Trehalose

Last Updated: September 28 2022

Trehalose is a sugar which, on a cellular level, appears to have therapeutic mechanisms by regulating protein unfolding. Practically, its low oral absorption in its intact form paired with rapid digestion may preclude any benefits of oral intake.

Trehalose is most often used for.



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    1.

    Sources and Composition

    1.1

    Sources and Structure

    Trehalose (synonyms ofmycose and tremalose) is a disaccharide (two sugar) comprised of two glucose molecules, named after its sources of trehala manna (from which 'Trehalose' was named from[1]) which is a sugary solution obtained from the nest and/or cocoon of some insects (larinus genera).[2] "Mycose" as a synonym was named after another common source of trehalose, mushrooms.

    Trehalose's main biological purpose in mushrooms and bacteria is water regulation, since it seems to form a gel phase during cellular dehydration protecting organelle during this time and then allows rapid rehydration when a proper environment is reintroduced.[3][4] It can serve a hydration function in humans as well as possessing general antioxidant properties, but its major role is as a cellular chaperone regulating intracellular functions such as protein folding and unfolding; it is one of few exogenous chaperones that can be consumed orally similar to the bile acid and chaperone TUDCA.[5]

    Trehalose is a dietary sugar found predominately in mushrooms that also appears to have a role in autophagy and protein folding, leading to pharmacological actions atypical of carbohydrates

    The structure for trehalose (α-D-glucopyranosyl-(1→1)-α-D-glucopyranoside) differs from the other disaccharide made from two glucose molecules known as maltose (4-O-α-D-Glucopyranosyl-D-glucose) as trehalose has a different bond between the two molecules (a 1,1-glucoside bond rather than an alpha linkage) and trehalose is made of two α-glucose molecules; α-glucose (and β-glucose) referring to the isomerization of the hydroxyl group on carbon 1 in the D-glucose molecule.

    Trehalose differs slightly from maltose despite both containing two glucose monosaccharides, as trehalose possesses a different bond and is exclusively comprised of alpha-glucose molecules

    1.2

    Biological Significance

    Despite being synthesized by a wide degree of bacteria, fungi, plants, and insects on an as-needed basis to protect the cells against dessication or states of extreme dryness, trehalose is not reportedly known to be synthesized by mammalian cells[2][6] despite application of trehalose to mammalian cells having a similar protective effect against dessication (200mM).[7]

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

    2.

    Molecular Targets

    2.1

    Autophagy

    Trehalose appears to be a disaccharide that can mimic a cellular chaperone, and increases autophagy in a cell via mechanisms independent of mTOR; mTOR is the most well researched regulatory of autophagy and its inhibition (which increases autophagy) the most common mechanism associated with nutraceuticals leading trehalose to be somewhat novel.

    The increase in autophagy appears to occur with an increase in FOXO1 translocation and activity[8] (FOXO1 being a positive regulator of autophagy[9]) and in cultured neurons is not related to ATF4 which is unchanged in protein content.Autophagy is increased by an enhancement of FOXO1 activation with no effect on ATF4[8] although protein content of various other autophagy related gene products (Lc3, Becn1, Sqstm1 and Atg5) appear to be increased at the mRNA level.[8]

    The inhibition of autophagy is blocked by standard inhibitors 3-methyladenine (Blocks the PtdIns3K initiation complex critical for autophagy[10]) and various lysosomal inhibitors. Due to it being independent of mTOR, combination with mTOR inhibitors such as rapamycin appear to result in additive effects.[11]

    Trehalose appears to increase autophagy in a manner independent of mTOR inhibition, which is atypical for nutraceuticals (as most that increase autophagy do so via attenuating mTOR's suppressive actions on this phenomena)

    2.2

    Protein Aggregation

    There appears to be an ability of trehalose to disaggregate proteins in cellular cultures, which is preserved even when autophagy is inhibited[8] suggesting it is a different mechanism.

    This has been noted with SOD1 aggregates in vitro[12] and in the spinal fluid of SOD1 mice (model for ALS)[8] which are misfolded proteins that seem to accumulate in pathological conditions (and are decreased by many autophagy interventions[13][14]) and have a pathological role as misfolded monomeric SOD1 is neurotoxic.[15] The protein α-synuclein (relevant to Parkinson's) has also been noted to be degraded with trehalose in vitro[16][11] along with tau protein[17] and huntingtin, a protein involved in the pathology of Huntington's Disease.[18][11]

    Various protein aggregates that accumulate during neurodegenerative diseases seen to be disaggregated when trehalose is introduced, suggesting a possible preventative/therapeutic role of trehalose that remains to be investigated

    3.

    Pharmacology

    3.1

    Absorption

    Trehalose has a variable absorption rate, but is slightly lesser than pure glucose on average; when measuring the relative absorption of glucose between trehalose and pure glucose in otherwise healthy people given 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).[19]

    In people who can not absorb trehalose normally due to a lack of trehalase it is thought that all absorption that occurs would be via passive diffusion; in regards to disaccharides in general, the amount absorbed by passive diffusion during instances of malabsorption tends to be around 0.5%.[20] Malabsorption of trehalose underlies an intolerance to mushrooms, since the lack of absorption results in diarrhea and intestinal distress.[21]

    It should be emphasized that when measuring the bioavailability of trehalose the amount of glucose that appears in the blood is used as the proxy measurement; trehalose itself is not readily absorbed, and must be digested into glucose via trehalase before appreciable absorption. This is similar to lactose, which needs to be digested into its monosaccharides (galactose and glucose) via lactase prior to absorption and a lack of the enzyme causes malabsorption.

    At the level of the intestines, trehalose appears to be absorbed to a rate slightly lesser than pure glucose although it is variable. In persons lacking the trehalase enzyme there is next to no absorption, and trehalose is absorbed in the form of glucose (as it is digested first, and then the glucose is absorbed)

    3.2

    Metabolism

    The enzyme that metabolizes trehalose into two alpha-glucose molecules known as trehalse is present in the mammalian intestinal tract[22] and kidneys[23] despite humans not being capable of synthesizing trehalose. Some intestinal microorganisms such as saccharomyces boulardii may also release this enzyme into the gut,[24] which was thought to be therapeutic for diarrhea in instances of trehalose deficiency.

    The highest estimate of trehalose deficiency (both total and partial) has been estimated to be around 8-10%[24][25]) but is thought to be lower on average, around 3.2-6.0%.[26] Due to low prevalence and minimal dietary sources of trehalose, it is not thought to be a significant nutritional concern like lactose deficiency is.[25]

    Humans do not appear to synthesize trehalose, but most people appear to be capable of digesting trehalose into its constituent alpha-glucose molecules as the intestines and kidneys expresses trehalase. An inability to digest trehalose may result in cramping and diarrhea in response to dietary trehalose such as mushrooms

    Trehalase also exists in the blood of mammals,[27] which suggests that the low amount of orally absorbed trehalose that escapes intestinal digestion can be eliminated in serum.

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

    4.

    Peripheral Organ Systems

    4.1

    Eyes

    Trehalose has been hypothesized to have a role in ophthamology related to anti-dessicative properties,[2] and one trial in which mice were placed in an environment conducive to forming symptoms of dry eyes (low-humidity airflow and temperature[28]) for three weeks had less symptoms of dry eyes and apoptosis than did control when they were given eyedrops containing trehalose (concentration of 87.6mM or 30mg/mL).[29]

    Eye cells may also experience less damage secondary to UVB radiation when in the presence of trehalose at the aforementioned 30mg/mL concentration[30][31] and can enhance the rate of healing when applied to the eye cell even after UVB-induced damage has occurred.[32] It is thought to be safe for direct application, as trehalose is included in two pharmaceuticals (Avastin and Lucentis) which are administered to the eye via intravitreal injection.[2]

    Trehalose appears to have protective effects at the level of the eye in regards to both preventing cellular damage induced by UVB rays and reducing the chance of getting dry eyes, and appears to avoid the problems of oral ingestion (low absorption and rapid digestion) when it is applied directly to the eyes via eye drops

    One study using two concentrations of trehalose solution (100mM or 200mM) in saline applied to one eye six times daily for four weeks, while using the other eye as a control, noted that both concentrations appeared to be beneficial to dry eyes with 100mM outperforming the higher dose in prolonging tear film breakup time.[33] These benefits have been noted elsewhere, with trehalose containing eye drops outperforming commercial products containing either hyaluronan (Hyalein) or hydroxyethylcellulose (MyTear).[34]

    Eye drops containing trehalose have been demonstrated effective in two trials in humans with dry eye symptoms, and at least one of those trials suggests that its potency is greater than the currently available options of hyaluronan or hydroxyethylcellulose

    5.

    Interactions with Medical Conditions

    5.1

    Amyotrophic Lateral Sclerosis (ALS)

    Trehalose has been investigated for delaying the pathology of amyotrophic laterial sclerosis (ALS) due to its ability to increase autophagy.

    It appears that in SOD1 mice (mouse model for ALS) that thrice weekly trehalose injections paired with 3% trehalose in the drinking water delayed the onset of ALS symptoms and increased lifespan relative to other sugars.[8]

    Administration of trehalose to mice predisposed to ALS appears to attenuate the severity of the disease and increases lifespan relative to other sugars and control

    This increase in lifespan seems to correlated with a decrease in spinal SOD1 aggregation and (subsequently) less glial cell activation,[8] this is thought to be secondary to increased rates of microglial autophagy.[8] When tested in vitro (100mM trehalose) SOD1 accumulation is maintained even when autophagy is blocked, suggesting dual mechanisms.[8]

    At least in mice, this increase in lifespan may be more pronounced in males[8] despite reduced SOD1 aggregation being similar in both groups.[8]

    There may be a reduction in spinal SOD1 aggregation in mice with ALS given trehalose, which is possibly distinct from the enhancement of autophagy

    References
    3.^Sussich F1, Skopec C, Brady J, Cesàro AReversible dehydration of trehalose and anhydrobiosis: from solution state to an exotic crystalCarbohydr Res.(2001 Aug 30)
    4.^Furuki T1, Oku K, Sakurai MThermodynamic, hydration and structural characteristics of alpha,alpha-trehaloseFront Biosci (Landmark Ed).(2009 Jan 1)
    5.^Lee YY1, Hong SH, Lee YJ, Chung SS, Jung HS, Park SG, Park KSTauroursodeoxycholate (TUDCA), chemical chaperone, enhances function of islets by reducing ER stressBiochem Biophys Res Commun.(2010 Jul 9)
    6.^Elbein AD1, Pan YT, Pastuszak I, Carroll DNew insights on trehalose: a multifunctional moleculeGlycobiology.(2003 Apr)
    7.^Eroglu A1, Russo MJ, Bieganski R, Fowler A, Cheley S, Bayley H, Toner MIntracellular trehalose improves the survival of cryopreserved mammalian cellsNat Biotechnol.(2000 Feb)
    8.^Castillo K1, Nassif M, Valenzuela V, Rojas F, Matus S, Mercado G, Court FA, van Zundert B, Hetz CTrehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneuronsAutophagy.(2013 Sep)
    11.^Sarkar S1, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DCTrehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synucleinJ Biol Chem.(2007 Feb 23)
    13.^Vidal RL1, Figueroa A, Court FA, Thielen P, Molina C, Wirth C, Caballero B, Kiffin R, Segura-Aguilar J, Cuervo AM, Glimcher LH, Hetz CTargeting the UPR transcription factor XBP1 protects against Huntington's disease through the regulation of FoxO1 and autophagyHum Mol Genet.(2012 May 15)
    14.^Harris H1, Rubinsztein DCControl of autophagy as a therapy for neurodegenerative diseaseNat Rev Neurol.(2011 Dec 20)
    16.^Lan DM1, Liu FT, Zhao J, Chen Y, Wu JJ, Ding ZT, Yue ZY, Ren HM, Jiang YP, Wang JEffect of trehalose on PC12 cells overexpressing wild-type or A53T mutant α-synucleinNeurochem Res.(2012 Sep)
    17.^Krüger U1, Wang Y, Kumar S, Mandelkow EMAutophagic degradation of tau in primary neurons and its enhancement by trehaloseNeurobiol Aging.(2012 Oct)
    18.^Tanaka M1, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, Kurosawa M, Nekooki M, Nukina NTrehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington diseaseNat Med.(2004 Feb)
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    20.^van Elburg RM1, Uil JJ, Kokke FT, Mulder AM, van de Broek WG, Mulder CJ, Heymans HSRepeatability of the sugar-absorption test, using lactulose and mannitol, for measuring intestinal permeability for sugarsJ Pediatr Gastroenterol Nutr.(1995 Feb)
    24.^Buts JP1, Stilmant C, Bernasconi P, Neirinck C, De Keyser NCharacterization of alpha,alpha-trehalase released in the intestinal lumen by the probiotic Saccharomyces boulardiiScand J Gastroenterol.(2008)
    25.^Gudmand-Høyer E1, Fenger HJ, Skovbjerg H, Kern-Hansen P, Madsen PRTrehalase deficiency in GreenlandScand J Gastroenterol.(1988 Sep)
    26.^Gudmand-Høyer E1, Skovbjerg HDisaccharide digestion and maldigestionScand J Gastroenterol Suppl.(1996)
    27.^Eze LCPlasma trehalase activity and diabetes mellitusBiochem Genet.(1989 Oct)
    28.^Chen W1, Zhang X, Zhang J, Chen J, Wang S, Wang Q, Qu JA murine model of dry eye induced by an intelligently controlled environmental systemInvest Ophthalmol Vis Sci.(2008 Apr)
    29.^Chen W1, Zhang X, Liu M, Zhang J, Ye Y, Lin Y, Luyckx J, Qu JTrehalose protects against ocular surface disorders in experimental murine dry eye through suppression of apoptosisExp Eye Res.(2009 Sep)
    33.^Matsuo T1, Tsuchida Y, Morimoto NTrehalose eye drops in the treatment of dry eye syndromeOphthalmology.(2002 Nov)