The chemical warfare on your plate

The fascinating story of how natural insecticides in plants can be good for us, but how wheat has evolved the ability to turn an insect’s immune system against itself… oh, and us.

• Why insecticides in your veg can be healthy (sometimes)
• SCOOP: The remarkable story of how wheat learned to turn an insect’s immune system against itself
• Why that might not be so great for us humans

Graphic by K Watson, USING original ‘killer vegetable’ cartoon by Ken Turner

Plants are in constant chemical warfare with the insects, microbes and animals that want to eat them. Unlike animals they cannot run away (although the angry sweetcorn dude in the image above suggests otherwise!) so their only option is to develop chemical deterrents. Consequently plants are chock-full of natural pesticides such as taninns, polyphenols, saponins, oxalates, cyanides, protease inhibitors, lectins and alkaloids to name just a few. Because predators eventually evolve tolerance to these toxins, plants are forced to continuously evolve new compounds to defeat them. So the chemical weapon development escalates.

According to new research, wheat may have developed a particularly clever chemical weapon in this insecticidal battle, and the extraordinary story of how it directly contributes to coeliac disease makes up the second half of this post. However, back to the story…

Most people don’t want pesticides sprayed on their foods, but they can’t avoid the natural pesticides found in the fruit and veggies they eat. Surprisingly, however, those endogenous plant toxins are not necessarily harmful. At normal doses many are harmless, and frequently beneficial – for example the sulphur containing compounds in broccoli, kale and cabbage appear to have anti-cancer properties. At higher doses though, plant insecticides may threaten health – for example the cyanide in almonds, especially bitter almonds, which can sometimes exceed safe limits as happened in the USA in 2014 leading to bags of healthy sounding ‘organic raw almonds’ being removed from the shelves due to their high cyanide content.

So how can these plant-made insecticides ever be good for us?

The answer: hormesis.

Hormesis

Hormesis can be summed up by the phrase a little of what is bad for you does you good. Hormesis works because the body reacts to low levels of toxins such as those found in plant foods by upregulating cellular detoxification and anti-oxidant pathways. One of the most significant of these pathways is the Nrf2 antioxidant ‘master switch’ (ref) which stimulates our own most powerful antioxidant glutathione.

Upregulating our own antioxidants via hormesis appears much more effective than taking supplementary antioxidants. Over the last thirty years trials of antioxidant supplements have often lead to disappointing results, with either no effect or in some cases an increase in harm (e.g. see our post on vitamin A from animal sources). Many researchers, including nobel prize winning James Watson (co-discoverer of the structure of DNA) now believe that unless you are actually deficient, additional dietary or supplemental antioxidants actually promote disease.

Instead, scientists are increasingly ascribing many of the benefits of eating fruit and vegetables to the hormetic effect caused by their toxins rather than to their antioxidants.

“Hormesis is what makes fruit and vegetables healthy, not antioxidants”, Mattson Mattson & Calabrese, New Scientist 2008

The key to maximising the hormetic benefits from fruit and vegetables is to eat as wide a range as possible so that you do not get excess of any one toxin. The recommendation to eat a wide variety of different coloured fruit and vegetables comes from the idea that the different colours indicate different phytochemical compositions.

Studies of contemporary hunter-gatherers show that they eat many more plant species than their farming counterparts which may be one reason that they are invariably healthier. For example a recent study compared food systems and visual acuity across isolated Amazonian Kawymeno Waorani hunter-gatherers and neighboring Kichwa subsistence farmers. The hunter-gatherers consumed 130 food species (inc. 80 wild plants) whereas the farmers consumed only 63 species (and only 4 wild plants) and their eyesight declined faster with age.

So here’s a question: How many species do you consume? How many wild foods? The shocking answer for the world as a whole is provided to us by the United Nations:

The world has over 50 000 edible plants [yet] just 15 crop plants provide 90 percent of the world’s food energy intake, with three –  rice, maize and wheat – making up two-thirds of this.  United Nations, FAO

The role of agriculture

During the past 10,000 years of agriculture farmers have selected crops with high pest resistance. In some cases this has led to increased levels of certain plant toxins in the diet. High levels of gluten in wheat being an example.

Simultaneously, our preference for more palatable foods has led to the production of agricultural varieties that contain lower levels of bitter, sour or acrid compounds – for example modern salad lettuces are a lot less bitter than their wild counterparts, and apples are sweeter than their astringent crab-apple ancestors. This has reduced our exposure to the original diversity of plant compounds in the human diet.

Further changes caused by agriculture are due to selecting for high levels of sugars, starches and juiciness (water). The end result is a dilution of the phytochemicals in fruit and vegetables, requiring us to eat more of them, along with more simple sugars in the process, to gain the same quantity of plant micronutrients. A modern paleo diet, therefore, recommends eating berries – which are closer to their wild counterparts – rather than, say, apples and grapes, as they deliver more micro-nutrients per calorie consumed.

Furthermore, our reliance on a limited number of high yielding staple crops such as wheat and potatoes means that compared to our paleolithic forefathers we are exposed to a much lower diversity of phytonutrients, but much higher levels of the toxins and anti-nutrients they contain.

An example is the plant anti-nutrient phytate (phytic acid) which is found in its highest levels in cereal grains and nuts. It binds dietary iron, zinc, calcium and magnesium in the gut, reducing the quantities that can be absorbed. In developing countries where diets are limited with a high dependence on cereal grains phytate is a leading cause of mineral deficiency, especially in infants.

one third of world’s population suffers from anemia and zinc deficiency, particularly in developing countries.  Phytic acid is known as a food inhibitor which chelates micronutrient and prevents it to be bioavailabe for…  humans, because they lack enzyme phytase in their digestive tract – Gupta RK et al (2015)

In more affluent countries phytate is less problematic as the diet is more varied, but with grains typically making up 25% of the calories consumed in developed countries it still contributes to the risk of mineral deficiencies. For example last year a paper from the University of Texas examined how phytates in grains were responsible for zinc deficiency among US Mexican-American children, and US premenopausal women. On the other hand some possible positive effects of dietary phytates have been identified, including some anti-proliferative and anti-inflammatory actions. Small amounts in a varied diet, then, probably does some good and little harm.

Recently, a particularly interesting aspect of plant v insect chemical warfare has come to light as part of the explanation for coeliac disease. To my knowlegde, the remarkable story below has not been reported in the media or blogosphere before, so dear reader, you will be one of the first to hear of this research. Prepare to be amazed…

How a natural insecticide in gluten contributes to coeliac disease

Insects have a much simpler immune system than we do. They don’t have an adaptive immune system, relying on simpler innate immunity. However, they do have phagocytosis – the ability of certain cells to engulf microbes and then digest them inside the cell. But what do they do if the foreign particle is too large for phagocytosis? Below are mosquito larvae showing how they cope:

If an insect is invaded by a foreign particle too large for phagocytosis – a parasite or splinter for example – it will encapsulate it instead. This process requires immune cells called haemocytes to form a pallisade (fence) around the invading foreign body, thus immobilising it. The initial cells that bind this foreign body are broken down as further cells rapidly grow extensive sheets to wall off the invader, effectively locking it away in a cage from which it cannot escape. This is what has happened to the nemetodes inside the bodies of the mosquito larvae above. Cells then release glue-like glycose amino glycans (GAGs) which create a tangled water-holding matrix that prevents nutrients reaching the ensnared parasite. It’s an effective strategy for these lavae, but what has this got to do with gluten?

A recent study by Prof Simon Murch’s team at the University of Warwick investigated one aspect of the mechanism of intestinal damage (villous atrophy) in coeliac disease. They were interested in the way that the lower layer – the lamina propria – increases in thickness as the lining of the intestine becomes damaged. What they found was a direct link to insect encapsulation processes.

Perhaps the reason their paper didn’t get picked up by the press is the title: Matrix Expansion and Syncytial Aggregation of Syndecan-1⁺ Cells Underpin Villous Atrophy in Coeliac Disease. It doesn’t sound very promising does it? Yet it explores a  fascinating hypothesis that brings together many of the threads I have been working up to in this post. I will attempt to elaborate below…

First, a bit of background:

Villi are microscopic projections covering the inside of the small intestine, providing a huge surface area essential for absorption of nutrients. (Upper image: biopsy showing healthy villi)

In coeliac disease the villi are eroded, leaving sections of the intestine that are flat and unable to absorb nutrients. (Lower image: coeliac biopsy showing villous atrophy) How gluten can cause these changes in the small intestine is currently the subject of intensive research efforts.

One little appreciated fact in this process is that the damage to the villi is bottom up, not top down. If you look carefully you can see that the lower layers of cells (the lamia propria) has actually expanded upwards, increased in thickness, and destroyed the structure of the villi above.

Prof Murch’s team investigated the mechanism of this cell overgrowth in the lamia propria. What they found is that it shares many biological features with insect encapsulation.

We hypothesise that our findings, of syndecan-1+ cell syncytial aggregation with excess GAG production, recapitulate core elements of the invertebrate encapsulation reaction, in which insect haemocytes form palisades around an invading pathogen or object too large to phagocytose

Recruited cells are characterised by syndecan expression, required for invertebrate haemocyte binding to laminin and cell cluster formation. Our findings in coeliac mucosa show a similar palisading of syndecan-expressing leukocytes to form syncytial aggregates, together with a lysis of a proportion of these cells, with loss of their plasma membrane. Sulphated GAG including HSPG accumulated around these aggregates in an expansion of the lamina propria.

In insects, the GAG production and matrix expansion is limited by a subsequent melanisation reaction dependent on the enzyme prophenoloxidase, in which haemocyte responses are downregulated by α-melanocyte stimulating hormone (α-MSH). In coeliac mucosa the gliadin-induced IL-6 response is similarly attenuated by α-MSH.

The release of GAGs during insect encapsulation, remember, prevents nutrients reaching the parasite. In the lamina propria the GAGs will similarly reduce nutrient uptake – a double whammy for the coeliac intestine – villous atrophy reduces surface area for absorption, then excess GAGs reduce it further!

Another similarity in both insect encapsulation and coeliac disease development is the stimulation of tissue transglutaminase (tTG), which is an enzyme that causes gluing together of tissues.  tTG is a major player in coeliac disease as in the presence of gliadin it can become the target of autoimmunity. (The primary coeliac blood test is for tTG antibodies).

This is all fascinating and points to an evolutionarily conserved mechanism shared by both invertebrates and mammals. However, it begs the question – Why would gluten stimulate a response in the human intestine that is equivalent to what insects do when they are invaded by parasites? The answer to that question is where the true awesomeness of this story lies…

Gluten as a wheat-made insecticide

It is notable that wheat grain has very few insect pests – a fact that made it a good crop to domesticate ten thousand years ago.

A clue as to why this may be is that the few insect species that are able to predate it have all evolved enzymes that can break down gluten. Gluten is very resistant to normal digestive enzymes. That is why many gluten proteins reach the human intestine relatively intact – and why it can set off an immune reaction.

It is notable in this context that the glutenin moiety of wheats provides an effective barrier to predation by most insect species, and there are notably few successful phytophagous predators. Insects able to predate wheat share a common ability to predigest gluten with salivary enzymes, which has evolved separately in species from the northern and southern hemispheres.

The final piece of this story is how gluten pulls off this trick. It appears that the insect immune response to parasites involves the release of two proteins during the early stages of encapsulation. These have been found to have uncanny similarities to some proteins in gluten. The implication is that wheat may have evolved these gluten proteins as an effective insecticide strategy that works by over-stimulating the insect’s own defense system by triggering the encapsulation process inappropriately and presumably fatally! In humans a similar inappropriate triggering is caused by gluten ingestion that can lead to the destruction of the small intestinal villi, via a process which is extremely similar to insect encapsulation.

Cool or what?

Hats off to Prof Murch’s team!

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