Faecal Transplants for Bipolar Depression: Moving out of the Periphery?

There is increasing recognition of the role of the gut microbiota in mental health disorders.^1,2 This has led to the proposal of faecal microbiota transplantation (FMT) as both a potential therapeutic strategy and a tool for causal inference.^3,4 However, studies in bipolar disorder remain limited, and conclusions drawn from studies of unipolar depression should be interpreted with caution, given the clear differences in phenomenology. In this context, Shekarriz et al., ⁵ in this issue, report an important double-blind randomized controlled trial evaluating whether FMT can improve outcomes in patients with bipolar disorder who are currently depressed and unresponsive to standard treatment.

There are several reasons, largely derived from preclinical research, for undertaking such a study. FMT represents the most direct means of modifying the gut microbiome, and interest in its psychiatric applications arises from the evolving concept of the microbiota–gut–brain axis. To date, claims regarding the efficacy of psychobiotics remain limited and do not necessarily translate into meaningful or sustained alterations of the gut microbiota.

Considerable effort is now directed towards elucidating the communication pathways of the microbiota–gut–brain axis, ⁶ which include neural routes—most notably the vagus nerve—as well as immune signalling via cytokines and endocrine pathways such as the hypothalamic–pituitary–adrenal axis, which has long been recognized as dysregulated in some mood disorders.

Nutrition undoubtedly plays an additional role, with fibre metabolism generating short-chain fatty acids such as butyrate, and certain microbial–dietary interactions increasing levels of the amino acid tryptophan. ⁷ Animal studies further demonstrate that microbiota transfer can induce changes in behavioural phenotypes, including anxiety-like and depression-like behaviours. Notably, rodents receiving transplants from patients with depression develop depressive-like phenotypes. ⁸ Moreover, improvements in depressive symptoms have been reported following FMT in patients with irritable bowel syndrome. ⁹

Against this background, the study by Shekarriz et al. ⁵ represents a timely and methodologically ambitious contribution. Thirty-five participants were randomized to receive either allogenic (donor) or autologous (self-derived) FMT via colonoscopy, with follow-up extending to 24 weeks. Although the modest sample size may be viewed as a limitation, such criticism would be unduly harsh given the practical, regulatory, and ethical challenges inherent in conducting a trial of this complexity and unconventional nature.

Efforts were made to minimize potential confounding effects. Participants were asked to maintain their usual diet and exercise levels, and food intake was systematically recorded. This approach is desirable not only in FMT studies but also in all trials of therapeutic interventions in mood disorders. Diet and physical activity both influence the gut microbiota, and exercise itself can exert potent antidepressant effects. Both groups in the present study showed significant improvements in depression scores, as measured by the Montgomery–Åsberg Depression Rating Scale, but there was no meaningful difference between donor and autologous FMT in terms of clinical efficacy. Anxiety, global functioning, and tolerability outcomes were similarly comparable. Microbiome sequencing demonstrated that only the allogenic FMT group developed a more donor-like and more diverse microbial profile at 6 months.

The intervention was well tolerated, with no major adverse events and generally acceptable despite its unconventional nature. This is arguably the most important finding. Overall, the study demonstrates feasibility and safety. However, as the authors highlight, the absence of clinical differences between donor and autologous FMT, despite detectable microbiome shifts, underscores the need for improved placebo controls and deeper investigation into which microbial changes drive therapeutic effects.

By comparison, FMT in the treatment of recurrent Clostridioides difficile infection achieves remission rates approaching 90%. Even if FMT proves effective in bipolar depression, it is unlikely to yield comparable outcomes. In C. difficile studies, so-called “super-donors” have been identified—individuals whose stool consistently produces higher remission rates than those of other donors. These donors tend to exhibit higher levels of Bifidobacterium species and enhanced metabolite production. Systematic identification and screening of such individuals may represent an important strategy for improving response rates in mood disorders. Of additional interest from a gastrointestinal perspective is the finding that dyspepsia demonstrated a statistically significant between-group difference. Participants in the allogenic group experienced greater reductions in both frequency and severity compared with those receiving autologous FMT. This finding further supports a role for microbial mechanisms in dyspeptic symptomatology.

Moving forward, regulatory frameworks also pose substantial challenges. Agencies such as the U.S. Food and Drug Administration currently classify FMT as an investigational therapy outside recurrent C. difficile infection, creating barriers to large-scale clinical research. Furthermore, opportunities for intellectual property protection remain limited unless specific strains, microbial consortia, or metabolites can be isolated and characterized.

Nonetheless, the study by Shekarriz et al. ⁵ serves several important purposes, not least in highlighting a fundamental challenge for the field: autologous transplantation cannot be regarded as an inert placebo, and without more rigorous control conditions, progress will remain constrained. While a cohort of 35 participants is entirely defensible for a feasibility study, a definitive trial will likely require at least 180 participants. The central obstacle, however, is perhaps not methodological but financial. In a research ecosystem driven by patentability, branding, and shareholder value, microbiome-based therapies derived from human waste remain inherently unattractive. There is, quite literally, little glamour and limited profit in faeces. Without sustained public and philanthropic investment, microbiome-based psychiatry risks remaining scientifically intriguing but clinically peripheral.