Fluorescent images show stomach-injected AAV drives transgene expression in the NTS, and activating vagal sensory neurons increases c-Fos–positive cells there.
A new study from Weill Cornell Medicine demonstrates a novel approach to modifying eating behavior by precisely targeting neural circuits that connect the gastrointestinal tract and the brain. The findings, based on preclinical mouse models, advance understanding of gut–brain signaling and may inform future research into obesity and metabolic disorders.
The study, published in Scientific Reports by Springer Nature, highlights the collaborative work of Drs. Michael Kaplitt and Roberta Marongiu, whose expertise in molecular neuroscience and gene therapy based neurosurgical innovation enabled the approach.
Targeting Stomach‑Innervating Neurons With Precision
Sensory nerve fibers of the vagus nerve carry critical information about fullness and digestive state from the gastrointestinal tract to the brainstem. While the vagus nerve plays a central role in appetite regulation, its sensory pathways have historically been difficult to target with precision.
In this study, researchers developed a modified retrograde adeno‑associated virus vector and delivered it directly into the stomach wall. This approach allowed the vector to selectively deliver genetic instructions only to sensory nerve cells connecting the stomach to the brain without affecting vagal pathways serving other organs.
Roberta Marongiu, PhD
The targeted nerve cell bodies reside in the nodose ganglion, a small cluster of neurons at the base of the skull that acts as a relay station between the gut and the brainstem.
Using this method in mice, the team expressed a chemogenetic receptor that enabled controlled activation of these stomach‑innervating neurons. Acute activation suppressed food intake by more than 50 percent and triggered robust neuronal activity in brain regions involved in appetite regulation including the nucleus tractus solitarius and hypothalamic nuclei.
Chronic Stimulation Reduces Diet‑Induced Weight Gain
When activation of this gut–brain pathway was applied chronically during high‑fat feeding, mice exhibited nearly a 40 percent reduction in diet‑induced weight gain. These findings demonstrate that organ‑targeted gene delivery can exert sustained effects on complex behaviors such as feeding without the need for invasive brain surgery.
Clinical Context: Understanding the Gut–Brain Axis
Dr. Carolyn Newberry, associate professor of clinical medicine and director of nutrition services in the Division of Gastroenterology and Hepatology at Weill Cornell Medicine, said the findings underscore the importance of communication between the gastrointestinal tract and the brain in regulating appetite and body weight.
“One of the key ways the body regulates satiety is through stretch‑sensing receptors in the gastrointestinal tract that signal fullness to the brain via the vagus nerve,” Dr. Newberry said. “Sensitivity to these signals can vary among individuals, which may help explain differences in appetite regulation and weight gain.”
Despite advances in lifestyle interventions and medication‑based therapies, long‑term management of obesity and metabolic disorders remains challenging.
“Even with newer gut‑derived hormone therapies, not all patients respond to or tolerate current treatments,” she said. “Developing additional and more precise targets for appetite regulation could help move the field toward more individualized approaches to metabolic disease.”
Dr. Newberry emphasized the importance of interdisciplinary collaboration.
“Only through strong collaboration between neuroscience neurosurgery and gastroenterology will we be able to better understand the gut–brain axis and address the complex biological factors contributing to metabolic disease,” she said.
Collaborative Innovation in Gene Therapy and Neuroscience
Dr. Kaplitt, executive vice chair and professor of neurological surgery at Weill Cornell Medicine and director of the Movement Disorders and Pain Program, noted that the study builds on decades of progress in viral vector based therapies.
Michael Kaplitt, MD
“Our findings show that organ‑specific gene delivery can be used to modulate complex behaviors like feeding in a controlled and reversible manner,” Dr. Kaplitt said. “The ability to regulate specific neuronal populations governing individual organ function has significant therapeutic potential.”
Dr. Marongiu, assistant professor of genetics and neuroscience in the Department of Neurological Surgery and the study’s lead author, emphasized the translational significance of the work.
“This approach allows us to reversibly control visceral sensory pathways with a level of precision that has not previously been possible,” she said. “It opens new avenues for studying and potentially treating disorders driven by dysregulated gut–brain signaling.”
Dr. Marongiu continues to investigate the molecular mechanisms underlying sex differences in neurological disorders including Parkinson’s disease and Alzheimer’s disease. She also co‑founded stoPD, a nonprofit organization focused on education and quality of life initiatives for individuals living with Parkinson’s disease.
Study Authors
In addition to Drs. Kaplitt and Marongiu, the study was authored by Jingjing Wang, Santiago R. Unda, Julie Barbera, Leandra Velazquez, Rosemary Li, Maria Jimenez Gonzalez, William Tower, Neranjan de Silva, Rachel Retik and Sarah A. Stanley.