A Molecular Boondoggle: Commercial Trehalose and Pathogenic Virulence

A few weeks ago, news circulated that a research group may have identified the root cause of a deadly strain of the intestinal pathogen called Clostridium difficile (c-diff). The researchers discovered that it wasn’t a new super pathogen. Nor was it antibiotic resistance causing the growing deadly epidemic of c-diff, although those are certainly contributing factors. Rather, it was due to an additive in ice cream and wide range of other processed foods, called trehalose. Admittedly, I had never heard of trehalose, but its presence in ice cream, a high sugar food, and its role in c-diff triggered a couple of connections that I had to investigate. Could trehalose somehow damage the mitochondria? Could that damage somehow feed more sugar to gut bacteria or into the mitochondria, thereby increasing their pathogenic growth and reticence to die off? Could those changes disable mitochondrial response mechanisms? And finally, would thiamine somehow be involved? Interestingly enough, my hunches may be correct. Here is what I learned.

Trehalose: A Not So Simple Sugar

Trehalose is basically a preservative disguised as sweetener produced by the chemical company Cargill. The commercial form arrived on the market in 2000 and since then has found its way into all types of foods as a sugar additive, a salt-substitute, and preservative. It is even sprayed on produce to prolong the appearance of freshness. Interestingly, because of its unique preservative qualities, it is also used in cosmetics, medicines, and for medical and laboratory applications. According to the manufacturer, it is a wonderful, super safe, and totally natural additive:

“Trehalose is an ideal ingredient for generating exciting market possibilities for your latest product concepts and also for adding new life to existing food and beverage brands. Trehalose, a diglucose sugar found in nature, confers to certain plant and animal cells the ability to survive dehydration for decades and to restore activity soon after rehydration. This observation has led to the use of trehalose as excipient during freeze drying of a variety of products in the pharmaceutical industry and as an ingredient for dried, baked and processed food, as well as a non-toxic cryoprotectant of vaccines and organs for surgical transplants.

It is especially well suited for sweetening nutritional drinks and other energy products used by consumers as part of their daily eating habits. As a multi-functional sugar with nearly half the sweetness of sucrose, trehalose will strongly improve the taste, texture and appeal of your foods and beverages. Trehalose can bring out the best in your products and your processes, enhancing functionality and improving stability in several key ways.”

I don’t know about you, a few things struck me as troubling regarding commercial trehalose. Firstly, it allows cells to survive dehydration. On the surface, being able to survive low fluid environments might be a good thing, particularly for desert plants and insects, but do we really want human cells, microbiota, and mitochondria, to be impervious to changes in fluidity? Perhaps for experimental purposes in culture, but really, is it a good idea to consume vast quantities of a substance that prevents apoptosis (natural cell death), particularly in the long term? We want certain bacteria and fungi to die off and not survive. We also want damaged mitochondria and damaged cells to die off. That’s why apoptosis is built into the dynamics of organismal health. It is a protective mechanism against the death of the organism itself. Absent a regulated apoptotic process, all sorts of things go awry, until ultimately, death itself happens.

Secondly, while it is true that trehalose is a sugar, a non-reduceable disaccharide, not too much unlike sucrose – table sugar – and it is also true that it is found naturally in a variety of microorganisms, plants, and insects, neither the healthiness of the natural variety nor that of the manufactured variety is clear, particularly in the concentrations that we are now consuming it. Natural trehalose is found in very low concentrations in insects and drought tolerant plants but not at all in mammals. Although humans cannot synthesize trehalose, we can metabolize it. The enzyme that metabolizes trehalose, called trehalase, is found in mammalian kidneys and small intestines. This suggests that when it is ingested, at least in quantities found in nature and before commercial applications became prominent, metabolism was likely in most of the population. About 8% of the population of Greenland have a genetic trehalase deficiency, but there are no data for the population as a whole.

Trehalose in Nature

In lower species and a variety of microorganisms, trehalose is a stress response sugar of sorts, used as a backup energy source when other sources are unavailable. In that regard, it is useful. In fact, in cell culture, and in fruit fly, worm and even in some rodent research, trehalose ingestion has been associated with all manner of beneficial effects. These include the amelioration of oxidative stress (culture) and the prevention of protein aggregation associated with Huntington’s disease (mouse) and Alzheimer’s disease (culture). It extends longevity in fruit flies, suppresses inflammation and oxidative stress during hemorrhage (rabbits), prevents bone loss in ovariectomized female mice and is even an antidepressant (mice). In other words, it does what it is supposed to do. It prevents stressor related cell death by a number of mechanisms. It extends the possibility of life until circumstances change, keeping the organism alive, at least in the short term and in lower species.

The research on humans is lacking, however, and limited entirely to the initial single dose-response toxicology studies. These studies not only ignore the obvious effects that trehalose would have on microbial populations, looking only at gross and acute observable effects, like gastrointestinal distress, but they also fail to address cumulative, longer term effects. To the extent that trehalose is a stress response molecule, utilized by lower organisms to withstand stressors like dehydration and the lack of other sugars for fuel, it seems like this would be an important consideration before releasing trehalose into the foodstream, where it will be ingested in large quantities on a daily basis. It wasn’t.

We know from several sources, that pathogenic microorganisms love trehalose. In microorganisms, like the mycobacterium tuberculosis or in many fungal pathogens, the ability to synthesize and utilize trehalose effectively is tied directly to virulence, to whether the pathogen survives and flourishes or dies off. This seems to be the case with the virulent c-diff bacterial strains as well. The most virulent strains of c-diff were those that adapted to utilize trehalose the most effectively. This again, begs the question, what happens when we provide these microbes with a constant supply of trehalose? Very conservative estimates suggest that we’re eating at least 6-20 grams of trehalose per day (1-4 teaspoons), over extended periods of time. Might we get increased virulence like that proposed by the authors of the c- diff study? Yes. In fact, these authors tested ileostomy effluent in three people after they consumed a ‘normal’ diet and found that not only was the consumed trehalose present in the fluid, and thus bioavailable, but the enzyme that metabolizes trehalose was upregulated in the particular strain of c-diff associated with virulence.

To recap, we have a sugar used as fuel source by microbes under extreme stress, one that helps its host resist death, to survive the most inhospitable climes and energy intensive situations. Sounds like a wonderful discovery. Unless of course, it isn’t. Returning to the notion that the death of diseased or damaged cells should happen in a regulated manner, we have to ask ourselves the obvious question, what happens when we forestall or override those processes by manipulating, and indeed, exponentially increasing exposure to a preservative substance like trehalose? Just as important, what happens when said substance itself resists degradation?

We make deodorant.

Seriously.

From Foodstuff to Cosmetic: An All Purpose Product

The commercial version of trehalose doesn’t seem to degrade – ever – except under ever extreme circumstances. It is stable in a wide range of pH values and at extreme temperatures. By those standards, trehalose is a fantastic preservative. Accordingly, the developers boast that it is “an extremely attractive substance for industrial applications”. When food is referred to as an industrial application, I cannot help but cringing. Perhaps some of you are thinking, “So what? It’s a preservative and we eat lots of preservatives already. What’s the big deal?” Well, considering obesity and metabolic diseases represent the top health concerns of modern medicine; considering we are living sicker and dying younger than previous generations and considering that for most Americans polypharmacy is the norm, I think it’s a pretty big deal. Ingesting mass quantities of manufactured foods isn’t working out too well for us.

When we consider preservatives, we have to consider what metabolic processes that the substance blocks and the role those processes play in health. In this case, trehalose suppresses fatty acid oxidation, particularly linolenic acid oxidation. In other words, it prevents the breakdown of fats, and since those breakdown products make foods smell foul, adding trehalose can extend the shelf-life of a product significantly, perhaps well beyond when it is safe to consume. And who doesn’t want to eat rotten food, as long as it doesn’t stink?

More seriously though, what happens when a substance that effectively blocks fatty acid metabolism is ingested regularly. We need fatty acids for all sorts of processes, from cell wall integrity to mitochondrial energy. Might it be problematic if fatty acids did not metabolize appropriately? This wasn’t a consideration in either the initial or subsequent safety studies. What was considered, however, were the benefits of blocking these pathways. Aldehydes, by-products of fatty acid metabolism, stink. The developers wondered, if we block this pathway, can it be as a deodorant of sorts. And well, lo and behold, it can. When sprayed on older folks, that ‘old folks smell’ goes away. I kid you not. Not only did they tout this as a benefit, but they did tests to prove it.

“…we examined the suppressive effect of trehalose on human body odor. The typical odor of a senior layer (odor from seniors) increases with age, especially 55 years or older…

The subjects (55 years or older) were selected from our company. After a shower, their body was sprayed with a 2 % trehalose solution. They put on new underwear after the spray…

Twenty hours later, the unsaturated aldehydes were sampled from the used underwear shown in this system using a DNPH-column. The trapped aldehydes were eluted from this column and were analyzed by gas chromatography. The results showed a decrease of about 70 % in odor from seniors due to the action of trehalose (Fig. 7). This result indicates that trehalose has a suppressive effect on the formation of the odor released by the seniors’ bodies. The same results came out with the oxidation of fatty acid. Therefore, the application of trehalose for cosmetic fields is expected. “

Well, if that isn’t just peachy. Let’s preserve our insides so our undies don’t smell. Cosmetics for our digestive track. Mmmm.

In all seriousness though, doesn’t it seem just a little bit hinky to ingest something that suppresses so many functions that we need to survive? Doesn’t it seem just a little bit troubling that a commercial food additive is also marketed as a cosmetic? I am all for cosmetics being safe enough to eat, we shouldn’t be putting chemical toxicants on our skin, but I am not sure that means we should eat cosmetic preservatives, but that is exactly what we are doing when we consume trehalose laden food. And if we consider that the commercially available version of trehalose is enzymatically derived from cornstarch, glyphosate laden and bt toxin cornstarch, the depth of damage this product may induce is considerable, particularly when ingested regularly over extended periods of time.

The Virulence Recipe: High Trehalose, Low Thiamine

Here is where this gets really interesting. The researchers investigating the connection between trehalose and c-diff did several experiments to determine the mechanisms by which trehalose interacted with different strains of c-diff bacteria and under different circumstances. They found that the most virulent strains under stress (starvation for cell culture) were able to mutate in a particular manner which allowed them to transport and metabolize more trehalose than the less virulent species of the bacteria. In other words, they adapted more readily to the nutrient poor environment. The mutation that developed upregulated an enzyme involved in the trehalose to glucose conversion pathway (trehalose 6 phosphate synthase – tps1). From other research, we know that this particular enzyme  is thiamine dependent. In this case, the enzyme upregulates when thiamine is depleted. That’s right, when thiamine is absent, in order to provide more energy to these microbes, the tsp1 enzyme kicks into high gear and preferentially shuttling trehalose into the cells where it accumulates. Since we are providing a continuous supply of abnormally high doses of trehalose, we have made adapting to poor nutrient environments easier than ever.

Consider the implications of this. Thiamine depleted microbes upregulate the trehalose enzyme and the measure of success or survival is the ability to mutate the protein encoding the enzyme to permanently upregulate enzyme activity. That means, virulence is no more than a successful adaptation to a nutrient starved environment. And we make virulence easy. With everything from the high calorie, low nutrient diets, to the very antibiotics used to treat these pathogens, we deplete nutrients, particularly thiamine. Indeed, there is no better way to produce a low thiamine environment than the one produced by the highly processed western diet. Empty calories that are high in sugars, simultaneously fail to provide the requisite nutrients for survival, but also, deplete thiamine from the mitochondria directly, where it is needed most. When our mitochondria are starved for thiamine and other nutrients, they too set into play adaptive mechanisms geared toward organismal survival. These include sending danger signals to the microbes, signals that perhaps initiate some of the pathogenic behavior observed in c-diff and other increasingly virulent disease processes.

But hey, our insides are preserved and our undies don’t smell. Sounds like a good trade off to me.

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