Major depressive disorder (MDD) is a severe mental health condition that profoundly affects both psychological and physical well-being. Growing evidence indicates that targeting the gut-brain axis could present new therapeutic opportunities for MDD, given the role of gut microbiota and their metabolites in its pathophysiology. One promising approach involves supplementation with butyrate, a short-chain fatty acid that has demonstrated antidepressant potential in preclinical models of depression. However, clinical research exploring the effects of butyrate supplementation in individuals with MDD remains lacking.

This study is a double-blind, parallel, 1:1 randomised placebo-controlled trial. The primary aim of this pilot study is to assess the feasibility and acceptability of an 8-week oral supplementation with tributyrin, a triglyceride form of butyrate (4 g/day), added to usual treatment with antidepressant medication in 24 patients with mild-to-severe MDD aged 18–65 years. Secondary outcomes include changes in depressive symptoms, assessed weekly throughout the supplementation period and at 16 weeks post-supplementation during follow-up, as well as changes in anhedonia and affect, measured multiple times per day via a smartphone application throughout the supplementation period. Additional outcomes include changes in gastrointestinal symptoms, changes in faecal microbiome, metabolites in blood and faeces, inflammation, epigenetic markers, stress and intestinal permeability.

The study has been approved by the Medical Research Ethics Committee of the Amsterdam University Medical Centre, the Netherlands.

Should the pilot demonstrate feasibility and acceptability, a larger-scale study will be warranted to evaluate the efficacy of tributyrin supplementation in alleviating depressive symptoms. This pilot will provide valuable insights to guide sample size calculations and refine study design for subsequent trials. Ultimately, this research could lead to novel adjunctive treatments for MDD targeting gut-brain signalling, offering new therapeutic avenues for patients with MDD.

This trial has been registered in the International Clinical Trials Registry Platform (registry number: NL-OMON57116).