Gastrointestinal Interoception and Relapse in Anorexia Nervosa.

Importance: Anorexia nervosa (AN) is a deadly psychiatric disorder with relapse rates approaching 50% after weight restoration. Disrupted gastrointestinal interoception may underlie persistent symptoms and relapse vulnerability. Objective: To examine behavioral, computational, neural, and physiological markers of gastrointestinal interoception in weight-restored individuals with AN and test their association with relapse. Design, Setting, and Participants: This crossover trial was a single-blind, within-participant, randomized (block-order) trial conducted at the Laureate Institute for Brain Research between August 2021 and February 2025. Participants were females with weight-restored restrictive AN and age- and sex-matched healthy comparators (HCs). All participants ingested a vibrating capsule that delivered counterbalanced blocks of normal- and enhanced-intensity gut stimulation. Behavioral detection performance, electroencephalography, peripheral physiology, and computational modeling were used to assess interoception. Main Outcomes and Measures: Experimental-session measures included interoceptive accuracy, prior beliefs, interoceptive precision, learning rates, gastric-evoked potentials (GEPs), and hunger. Main clinical outcomes at 6 months included relapse status and symptom severity. Results: The cohort included 62 female participants with weight-restored restrictive AN (mean [SD] age, 18.9 [4.5] years) and 57 age- and sex-matched healthy comparators (HCs; mean [SD] age, 20.7 [5.3] years). Six-month follow-up data were collected for 54 participants with AN. Compared with HCs, participants with AN showed lower perceptual accuracy (Cohen d = -0.98; 95% CI, -1.51 to -0.44; P = .001) and higher miss rates (Cohen d = 1.02; 95% CI, 0.55 to 1.48; P < .001). Computational modeling revealed in the AN group stronger prior expectations that capsule vibrations would not be present (Cohen d = -0.31; 95% CI, -0.67 to 0.05; P = .05), greater shifts in interoceptive precision between blocks (Cohen d = 0.38; 95% CI, 0.02 to 0.75; P = .01), and learning asymmetries (vibration: Cohen d = -0.40; 95% CI, -0.77 to -0.04; P = .007; no-vibration: Cohen d = 0.35; 95% CI, -0.02 to 0.71; P = .01). GEP amplitudes did not differ by group but were correlated with accuracy and learning in AN. Capsule stimulation induced greater hunger increases in AN (interaction: η2p = 0.04, P = .04; AN: Cohen d = 0.94; 95% CI, 0.57 to 1.30; HCs: Cohen d = 0.40; 95% CI, 0.03 to 0.77). At follow-up, relapse was predicted by initial priors (odds ratio [OR], 3.82; 95% CI, 1.02 to 15.91; P = .05), response bias (OR, 5.37; 95% CI, 1.15 to 32.04; P = .04), and stomach unpleasantness (OR, 5.73; 95% CI, 1.38 to 33.5; P = .03), while eating disorder symptom severity was predicted by miss rate (β = 1.05; R2 = 0.08; P = .05), difference in interoceptive precision (β = 5.84; R2 = 0.16; P = .004), and initial priors (β = -2.99; R2 = 0.09; P = .05). Conclusions and Relevance: In this study of weight-restored females with AN, gastrointestinal interoception was disrupted across multiple domains, including reduced accuracy detecting gut signals, maladaptive priors, rigid learning, and abnormal hunger rating. Several interoceptive markers predicted relapse and symptom severity at follow-up. These findings support the use of ingestible mechanosensory probes and computational modeling as scalable tools to monitor treatment response and guide relapse prevention in eating disorders. Trial Registration: ClinicalTrials.gov Identifier: NCT05111977.