By Deborah Burwitz
Gastrointestinal sensations profoundly impact mental health through a bidirectional gut-brain axis, and in the case of anorexia nervosa (AN) it tends to do so in crisis proportions. The disorder has one of the highest mortality rates of any psychiatric disorder, with suicide being the leading cause of death, said Sahib Khalsa, M.D., Ph.D., a psychiatrist and neuroscientist who serves as director of anxiety disorders research and associate professor in residence at the Semel Institute for Neuroscience and Human Behavior at UCLA.
Over the past two decades, research has confirmed that gastrointestinal signaling plays an important, previously unappreciated role in the onset of IBD and high relapse rates, he points out, meaning it has complex biological roots that effectively shape disease severity and recovery. Khalsa works to take advantage of an easily digestible substance. Vibrating capsule Technology approved by the FDA to treat chronic idiopathic constipation in a study recently found it to be useful in predicting the risk of relapse and severity of symptoms (JAMA Psychiatry, DOI: 10.1001/jamapsychiatry.2026.1301).
This is the latest crossover experience, Funded by the National Institute of Mental Health, Khalsa says, it provides evidence that disorders of gastrointestinal interception, 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. Up to 50% of AN patients will relapse within a year or two after being discharged from the hospital for the first time for many possible and often unknown reasons.
Recovery from ulcerative colitis 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 prolonged requirement is related to the recognition that the processes that generate illness are slow and persistent and that significant effort is required to ensure that symptoms and behaviors abate or reverse.
For some people, struggles around eating can be lifelong, continuing for many years even after a single hospitalization, Khalsa says. Diagnostic criteria for AN, in addition to internal oppositional disorder, include low body weight, fear of food, and abnormal body image, the last of which are known to persist for many years in some people even after normal body weight and eating habits are redeveloped.
The suggestion here, he adds, is that many people may never recover because they “still see themselves and relate to their bodies in very different ways than the unaffected population.” The pure theory is that objectification and abnormal body image are linked through a An area deep in the brain called the insular cortex, acts as a neurobiological bridge (Current topics in behavioral neuroscience, doi: 10.1007/7854_2025_581).
Interesting possibilities
For the latest study, Khalsa and his team recruited 62 women and girls, ages 13 to 40, who were hospitalized for hidradenitis and whose weight had been restored to healthy levels and 57 healthy controls. Participants swallowed a capsule that produced pleasant sensations of varying intensity, which the researchers could control remotely, and were then asked to press a button when they felt a vibration in their stomach. Brain, heart and stomach rhythm activity was monitored simultaneously, and participants reported their hunger levels. The anorexia group also received follow-up evaluations six months after hospital discharge.
The data was analyzed using a computational model designed to estimate how strongly participants expected to feel stomach sensations, how much their brains relied on incoming physical cues, and how quickly they updated their expectations when the cues were present or absent, he said. Relative to healthy individuals, participants were less accurate in detecting subtle stomach sensations, more likely to believe that no sensation occurred even when the pill was shaking, and were slower to revise those expectations when stomach signals were present. Many of these gut and brain measures were associated with risk of relapse during the six-month follow-up period.
What has been demonstrated here is the ability to use non-pharmacological devices to make diagnostically relevant differences between patients and make prognostic inferences about future health conditions in eating disorders, Khalsa says. It is also possible to use this approach to treat other disorders of gut-brain interaction, such as irritable bowel syndrome and functional dyspepsia, and is another avenue planned to be explored in his lab.
Anorexia nervosa affects women 10 times more than men, Khalsa says, explaining the patient group in the latest study. Participants were also recruited from one treatment center, the Nobel Prize-winning Eating Disorders Program in Tulsa, Oklahoma, which treats exclusively females.
He adds that it was not difficult to find people to volunteer for the study. In his experience, most AN patients are averse to the idea of participating in research studies.
He points out that this disorder often occurs in the period surrounding puberty when hormones begin to change, especially in females. “It is not uncommon for this diagnosis to appear…in the early teens as well as the early twenties.”
Emerging genetic studies have identified some hormones associated with metabolic signaling and energy regulation, Khalsa says, suggesting that rheumatoid arthritis is not necessarily just a disorder of the brain and gut. These particularly include peptides that link digestive conditions to decision-making in the brain, and estrogen-related receptors that drive mitochondrial energy production throughout the body.
The “dark matter” of the body
The lifetime clinical prevalence of AN in the United States is less than 1% in the general population, but in terms of impact over the lifespan, the condition is on par with disorders such as schizophrenia and autism, Khalsa says. Suicide is one of the leading causes of death, but there are also deaths due to medical causes associated with self-starvation.
The latter cause of death, whether intentional or unintentional, is the result of a “self-perpetuating process of maladaptation,” he says, which brings us back to the chronic and severe nature of the condition. Patients with anorexia who die by suicide often have a higher degree of symptom severity or longer duration of depressive episodes.
Although the concept of interoception was introduced 120 years ago, it is still not well understood how the brain helps maintain homeostasis within the body, says Khalsa, who views the process as the body’s “dark matter” because it operates largely in the shadows of the unconscious. His interest in studying the complex sensory phenomenon of hidradenitis began during his residency training because it was not well studied in scientific circles and because the condition did not respond well to evidence-based treatments.
This condition was first recognized in English and called “anorexia nervosa” about 150 years ago in London. Many of the primary “phenomena,” or lived experience of patients, included interstitial dysfunctions such as premature fullness with small amounts of food, flatulence, cramping, or restlessness, 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.
Regarding the theoretical link between interoception and body image, several years ago, Khalsa led a randomized controlled trial demonstrating the effectiveness of flotation-REST (reduced environmental stimulation therapy), a form of sensory deprivation, in reducing anxiety and improving visual perception of body size among people with AN. (Clinical medicine, doi: 10.1016/j.eclinm.2023.102173). “If you can’t feel the inner body, you may become more focused on and dependent on features in the outside world,” he explains, so “by balancing those signals, you may actually be able to improve internal interoception and perception of the external body image.”
Social media has certainly had an impact, Khalsa says, citing rising rates of neurological disease during the pandemic linked to visual content consumed on platforms like Instagram. But it is not causal. Before the age of social media, triggers for people with anorexia would have been strict dieting to fit into a dress, comments about their appearance, or pressures during sports such as gymnastics or cross-country training to fit the ideal body for that specific sporting activity. TThere is no single starting point for an eating disorder.
The way forward
The most obvious possibility for repurposing vibrating pills in treating AN patients is to speed up relapse prevention efforts, Khalsa says. But it may have an additional therapeutic use, as the capsule, unexpectedly, also disproportionately increased reports of hunger in people with rheumatoid arthritis compared to healthy people.
“One question I would have, and I’m interested in the study, is whether you’ll be able to use mechanosensory stimulation with these capsules to help individuals with sore throats become more sensitive to their hunger cues,” Khalsa says. According to this logic, the vibrating bead could be used before a meal to stimulate the intestines, helping hospitalized patients more easily recognize the sensations of hunger.
He explains that this would be a form of cognitive feedback where they are “directed towards those cues” under the guidance of the therapist. “They won’t leave the hospital or treatment program always swallowing capsules in order to feel hungry; it will be a way for them to learn to respond to their natural hunger state.”
Next steps include seeking to renew funding for this type of research, Khalsa says, noting the scarcity of research funding for anorexia nervosa and eating disorders in general compared 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 disorders.” He adds that specific feeding and eating disorder, or OSFED, is the category most people fall into.
Among people with anorexia or bulimia nervosa, it is not uncommon for people over time to change categories, raising the question of whether eating disorders share an underlying dysfunction. “One of my views is that abnormal digestive interception in one form or another may be a major contributor to most, if not all, eating disorders,” says Khalsa. “It’s really a neglected and unexplored aspect.”
Of most immediate consideration is how best to translate the use of ingestible mechanosensory sensors and computational modeling into real-world healthcare. Potential beneficiaries include not only patients in hospital preparing for discharge, but also the larger group of people already in the community with anorexia to better predict relapse risk.
Khalsa and his team also plan to expand their research by looking at males with anorexia nervosa as well as patients at multiple sites across the country. He notes that the technology still needs improvement to make it suitable for everyday treatment settings. EEG techniques previously used in the research setting require sophisticated setup to accurately capture the neural signatures of gut sensations. The future goal is to develop this technology into a simpler clinic-based application.
Khalsa and his team also hope to explore the use of the vibrating capsule to study the effects of GLP-1 weight-loss drugs. Specifically, they are seeking grant funding to learn how signals between the body and the brain change in response to the rapid decline in obesity.
