Effects of butyrate on depressive symptoms and affect in depression - a pilot randomized controlled trial

Major depressive disorder (MDD) is a serious mental health issue associated
with poor mental and physical health. A large proportion of MDD patients does
not respond successfully to pharmacological and/or psychological treatments and
continue to suffer from symptoms. Hence, the need for alternative treatment for
MDD remains. As the aetiology and pathophysiology of depression may be
influenced by intestinal dysbiosis, studies have been investigating the
therapeutic effects of compounds that target the intestinal environment.
Administration of probiotics and synbiotics have shown promise in reducing
depressive symptoms, yet less is known about the effects of administering
metabolites that are widely produced by resident microbes. One promising
metabolite is butyrate, a short-chain fatty acid (SCFA) that is thought to
influence depressive behaviour via the microbiota-gut-brain axis (MGBA). The
gut microbiome of MDD patients consists of less butyrate-producing bacteria and
administration of butyrate in rodent models of depression has been shown to
reduce depressive-like behaviours. Yet, it is unknown whether butyrate has
antidepressant effects in MDD patients. Butyrate is a food supplement and its
safety as an orally-ingested supplement has been established in previous
clinical trials, including trials performed at the Amsterdam UMC. To the best
of our knowledge, effects of oral butyrate supplementation has not been
investigated in psychiatric population.

The primary objectives are to study the feasibility and acceptability of an
8-week daily oral supplementation with tributyrin (4 g/day) - the triglyceride
form of butyric acid - on top of treatment as usual (TAU) in adults (18 up to
65 years) with mild-to-severe MDD. Secondary objectives are to obtain
estimations of therapeutic efficacy of tributyrin supplementation regarding
depressive symptoms and affect. Other objectives are to obtain insights into
butyrate*s potential mechanisms of influencing depressive symptoms by assessing
measures associated with the MGBA.

Pilot Study. Double-blind randomized placebo-controlled, parallel design.

Both interventions will be provided on top of participant*s TAU. The
intervention group will receive oral supplementation twice daily with 2 grams
of tributyrin (Taubiotic®), totalling to 4 grams of tributyrin a day during an
intervention period of 8 weeks (TAU + tributyrin). The control group will
receive oral supplementation with a daily equal volume of sunflower oil as a
placebo (TAU + placebo).

Patients will visit the Amsterdam UMC - location AMC 5 times: at screening (V1;
week -2; circa 70 minutes), baseline (V2; week 0; circa 105 minutes), mid-trial
(V3; week 4, circa 65 minutes), at the end of the trial (V4; week 8, circa 65
minutes), and at the 6 months follow-up (V5; week 24; circa 75 minutes). Before
each visit - with the exception V1 - patients will be asked to fast overnight,
collect faecal samples at home and fill in a nutritional diary. During visits,
patients will undergo interviews and will fill in questionnaires, scalp hair
will be collected, and fasting blood will be drawn. The maximum amount of blood
that will be drawn over 4 study visits is 82 mL per patient. Using a mobile
application, patients will report how they are feeling on 16 affect items five
times a day, five days a week starting two weeks prior to the intervention
period and during the intervention period (i.e., week -2 to week 8). Tributyrin
is a food supplement. Patients could experience side effects of the tributyrin
supplementation, however, previous trials with tributyrin capsules and sodium
butyrate capsules have reported no side effects. There is no direct benefit for
the volunteers, but this research might provide new insights into the
pathogenesis of depression.