As mentioned in a previous post, there is increasing evidence of adaptation to gluten consumption by humans. This adaptation is not genetic, but symbiotic. It appears that we have developed new symbiotic relationships with specific microorganisms to help us degrade gluten, and by doing so, being able to exploit an unnatural food source.
Aside from resistance to degradation by mammalian enzymes and creation of neo-epitopes from partial gliadin digested peptides, one common reason given for avoiding gluten by paleo advocates is its phytate content (1, 2). Phytate is an anti-nutrient which binds to and form complexes with proteins, lipids, carbohydrates, and metal ions (zinc, iron, calcium and magnesium) thereby reducing their bioavailability. Phytate is the common name for myo-inositol-(1,2,3,4,5,6)-hexakiphosphate (InsP6).
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From its chemical structure, we can see that it is basically a myo-inositol with six phosphate groups. The ability to degrade InsP6 is conferred by phytases. There are three types of phytases, namely, 3-phytase, 5-phytase and 6-phytase. The differences between these phosphatases is the position on the inositol ring at which the initial attack of a phosphoester bond takes place. Thus, attack by different phytases produce different isomers. Phytase production and activity in humans is relatively low (mainly in the small intestine) (3), so the greatest source of phytases is the gut microbial community .
Gut flora phytase activity
Gut flora phytase activity
Of the Bifidobacteria species which predominate in the human gut, the B. catenulatum group (B. catenulatum and B.pseudocatenulatum) is the most common. Haros et al (4) examined the InsP6 degrading capacity of B.pseudocatenulatum ATCC2919, isolated from the human gut. It was found that B.pseudocatenulatum is able to degrade InsP6 in sequential dephosphorylations (starting in the 6-position of the myo-inositol ring, followed by the 5-position). The solubility of mineral chelates of myo-inositol phosphates is related to the number of phosphates per molecule. InsP6 and InsP5 have adverse effects on mineral absorption. On the contrary, breakdown products with 1,2,3-grouping interact specifically with iron, increasing its solubility and preventing its ability to catalyse hydroxyl radical formation. Overall, the mineral-binding strength to inositol phosphates becomes progressively lower when phosphate are removed from the molecule (with the exception of the 1,2,3-grouping mentioned above). B.pseudocatenulatum also showed selective adhesion to Caco-2 epithelial cells and tolerance to increased concentrations of bile, which reflects its adaptation to the human gut. A previous study (5) found that B.infantis is able to degrade 100% of InsP6, producing InsP3 as the main product. The optimal pH for the phytase activity of B.infantis was 6.0-6.5, with an activity of 51.2% at 37C; similar to that observed for B.pseudocatenulatum. Other Bifidobacteria species present in the human gut have also phytase activity, although to a lesser extent.
InsP6 antinutrient effect
Typically, InsP6 and fiber occur together in whole foods. This is problematic for analyzing the antinutrient effect of InsP6 as there is evidence that fiber also reduces mineral bioavailability (6). When given alone in animal models, InsP6 does not show toxic effects on bone minerals (7):
This suggests that its the combination of fiber and InsP6 which causes the antinutrient effect observed.
The type of fiber seems to be important on mineral bioavailability. The addition of FOS to a diet high in InsP6 improves cecal absorption of minerals and stimulates bacterial hydrolysis of InsP6 (8, 9), counteracting the negative effects of high doses of InsP6. Inulin has also shown to improve calcium balance and absorption (10). The importance of the fiber type on the effects of phytic acid is highlighted by a study in which healthy women following the recommended daily intake of fiber-rich wheat bread (300g/day) showed impaired iron status independent of the phytic acid content (11).
Anti-cancer properties
InsP6 is a broad-spectrum antioneoplastic agent in vitro and in vivo (12). Structurally, InsP6 is similar to D-3-deoxy-3-fluoro-ptdIns, a potent PI3K inhibitor. Accordingly, InsP6 is able to inhibit PI3K and ERK phosphorylation (13), thereby inhibiting AP-1 activation. InsP6 has also been shown to activate PKC delta and decrease phosphorylation of Erk1/Erk2 and Akt, causing upregulation of p27-Kip1 and reduction of pRb phosphorylation (14). Other protective effects include the induction of apoptosis by inhibiting the Akt-NFkB pathway and increasing cytochrome C release (15), downregulation of constitutive and ligand-induced mitogenic and cell survival signaling (showing different effects on ERK1/2, JNK1/2 and p38 in response to different mitogens) (16), its antioxidant effect (17), enhancement of NK cell activity (18), modulation of expression of TNF-alpha and its receptors genes (19), inhibition of angiogenesis (20) and metastasis, by modulation of integrin dimerization, cell surface expression and integrin-associated signaling pathway (lack of clustering of paxilin and reduced FAK autophosphorylation) (21, 22). Utilization of InsP6 has been shown to offer some benefits during chemotherapy (23) and future trials are on their way.
Are whole grains inherently unhealthy?
Because whole-grains and legumes are high in phytic acid, it is plausible to hypothesize that intake of these foods will reduce to some extent the risk of developing cancer. Whole-grain intake has been associated with reduced risk of cancers (24, 25) as well as intake of legumes (26). However, some studies have found no association (27, 28). Because of the nature of these studies, it is not possible to draw causative conclusions. Most people eating the supposedly healthy foods have low intakes of harmful foods, so the decreased risk in some studies might be due to the exclusion and not the inclusion of some foods. In either case, most studies have not observed an increased cancer risk associated with these foods*. Other food sources rich in phytic acid include nuts and cocoa.
Conclusions
The dangers of phytic acid have been overestimated. Contrary to popular the paleo belief, phytic acid might be beneficial in small doses and might have anticancer effects. As seen with gluten degradation by Rothia species, the phytase activity present in some exclusive human Bifidobacteria shows that adaptation to wheat/grains is indeed happening. Once again, the microbiota plays a dominant role.
From epidemiological data, foods with high phytate content are not associated with increased risk for several chronic diseases. As association doesnt means causation, we cannot conclude that whole-grains are healthy but we cant also conclude that whole-grains are unhealthy. With the increasing attention to paleolithic and similar diets, it is of utmost importance that all evidence is critically analyzed and reviewed. Making unsupported statements and cherry-picking data would only cause rejection by scientists. Dogma is not good in science (or in anything else, for that matter).
I dont recommend whole-grains and legumes because there are foods more nutritious, as well as because whole-grains and legumes are very high in carbohydrates. The potential benefits of phytate can be obtained by eating other phytate rich foods, such as nuts and cocoa; as well as soluble fiber and oligosaccharides as the main dietary fiber type. The problem with high levels of phytate is only relevant when the diet is deficient in micronutrients and essential food sources. Finally, maintaining a proper gut flora is essential for phytic acid metabolism and adequate mineral absorption.
*Any evidence of a significant increased risk from these foods would be greatly appreciated.
InsP6 antinutrient effect
Typically, InsP6 and fiber occur together in whole foods. This is problematic for analyzing the antinutrient effect of InsP6 as there is evidence that fiber also reduces mineral bioavailability (6). When given alone in animal models, InsP6 does not show toxic effects on bone minerals (7):
This suggests that its the combination of fiber and InsP6 which causes the antinutrient effect observed.
The type of fiber seems to be important on mineral bioavailability. The addition of FOS to a diet high in InsP6 improves cecal absorption of minerals and stimulates bacterial hydrolysis of InsP6 (8, 9), counteracting the negative effects of high doses of InsP6. Inulin has also shown to improve calcium balance and absorption (10). The importance of the fiber type on the effects of phytic acid is highlighted by a study in which healthy women following the recommended daily intake of fiber-rich wheat bread (300g/day) showed impaired iron status independent of the phytic acid content (11).
Anti-cancer properties
InsP6 is a broad-spectrum antioneoplastic agent in vitro and in vivo (12). Structurally, InsP6 is similar to D-3-deoxy-3-fluoro-ptdIns, a potent PI3K inhibitor. Accordingly, InsP6 is able to inhibit PI3K and ERK phosphorylation (13), thereby inhibiting AP-1 activation. InsP6 has also been shown to activate PKC delta and decrease phosphorylation of Erk1/Erk2 and Akt, causing upregulation of p27-Kip1 and reduction of pRb phosphorylation (14). Other protective effects include the induction of apoptosis by inhibiting the Akt-NFkB pathway and increasing cytochrome C release (15), downregulation of constitutive and ligand-induced mitogenic and cell survival signaling (showing different effects on ERK1/2, JNK1/2 and p38 in response to different mitogens) (16), its antioxidant effect (17), enhancement of NK cell activity (18), modulation of expression of TNF-alpha and its receptors genes (19), inhibition of angiogenesis (20) and metastasis, by modulation of integrin dimerization, cell surface expression and integrin-associated signaling pathway (lack of clustering of paxilin and reduced FAK autophosphorylation) (21, 22). Utilization of InsP6 has been shown to offer some benefits during chemotherapy (23) and future trials are on their way.
Are whole grains inherently unhealthy?
Because whole-grains and legumes are high in phytic acid, it is plausible to hypothesize that intake of these foods will reduce to some extent the risk of developing cancer. Whole-grain intake has been associated with reduced risk of cancers (24, 25) as well as intake of legumes (26). However, some studies have found no association (27, 28). Because of the nature of these studies, it is not possible to draw causative conclusions. Most people eating the supposedly healthy foods have low intakes of harmful foods, so the decreased risk in some studies might be due to the exclusion and not the inclusion of some foods. In either case, most studies have not observed an increased cancer risk associated with these foods*. Other food sources rich in phytic acid include nuts and cocoa.
Conclusions
The dangers of phytic acid have been overestimated. Contrary to popular the paleo belief, phytic acid might be beneficial in small doses and might have anticancer effects. As seen with gluten degradation by Rothia species, the phytase activity present in some exclusive human Bifidobacteria shows that adaptation to wheat/grains is indeed happening. Once again, the microbiota plays a dominant role.
From epidemiological data, foods with high phytate content are not associated with increased risk for several chronic diseases. As association doesnt means causation, we cannot conclude that whole-grains are healthy but we cant also conclude that whole-grains are unhealthy. With the increasing attention to paleolithic and similar diets, it is of utmost importance that all evidence is critically analyzed and reviewed. Making unsupported statements and cherry-picking data would only cause rejection by scientists. Dogma is not good in science (or in anything else, for that matter).
I dont recommend whole-grains and legumes because there are foods more nutritious, as well as because whole-grains and legumes are very high in carbohydrates. The potential benefits of phytate can be obtained by eating other phytate rich foods, such as nuts and cocoa; as well as soluble fiber and oligosaccharides as the main dietary fiber type. The problem with high levels of phytate is only relevant when the diet is deficient in micronutrients and essential food sources. Finally, maintaining a proper gut flora is essential for phytic acid metabolism and adequate mineral absorption.
*Any evidence of a significant increased risk from these foods would be greatly appreciated.
Haros M, Carlsson NG, Almgren A, Larsson-Alminger M, Sandberg AS, & Andlid T (2009). Phytate degradation by human gut isolated Bifidobacterium pseudocatenulatum ATCC27919 and its probiotic potential. International journal of food microbiology, 135 (1), 7-14 PMID: 19674804Haros M, Bielecka M, Honke J, & Sanz Y (2007). Myo-inositol hexakisphosphate degradation by Bifidobacterium infantis ATCC 15697. International journal of food microbiology, 117 (1), 76-84 PMID: 17462768
Great post Lucas! It's all too easy for the layman to take the simple approach and follow the dogma, but it's analyses such as yours that helps keep us open minded and ready to adjust our diet as we continually learn more.
ReplyDeleteThanks for your work.
Great job! I've been thinking about this a lot over the past few months as phytates are so demonized in the paleo community.
ReplyDeleteI'm sure you've seen these but here are a couple of other good reviews
http://www.sciencedirect.com/science/article/pii/027153179500040P
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2266880/
I've also been working on a review paper that includes anti-nutrient content in gluten-free grains which is about to be submitted for publication.
keep up the good work!
best, Jeff
Would the degradation of gluten and phytic acid occur downstream enough in the GI tract that the damaging effects of the former by way of villous atrophy, crypt elongation, immune/inflammatory response in the small intestine would already have occurred and that most of the mineral absorption blocking of the latter (also in the small intestine) would too have already occurred?
ReplyDeleteThanks Carl and jeff.
ReplyDeleteTravis,
Well, Rothia bacteria are normal commensals of the oral cavity. The studies done with these bacteria at different pH suggests that gluten-degrading enzymes would be active in the mouth, then inactivated momentarily in the stomach and re-activated in the duodenum. So probably, by the time gliadin peptides arrive at the intestines, most of them are already partially digested, being completely digested in the duodenum. In this scenario, any epitope in the gliadin peptides would be absent, thus no immune reaction is developed.
Regarding phytate and minerals, the problem of absorption is mainly in the intestines. If bacteria with phytase activity are present, there should not be significant mineral binding, and probably, some degradation products would enhace solubility of some metals. I think the key aspect is the avaiability of phytate for phytases. If it is very "coated" (for instance, by wheat bran or insoluble fiber), phytases can't do much.
So, based on the studies done, it seems plausible that by the time gluten gets to the duodenum, most of it would be digested. Phytase-degrading bacteria are gut commensals, so it should help degrading phytate in situ.
The thing I'm generally concerned about is the small amount of active phytate necessary to disproportionately bind with those minerals that are very poorly represented in any diet. Manganese, chromium, nickel etc. are present in such tiny amounts that there is a much greater chance of the entire amount being bound from a meal, whereas zinc, calcium, iron etc. will probably get through to some extent, though perhaps it's the same because we likely need more of the "macrominerals." I guess we'd have to look at the phytate:[mineral] molar ratios and see how things actually work in vivo.
ReplyDeletePerhaps this explain the upswing in the instance of poor insulin management as people are highly deficient in chromium due to depletion in the diet coupled with all dietary sources being coupled with phytate-rich foods.
This would be an argument not for the total removal of phytate from the diet, but rather simply for the segregation of phytate-rich foods like potatoes, nuts, rice etc. from mineral-rich foods like meat, organs, sea creatures and so on. This is what I do just in case and I find that at the very least my perception of digestion is improved.
"So, based on the studies done, it seems plausible that by the time gluten gets to the duodenum, most of it would be digested."
ReplyDeleteForgive me Lucas, I find this confusing. If this is true, then how is celiac disease or gluten intolerance possible? I assume you do not deny the existence and seemingly enormous increase in these diseases, do you? Thanks!
moreporkplease,
ReplyDeleteThe key point is that for developing celiac disease, it is necessary a trigger (ie. inflammation). This produces dysbiosis and immune dysregulation. An aberrant establishment of gut microbiota during childhood is also an important factor. The increase in celiac over the years, in my opinion, has its basis on increased inflammation.
Interesting stuff. Thanks.
ReplyDeleteI wonder about the interactions- see:
http://donmatesz.blogspot.com/2011/11/pharmaceutical-antibiotics-probably.html
We typically kill off our gut flora quite a bit with antibiotics, while continuing our phytate heavy diets. What is good in strong healthy guts, may not be in unhealthy guts. Not only that but the exact times we kill off our gut flora are the times when our immune system is compromised..
--Q
Hi Quarrel,
ReplyDeleteYou are correct, the combination of extreme hygiene, antibiotic abuse and grain-based/low fat diets are the common factors for dysbiosis.
Thanks, Lucas. This helped me a lot with getting a clearer picture of phytic acid. I am curious about further research.
ReplyDeleteGood stuff. Is phytate a source of inositol?
ReplyDeleteWe adapted to phytate earlier than gluten as nuts have always been on the menu (including pine nuts in ice-age times) and phytates are far more prevelant than gluten-type prolamines.
Of course, radiation is also antineoplastic. That isn't always a recommendation.
Aspergillus (bread mould) can digest gluten.
But digesting gluten is what releases exorphins; we ideally want something that digests a wide range of prolamines to dipeptide or smaller before they even reach the gut, unless it's a case of simple gluten allergy, which is seldom the case.
A species only adapts when the unadapted die off.
Hi George,
DeleteNice comment. The problem is not digesting gluten but PARTIALLY digesting it, as you mention. This is the case for gluten digestion by Rothia, it digests the problematic peptides with the most immunogenic epitopes.
Hi Lucas,
ReplyDeleteDo you think that with gluten and phytic acid, the "dose makes the poison?" Based on the fact that grains (and I think legumes as well) have only become mass available after agriculture-relatively recent in evolutionary terms as per many people-do you think we are not adapted to consuming a lot of gluten and phytic acid-containing foods unless they have been soaked/sprouted/fermented? Also, do you think that that the modern, hybridized wheat, which has been bred in such a way that increases its antinutrient content such as gluten- can be problematic?
This is much more in-depth than anything else I've read. I like the information, but I think there is a real conclusion to be made in favor of paleo.
ReplyDeleteHow is an individual supposed to know, at the time of ingesting a phytate-rich food, whether or not his gut flora is in a proper state to nullify the anti-nutrient effects? More importantly, what is the average state of his gut flora over his next thousand meals? Many people are not even aware of gut flora or the possibility of having some sort of imbalance. I agree that, if your information is correct, phytates have no anti-nutrient effects under the conditions you specified. However, that's a pretty big caveat, given the difficulty of knowing the exact conditions of your gut at every meal. For the average person, and as a good heuristic, I'd say the paleo folks have it right.
I might take an antidote before my poison once or twice as a cute experiment, but I wouldn't make it a thrice-daily habit.
It is hard to understand this scientific explanation.
ReplyDeleteHello, Lucas. I don't know if you've read this post by Dr. Art Ayers, where he hypothetyzes that phytates, as long as extricated from their insoluble fibre, may have an anti-inflammatory effect. So, he recommends boiling soy beans for several hours and just drinking the water (at least, that's what I understood from the text, it does get rather technical). Would you second his opinion?
ReplyDeletehttp://coolinginflammation.blogspot.pt/2008/11/fiber-phytate.html