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

Abstract

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.

Oral Administration of Bifidobacterium lactis Ameliorates Cognitive Deficits in Mice Intracerebroventricularly Administered Amyloid Beta via Regulation the Activation of Mitogen-activated Protein Kinases

“…Although the actual mediator that connects BL in the gut and brain of ICV Aβ-injected mice could not be elucidated in this study, BL-derived short-chain fatty acids (SCFAs), such as butyrate, propionic acid, and acetate, may be possible candidates for transmitting the beneficial effects of BL in the mouse gut to the brain. SCFAs produced by the gut microbiota are known to play critical roles in many physiological processes such as metabolism, immunological responses, and intestinal integrity ( Quagebeur et al, 2023 ). In addition, studies have shown that SCFAs produced by the gut microbiota move into the bloodstream and finally reach the brain by penetrating the blood-brain barrier ( Kekuda et al, 2013 ; Oldendorf, 1973 ).…”

“…In addition, studies have shown that SCFAs produced by the gut microbiota move into the bloodstream and finally reach the brain by penetrating the blood-brain barrier ( Kekuda et al, 2013 ; Oldendorf, 1973 ). SCFAs are endogenous ligands that regulate gene expression by binding to G protein-coupled receptors ( Quagebeur et al, 2023 ) and attenuating the activity of histone deacetylases ( Fischer et al, 2007 ; Schroeder et al, 2007 ). Therefore, although the effects of BL on the changes in SCFAs in our animal study were not determined, BL-mediated SCFAs may affect gene regulation related to cognitive impairment in the brain tissue of an AD-like mouse model.…”

The effect of prebiotic and probiotic food consumption on anxiety severity: a nationwide study in Korea

“…The SCFAs butyrate, propionate, and acetate are important products of bacterial fermentation in the human intestine and are known to have the ability to regulate anxiety-like behavior ( 35 ). Emerging research has demonstrated that SCFAs may regulate the effects of gut bacteria on stress responses of the HPA axis and attenuate the cortisol response to acute psychosocial stress ( 36 ).…”

Potential Molecular Mechanisms of Alcohol Use Disorder with Non-Coding RNAs and Gut Microbiota for the Development of Superior Therapeutic Application

“…The gut microbiota has various effects on host physiology, including host metabolism, the development of the immune system, and even behaviors [51]. The complex interplay between the gut, stress, and eating/drinking behavior may facilitate new therapeutic targets for stress-related psychiatric disorders [51].…”

“…The gut microbiota has various effects on host physiology, including host metabolism, the development of the immune system, and even behaviors [51]. The complex interplay between the gut, stress, and eating/drinking behavior may facilitate new therapeutic targets for stress-related psychiatric disorders [51]. Remarkably, short-chain fatty acids (SCFAs), namely acetate, propionate, and butyrate, might be mediators of microbiota-gutbrain interactions on the stress response and/or eating/drinking behavior.…”