Prebiotic Treatment in People With Schizophrenia

Over the past 10 years, considerable evidence has emerged from animal studies to suggest that
the gut microbiome has significant effects on brain development and behavior, with
bidirectional communication between the enteric nervous system, gut and the central nervous
system (CNS) (Diaz Heijtz et al, 2011; Douglas-Escobar et al, 2013; Dinan et al, 2014). The
gut microbiota have been shown to: a) produce multiple neurotransmitters, including
gamma-aminobutyric acid (GABA), dopamine, norepinepherine, and serotonin, and may regulate
CNS levels of these neurotransmitters; b) modulate brain development through the regulation
of synaptogenesis; and c) modulate the levels of stress hormones during brain development,
which may affect stress response and anxiety behavior (Diaz Heijtz et al, 2011; Dinan et al,
2014; Sudo et al, 2004; O'Mahony et al, 2015). Moreover, the gut microbiota effects the
production of neurotrophins, including brain-derived neurotrophic factor (BDNF), which plays
a significant role in neurogenesis and synaptic plasticity (Sudo et al, 2004; Nemani et al,
2015).

The gut microbiome may also affect brain development and function through its regulation of
immune system function, which is mediated, in part, through the production of short-chain
fatty acids (SCFA). There are three major SCFAs: butyrate, propionate, and acetate. Butyrate
is of particular interest, since it plays a key role in maintaining gut homeostasis and
epithelial integrity: butyrate is the primary energy source for intestinal colonocytes; and,
of the three SCFAs, butyrate appears to have the most pronounced effects on immune system
function and may exert its effects directly through immune pathways and indirectly through
the maintenance of the integrity of the intestinal-blood barrier (Hamer et al, 2008; Louis et
al, 2010; Brahe et al, 2013; Vital et al, 2014). The intestinal-blood barrier restricts the
entrance of toxins, pathogens and antigens into the blood circulation; thus, increased
permeability could lead to the entrance of substances and subsequent immune response.

The multiple effects of the gut microbiome on brain development and behavior, suggest that
alterations in the gut microbiome may occur in schizophrenia and play a part in the
pathophysiology of the disorder. The increased prevalence of gastrointestinal disorders in
schizophrenia; the association of infections, including infections with Toxoplasma gondii,
which can induce intestinal inflammation, with the risk for the development of schizophrenia;
and evidence of increased gut permeability provide further indirect evidence for disruption
of the gut microbiome in this disorder (Dinan et al, 2014; Nemani et al, 2015; Severance et
al, 2012; Severance et al, 2014). Although a number of studies have been conducted in other
neuropsychiatric disorders, including autism (Parracho et al, 2005; Tomova et al, 2015),
which demonstrate altered bacterial composition of the gut microbiome, there is only one
published study of the microbiome in schizophrenia. Yolken and colleagues examined the
oropharyngeal microbiome in people with schizophrenia, and found that there were increased
levels of the bacteriophage, Lactobacillus phage phiadh, genome in the schizophrenia group,
which were correlated with co-occurring immunological disorders (Yolken et al, 2015). There
is one published study of gut microbiota in schizophrenia. Shen and colleagues found a
significant reduction in butyrate producers in people with schizophrenia compared to healthy
controls (Shen et al. Schiz Res, https://doi.org/10.1016/j.schres.2018.01.002).

The purpose of this study is to examine changes in serum butyrate levels with the prebiotic:
Prebiotin (12g/day), an oligofructose-enriched inulin (FOS); the effect of FOS on the
composition of the gastrointestinal microbiota in people with schizophrenia; and the
relationship of the composition of the gut microbiota to various clinical, cognitive, and
neuroimaging variables.

Inclusion Criteria:

1. DSM-IV-TR /DSM 5 diagnosis of schizophrenia or schizoaffective disorder;

2. Age 18-60 years;

3. currently hospitalized for at least 7 days

4. currently treated with an antipsychotic, with no dose changes in last 14 days

5. ability to participate in the informed consent process, as determined by a score of 10
or greater on the Evaluation to Sign Consent.

6. BMI ≤ 35

Exclusion Criteria:

1. Gastrointestinal disorders, including, but not limited to Crohn's Disease, Irritable
Bowel Syndrome, Celiac Disease, whose pathology or treatment could alter the
presentation or treatment of schizophrenia or significantly increase the risk
associated with the proposed treatment protocol

2. Organic brain disorder, including cerebrovascular accident; epilepsy; traumatic brain
injury, Loss of consciousness (LOC) for more than 30 minutes

3. Mental retardation

4. Antibiotic or immune therapy within the last three months

5. Prebiotic or probiotic treatment within the last three months

6. Inability to understand English

7. Inability to cooperate with study procedures

8. Pregnant or lactating women

9. Meet DSM-5 criteria for alcohol or substance use disorders (except Tobacco Use
Disorder) within last 3 months