Project details


Gastrointestinal treatment of severe mental disorders (GUTS)

severe mental disorders probiotics randomized controlled trial

Dr. J. Fu
I.E.C. Sommer
B. Haarman
S. El Aidy
N. Festen

Nature of the research:
Randomized controlled clinical trial to investigate the probiotics in psychotic and bipolar disorders.

Fields of study:
gastroenterology psychiatry molecular biology

Background / introduction
Schizophrenia and bipolar disorder are severe mental disorders, both placing significant burden on global health. In both disorders, patients suffer from a variety of psychotic, depressive and manic symptoms.
Recent investigations have pointed to the gut-brain axis as a new venue for treatment, with increased inflammation stemming from increased intestinal permeability to further affect brain functioning in a significant subset of patients. In multiple studies increased intestinal permeability in schizophrenia and bipolar disorders is demonstrated by translocation of food and bacterial antigens, as well as intestinal microbiome disturbances. This is associated with dysregulation of the immune system, precipitation and exacerbation of psychiatric symptomatology, metabolic complications and increased cognitive impairment. Probiotics are promising candidates to improve patients’ symptomatology and functioning and there are rational methods to personalize its application with accessible and tolerable predictive biomarkers.
We hypothesize (1) that treating patients with intestinal permeability improving probiotics (in addition to usual treatment; antipsychotic / mood stabilizing treatment) will cause a decrease in psychiatric symptoms (measured with the Brief Psychiatric Rating Scale (BPRS)), such as psychotic, depressive and manic symptoms, in patients with psychotic and bipolar disorders with increased intestinal permeability. We also expect improvement of intestinal permeability and inflammation, immune parameters, metabolic syndrome features, cognition, general functioning and gastro-intestinal (GI) complaints in these patients. Additionally, we hypothesize (2) that individual treatment response to intestinal permeability improving probiotics can be predicted by measurement of intestinal permeability, intestinal inflammation, or a combination of these and other immunological, medical or psychiatric factors.
Research question / problem definition
The primary objectives of this trial are to investigate (1) the effects of intestinal permeability improving probiotics, compared to placebo, when given in addition to usual treatment, on symptom severity and secondary outcomes in patients with psychotic and bipolar disorders that have increased intestinal permeability (Lipopolysaccharide Binding Protein (LBP) ≥ median (9 ng/ml)); (2) which factors (intestinal permeability (LBP), intestinal inflammation (fecal calprotectin), intestinal microbiome, as well as immune activation and other medical or psychiatric factors) can best predict the individual treatment response to probiotics. Our aim will be to lower diverse symptom severity (including psychotic, depressive and manic symptomatology) as measured with the BPRS to assess if probiotics can form an effective and personalized treatment paradigm for psychotic and bipolar disorders. Secondary objectives are to investigate whether the treatment effect of intestinal permeability improving probiotics have a beneficial effect on immune parameters, metabolic syndrome features, cognition, side-effects, general functioning, and GI complaints; and to attempt to unravel the relationship between these measures during treatment.
In this RCT, patients (n=145) aged 18-65 years, diagnosed with a psychotic or bipolar disorder with BPRS scores of >41 willl enter a 12 week treatment period in which they are randomized 1:1 to either twice daily 2 gram probiotic formulation or placebo twice daily. Outcome measurements will be assessed at baseline, half way treatment, end of treatment, and at a follow-up 3 months post-treatment.
Students and PhD-candidates are able to participate in different parts of the project, focussing on a variety of psychological and (molecular) biological research aspects of the study.
1. Genedi M, Janmaat IE, Haarman B (Benno) CM, Sommer IEC. Dysregulation of the gut–brain axis in schizophrenia and bipolar disorder. Curr Opin Psychiatry. 2019 Mar 10;1.
2. Rudzki L, Szulc A. “Immune Gate” of psychopathology-The role of gut derived immune activation in major psychiatric disorders. Front Psychiatry. 2018;9(MAY).
3. Dickerson F, Severance E, Yolken R. The microbiome, immunity, and schizophrenia and bipolar disorder. Brain Behav Immun [Internet]. 2017;62:46–52. Available from:
4. Dickerson F, Adamos M, Katsafanas E, Khushalani S, Origoni A, Savage C, et al. Adjunctive probiotic microorganisms to prevent rehospitalization in patients with acute mania: A randomized controlled trial. Bipolar Disord [Internet]. 2018 Apr 25;1–8. Available from:
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