Trial Targets the Vagus Nerve as a Treatment for Ulcerative Colitis

A new study published in Bioelectronic Medicine has investigated vagus nerve stimulation (VNS) as a new treatment for Crohn’s disease and ulcerative colitis.

The small proof-of-concept study explored how VNS applied through the ear reduced the symptoms of these stubborn diseases, while also investigating how the treatment altered a promising diagnostic biomarker called fecal calprotectin (FC). While the study produced some hopeful results, the trial’s small size means further research will be required to determine whether VNS could help relieve these conditions’ painful symptoms.

The study was organized by researchers at the Feinstein Institutes and Northwell Health’s Steven & Alexandra Cohen Children’s Medical Center.

A gut feeling

Crohn's disease and ulcerative colitis are long-lasting conditions. In both diseases, the gastrointestinal tract becomes inflamed, resulting in abdominal pain, diarrhea and fatigue. The two conditions are the main types of inflammatory bowel disease (IBD). Together, they affect an estimated three million US adults. IDB rates have surged over the 21^st century. While some of that increase is likely due to improved diagnostics, effective treatments are desperately needed.

The vagus nerve has become a hot target of so-called bioelectronic medicine. This electrical highway connects the brain to other major organs. Through its control of the parasympathetic nervous system, the vagus nerve regulates involuntary bodily functions, like digestion and heart rate. Modulation of the nerve is thought to also play a role in the body’s immune response. “In the case of an inflammatory disorder, the effect of this therapy is to reduce signals of inflammation in the tissue,” said lead author Benjamin Sahn, who is co-director of the Pediatric Inflammatory Bowel Disease Center at Cohen Children’s Medical Center.

The trial enrolled 22 volunteers with mild-to-moderate IBD. All were 10–21 years old. They were all tested for levels of FC in their feces. This protein is thought to be an indicator of intestinal inflammation.

In-ear stimulation

The study happened over two phases. In phase one, the cohort was given either VNS or sham stimulation. The participants didn’t know which treatment they had received. The type of VNS used in the trial is called transcutaneous auricular vagus nerve stimulation (ta-VNS). This technique uses an electrical unit with sensor probes inserted into the left ear, where the vagus nerve is easily accessible. The technique is thought to be an effective but far less invasive alternative to electrical implants placed under the skin.

Over the first four weeks, each group received two weeks’ worth of real stimulation. One half began with two weeks of sham stimulation and the other began with real VNS before both groups switched. Only 12 of the initial 22 volunteers were found to have high clinical scores at the start of the study, while only 17 had high FC levels.

Of the 12 patients with high clinical scores, 6 had Crohn’s disease and 6 had ulcerative colitis. In the first two weeks, four of these patients receiving VNS responded to the treatment with a reduction in symptoms. However, two patients receiving the sham treatment also responded. There was a mixed response among patients who had low clinical scores, with most not responding to the treatment.

FC levels were also analyzed during this period. After two weeks, levels of this inflammatory marker decreased in both groups. But in the second two-week period, FC levels jumped in people who switched from treatment to sham stimulation, while the other group’s FC levels declined. The small group size here made it hard to identify the significance of this change.

Achieving remission

Over the study’s remaining 12 weeks, all volunteers were given true VNS. At the end of the trial, 5 of 12 of the volunteers with mild to moderate disease had achieved clinical remission. One patient’s symptoms got worse over the course of the trial. Sahn said these results “met and exceeded our expectations.” He said that more research would be needed to tease out the fine points of the data – children with ulcerative colitis appeared to have a slightly faster symptom reduction, but the reasons why remain unclear.

He added that the patients benefiting from a potential VNS treatment would likely need a long-term solution: “We typically see relapses when medications are withdrawn, so we would expect vagus nerve stimulation to follow the same paradigm and be needed on an ongoing basis to remain effective.”

Sahn said the next steps would involve studying ulcerative colitis and Crohn’s disease separately. “We currently have an open clinical trial for children and adults aged 10-39 with ulcerative colitis. We hope soon to have a trial of those with Crohn’s disease as well,” he concluded.

Reference: Sahn B, Pascuma K, Kohn N, Tracey KJ, Markowitz JF. Transcutaneous auricular vagus nerve stimulation attenuates inflammatory bowel disease in children: a proof-of-concept clinical trial. Bioelectronic Medicine. 2023;9(1):23. doi:10.1186/s42234-023-00124-3