Investigating the role of the endocannabinoid system and gut-microbiome in psychotic and severe mental illness: a focus on negative symptoms
Keywords: amotivation
depression
microbiome
anhedonia
negative symptoms
psychosis
endocannabinoids
schizophrenia

Negative symptoms, such as anhedonia and amotivation, represent unmet therapeutic needs and key determinants of functional loss in severe mental illness. Albeit traditionally considered a unique feature of schizophrenia, anhedonia and amotivation manifest outside the psychotic spectrum, where they are equally debilitating and difficult to treat. A number of clinical trials using newly developed compounds or re-repurposing existing drugs have tried to treat negative symptoms without success. There is therefore urgent need of clarifying the mechanisms underlying negative symptoms, before engaging in further trials. The aim of my DPhil was to investigate the relevance for negative symptoms of two recently discovered biological systems, the gut-microbiome and the endocannabinoid systems. The rationale was based on emerging evidence showing an independent contribution of these two systems to the pathophysiology of severe mental illness and their proven interplay in other fields of medicine. I initially explored the independent contribution of the endocannabinoid system and the gut microbiome to schizophrenia and severe mental illness through two systematic reviews and meta-analyses. The first meta-analysis aimed at investigating disturbance of the endocannabinoid system in psychotic illness. Pooled results from 18 studies including 442 patients and 590 controls showed that anandamide, the main agonist of the endocannabinoid system, was increased in blood and cerebrospinal fluid of patients with psychotic illness, at any stage (including the prodrome) and independent of medication status. Across the included studies the increase in anandamide was inversely related to the severity of negative symptoms, suggesting endocannabinoids are protective towards illness mechanisms and severity of clinical features. The second meta-analysis aimed at investigating blood biomarkers of reduced microbial diversity (gut dysbiosis) in severe mental illnesses (schizophrenia, depression, and bipolar disorder) and chronic fatigue. Pooled results from 33 studies including 2,761 patients and 1,847 controls showed that blood biomarkers of gut dysbiosis were increased and positively associated with severity of negative symptoms in patients vs controls, independent of medication status and across diagnostic boundaries. I then brought the gut-microbiome and the endocannabinoid system together and explored the relevance of their interplay for negative symptoms in a general population cohort (TwinsUK). Data from 786 individuals showed that the endocannabinoid system mediated the association between gut dysbiosis and the severity of negative symptoms. In particular, gut dysbiosis was associated with increased faecal excretion of endocannabinoids (protective for mental health), which in turn was associated with more severe symptoms. These findings advocate for the existence of a gut microbiome- endocannabinoid axis, relevant for negative symptoms and a putative novel target for intervention.
I therefore explored if existing molecules targeting the first node of this axis, the gut-microbiome, could palliate negative symptoms in severe mental illness using two systematic reviews and meta-analyses. The first meta-analysis investigated the efficacy of already known gut-microbiome-targeted therapeutics (antibiotics, antimicrobials, pre and probiotics) for the treatment of negative symptoms in psychotic illness. Pooled results from 28 eligible randomised controlled trials showed that none of the already known gut-microbiome based therapeutics were effective for treating negative symptoms of psychotic illness. Results were mainly led by antibiotics and antimicrobics (25 trials), with paucity of evidence on pre and probiotics. The second meta-analysis investigated the efficacy of metformin, which novel evidence showed to have a specific action on the gut-microbiome (i.e., increase in the relative abundance of butyrate-producing bacteria, beneficial for the host’s mental health). Analyses on the TwinsUK cohort showed that the relative abundance of these bacteria is associated with fecal levels of endocannabinoid metabolites. Pooled results from 5 eligible randomised controlled trials showed that metformin has pro-cognitive effects, with preliminary evidence showing efficacy on negative symptoms. Altogether these findings suggest that aspecific approaches targeting the gutmicrobiome are not effective for the treatment of negative symptoms, while more defined approaches targeting a specific biological axis might translate into clinically meaningful results. In conclusion, findings from my DPhil advocate for the existence of a gut microbiome-endocannabinoid axis, which might be relevant for negative symptoms across severe mental illness and beyond, such as in chronic fatigue and in general population. Future studies should validate findings in a well-powered clinical sample of patients with severe mental illness and test the efficacy of compounds targeting this axis.