IngredientsTrehalose is a naturally occurring, non-reducing disaccharide comprising two covalently-linked glucose molecules. Its molecular structure is formally designated α-D-glucopyranosyl α-D-glucopyranoside (α,α-trehalose), with a registry number of 99-20-7 and a molar mass of 342.296 g/mol (anhydrous) or 378.33 g/mol as the dihydrate.
Trehalose is a non-reducing sugar formed from two glucose units joined by a 1-1 alpha bond, which makes it very resistant to acid hydrolysis and therefore stable in solution at high temperatures even under acidic conditions. This bonding also keeps non-reducing sugars in closed-ring form, such that the aldehyde or ketone end-groups do not bind to the lysine or arginine residues of proteins — a process called glycation.
Two other stereoisomers of trehalose exist: α,β-trehalose (also called neotrehalose) and β,β-trehalose (also called isotrehalose). Neither of these alternate isomers has been isolated from living organisms, though isotrehalose has been found in starch hydroisolates.
Trehalose has about 45% the sweetness of sucrose and is less soluble than sucrose except at high temperatures above 80°C. It forms a rhomboid crystal as the dihydrate and has 90% of the calorific content of sucrose in that form.
Trehalose is found in various organisms including bacteria, plants, insects, yeasts, fungi, and invertebrates. Trehalose does not occur in mammalian cells, but humans possess the enzyme trehalase, which converts trehalose to glucose.
Modern food sources that may contain substantial quantities of trehalose include honey (0.1–1.9%), mirin (1.3–2.2%), sherries (<10–391 mg/l), brewer's (0.01–5.0%) and baker's yeasts (15–20%). Commercially grown mushrooms can contain 8–17% (w/w) trehalose. It also occurs in invertebrates such as lobster (2.5 mg/100 ml blood), crab (1.5 mg/100 ml blood), and prawns (0.5% dry weight).
Some bacteria, fungi, plants, and invertebrate animals synthesize trehalose as a source of energy, and to survive freezing and lack of water.
As a food additive, trehalose is artificially produced from corn starch using several bacterial enzymes such as alpha-amylase, obtained from Bacillus licheniformis, and isoamylase from Pseudomonas amyloderamosa. In 1994, the Japanese company Hayashibara Co., Ltd. developed a way to mass produce trehalose. The use of trehalose in the US and Europe was limited prior to 2000 due to high cost of production (approximately $700/kg). The innovation of a novel enzymatic method for low-cost production from starch made it commercially viable (approximately $3/kg). It was granted GRAS (Generally Recognized As Safe) status by the FDA in 2000 and approved for use in food in Europe in 2001.
In the past few decades, intensive research on trehalose has extended its uses as a sweetener and stabilizer in the food, medical, pharmaceutical, and cosmetic industries. Common commercial forms include:
Trehalose was isolated in the mid-19th century by the French chemist Marcellin Berthelot, from Trehala manna, a sweet substance obtained from the cocoon of a weevil. This isolation event gives the compound its name, and the compound's history as a recognized substance in Western science therefore dates from that time.
Although trehalose is not presently a significant part of the modern diet, the high concentration of trehalose in insects and fungi may have constituted a relatively large source of the sugar in the diet of ancient humans. Certain cultures still eat a much higher proportion of invertebrates and fungi as part of their diets and therefore consume more trehalose than does Western man.
Trehalose has been used safely as a food ingredient in Japan for more than 20 years, and its widespread incorporation into the Japanese food supply preceded its adoption in Western markets. Anhydrous trehalose is used as a desiccant, sweetener, taste-improving agent, and quality-improving agent in a broad range of traditional Japanese seasonings and food products, including soy sauce preparations, miso, mirin, and various wagashi (traditional Japanese confections).
There is no documented history of trehalose being used as a traditional medicinal remedy in any formally codified system of traditional medicine (such as Chinese medicine, Ayurveda, or Western herbalism). Rather, its consumption has always been incidental, through the eating of trehalose-rich foods such as mushrooms, fermented products, and invertebrates.
As trehalose is a single, chemically defined compound (a disaccharide), its pharmacological interest does not derive from a complex mixture of constituents, but rather from its unique physical chemistry and its established biological effects upon ingestion and cellular uptake.
Due to its unique structure, trehalose only breaks down into two reducing monosaccharides under extreme hydrolysis conditions, or in the presence of enzymes, while sucrose quickly decomposes when exposed to reactive amino groups. Trehalose has the ability to protect cellular membranes and labile proteins against damage and denaturation as a result of desiccation and oxidative stress. Trehalose appears to be the most effective sugar for protection against desiccation.
The most intensively studied mechanism of trehalose's biological actions in the context of disease is its ability to induce autophagy — the cellular "self-cleaning" process by which misfolded proteins and damaged organelles are degraded and recycled.
Trehalose is an mTOR-independent autophagy inducer. This natural compound has been acknowledged as an mTOR-independent autophagy inducer for its ability to promote the recruitment of LC3-II and the subsequent autophagosome formation, presumably via modulation of the AMPK/ULK1 pathway.
It has been proposed that trehalose can act as an autophagy inducer through an mTOR-independent pathway and enhances the clearance of aggregate-prone proteins like α-synuclein, mutant huntingtin, and prion protein (PrPSc). In a key report, trehalose induced autophagy in hepatocytes through an AMPK-dependent pathway, downstream of GLUT8. However, as the GLUT8 transporter is tissue-specific and neurons do not contain SLC2A8 (GLUT8) in their plasma membrane, this pathway may not occur in brain tissue.
In hepatocytes, the main target of trehalose is the activation of mTOR-independent autophagy, which is achieved by inhibiting the glucose transporter GLUT8, leading to energy deficiency. An increase in AMP levels activates AMP-dependent kinase AMPK by phosphorylation at Thr172 and further activates autophagy regulator kinase ULK1.
There are four main mechanisms for autophagy regulation in eukaryote cells: PI3K/Akt/mTOR, AMPK/ULK1/mTOR, Bcl-2/Beclin-1, and TFEB pathways. At present, most evidence suggests that trehalose can activate autophagy via each of these pathways, depending on the type of disease and cell.
Trehalose is considered a new candidate for the treatment of neurodegenerative diseases. It has a chaperone-like activity, prevents protein misfolding or aggregation, and by promoting autophagy, contributes to the removal of accumulated proteins. The neuroprotective effect of trehalose includes a chaperone-like effect, inhibition of the accumulation of aberrant proteins, reduction of oxidative stress, and increased antioxidant protection.
When ingested, trehalose is not assimilated as a disaccharide into the bloodstream. Rather, it is enzymatically hydrolyzed in the small intestine by a trehalose-specific disaccharidase into two D-glucose molecules, which are subsequently absorbed and metabolized. The same physiological processes are used to digest other common disaccharides like maltose, sucrose, and lactose. The disaccharidase specific for trehalose is called trehalase.
Trehalose increases blood glucose levels slowly and induces a slight insulin response. Trehalose and glucose are metabolized differently in the human body, as the glucose released from trehalose is taken up by different parts of the gastrointestinal tract than that of trehalose itself.
This is the area of most mature and clinically translated human evidence for trehalose. Trehalose protects against corneal damage due to desiccation. Trehalose has attracted increasing attention for its multifaceted biological properties, including antioxidant, anti-inflammatory, and osmoprotective effects. It has been shown to maintain cellular morphology, prevent oxidative damage, stabilize lipid membranes, and activate autophagy-related signaling pathways, all of which contribute to epithelial preservation and tear film homeostasis.
Clinical studies on trehalose 3% (Thealoz®) and the combination of sodium hyaluronate 0.15% and trehalose 3% (Thealoz Duo®) confirmed that these agents are valuable options in the management of dry eye disease, allowing protection, hydration and lubrication of the eye, and improving ocular symptoms and signs. The combination of sodium hyaluronate 0.15% and trehalose 3% (Thealoz Duo®) is well tolerated and safe for the treatment of dry eye disease.
Hyaluronic acid plus trehalose significantly reduced ocular surface damage and improved tear film stability after 84 days, as demonstrated by significant improvements in ocular staining, in the Schirmer's test, and in tear break-up time. Patient satisfaction was also increased, as demonstrated with higher overall treatment satisfaction scores from baseline to day 28 and after 84 days of treatment. This study supports the finding that hyaluronic acid plus trehalose is a safe and effective treatment for dry eye disease.
Evidence strength: Moderate to strong for ophthalmic applications. Multiple randomized controlled trials support trehalose-containing eye drops for dry eye disease. Products containing 3% trehalose have achieved regulatory approval in multiple markets. Ongoing phase 4 trials continue to characterize benefits in broader patient populations.
Human clinical evidence here is present but still limited in scale, and some studies have been conducted with potential conflicts of interest (sponsor-affiliated personnel as authors).
Several clinical contexts have been examined in small human trials. In healthy Japanese subjects, acute trehalose gavage increased blood glucose to a lesser extent than glucose gavage. Trehalose gavage acutely invoked a significantly lower insulin and plasma active gastric inhibitory peptide GIP response when compared with oral glucose gavage.
In a double-blind parallel treatment group comparison study, 34 healthy subjects (BMI > 23) fed 10 g/day trehalose over a 12-week period had a significantly lower peak serum glucose concentration during oral glucose tolerance testing compared with baseline. Stratified analysis of patients within this cohort who had increased truncal fat exhibited significant reductions in truncal fat, body weight, waist circumference, and systolic blood pressure after trehalose treatment.
In a separate randomized, double-blind, placebo-controlled study of healthy Japanese participants (n = 50), each consumed 3.3 g of trehalose (n = 25) or sucrose (n = 25) daily for 78 days. Body compositions were assessed following 0, 4, 8, and 12 weeks, and serum biochemical parameters and oral 75-g glucose tolerance tests were performed at baseline and after 12 weeks. The findings suggest that trehalose helps lower postprandial blood glucose in healthy humans with higher postprandial glucose levels within the normal range, and may therefore contribute to the prevention of pathologies predisposed to by postprandial hyperglycemia, even if the daily intake of trehalose is only 3.3 g.
Regarding type 2 diabetes specifically: In the first randomized dietary intervention trial to assess the anti-hyperglycemic effects of trehalose in patients with type 2 diabetes, 40 participants aged 35–85 years were enrolled in a parallel, double-blind, randomized, placebo-controlled clinical trial. CRP was significantly lower with trehalose treatment (–0.62 ±0.3 mg/l, p = 0.02); however, no differences in glycemic indices of fasting blood glucose, glycated hemoglobin (HbA1c), insulin, or insulin resistance (HOMA-IR) were seen. It showed that trehalose decreases CRP as a mediator of inflammation and there was an indication of overall quality of life being improved by trehalose supplementation. Whilst fasting blood glucose, insulin, insulin resistance, and HbA1c did not differ over the 12-week period, the change in CRP may, over a longer period, affect glycemic control and potentially diabetes-related complications.
The limitations of the study include that the participants were healthy volunteers and employees of Hayashibara Co. Ltd., the study sponsor. Further work is necessary to verify whether trehalose also improves glucose metabolism in patients with pre-diabetes.
Evidence strength: Preliminary. Small-scale human trials suggest modest favorable effects on postprandial blood glucose and insulin in healthy and overweight individuals. The evidence in established type 2 diabetes is weak, with the key pilot RCT showing no significant glycemic improvement over 12 weeks. Conflicts of interest in several studies warrant caution in interpreting results.
Trehalose has been reported to have neuroprotective effects in animal models of various neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Cellular aggregations of misfolded proteins are the most common pathological hallmark of many late-onset neurodegenerative diseases (proteinopathies).
The initial motivation for broad research on trehalose's therapeutic effect on neurodegeneration seems to be connected with successful alleviation of Huntington's disease (HD) in an animal model featuring the accumulation of aberrant cellular proteins. Trehalose inhibited the aggregation of polyglutamine proteins, weakened neurodegeneration, reduced motor failure, and extended mice's lifespan in the transgenic model of HD. Later, its ability to activate autophagy in cultured cells through the mTOR-independent pathway was discovered, and a neuroprotective effect on cell models of Parkinson's disease and HD was shown.
Trehalose has received attention for the past few decades for its role in neuroprotection, especially in animal models of various neurodegenerative diseases, such as Parkinson and Huntington diseases. The mechanism underlying the neuroprotective effects of trehalose remains elusive. The prevailing hypothesis is that trehalose protects neurons by inducing autophagy, thereby clearing protein aggregates. Some animal studies showed activation of autophagy and reduced protein aggregates after trehalose administration in neurodegenerative disease models, seemingly supporting the autophagy induction hypothesis.
Nevertheless, there is controversy surrounding the effect of trehalose on autophagy activation in Parkinson's disease treatment. Trehalose has been shown to exert neuroprotective effects by enhancing autophagy, mitigating oxidative stress, reducing neuroinflammation, and stabilizing cellular membranes, all of which are critical in slowing disease progression — though these effects have been observed primarily in preclinical models.
A systematic review conducted on animal studies of neurodegenerative diseases identified all animal studies that had used trehalose as a possible disease-modifying treatment using the Medline and Scopus databases. Studies included animal models of neurodegenerative diseases with trehalose as intervention and physiological or behavioral changes as outcome measures. Apart from blinding of outcome assessors, none of the studies reported randomization status, blinding of caregivers and researchers, random housing, or allocation concealment, which may increase the risk of false alarms.
Evidence strength: Preclinical (animal and cell culture) only for neurodegeneration at present. No published large-scale human clinical trials demonstrating efficacy in Alzheimer's, Parkinson's, or Huntington's disease have been identified. The body of animal evidence is substantial but methodologically limited, and translation to humans remains undemonstrated.
Trehalose reduced cardiometabolic disease burden in diet-induced and genetic models of atherosclerosis, dyslipidemia, hepatic steatosis, and insulin and glucose tolerance. The mechanism by which these effects occurred was pleiotropic and involved activation of fasting-like processes, including autophagic flux and transcription factor EB. This suggests that high peripheral bioavailability is not categorically required to exert clinically important metabolic effects.
In animal studies, 8-week trehalose treatment reduced hepatic triglyceride content and serum AST and ALT as markers of hepatocyte injury. In a high-fructose diet-fed model, oral trehalose (3% trehalose in water fed ad libitum) blocked fructose-induced hepatic triglyceride accumulation.
Trehalose inhibited atherosclerosis and attenuated hepatic steatosis in apoE-knockout mice. These effects were not associated with changes of plasma cholesterol, LDL, or HDL. The anti-steatotic action of trehalose in the liver was associated with the induction of autophagy. The exact molecular mechanisms of both the anti-atherosclerotic action and its inhibitory effect on liver steatosis require further clarification.
Trehalose has been identified to reduce hepatic steatosis and glucose intolerance, though its underlying mechanisms for NAFLD remain unclear. Results of one study indicated that trehalose supplementation ameliorated hepatocyte lipid deposition in vitro, as well as hepatic steatosis and hyperlipidemia in vivo, and mechanistically alleviated both autophagy flux dysfunction and endoplasmic reticulum (ER) stress.
Evidence strength: Animal and cell culture data are promising but no robust human clinical trials on trehalose specifically for NAFLD/MASLD have been reported in the literature reviewed.
A growing body of evidence suggests that due to its numerous favorable molecular effects, trehalose may exert beneficial effects in counteracting liver steatosis. Its antiatherosclerotic and antisteatotic properties have been attributed to the induction of autophagy. In a murine model of cardiac remodeling after acute ischemic insult, mice were treated with or without combined oral and intraperitoneal trehalose following left anterior descending arterial ligation. Trehalose-treated mice exhibited reduced left ventricular dilation and increased left ventricular systolic function after ligation compared with untreated mice.
Evidence strength: Preclinical only. Data derive exclusively from animal models. No human trials on cardiovascular endpoints have been published.
One study aimed to investigate the effect of trehalose on prolonged exercise performance in 12 healthy men (age 21.3 ± 0.9 years). Trehalose increases blood glucose levels slowly and induces a slight insulin response. Each participant ingested 500 mL water (control), 8% glucose, or 8% trehalose in three trials, which were at least one week apart and conducted in a double-blind and randomized crossover manner.
Evidence strength: Very preliminary. Single small crossover study. Insufficient to draw clinical conclusions.
In addition to potential therapeutic benefits, trehalose incorporated into diets can alter the composition of the human intestinal microbiota. In the human digestive tract, trehalose is metabolized by host-produced trehalase enzymes located at the intestinal brush border, as well as microbial-produced trehalases. Many intestinal bacteria and yeasts produce trehalase enzymes, including Bacillus spp., Escherichia coli, Blautia spp., Lactobacillaceae, and the nosocomial pathogen Clostridioides difficile.
In one in vitro colonic model study, the human microbiota remodeled to utilize bioavailable trehalose. While clindamycin induction caused simulated C. difficile infection (CDI) in models supplemented with either glucose or saline, trehalose supplementation did not result in CDI. The absence of CDI in the trehalose model was associated with enhanced abundances of Finegoldia, Faecalibacterium, and Oscillospira, and reduced abundances of Klebsiella and Clostridium spp., compared with the other models.
Evidence strength: Preliminary in vitro and animal model data. Microbiome interactions are complex and require further controlled human research.
Data support safe human consumption of trehalose in doses up to 50 g, and the physiologic ability of humans to digest it. No consistent treatment-related, dose-dependent adverse effects were observed in any of the eight safety studies performed at doses up to 10% of the diets. On the basis of these toxicity studies, human studies in which doses of trehalose were administered to various populations, and consumption of trehalose in commercial products in Japan, it is concluded that trehalose is safe for use as an ingredient in consumer products when used in accordance with current Good Manufacturing Practices.
A case of trehalose malabsorption causing intolerance to mushrooms was reported in a 71-year-old woman. The syndrome could be reproduced by ingestion of trehalose. The small variations of blood glucose during a trehalose tolerance test suggested very poor, if any, hydrolysis of trehalose. It was concluded that malabsorption of trehalose owing to a selective deficiency in intestinal trehalase could be the cause of this intolerance to mushrooms.
Trehalase values less than 5 U/g protein would likely result in intolerance to the ingestion of large amounts of trehalose. It appears that most humans are born with a three- to four-fold excess of intestinal trehalase activity. Trehalase deficiency is a rare but documented condition that can cause gastrointestinal symptoms (bloating, diarrhea, cramping) upon trehalose consumption, analogous to lactase deficiency in lactose intolerance.
Children and older adults have the same metabolic capacity to digest trehalose as do normal adults with intact intestinal anatomy.
Trehalose is used as an additive in thousands of foods, cosmetics, and pharmaceutical products. Its ability to be used as a carbon source by microbes is a concern, as highlighted by the finding that trehalose can be metabolized by and potentially enhance the virulence of epidemic Clostridioides difficile.
C. difficile ribotypes RT027 and RT078 have evolved efficient trehalose uptake and phosphotrehalase (TreA)-mediated breakdown pathways that enable growth on low concentrations of trehalose. The expansion of these strains in humans is proposed to have been driven in part by trehalose consumption, which escalated dramatically since trehalose received GRAS status from the FDA in 2000.
However, subsequent research has complicated this picture. Trehalose has been reported to enhance virulence of certain C. difficile ribotypes; however, such variants are widespread and not correlated with clinical outcomes for patients suffering from C. difficile infection. It has been reported that such variants are common in C. difficile isolates and comparison of the clinical outcome of CDI patients to trehalose metabolic genotype of the isolated strain found no correlation between 30-day mortality and the trehalose metabolic genotype. No statistically significant association between the presence of trehalose utilization variants in infecting C. difficile strains and the development of severe infection outcome was found.
In a study of high-dose intravenous trehalose administration, no increase in insulin levels was found. Short-term glycosuria was recorded, probably due to trehalase activity in the kidney. This effect appears specific to parenteral routes of administration.
Trehalose, in its dihydrate form, has 90% of the calorific content of sucrose. Consumers substituting trehalose for other sweeteners should account for its caloric contribution, particularly at the higher doses used in metabolic studies (10 g/day or more).
All authors of at least one key clinical study on trehalose and glucose homeostasis are employees of Hayashibara Co. Ltd., the study sponsor, which bore all costs of the trial. Independent replication of results in clinical populations by researchers without commercial ties to trehalose manufacturers remains limited.
Health conditions that Trehalose may help support.
Body systems that Trehalose may help support.
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