The role of short-chain fatty acids (SCFAs) in regulating stress responses, eating behavior, and nutritional state in anorexia nervosa: protocol for a randomized controlled trial

OBJECTIVE: This protocol proposes investigating the effects of short-chain fatty acids (SCFAs)—namely acetate, propionate, and butyrate—as mediators of microbiota-gut-brain interactions on the acute stress response, eating behavior, and nutritional state in malnourished patients with anorexia nervosa (AN). SCFAs are produced by bacterial fermentation of dietary fiber in the gut and have recently been proposed as crucial mediators of the gut microbiota's effects on the host. Emerging evidence suggests that SCFAs impact human psychobiology through endocrine, neural, and immune pathways and may regulate stress responses and eating behavior. METHOD: We will conduct a randomized, triple-blind, placebo-controlled trial in 92 patients with AN. Patients will receive either a placebo or a mixture of SCFAs (acetate propionate, butyrate) using pH-dependent colon-delivery capsules for six weeks. This clinical trial is an add-on to the standard inpatient psychotherapeutic program focusing on nutritional rehabilitation. HYPOTHESES: We hypothesize that colonic SCFAs delivery will modulate neuroendocrine, cardiovascular, and subjective responses to an acute laboratory psychosocial stress task. As secondary outcome measures, we will assess alterations in restrictive eating behavior and nutritional status, as reflected by changes in body mass index. Additionally, we will explore changes in microbiota composition, gastrointestinal symptoms, eating disorder psychopathology, and related comorbidities. DISCUSSION: The findings of this study would enhance our understanding of how gut microbiota-affiliated metabolites, particularly SCFAs, impact the stress response and eating behavior of individuals with AN. It has the potential to provide essential insights into the complex interplay between the gut, stress system, and eating behavior and facilitate new therapeutic targets for stress-related psychiatric disorders. This protocol is prospectively registered with ClinicalTrials.gov, with trial registration number NCT06064201.