Trehalose: What is it? Biological Significance, Protein Aggregation, Pharmacology, and Interactions with Medical Conditions

“Micelosa” was named synonymously after another common source, mushrooms.

Trehalose (synonymous with  mycelose ) is a disaccharide composed of two glucose molecules, named after their sources of trehala manna (from which ‘Trehalose’ was named) which is a sugary solution obtained from the nest and / or cocoon of some insects.

The main biological purpose of trehalose in fungi and bacteria is water regulation as it appears to form a gel phase during cell dehydration protecting the organelle during this time and then allowing rapid rehydration when a suitable environment is reintroduced.

It can serve a hydration function in humans as well as possess general antioxidant properties, but its main function is as a cellular chaperone that regulates intracellular functions such as protein folding and unfolding.

It is one of the few exogenous chaperones that can be consumed orally in a similar way to bile acid and the TUDCA chaperone.

Trehalose is a dietary sugar found predominantly in fungi that also appears to play a role in autophagy and protein folding, leading to atypical pharmacological actions of carbohydrates.

The structure of trehalose (α-D-glucopyranosyl- (1 → 1) -α-D-glucopyranoside) differs from the other disaccharide formed by two glucose molecules known as maltose (O-α-D-Glucopyranosyl-D-glucose) .

Since trehalose has a different bond between the two molecules (a 1,1-glucoside bond rather than an alpha bond) and trehalose is made up of two a-glucose molecules; α-glucose (and β-glucose) which refers to the isomerization of the hydroxyl group at carbon 1 in the D-glucose molecule.

Trehalose differs slightly from maltose despite containing both two glucose monosaccharides, since trehalose has a different bond and is composed exclusively of alpha-glucose molecules.

Biological importance

Despite being synthesized by a wide range of bacteria, fungi, plants and insects as necessary to protect cells against desiccation or states of extreme dryness.

Trehalose is not known to be synthesized by mammalian cells despite application of trehalose to mammalian cells that have a similar protective effect against desiccation (200 mM).

Trehalose is not synthesized in humans, and any biological effects could be due to oral ingestion (dietary supplements or dietary sources such as mushrooms); administration of trehalose secondary to synthesis from intestinal bacteria is plausible but not yet proven.

Autofagia

Trehalose appears to be a disaccharide that can mimic a cellular chaperone, and increases autophagy in a cell through mechanisms independent of mTOR.

MTOR is the most well-researched regulator of autophagy and its inhibition (which increases autophagy), the most common mechanism associated with nutraceuticals leading to trehalose is somewhat novel.

The increase in autophagy appears to occur with an increase in the translocation and activity of FOXO1 (FOXO1 is a positive regulator of autophagy) and in cultured neurons it is not related to ATF4 which is not modified in protein content.

Atyphagy increases with enhanced FOXO1 activation with no effect on ATF4, although the protein content of several other autophagy-related gene products (Lc3, Becn1, Sqstm1, and Atg5) appear to increase at the mRNA level.

Inhibition of autophagy is blocked by standard 3-methyladenine inhibitors (Blocks  PtdIn s3K initiation complex  critical for autophagy) and various lysosomal inhibitors.

Because it is independent of mTOR, combination with mTOR inhibitors such as rapamycin appears to result in additive effects.

Trehalose appears to increase autophagy independently of mTOR inhibition, which is atypical for nutraceuticals (since most of those that increase autophagy do so by attenuating the suppressive actions of mTOR on this phenomenon).

Protein aggregation

There appears to be an ability of trehalose to disaggregate proteins in cell culture, which is conserved even when autophagy is inhibited, suggesting that it is a different mechanism.

This has been noted with SOD1 aggregates in vitro and in the spinal fluid of mice SOD1 (model for ALS) which are misfolded proteins that appear to accumulate under pathological conditions (and are diminished by many autophagy interventions).

They have a pathological role since misfolded monomeric SOD1 is neurotoxic.

The α-synuclein protein (relevant for Parkinson’s) has also been shown to be degraded by trehalosein vitro along with the protein tau and huntingtin, a protein implicated in the pathology of Huntington’s disease.

Various protein aggregates that accumulate during neurodegenerative diseases that break down when trehalose is introduced, suggesting a possible preventive / therapeutic role for trehalose that has yet to be investigated.

Pharmacology

Absorption

Trehalose has a variable absorption rate, but it is slightly less than pure glucose on average.

When measuring the relative absorption of glucose between trehalose and pure glucose in healthy people who received 50 grams of trehalose and measured over the next hour, the relative absorption of trehalose varies between 0.3-1.5 with an average of 0.7 (70% as bioavailable as pure glucose).

In people who cannot absorb trehalose normally due to a lack of  trehalase  , it is believed that all absorption that occurs is through passive diffusion; With respect to disaccharides in general, the amount absorbed by passive diffusion during cases of malabsorption tends to be around 0.5%.

The malabsorption of trehalose is the cause of intolerance to fungi, since the lack of absorption causes diarrhea and intestinal discomfort.

It should be emphasized that when trehalose bioavailability is measured, the amount of  glucose  that appears in the blood is used as a proxy measure; trehalose itself is not readily absorbed, and must be digested into glucose via trehalose before appreciable absorption.

This is similar to lactose, which must be digested into its monosaccharides (galactose and glucose) through lactase before absorption, and the lack of the enzyme causes malabsorption.

At the level of the intestines, trehalose appears to be absorbed at a slightly slower rate than pure glucose, although it is variable.

In people who lack the enzyme trehalse there is almost no absorption, and trehalose is absorbed as glucose (since it is digested first, and then glucose is absorbed).

Metabolism

The enzyme that metabolizes trehalose into two alpha-glucose molecules known as trehalose is present in the intestinal tract of mammals and in the kidneys despite the fact that humans are not capable of synthesizing trehalose.

Some intestinal microorganisms such as saccharomyces boulardii can also release this enzyme in the intestine, which was thought to be therapeutic for diarrhea in cases of trehalose deficiency.

The highest estimate of trehalose deficiency (both total and partial) has been estimated to be around 8-10%    ), but is believed to be lower on average, around 3.2-6.0%.

Due to the low prevalence and minimal dietary sources of trehalose, it is not believed to be a significant nutritional concern like lactose deficiency.

Humans do not appear to synthesize trehalose, but most people appear to be able to digest trehalose into its constituent alpha-glucose molecules since the intestines and kidneys express trehalose.

The inability to digest trehalose can lead to colic and diarrhea in response to trehalose in the diet, such as mushrooms.

Trehalose also exists in mammalian blood, suggesting that the low amount of orally absorbed trehalose that escapes intestinal digestion can be eliminated in serum.

Trehalose that reaches the blood can also be digested into glucose at this point, resulting in glucose.

Peripheral organ systems

Eyes

Trehalose has been suggested to have a role in ophthalmology related to anti-seizure properties, and a trial in which mice were placed in an environment conducive to forming dry eye symptoms (air flow and low humidity temperature).

Three weeks they had fewer symptoms of dry eye and apoptosis than the control when they received eye drops containing trehalose (concentration of 87.6m or 30mg / mL).

Eye cells can also experience less secondary damage from UVB radiation when in the presence of trehalose at the concentration of 30 mg / ml and can improve the healing rate when applied to the eye cell even after UVB-induced damage. occurred.

It is believed to be safe for direct application, as trehalose is included in two drugs (Avastin and Lucentis) that are administered to the eye by intravitreal injection.

Trehalose appears to have protective effects at the eye level in terms of preventing UVB-induced cell damage and reducing the possibility of dry eyes, and appears to avoid oral ingestion problems (poor absorption and rapid digestion) when applied directly. to the eyes through eye drops

A study using two concentrations of trehalose solution (100 mM or 200 mM) in saline applied to one eye six times a day for four weeks, while using the other eye as a control, found that both concentrations appeared to be beneficial to the eyes. dry.

With 100mM it exceeded the highest dose in prolonging the tear film breakdown time.

These benefits have been seen elsewhere, with eye drops containing trehalose outperforming commercial products containing hyaluronan (Hyalein) or hydroxyethylcellulose (MyTear).

Eye drops containing trehalose have been shown to be effective in two human trials with dry eye symptoms, with at least one of those trials suggesting that their potency is greater than the currently available options of hyaluronan or hydroxyethylcellulose.

Interactions with medical conditions

Amyotrophic lateral sclerosis (ALS)

Trehalose has been investigated to delay the pathology of amyotrophic laterotic sclerosis (ALS) due to its ability to increase autophagy.

It appears that in SOD1 mice (mouse model for ALS) three times weekly injections of trehalose paired with 3% trehalose in drinking water delayed the onset of ALS symptoms and increased shelf life compared to other sugars.

Administration of trehalose to mice predisposed to ALS appears to lessen the severity of the disease and increase life expectancy relative to other sugars and control

This increase in life expectancy appears to be correlated with a decrease in spinal SOD1 aggregation and (subsequently) with less glial cell activation, this is believed to be secondary to increased rates of microglial autophagy.

When tested in vitro (100 mM trehalose) the accumulation of SOD1 is maintained even when autophagy is blocked, suggesting dual mechanisms.

At least in mice, this increase in life expectancy may be more pronounced in males, although the reduced aggregation of SOD1 is similar in both groups.

There may be a reduction in spinal SOD1 aggregation in ALS mice receiving trehalose, which is possibly distinct from improved autophagy.