Scientists May Have Finally Found the “Holy Grail” of Sugar Substitutes

Scientists have created a new way to make a rare sugar that tastes almost identical to table sugar but comes with far fewer health drawbacks.

The result is a sweetener with fewer calories, minimal impact on blood sugar, and potential benefits for oral and gut health. It could offer a long-sought alternative to traditional sugar.

A Century-Long Search for Better Sweetness

For generations, scientists and food companies have been trying to recreate the taste of sugar without the health problems that come with it. From saccharin in the 19th century to newer alternatives like stevia and monk fruit in the 21st, the goal has been to keep sweetness while reducing excess calories, tooth decay, and the growing risks of obesity, insulin resistance, and diabetes.

Researchers at Tufts University now report progress toward that goal. In a study published in Cell Reports Physical Science, the team describes a new biosynthetic method for producing tagatose, a naturally occurring but very rare sugar. Tagatose closely resembles table sugar in taste and could offer a way to sweeten foods with fewer negative effects. Scientists say it may also come with additional health benefits.

Where Tagatose Is Found Naturally

Compared with common sugars such as glucose, fructose, and sucrose, tagatose exists only in tiny amounts in nature. It appears in milk and dairy products when lactose is broken down by heat or enzymes, a process that occurs during the production of foods like yogurt, cheese, and kefir.

Small traces of tagatose are also present in fruits such as apples, pineapples, and oranges. Even so, it usually accounts for less than 0.2% of the sugars found in these foods. Because natural sources contain so little of it, tagatose is typically produced through manufacturing rather than extracted directly for use.

Why Making Tagatose Has Been Difficult

“There are established processes to produce tagatose, but they are inefficient and expensive,” said Nik Nair, associate professor of chemical and biological engineering at Tufts.

To overcome those limitations, the research team developed a new approach that relies on genetically engineered bacteria. “We developed a way to produce tagatose by engineering the bacteria Escherichia coli to work as tiny factories, loaded with the right enzymes to process abundant amounts of glucose into tagatose. This is much more economically feasible than our previous approach, which used less abundant and expensive galactose to make tagatose.”

Turning Glucose Into a Rare Sugar

The modified bacteria were designed to carry a newly discovered enzyme from slime mold known as galactose-1-phosphate-selective phosphatase (Gal1P). This enzyme allows the bacteria to convert glucose directly into galactose. A second enzyme produced by the bacteria, called arabinose isomerase, then completes the transformation by converting galactose into tagatose.

Using this process, the bacteria can produce tagatose from glucose with yields reaching up to 95%. That is a major improvement over conventional manufacturing methods, which typically achieve yields between 40 and 77%. The higher efficiency also makes the process far less costly.

Sweetness, Calories, and Food Safety

Tagatose provides about 92% of the sweetness of sucrose — table sugar — while containing roughly 60% fewer calories. It has been classified by the FDA as “generally recognized as safe,” meaning it can be used in consumer food products. This designation is the same one applied to common ingredients such as salt, vinegar, and baking soda.

Effects on Blood Sugar and Gut Bacteria

One reason tagatose may be helpful for people with diabetes is how the body processes it. Only part of the sugar is absorbed in the small intestine, while much of it is fermented by gut bacteria in the colon. Because of this, tagatose causes much smaller increases in blood glucose and insulin levels than conventional sugar. Clinical studies have shown very low rises in plasma glucose or insulin after people consume tagatose.

Tagatose may also support oral health. Unlike sucrose, which feeds bacteria that contribute to cavities, tagatose appears to slow the growth of some of those microbes. Research also suggests it may have probiotic effects that support healthier bacteria in both the mouth and the gut.

A Sugar That Works in Cooking and Baking

Because it is low in calories and poorly absorbed by the body, tagatose functions well as a “bulk sweetener.” This means it can replace sugar not only for sweetness but also for the physical structure sugar provides in cooking and baking. High-intensity sweeteners cannot replicate this effect. Tagatose browns during cooking just like table sugar, and taste tests show it comes closer to sugar than other sweeteners.

Why This Breakthrough Matters

“The key innovation in the biosynthesis of tagatose was in finding the slime mold Gal1P enzyme and splicing it into our production bacteria,” said Nair. “That allowed us to reverse a natural biological pathway that metabolizes galactose to glucose and instead generate galactose from glucose supplied as a feedstock. Tagatose and potentially other rare sugars can be synthesized from that point.”

The researchers say this strategy could make it possible to produce other rare sugars more efficiently, potentially reshaping how sweeteners are developed and used in the future.

Reference: “Reversal of the Leloir pathway to promote galactose and tagatose synthesis from glucose” by Aaron M. Love, Christopher G. Toomey, Abhishek Kumar, Sukesh Narayan Kashyap, Dhinesh Kumar Santhamoorthy, Likith Muthuraj, Hannah L. Lynch, Parayil Kumaran Ajikumar, Pravin Kumar R., Nikhil U. Nair and Christine N.S. Santos, 11 December 2025, Cell Reports Physical Science.
DOI: 10.1016/j.xcrp.2025.102993

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