AbstractMajor Depressive Disorder (MDD) is a common and debilitating condition; however, many people with MDD do not respond fully to current treatments. Research over recent years has recognised the role of the microbiota-gut-brain axis in the pathophysiology of MDD, which has given rise to the development of novel treatment strategies, such as probiotics. However, relatively few clinical trials have been conducted to date and the mechanisms of action of probiotics in humans remain largely unexplored.
The overarching aims of this thesis are: (i) to improve the understanding of the role of the gut microbiota in MDD; (ii) to examine whether probiotics are a suitable treatment option for people with MDD; and (iii) to advance the understanding of the mechanisms underlying the putative antidepressant properties of probiotics. To address the first aim, a case-control study (Chapter 5) and a meta-analysis of existing literature (Chapter 3) were performed. To address the second and third aims, a double-blind randomised placebo-controlled pilot and mechanistic trial was conducted (Chapters 6 and 7). The design of this trial was informed by a systematic review and meta-analysis of the literature (Chapter 2).
An extensive umbrella review and meta-analysis (Chapter 3), demonstrated that several psychiatric conditions present with a transdiagnostic pattern of gut microbial alterations, characterised by depletions of some anti-inflammatory butyrate-producing bacteria and an enrichment of pro-inflammatory bacteria. In the subsequent case-control study (Chapter 5) the gut microbiota of a UK-based sample with MDD was found to exhibit deficiencies of lactic acid bacteria (Lactobacillaceae) and bacteria linked to healthy diets (Prevotella_9), whereas bacteria associated with inflammatory signalling and metabolic disorders were more abundant (e.g., Flavonifractor, Bacteroides). Subsequently, these patients were randomised to receive a multistrain probiotic or placebo for 8 weeks, in addition to their ongoing antidepressant. Participants in the probiotic arm experienced greater improvements in depressive and anxiety symptoms compared to placebo, with promising effect sizes that encourage further investigation in a definitive efficacy trial (Chapter 6). The acceptability, tolerability and safety of the treatment were also confirmed. Exploratory sub-group analysis indicated the supplement may be most efficacious against anxious somatic depressive presentations. Regarding the underlying mechanisms, probiotics were able to modulate the composition of the gut microbiota by normalising richness and diversity towards the levels seen in the healthy controls and by increasing levels of specific health-related taxa, such as Bacillus. The probiotic intervention did not affect circulating levels of pro-inflammatory cytokines. However, it showed promise in potentially modifying affective cognition, by increasing positive biases in emotion recognition (Chapter 7).
Taken together, these results contribute to our understanding of the gut microbiota abnormalities in a UK-based population with depression, provide further support for probiotics as an acceptable, well-tolerated and potentially efficacious adjunctive treatment for MDD, and help outline some of the underlying mechanisms of action in humans, as well as some translational challenges. For the successful incorporation of probiotics into clinical practice, larger efficacy trials in well-characterised MDD populations also evaluating relevant mechanistic outcomes are needed.
|Date of Award||1 Apr 2023|
|Supervisor||James Stone (Supervisor), Anthony Cleare (Supervisor) & Allan Young (Supervisor)|