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Ever since I learned about connections between trehalose, the synthetic sugar now pumped into all food products (Figure 1.), and virulent infections, I could not help wondering if there were not some additional connections to be made; namely between our consumption of trehalose-laden products and the explosion in insect-borne illnesses over the last few decades. Illnesses of the tick-borne variety have become especially common here in the US, but mosquito carried illnesses seem also to be on the rise. In just a few decades, the incidence of Lyme disease has more than doubled and while we don’t talk about mosquito or other insect-borne illnesses as much in developed countries, a peek at the data suggests rates of these illnesses have tripled between 2004-2017.

Among the reasons cited for the increase in insect-borne illnesses, climate change is top among them. Shorter winters, and longer and warmer summers increase the breeding and survival capacity of the insects, their pathogens, and the animals that harbor and transport them. On the surface, this gives us little actionable information and often unleashes a political hailstorm of useless rhetoric. When we dig a little deeper, however, this may be a very important clue. For what is at the root of climate change is also at the root of a whole host of other problems, including possibly, the increase in insect-borne illnesses. It is none other than our decades-long love affair with synthetic chemicals. The chemicals we have dumped into the atmosphere, waterways, and soil and into and onto our bodies are causing a wholesale change in environmental and organismal metabolism. These chemicals impair mitochondrial functioning, diminish energy capacity and with that, reduce our ability to effectively meet the demands of living. So, when infection strikes, we are unable to clear it.

Metabolic Hypoxia

From a molecular standpoint, the constant exposure to synthetic chemicals causes a sort of functional hypoxia, for us and every other biological organism. It’s not a choking, obstructed airway kind of hypoxia, not yet anyway. It is a metabolic or cellular hypoxia that initiates slight perturbations in cellular functioning that accrue over time. Our cells breathe. They, or more specifically, the mitochondria within the cells, take the oxygen from the air we breathe and along with some nutrients convert this into usable energy. When damaged by synthetic chemicals and/or absent the nutrients, it does not matter how well we breathe, and chances are we do not breathe that well – think apnea – that oxygen cannot be used effectively. When that oxygen cannot be used, the cells become hypoxic and start sending out signals far and wide meant to mobilize more oxygen. These are meant to be short-term, stopgap survival measures until the toxicants are cleared and the nutrient-fueled enzymes kick everything back into gear. Increasingly, however, this does not happen since everything we consume or are exposed to, comes with an unhealthy dose of toxic crude and few of us consume sufficient nutrients to compensate.

What does this have to do with the increase in insect-borne illnesses? Everything. Just like us, when faced with unhealthy ecosystems, the insects and the microbes they carry enact adaptive mechanisms geared toward survival, mechanisms that ultimately favor increased virulence. Virulence from the insect’s/microbe’s perspective, if it were to have one, is nothing more than survival, the same survival we cling to, and the mechanisms, though slightly different in specifics, hold broadly to the same principles. Molecular hypoxia, the kind that develops from nutrient deficiency, is a stressor that demands survival cascades. For us, this involves inflammation, immune system re-regulation, and a myriad of molecular mechanisms designed to increase oxygen delivery and usage; think metabolic, autoimmune, cancers, and the other chronic illnesses that are endemic, including those of the insect variety. What is interesting though, is that for insects and microbes, including the microbes in our gut, the survival cascades involve the synthesis of a specific fuel that is used only as a last resort. And you guessed it, that fuel is trehalose.

It just so happens that from the year 2000 onward, we have been mass producing and consuming trehalose, the survival fuel of preference for insects, fungi, bacteria, and viruses. This is a boon for insects and microbes, but not so good for us. Before 2000, most of us would have rarely consumed trehalose and it is not something we synthesize endogenously to any great capacity. Sure the bacteria in our gut will synthesize this fuel but minimally compared to how much we consume these days (many grams or more, the data are lacking), and only when severely stressed. I have written about this sugar previously, here and here, but its likely relationship with the proliferation of insect-borne illnesses necessitates another look. Oh, and as you might expect, there is a thiamine connection.

Figure 1. Trehalose in Food Products

According to the company website: “TREHA™ trehalose can be incorporated into a wide variety of applications and is GRAS [generally accepted as safe] up to the use levels specified” above. In other words, these products can be composed of up to 5% trehalose. (Note, since originally publishing this article in 2019, the company has removed the page with this table.)

Trehalose, Thiamine, and Survival

All organisms, including the microorganisms that line every surface of our bodies and those in our gut, require thiamine (vitamin B1) to produce energy. Absent thiamine, fungi, bacteria, viruses (and insects, invertebrates, and plants), adopt secondary survival pathways using ‘rescue’ sugars for energy. The use of these rescue sugars bypasses the thiamine-dependent oxidative phosphorylation pathway. Trehalose is one of the primary rescue sugars used by microorganisms to withstand severe environmental stressors like desiccation, dehydration, heat, cold and oxidation, and a basic lack of nutrients. During times of stress, trehalose is synthesized de novo (from scratch) by most microbes. Though a simple sugar used for energy production, trehalose is essentially a preservative. It preserves the integrity of cells when nutrients are absent, hence its ability to withstand desiccation and dehydration.

In 2000, for the first time in history, trehalose was commercially produced and sold as a food additive by the chemical company Cargill. Since then, it has found its way into all types of processed foods as a sugar additive, a salt-substitute, and a preservative. It has even been bandied about as a healthy supplement for kids with Autism. From the company website:

“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.”

The downside of this wonder sugar substitute is precisely its claim to fame. It is a survival sugar. It helps microbes survive; the good ones, but most especially, the bad ones. Just last year we learned that the addition of trehalose to commercial foods is linked to the rise in treatment-resistant Clostridium difficile (c-diff). I would argue that it is also linked to the rise in glabrata infections, a nearly intractable yeast infection. Indeed, one test to determine glabrata relies on its ability to identify trehalose in the specimen. Research shows a connection to intractable tuberculosis and I suspect also that trehalose is involved with the increasing number of foodborne outbreaks in listeria, salmonella, and e coli infections.

As a survival sugar, the adaptability of organisms to activate the trehalose pathway confers virulence – survivability, even in the face of strong antibiotics. It should be no great surprise then, that when consumed in great quantities, it does just that. The question is why do only the ‘bad’ microbes seem to benefit? Wouldn’t all microorganisms benefit equally from trehalose? Perhaps not. The researchers in the C-diff study suggested that trehalose differentially affects microbe survivability and that only the most virulent and the strongest survive. They found that the most virulent strains under stress (starvation for cell culture) were able to mutate in a particular manner that allowed them to transport and metabolize more trehalose than the less virulent species of the bacteria. The mutation that developed, unregulated 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.

Arguably then, host thiamine deficiency alone, absent a ready supply of exogenous trehalose, contributes greatly to the increase in highly virulent, treatment-resistant infections that we have seen over the last few decades. Standard treatment protocols which involve antibacterials, antifungals, and the like, exacerbate thiamine deficiency further by the damage done to the mitochondria. This then leads to and reinforces treatment resistance by upregulating microbial trehalose production. It is a vicious cycle.

Low Thiamine Plus Dietary Trehalose?

We know from research with plants, that thiamine does more than just divert energy synthesis away from the trehalose pathway. Thiamine signals a myriad of protective pathways to prevent pathogens from gaining a foothold in the first place. It is an immune reaction of sorts. Interestingly, thiamine not only confers a quicker response, it seems to induce a future resistance towards that pathogen. That means that thiamine elicits a faster, stronger, and longer lasting immune response, than compared to conventional antimicrobials, but it also primes or trains the immune system conferring future resistance. Of course, this is in plants, but it suggests we may be going about fighting these infections all wrong. Perhaps rather than attempting to kill everything, we ought to be bolstering host defenses.

Returning to the problem of dietary trehalose, the question remains: what happens when we combine a thiamine deficient host and a diet packed with trehalose? The modern diet is such that even without the addition of trehalose to foods, many folks exist in a state of nutritional deficiency. The trehalose only adds to these deficiencies, providing nothing more than empty calories. That alone is problematic, but because of its unique role as a microbial rescue sugar, we are now bolstering the survivability of pathogenic microbes by providing them with a ready and continuous fuel source while simultaneously starving the host of critical nutrients. It is a double hit that confers virulence, with the diet of the host as much or more responsible for the virulence of the insect-borne pathogens. One could argue based on the chemistry that the mutations in the microbes that lead to pathogenesis are controlled, not by some unique mechanism of the bacteria, but by the interaction with the host’s nutrient status.

Returning to insect-borne illnesses, are these dietary changes making us more attractive to the biting insects like ticks or mosquitoes, and once bitten, could the lack of thiamine paired with the ready supply of trehalose maximize the growth potential of the pathogens carried by these bugs? The research on this is circumstantial at best. We know that both the tick and the bacteria that lead to Lyme disease both use trehalose.  Additionally, we know that ticks and mosquitoes are attracted to both excessively high and low concentrations of lactic acid – characteristics of low thiamine and that thiamine is used prophylactically to repel insects, though the research is limited and contradictory.  Perhaps thiamine does not repel insect bites as suggested anecdotally, but rather, bolsters the host’s immune system such that it is capable of clearing any potential pathogenic infections.

Interestingly, unlike every other bacterial organism, the Lyme bacteria Borrelia burgdorferi does not appear to require thiamine to survive. Does that mean that it will survive independently of host thiamine status? Maybe. Although I suspect that as with the plant research mentioned above, host thiamine status affects the strength of the immune response to the pathogen. I also cannot help but wonder if the lack of thiamine response in the Borrelia bacteria is not some recent evolutionary adaptation to trehalose availability. Remember, trehalose is the survival sugar of choice, whose synthesis is upregulated in the absence of thiamine. Twenty years of trehalose availability for insects and microbes is akin to a millennium in larger organisms – long enough to induce genetic and certainly epigenetic changes. If this is the case, the explosion in Lyme disease is only the tip of the iceberg.

Although these connections are purely hypothetical at the moment, with little direct research to prove causation, the patterns and chemistry fit. At the very least, there is sufficient circumstantial evidence to warrant exploration. For individuals struggling with insect-borne illnesses like Lyme disease and/or with intestinal manifestations of an altered microbiome, avoiding trehalose products and maximizing nutrient intake may make all the difference in fighting these infections.

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This article was published originally on May 28, 2019. 

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