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The Safety and Efficacy of Microbial Ecosystem Therapeutic-2 (MET-2) in People with Major Depression: Protocol for a Phase 2, Double-blind, Placebo-controlled Study (Preprint)


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 Background: The gut-brain axis (GBA) is a bidirectional signaling pathway between the gastrointestinal (GI) tract and the brain that is being studied due to its potential influence in mediating mood, anxiety, and other neuropsychiatric symptoms. Previous research looking into the effects of gut microbiota on neuropsychiatric disorders suggests that gut repopulation treatments such as probiotics, microbe therapy, and fecal microbiota transplantation (FMT), an intervention used to repopulate the gut of unwell participants with bacteria from healthy donors via stool administration, shows promising results in treating symptoms of anxiety and depression. This study explores the use of an alternative gut-repopulation treatment to FMT, known as Microbial Ecosystem Therapeutic-2 (MET-2) as an intervention against symptoms of depression. MET-2 is a capsule containing 40 strains of bacteria purified from a single healthy donor. Orally administered FMT capsules have advantages in safety and acceptability over FMT and the use of raw fecal material via rectal suspension.

Objective: The primary objective of this study is to assess mood changes in people with major depression that occur pre-, post-, and during administration of MET-2. The secondary objectives are to assess changes in anxiety symptoms, blood biomarker concentrations, and the level of repopulation in healthy gut bacteria as a response to treatment.

Methods: Sixty adults aged 18-45 with major depression will be recruited and randomly assigned to treatment or placebo groups. Those in the treatment group will receive oral MET-2 once daily for 6 weeks. Those in the placebo group will receive a matching placebo for 6 weeks. Participants will complete biweekly visits during the treatment period, as well as a follow-up visit at 8 weeks. As a primary outcome measure, participants mood will be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcome measures include any changes in mood, anxiety, early stress, GI symptoms, and tolerability of MET-2 using a series of clinical scales, changes in blood markers, particularly immunoglobulins (IgA, IgG, IgM) and inflammatory markers (CRP, TNF-a, TGF-b, IL-6, I-10). Changes in the relative abundance, diversity, and level of engraftment in fecal samples will be assessed using 16S rRNA sequencing. All data will be integrated to look for biomarkers that could potentially indicate disease state and/or predict improvement in depressive - symptoms in response to MET-2 treatment. 

Expected Results: Given the association between the gut microbiome and depression, we hypothesize that participants receiving MET-2 will experience greater improvement in depressive symptoms than those receiving placebo, due to the recolonization of the gut microbiome with healthy bacteria modulating the gut-brain axis connection. 

Trial Registration: Clinicaltrials.gov NCT04602715
