the study at hand). and protect healthy individuals against future damage by increasing the endogenous antioxidant system (as can be seen by the allegedly non-significant, but probably still physiologically relevant increase in SOD in figure 1, right)

"But this won't work in humans, will it?"

The above is certainly a good question, but in view of the fact that the short term benefits (e.g. +40% increase in insulin response in type II diabetic with -18% reduced postprandial glucose AUV with 1g of stevia in Gregersen et al. 2004), of which the Hermansen group at the Aarhus University Hospital in Aarhus, Denmark, argues that they are based on the interaction of rebaudioside A (cf. table 1) with the ATP-sensitive K-channels of the pancreatic cells in healthy and its glucagon (and thus gluconeogenesis) inihibiting effects in diabetic individual (Abdula 2004 & 2008; Jeppesen. 2007), have already been reproduced in human trials, I would say that it is more than likely that we will see similar effects in humans, as well, once the correct dosing has been established

Note: especially if you use those combination products of stevia + sugar alcohol you are very unlikely to get sufficient amounts of stevia to elicit those restorative effects; this does not mean that this is a better alternative than aspartame or cyclamate, but in those tiny amounts stevia is a sweetener, not a substance with almost drug-like effects.

Table 1: What's in stevia leaves?
(based on Yadav. 2012)

The latter is by the way all the more likely in view of the fact that Maryam Mohammadi-Sichani and her colleagues from the Falavarjan Branch-Islamic Azad University and the Esfahan University of Medical Sciences in Iran found that stevia extracts will also kill S. mutans, a common bacteria in your mouth that has its share in the development of dental caries and shows, irrespective of generally lower caries rates in type I diabetics, a hitherto not fully explained correlation with (poorly controlled) type I diabetes (Siudikiene. 2006).

Your gut starts in your mouth: The stevia - bacteria connection

These observations stand in line with previous results, of a whole host of peer-reviewed studies Yadav & Guleria summarize in a 2012 review that's about to be published in the November edition of Critical Revision of Food Science, as follows :

Image 2 (20th Century Fox): You better feed your gut bacteria right, otherwise they will disbehave just like the Alien in Ellen Ripley in Alien 3  - read more about the "Gut Type Diet" and how what you eat influences the bacterial composition of your gut on the SuppVersity

"[...] Different extracts showed differential inhibitory activity against various microbes. This experimentation confirmed the antibacterial as well as antifungal potential of Stevia leaf extract and documented that Stevia might be a source of new non-antibiotic antibacterial and antifungal agent. Its antifungal activity was estimated to be higher than the standard fungicide usually used against plant pathogens. Such extraordinary antimicrobial activity of Stevia has presented it as a potent non-antibiotic pharmaceutical and an efficient food preservative. Stevioside alone has been observed to significantly reduce the amount of inflammation mediators and activate cytotoxic cells of the host. These activities suggested that stevioside might play a synergistic role with the innate immunity of the host. Thus stevioside is antibacterial, antifungal, anti-inflammatory, anti-tumorous, and safe for use. While at the same time rebaudioside A has been reported to be clinically insignificant." (Yadav. 2012; my emphases)

In other words, stevia could exert part of it's beneficial effects via the immune-modulatory effects it exerts due to it's impact on the human gut microbiome, the contribution of which to the etiology of both diet-induced type II, but also auto-immune type I diabetes is getting more and more attention among researchers, as of late:

"[...] the autoimmune microbiome for T1D may be distinctly different from that found in healthy children. These data also suggest bacterial markers for the early diagnosis of T1D. In addition, bacteria that negatively correlated with the autoimmune state may prove to be useful in the prevention of autoimmunity development in high-risk children." (Giongo. 2011; my emphases)

And even if the whole "bacteria theory" of autoimmune disease and inflammation turns out to be yet another sidetrack - you will always have the

• beneficial effects on skeletal muscle insulin sensitivity and glucose uptake that has been established by Lailerd et al. in insulin sensitive and resistant mice and the 
• hopefully physiologically relevant increase in satellite cell activity, Bunprajun et al. observed earlier this year in response to lower NF kappa-beta activity (=modulation of inflammation) in an in-vitro model (Lailerd. 2004; Bunprajun. 2012) 

as additional* arguments to satisfy your sweet tooth with stevia instead of sugar or artificial alternatives (*in addition to being able to avoid the "alternatives").

And as long as you keep an eye on the overall amount of food you consume, instead of simply stuffing yourself until you feel like there was no tomorrow, the previously discussed effects any sweetener - natural, artificial, or whatever else the future may hold - could have on your ability to sense the energy density of your foods should not be all too much of a problem problem (cf. "Sweeter Than Your Tongue Allows").

References:

• Abudula R, Jeppesen PB, Rolfsen SE, Xiao J, Hermansen K. Rebaudioside A potently stimulates insulin secretion from isolated mouse islets: studies on the dose-, glucose-, and calcium-dependency. Metabolism. 2004 Oct;53(10):1378-81.
• Abudula R, Matchkov VV, Jeppesen PB, Nilsson H, Aalkjaer C, Hermansen K. Rebaudioside A directly stimulates insulin secretion from pancreatic beta cells: a glucose-dependent action via inhibition of ATP-sensitive K-channels. Diabetes Obes Metab. 2008 Nov;10(11):1074-85. Epub 2008 Apr 22.
• Das, K., R. Dang, L. Hegde and A.S. Tripathi. Assessment of heavy metals in dried stevia leaves by Atomic Absorption Spectrophotometer grown under various soil conditions. Middle–East J. Sci. Res. 2011; 8: 107-113.
• Giongo A, Gano KA, Crabb DB, Mukherjee N, Novelo LL, Casella G, Drew JC, Ilonen J, Knip M, Hyöty H, Veijola R, Simell T, Simell O, Neu J, Wasserfall CH, Schatz D, Atkinson MA, Triplett EW. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 2011 Jan;5(1):82-91.
• Gregersen S, Jeppesen PB, Holst JJ, Hermansen K. Antihyperglycemic effects of stevioside in type 2 diabetic subjects. Metabolism. 2004 Jan;53(1):73-6.
• Jeppesen PB, Dyrskog SE, Agger A, Gregersen S, Colombo M, Xiao J, Hermansen K. Can stevioside in combination with a soy-based dietary supplement be a new useful treatment of type 2 diabetes? An in vivo study in the diabetic goto-kakizaki rat. Rev Diabet Stud. 2006 Winter;3(4):189-99. Epub 2007 Feb 10.
• Sharma R, Yadav R, Manivannan E. Study of effect of Stevia rebaudiana bertoni on oxidative stress in type-2 diabetic rat models Biomedicine & Aging Pathology. 2012 August 28.
• Siudikiene J, Machiulskiene V, Nyvad B, Tenovuo J, Nedzelskiene I. Dental caries and salivary status in children with type 1 diabetes mellitus, related to the metabolic control of the disease. Eur J Oral Sci. 2006 Feb;114(1):8-14.
• Yadav SK, Guleria P. Steviol Glycosides from Stevia: Biosynthesis Pathway Review and their Application in Foods and Medicine. Crit Rev Food Sci Nutr. 2012 Nov;52(11):988-98. 

Thyrotoxins: Soy, Hormonal Contraceptives, Gut Bacteria or Simply Inflammation - Ladies (and Gents), You've Got the Choice, Hypothyroidism Lies Just Beyond the Corner.

Image 1: Thyroid for energy para-
thyroid for bone metabolism.

I don't know about you, but sometimes I get the feeling I am not doing enough for the female readers of this blog. And, while even this blogpost is not exclusively addressed to the ladies, the majority of hypothyroid patients are women. Part of the explanation for this phenomenon can be found in the title of this blogpost, already. Both, soy, as well as hormonal contraceptives are "ladylike", these days. Accordingly, overcolonization of Bifidobacterium and Lactobacillus, or inflammation is all that remains for "real men" (who obviously do not take synthetic gestagens and probably refrain from consuming soy products) to catch up on their female fellow sufferers. But before I totally confuse you, let's take a look at the most recent scientific results.

Still ahead of print is a paper by Claudia Lorenz and colleagues (Lorenz. 2011) in which the scientists report on the effects the synthetic gestagen levonorgestrel (LNG), which is "a widely used component of several hormonal contraceptives, such as the birth control pill, progestogen only pill or the emergency contraceptive pill" has on thyroid function of tadpoles (X. laevis). While this obviously is no adequate model for the human endocrine system, their finding that despite lack of histopathological changes in the thyroid glands, the aquatic organisms developed full blown hypothyroidism, which was presumably mediated via a large increases in prolactin and consequent interference with the thyroid system, would warrant further investigations in mammals and humans to exclude the possibly hitherto overlooked, histopathologically nondescript side effects of widely prescribed hormonal contraceptives, which is something the scientists from the German Institute of Freshwater Ecology and Inland Fisheries were obviously less interested in.

Figure 1: Isoflavone content in mg per 100g of various commercially available soy foods
(data calculated on the basis of soyfoods.com)

Much sturdier are the results a research group from India present in a paper published in the June issue of the Indian Journal of Medical Research (Mittal. 2011). The scientists  conducted a  randomized, double blind, placebo-controlled trial on 43 oophorectomised women [women who had their ovaries removed] to evaluate the effect of soy isoflavones (75 mg/day for 12 wk) on serum thyroid profile (free T3, free T4, TSH, TBG and anti–TPO antibody titres) at baseline, 6 and 12 wk after randomization.

Notice: You get the same overall amount of isoflavones that was administered to the women in this study from roughly 40g of mature soybeans, uncooked roasted soybeans or soy flour. Alternatively you can also drink 850ml soy "milk" or have a protein shake with 40g soy isolate (cf. figure 1).

The desired decrease in menopausal symptoms aside [induced by the estrogenic activity of the isoflavones], Mittal et al. found a 7% decrease in serum free T3 levels from 4.0 to 3.76pmol/l after 12 weeks and a 75% increase in TSH [thyroid stimulating hormone] the scientists obviously preferred to VERSCHWEIGEN in their abstract, in order to draw the ridiculously skewed conclusion that the

modest reduction in serum free T3 levels in the isoflavone group in the absence of any effect on other thyroid parameters might be considered clinically unimportant

If the data in table III of the studies (cf. figure 2) is not simply false, the above statement is at least premature. What's more is that the huge standard deviations (+/-3.01uIU/ml) of the TSH values after 12 weeks of treatment suggest that thyroid function may actually have compromised in some subjects, but in these cases even more severely. Allegedly, the "normal range of TSH is 0.5-5.5 micro IU/ml" and TSH increased in control, as well (cf. figure 2), but both the onset of the effect and the small dosage of isoflavones that has been used in this study would warrant further investigations into the effects of longer duration and/or higher dosages of isoflavone supplementation.

Figure 2: Serum value of Free T4, free T3 and TSH in control and soy treated women after 12 weeks.
(data adapted from Mittal. 2011)

In view of the positive reputation of soy products as being "cholesterol free", "low in fat" and "especially healthy for women", it cannot be excluded that a group of presumable female customers eats several of the products from figure 1 everyday and would thus potentially be exposed more than twice the amount of isoflavones used in the study for years. A continuous decline in the responsiveness of the thyroid to thyroid stimulating hormone (TSH), of which the decline in T3 despite rising TSH values is indicative, could easily make thyroid patients out of health-conscious costumers.

Contraceptives and soy, are yet by far not the most reliable tools to mess up your thyroid. Data from a  recent paper by Kiseleva et al. (Kiseleva. 2011)

are arguments in favour of the assumption of the possible role of PM [probiotic microorganisms] of the genera Bifidobacterium and Lactobacillus in triggering ATD [autoimmune thyroid disease] by the mechanism of molecular mimicry.

Or in other words, because the anti-bodies that attach to those two microorganisms are structurally almost identical to thyroid anti-bodies, it is possible, if not likely, that what was meant by our body as a means to ward off intestinal bacteria ends up attacking our thyroid, because the anti-bodies cannot distinguish one from another. The scientists do yet emphasize that

The data obtained in silico and in vitro should be proven by use of animal models and clinical studies for extrapolations to the whole body. Possible antigenic properties of components/proteins of bifidobacteria and lactobacilli, selectively binding anti-TPO and anti-Tg should be taken into consideration.

They also point out that current diagnostics using ELISA may even mistake "normal" bacterial antibodies for thyroid antibodies due to cross reactions which "can lead to unspecific false positive results and, hence, to an incorrect diagnosis."

Figure 1:  Drugs influencing thyroid economy
towards hyper (left) and hypothyroidism (right)
(adapted from Economidou. 2011)

The last thyroid related paper (Economidou. 2011) for today comes from Foteini Economidou, MD, PhD at the Department of Intensive Care Medicine of the University of Athens and his colleagues, whose review on Thyroid Function During Critical Illness may be of greater importance to many "hypothyroid" patients out there, than you would think. Reduced thyroid function is a protective mechanism the human body employs, when it is severely energy restricted or inflamed. Reduced TSH levels despite normal to low T4 and often low levels of T3, which are accompanied by increases in the purportedly unactive thyroid metabolite rT3, are clear signs of what is also called the euthyroid sick syndrome [euthyroid = healthy thyroid], where decreases in thyroid functions are only secondary to other health conditions (i.e. hypothyrodism is a symptom not a cause of your ailments) including constant dieting and (hidden) inflammation. You should keep that in mind, when even high doses of levothyroxin (T4) tablets won't solve your "pseudo-hypothyrodism". Chances are, the whole package would not produce any noticeable effects, because your body regulated the deiodinase enzymes, so that the inactive T4 will never be broken down to T3 or - if it is - the latter will immediately be "deactivated" into rT3. As Economidou et al. point out:

Only a few studies have examined the use of supplemental thyroid hormone therapy in critically ill [if you are chronically starved or inflamed you may consider yourself critically ill] general medical patients. Brent and Hershman examined the effect of thyroid hormone therapy in medical intensive care unit patients. The patients included in the study had serum T4 levels <5 µg/122 with no evidence of intrinsic thyroid dysfunction and were given either T4 or placebo intravenously [notice due to the low absorption of oral T3, the doses were obviously much lower than those you or your hypothyroid friend are taking] on a daily basis. There was no significant difference in mortality [take that as "no difference in how you will feel" in case of the euthyroid sick syndrome] between the two groups and the T4 replacement was detrimental to the restoration of normal pituitary-thyroid regulation.

This leads the scientists to conclude that ...

"levothyroxine therapy applied for the management of the euthyroid sick syndrome is not expected to have any effect because of the pronounced inhibition of conversion of T4 to T3 in these patients" (Economidou. 2011)

Bottom line, don't fix the symptoms (low thyroid) by popping T4 like candy (you know it doesn't help you), but try to find the original cause of disease, which -contraceptives, soy, gut bacteria and inflammation and overdieting aside (by the way, is it just me or do you also feel like you knew a young lady where all these come together) - could also be one of the drugs I listed in figure 3.

Something Fishy: Leucine-Rich Protein + Fish Oil Supplement Boosts White Blood Cell EPA Content and Immune Response

Regular readers of the SuppVersity, as well as people who religiously follow Carl Lenore's Super Human Radio and happened to listen to my 1st appearance on the show, will know that I am generally skeptic about the usefulness of unwarranted high dose (>1-2g of combined EPA + DHA) fish oil supplementation. This is not because I think fish oil is poison, but rather out of my awareness that its pharmacological effects have more similarity to those of a drug than to those of a "common food" (including possible side effects).

Now, a group of scientists from the Netherlands and the United Kingdom published the results of a study (Faber. 2011) which found another interesting stone from the fragmented mosaic our current understanding of the effects and nutritional interactions of fish oil, in general, and EPA, in particular, resembles. While the aim of the study, which was to quantify the incorporation of EPA and DHA into white blood cells, was nothing new, the nutritional supplement they used for this purpose, a mixture of 2.4 g EPA, 1.2 g DHA, 39.7 g protein (including 4.4 g L-leucine), and 5.6 g oligosaccharides was innovative and the results were astounding. After 1 week of 2x200ml of what the scientists label a "medical food" (beware there is probably somebody patenting the formula already ;-), ...

[... from 0.5% at baseline] the percentage of EPA [in white blood cell phospholipids] rose to 2.8% (P < 0.001). Additionally, the production of proinflammatory cytokines in LPS-stimulated whole blood cultures was significantly increased within 1 wk.

It appears that the addition of protein has a positive influence on the incorporation of EPA into white blood cells, which, in turn, boosts the natural immune response to lipopolysaccharides stimulation. This, however, brings me back to my initial comment about "pharmacological" effects of fish oil: While for a cancer patient with lowered immunity, the consumption of the "medical food" or, what I would consider equivalent, a combination of whey + fish oil, would unquestionably be beneficial - but what about someone with allergies or even auto-immune issues? I assume you would agree that to further boost an immune system that is already running havoc does not seem to be a good idea!? In the end, and here I do not mind repeating myself, it again all comes back to considering who you are and what your current medical and nutritional condition is, before you start taking a supplement of which the whole Internet community seems to believe that its the healthiest (if not the only healthy) fat on earth...