An ingestible vibrating pill identified relapse risk in weight-restored patients with anorexia nervosa (AN).

The researchers used an ingestible vibrating capsule to probe gut sensation and identify interoceptive markers associated with relapse risk in weight-restored patients with AN.

The technology provides an objective way to measure gastrointestinal interoception — the nervous system’s ability to detect and interpret signals from the gut — which has been implicated in AN but has been difficult to assess.

In a crossover trial, investigators enrolled 62 females with weight-restored restrictive AN and 57 healthy control participants. Participants underwent testing with the vibrating capsule while researchers assessed behavioral, physiologic, neural, and computational measures of gastrointestinal interoception.

Participants with AN were significantly less accurate at detecting normal-intensity gut vibrations. Computational modeling revealed that they held stronger expectations that no gut sensation would occur and were slower to update those expectations when sensations were present, suggesting a self-reinforcing perceptual bias that persisted even after weight restoration.

People with AN not only have difficulty detecting signals from the stomach but also seem less able to learn from the signals they do perceive, making it harder to update their expectations about gut sensations, said study investigator Sahib Khalsa, MD, PhD, director of anxiety disorders research and associate professor in residence at the Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.

The study was published online on June 17 in JAMA Psychiatry.

Gut-Brain Knowledge Gap

AN carries one of the highest mortality rates of any psychiatric disorder, and relapse rates approach 50% within a year of weight restoration. While restoring body weight remains a central treatment goal, many patients continue to struggle after reaching a healthy weight. However, clinicians lack objective tools to identify who is most vulnerable to relapse.

Interoception has long been implicated in AN, but most research has focused on cardiac and respiratory signals. Far less was known about gastrointestinal interoception, despite its direct relevance to hunger, satiety, and the visceral discomfort patients commonly report.

Khalsa said the findings suggest that disrupted gastrointestinal interoception may represent one mechanism that helps sustain AN and that objective measures of gut perception could provide new insights into the disorder. “The diagnostic symptoms in the DSM [Diagnostic and Statistical Manual of Mental Disorders] describe the illness, but they do not reveal the mechanisms that sustain it.”

“Colleagues would sometimes ask me: these are eating disorders, so why are you studying the heart and lungs instead of the gut?” Khalsa said. At the time, existing methods for studying gut perception in AN were “universally invasive,” so the team had to develop a practical, noninvasive way to study how the brain processes these signals.

The diagnostic symptoms in the DSM describe the illness, but they do not reveal the mechanisms that sustain it. What this study suggests is that abnormal gastrointestinal interoception is likely an underlying mechanism of this disorder — not the sole mechanism, but an important one.

Testing Gut-Brain Signaling

To determine whether gastrointestinal interoception could serve as an objective marker of relapse risk in AN, the researchers developed an ingestible vibrating capsule to noninvasively probe gut-brain signaling.

The study included females aged 13-40 years with weight-restored restrictive AN (BMI ≥ 18.5) from the Laureate Eating Disorder Program inpatient unit in Tulsa, Oklahoma, along with age- and sex-matched healthy control participants. The mean age of participants with AN was 18.9 years; 69% had comorbid anxiety, 37% had major depressive disorder, and 92% were taking psychiatric medication.

Each participant swallowed the capsule and received two counterbalanced blocks of approximately 60 vibrations, one at normal intensity and the other at enhanced intensity.

All participants pressed a button when they detected a vibration and released it when the sensation stopped, while EEG and other physiologic signals were recorded simultaneously. Before and after the task, participants rated hunger and other bodily sensations.

Individuals with AN ate lunch at noon on the inpatient unit, completed the capsule session at approximately 4 PM, and returned for dinner at 5 PM, placing them in a pre-meal fasting window during stimulation. Healthy control participants followed the same 3-hour fasting protocol.

Responses were analyzed using a Bayesian computational model that estimated underlying perceptual processes, including prior beliefs, the reliability assigned to incoming gut signals, and learning rates, all which weren’t visible in the button-press data alone.

During normal-intensity stimulation, participants with AN were significantly less accurate at detecting gut vibrations (P = .001) and had higher miss rates (P < .001) than healthy control participants. At enhanced intensity, the groups performed similarly, suggesting that the ability to perceive gut signals remained intact when the stimuli were sufficiently strong.

Among the 54 participants who completed the 6-month follow-up, 16 relapsed. Baseline computational measures were associated with relapse risk: stronger initial prior beliefs (odds ratio [OR], 3.82; P = .05), greater response bias (OR, 5.37; P = .04), and higher self-reported stomach unpleasantness (OR, 5.73; 95% CI, 1.38-33.5; P = .03).

Early but Promising Findings

Greater eating disorder symptom severity at follow-up was associated with a higher miss rate (P = .05) and larger differences in interoceptive precision between normal- and enhanced-intensity stimulation (P = .004).

First author Charles Verdonk, MD, PhD, of the Laureate Institute for Brain Research in Tulsa, Oklahoma, and Université Paris Cité, VIFASOM in Paris, France, explained that raw task performance — such as whether participants pressed the button correctly — did not by itself predict relapse.

“You could discriminate between two groups that could not be found if you focus on basic data alone,” Verdonk told Medscape Medical News.

He cautioned that it is too early to draw clinical conclusions. “It’s not because you feel your body better that you necessarily will implement adaptive behavior. Our findings are an early but promising step toward biomarker development, rather than something ready for routine clinical use,” he said.

Khalsa agreed. “We currently don’t have any objective measures beyond body mass index for diagnosing AN. We also don’t have any way to connect AN symptoms to communication between the gut and the brain on an ongoing basis.”

The study was limited by its female-only sample of patients with the restrictive subtype of AN, single-site recruitment, and a relatively short follow-up period of 6 months, although definitions of recovery often require at least 1 year of sustained improvement.

The longitudinal sample was also modest, and CIs for several relapse predictors were wide, highlighting the need for replication in larger, more diverse cohorts.

Verdonk said the findings suggest that physiologic recovery may lag behind clinical recovery.

“The result from this study takes us a meaningful step forward toward such a clinical test,” he said.

Khalsa noted that the vibrating capsule is already FDA cleared for treating chronic idiopathic constipation, although its use as a biomarker for AN remains investigational.

An Overlooked Connection

The findings highlight a gap in how anorexia is currently treated, said Nancy L. Zucker, PhD, professor of psychiatry and behavioral sciences at Duke University in Durham, North Carolina, whose research focuses on visceral processing and body-based aspects of eating disorders, commenting for Medscape Medical News.

“Our treatments for anorexia are missing the boat,” said Zucker, who was not involved in the study. “We just do not have enough somatically focused intervention strategies.”

Zucker said the study’s central contribution is linking disrupted gut sensing to relapse risk, providing a biological marker for something clinicians have long observed but lacked tools to measure.

“This is a way to biologically mark a lack of trust in one’s body, and the profound implications that has for psychological well-being,” she said.

She noted the finding that patients could detect gut signals at higher intensity but not at normal levels may itself be clinically meaningful.

“Trust is about reliability. If there are some conditions where you can read your body and some where you can’t, the overall reaction is, ‘I’m not going to trust it,’” she said.

Zucker added that the research points to the need for treatments that go beyond weight restoration and cognitive behavioral approaches to include somatic components, teaching patients to reconnect with and respond to bodily signals.

The study was funded by the National Institute of Mental Health, the William K. Warren Foundation, and the Laureate Institute for Brain Research. Disclosure information for study authors is available in the original study publication. Zucker reported no relevant financial relationships.