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.</p
