The gut and brain are in constant conversation, exchanging signals that regulate hunger and digestion, as well as the body's response to stress. But when that communication breaks down, the consequences can include chronic digestive disorders, which affect millions of people worldwide. 

Researchers at Lehigh University have developed one of the first comprehensive mathematical models of the neural circuitry that links the gut and brain to regulate stomach function. Described in an article recently published in Frontiers in Physiology, this digital twin could help researchers better understand disorders involving disrupted gut-brain communication and accelerate the development of therapies such as vagus nerve stimulation.

The gut-brain axis is a major area of interest in the medical community, but to date, there hasn't been a clearly defined mathematical model that captures how this communication loop functions quantitatively. Our work represents one of the first systematic approaches to building a digital twin that allows researchers to simulate that behavior." 

Mayuresh Kothare, co-author, R. L. McCann Professor of Chemical and Biomolecular Engineering and associate dean for research in Lehigh's P.C. Rossin College of Engineering and Applied Science

The gut-brain axis is the bi-directional highway in which electrical signals travel back and forth carrying messages. Signals from the gut help the brain monitor physical states such as hunger and satiety, while those from the brain influence digestion and respond to factors such as stress and emotion. The steady communication of these systems regulates healthy digestive function. 

When gut-brain communication breaks down

When that communication is disrupted, disorders of gut-brain interaction (DGBI)-including irritable bowel syndrome, gastroparesis, and functional dyspepsia-can cause chronic nausea, bloating, and abdominal pain that significantly affect quality of life. The National Institutes of Health estimates that globally up to 40 percent of adults experience at least one of these disorders, yet treatments often provide limited relief.

Because the vagus nerve serves as one of the primary communication pathways between the brain and digestive system, it has emerged as a target for neural stimulation therapy. By delivering carefully controlled electrical impulses to activate nerves, researchers hope to restore healthy signaling patterns.

"Our digital twin is like a virtual stomach that helps us understand what happens when signaling is disrupted and why," says lead author Shannon Q. Fernandes PhD'26, now a research scientist developing controlled drug delivery systems at AbbVie, a global biopharmaceutical company. "Ultimately, it could help researchers develop more effective neural stimulation therapies." 

A digital twin for testing future therapies

The project was funded by NIH through its Stimulating Peripheral Activity to Reduce Conditions (SPARC) program, which supports software and modeling tools designed to optimize neurostimulation therapies. This growing field, known as bioelectronic medicine, seeks to treat disease by using targeted electrical stimulation of the peripheral nerves. 

One potential neurostimulation treatment, for example, could involve battery-powered electrodes. Surgeons would implant them on a nerve and then inject a current to change the signaling of that nerve.

"Studying that would require extensive animal studies followed by human trials, which are both expensive and time-consuming," says Kothare. "If you have a digital twin that accurately represents the biological system, you can test different strategies virtually before moving into experiments. Models like ours help researchers focus on the approaches most likely to succeed while reducing the number of experiments needed."

Kothare and his collaborators are now exploring additional directions for the research. One goal is to develop algorithms that determine the precise level of electrical stimulation needed to restore healthy signal function. Another is to investigate a nonsurgical therapy method.

"One promising approach involves a small device worn in the ear that delivers electrical stimulation," he says. "Those signals actuate the auditory system, which is connected to the gut-brain axis. This could be a noninvasive way to treat these gastrointestinal conditions and improve quality of life."

Source:

Journal reference:

Fernandes, S. Q., & Kothare, M.V. (2026) A compartmental model for simulating the gut-brain axis in gastric function regulation. Frontiers in Physiology. DOI: 10.3389/fphys.2026.1727491. https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2026.1727491/full