Researchers at the Shanghai Academy of Natural Sciences have developed an engineered probiotic that detects elevated glucose in the gut and responds by secreting glucagon-like peptide-1 (GLP-1), a hormone that stimulates insulin release. The system, named GIFT (glucose-responsive insulinotropic factor therapy), is built into the harmless gut bacterium Escherichia coli Nissle 1917.
The bacteria carry a synthetic gene circuit controlled by the sensor protein HexR. In the absence of glucose, HexR binds a promoter and keeps GLP-1 production off. When glucose enters the bacterial cell, metabolism converts it to KDPG, which binds HexR and releases the promoter, switching on GLP-1 synthesis. The microbes are coated with FDA-approved tannic acid and poloxamer 188, extending their intestinal residence from 8 to 36 hours in mice.
In diabetic mice given daily doses for 30 days, GIFT activated only when blood sugar rose above a normal threshold and shut off as glucose returned to healthy levels. The treatment abolished persistent hyperglycemia, reduced fat mass and weight gain, lowered triglycerides and total cholesterol, and showed protective effects on liver and kidney function.
In naturally diabetic monkeys, a single oral dose boosted insulin and maintained glycemic control for up to three days. A five-week regimen of dosing every three days restored healthy blood sugar balance, significantly reduced insulin resistance, and improved cholesterol profiles.
Direct comparison with the GLP-1 receptor agonist semaglutide showed differences in safety and body composition. Mice receiving semaglutide plus insulin experienced more hypoglycemia, while the probiotic combination reduced that risk. Over two months, semaglutide-treated mice lost lean muscle mass, whereas GIFT-treated mice preserved or slightly increased lean muscle.
The approach represents a self-regulating therapy that delivers hormone only on demand, potentially avoiding the constant high exposure associated with injected GLP-1 drugs. Because the treatment uses a genetically modified organism, translation to human use will require safety trials, stability testing, and regulatory approval.
The study was published in Nature (DOI: 10.1038/s41586-026-10909-6) by Ningzi Guan and colleagues.
Smart probiotics can sense high blood sugar and release GLP-1 on demand
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