July 22, 2026 | Digestive sensations profoundly affect mental health through the bidirectional gut-brain axis, and in the case of anorexia nervosa (AN) tends to do so at crisis proportions. The disorder has one of the highest mortality rates of any psychiatric disorder with suicide being the leading cause of death, according to Sahib Khalsa, M.D., Ph.D., psychiatrist and neuroscientist who serves as director of anxiety disorders research and associate professor in residence at the UCLA Semel Institute for Neuroscience and Human Behavior.
Over the past two decades, research has confirmed that gastrointestinal signaling plays an important and previously underappreciated role in the onset of AN and the high rates of relapse, he points out, meaning it has complex biological roots that actively shape disease severity and recovery. Khalsa’s work leverages an ingestible, vibrating capsule technology that is FDA-cleared for treating chronic idiopathic constipation in a study that recently found it helpful to predict the risk of AN relapse and symptom severity (JAMA Psychiatry, DOI: 10.1001/jamapsychiatry.2026.1301).
This latest crossover trial, funded by the National Institute of Mental Health, provides evidence that disruptions of gastrointestinal interoception, the nervous system’s process of sensing and interpreting internal signals from the digestive tract, may provide scalable biomarkers to personalize treatment and prevent recurrence, says Khalsa. Up to 50% of AN patients will relapse in the year or two following their first inpatient discharge for many possible and often unknown reasons.
Recovery from AN is defined as a symptom-free period of more than one year, he says, noting that inpatient hospitalization itself can take two to three months. The lengthy requirement is tied to the recognition that the processes that generate the disease are slow and persistent and that it takes substantial effort to ensure AN symptoms and behaviors have either receded or reversed.
For some people, the struggle around eating can be lifelong, persisting many years beyond even a single hospitalization, says Khalsa. The diagnostic criteria for AN, in addition to disrupted interoception, includes low body weight, fear of food, and abnormal body image, the last of which is well known to continue for many years in some people even after they have redeveloped normal body weight and eating habits.
The suggestion here is that many people may never truly recover because they “still see themselves and relate to their bodies in ways that are very different from non-affected populations,” he adds. Khalsa’s theory is that interoception and abnormal body image are related through a region deep in the brain called the insular cortex, serving as a crucial neurobiological bridge (Current Topics in Behavioral Neurosciences, DOI: 10.1007/7854_2025_581).
For the latest study, Khalsa and his team recruited 62 women and girls, ages 13 to 40 years old, hospitalized with AN whose weight had been restored to healthy levels and 57 healthy controls. Participants swallowed a capsule producing gentle sensations of varying intensity, which researchers could remotely control, and were then asked to press a button when they felt the vibration in their stomach. Their brain, heart and stomach rhythm activity were simultaneously monitored, and participants self-reported their hunger levels. The anorexia group also received follow-up evaluations for six months post-discharge.
The data were analyzed using a computational model designed to estimate how strongly participants expected to feel stomach sensations, how much their brains relied on incoming bodily signals and how quickly they updated their expectations when signals were present or absent, he reports. Relative to healthy individuals, AN participants were less accurate at detecting subtle stomach sensations, more likely to believe that no sensation was occurring even when the pill was vibrating, and slower to revise those expectations when stomach signals were present. Several of these gut-brain measures were associated with relapse risk during the six-month follow-up period.
What was demonstrated here was the capability of using non-pharmacologic devices to both make diagnostically relevant distinctions between patients and prognostic inferences about future health states in eating disorders, says Khalsa. The approach could possibly also be deployed for other disorders of gut-brain interaction such as irritable bowel syndrome and functional dyspepsia, which is another planned avenue of exploration for his lab.
Anorexia nervosa affects women 10 times more than men, says Khalsa, in explaining the patient pool for the latest study. Participants were also recruited from a single treatment center, the Tulsa, Oklahoma-based Laureate Eating Disorders Program, which exclusively treats females.
It was not difficult finding people to volunteer for the study, he adds. In his experience, most AN patients aren’t averse to the idea of participating in research studies.
The disorder often strikes around the peripubertal period when hormones start changing, particularly in females, he notes. “It’s not uncommon for that diagnosis to emerge ... in the early teens as well as the early 20s.”
Emerging genetic studies have identified some hormones associated with metabolic signaling and energy regulation, Khalsa says, suggesting AN is not necessarily just a brain-gut disorder. These notably include peptides linking digestive states to brain decision-making, and estrogen-related receptors driving mitochondrial energy production body-wide.
‘Dark Matter’ of the Body
Clinical lifetime prevalence of AN in the United States is less than 1% of the general population, but in terms of the impact over a lifetime the condition is on par with disorders such as schizophrenia and autism, says Khalsa. Suicide is one of the major causes of mortality, but there are also deaths related to medical causes associated with self-starvation.
The latter cause of death, intended or otherwise, is the result of a “self-sustained maladaptive process,” he says, getting back to the chronic and unrelenting nature of the condition. Patients with anorexia who die by suicide often have either a higher degree of symptom severity or a longer duration of depressive episodes.
While the concept of interoception was introduced 120 years ago, it remains poorly understood how the brain helps maintain balance within the body, says Khalsa, who views the process as “dark matter” of the body because it operates largely in the unconscious shadows. His interest in studying the complex sensory phenomenon in relation to AN began during his residency training both because it was understudied in scientific circles, and the condition didn’t respond particularly well to existing, evidence-based treatments.
The condition was first identified in the English language and named “anorexia nervosa” about 150 years ago in London, he continues. Much of the initial “phenomenology,” or lived experience of patients, included interoceptive dysfunctions such as premature fullness when eating small amounts of food or abdominal bloating, cramping, or discomfort, all of which are included in the current description of the illness in the Diagnostic and Statistical Manual of Mental Disorders published by the American Psychiatric Association, but as associated features rather than diagnostic criteria.
In terms of the theoretical tie between interoception and body image, several years ago Khalsa led a randomized controlled trial demonstrating the efficacy of flotation-REST (reduced environmental stimulation therapy), a form of sensory deprivation, in both reducing anxiety and improving visual perception of body size among people with AN (eClinicalMedicine, DOI: 10.1016/j.eclinm.2023.102173). “If you can’t sense the internal body, perhaps you become more fixated and reliant on features in the outer world,” he reasons, so that “by balancing those signals you might actually be able to improve interoception and external body image perception.”
Social media has certainly had an impact, says Khalsa, citing rising rates of AN during the pandemic linked to visual content consumed on platforms like Instagram. But it’s not causative. Prior to the social media era, the triggering stimuli for people with anorexia could have been going on a crash diet to fit into a dress, a comment about how they looked, or pressures during sports such as gymnastics or cross-country training to fit the ideal body for that specific athletic activity. There is no singular starting point for the eating disorder.
The most obvious repurposing potential for the vibrating pill in treating AN patients is to accelerate relapse prevention efforts, Khalsa says. But it might have an additional therapeutic use since, unexpectedly, the capsule also disproportionately increased reports of hunger sensation in people with AN versus healthy controls.
“One question I would have, and I’m interested in studying, is might you be able to use mechanosensory stimulation with these capsules to help individuals with AN become more sensitive to their hunger cues,” says Khalsa. According to this logic, the vibrating pill might be used before a meal to stimulate the gut, helping hospitalized patients learn to more readily recognize hunger sensations.
This would be a form of interoceptive feedback where they would be “oriented to those signals” with the guidance of a therapist, he explains. “They wouldn’t leave the hospital or treatment program always swallowing capsules in order to feel hunger; it would be a way for them to learn to respond to their natural hunger state.”
Next steps include seeking renewal of funding for this line of research, Khalsa says, noting the paucity of research funding for anorexia nervosa and eating disorders in general relative to other disorders with similar prevalence rates. AN is one of the most studied conditions in a family of disorders that also includes bulimia nervosa, binge-eating disorder, and “other specified feeding and eating disorder,” or OSFED—the category into which most people fall, he adds.
Among people with anorexia or bulimia nervosa, it is not uncommon over time for people to switch categories, raising the question about whether eating disorders share a fundamental abnormality. “One of my perspectives is that abnormal gastrointestinal interoception in one form or another may be a major contributor to most if not all the eating disorders,” says Khalsa. “It is really an overlooked and underexplored facet.”
Most immediately under consideration is how best to translate the use of ingestible mechanosensory probes and computational modeling into real-world healthcare. The potential beneficiaries include not only hospitalized patients to prepare for discharge but also the larger group of people already in the community living with anorexia to better predict relapse risk.
Khalsa and his team also plan to expand their scope of inquiry by looking at males with anorexia nervosa as well as patients located at multiple sites across the country. The technology still needs to be improved to make it suitable for everyday treatment settings, he notes. The electroencephalography techniques previously employed in the research environment require a sophisticated setup to precisely capture neural signatures of gut sensations. A future goal is to develop this technology into a simpler clinic-based application.
Khalsa and his team also hope to explore use of the vibrating capsule to study the effects of GLP-1 weight loss drugs. Specifically, they are seeking grant funding to learn how signaling between the body and the brain changes in response to a rapid reduction in adiposity.