Does schizophrenia shift the gut-brain axis?

1 Feb 2024

Interest in the role of the gut microbiome in health and disease has continued to grow in recent years. Trillions of microorganisms, containing more than 2 million bacterial genes, occupy the gut, and affect many aspects of human health, potentially including brain functions, such as cognition and mood. Altered composition of the gut microbiome has also been implicated in psychiatric disorders, such as schizophrenia.

Svetlina Vasileva, a PhD student in the Eyles lab at the Queensland Brain Institute (QBI), has led a study, in collaboration with Professor Dan Siskind, the Gratten lab at the Mater Research Institute and QCMHR, to explore associations between the composition of the gut microbiome, schizophrenia and its treatment.

Ms Vasileva, you’ve spent the last few years exploring the role of the gut microbiome in individuals diagnosed with schizophrenia. Can you tell us why you decided to embark on this work?

Numerous studies have suggested there are links between the gut and the brain. We know that individuals diagnosed with schizophrenia have a high incidence of physical comorbidities, compared to the general population, including metabolic, gastrointestinal, and cardiovascular problems. Previous studies have failed to account for these comorbidities and associated lifestyle factors, and the role they play in gut microbiome composition. 

We set out to address this gap in the research. And, because the gut microbiome plays a role in metabolism and human health, we investigated whether its composition was associated with treatment response and resistance in schizophrenia. 

We analysed the relationship between the composition of the microbiome in three groups of people diagnosed with schizophrenia, varying in their response or lack of response to treatment, versus healthy controls, to explore the role that microbiome alterations play in the disorder.

You mention treatment-resistant schizophrenia. Could you explain what this means? Why is this distinction important for the study?

Treatment-resistant schizophrenia (TRS) refers to the persistence of symptoms despite two or more trials of antipsychotic medications. When someone is diagnosed with TRS, a trial of a medication called clozapine is recommended. 

In the context of this study, differentiating between treatment-resistant versus treatment-responsive schizophrenia allowed us to account for treatment resistance as a trait that may be associated with a particular microbiome profile.

How did you carry out the study? 

We collected data from 97 adults in Brisbane over a year-long period. We collected stool samples and gathered data on physical health, diet, activity, and medication use from four participant groups: individuals with treatment-responsive schizophrenia, individuals with treatment-resistant schizophrenia responding well to clozapine, individuals with treatment-resistant schizophrenia who were clozapine non-responsive, and control individuals with no history of psychiatric diagnosis. 

We analysed the data to identify broad patterns of the various microbiota species found and functional microbiome associations with schizophrenia diagnosis, after adjusting for physical and lifestyle characteristics.

And what did you find?

We do see differences in the gut microbiome between all groups of people with schizophrenia and control individuals, confirming findings from previous studies about a distinct gut microbiome in people with schizophrenia.

We also identified strong associations between the gut microbiome and treatment resistance in people with schizophrenia, most likely driven by clozapine use (although we don’t have sufficient data to confirm this hypothesis). 
Because we gathered data on demographic and lifestyle factors such as diet, physical exercise and metabolic health, we were able to confirm that the differences in the gut microbiome were not due to these factors. 

We also found strong differences between those people who are treatment resistant and taking clozapine, and those who are responding well to other antipsychotic medications. Importantly, the microbiomes of treatment-responsive individuals were more similar to the microbiomes of controls than to treatment-resistant individuals. 
After conducting a series of additional analyses, we suggest that the differences observed in individuals with treatment-resistant schizophrenia could be influenced by clozapine use, which is prescribed only to individuals with treatment resistant schizophrenia. 
However, only longitudinal studies involving analysis of the microbiome before and after starting clozapine use will be able to confirm this. 
Why is this study significant to this area of work?
This is the first study to investigate the gut microbiome in relation to treatment response and treatment resistance in schizophrenia. We employed a highly rigorous methodology, going beyond the common analyses used in the gut microbiome field such as microbial abundance and diversity, to perform powerful mixed model analyses that consider all microbiome features concurrently. 
Unlike some previous studies, we also adjusted for factors commonly confounded with schizophrenia and gut microbiome composition, including lifestyle factors like diet, physical health, and medications. 
Our study provides novel insight in the field, suggesting that lifestyle factors, specifically medication intake, might have a larger influence on the gut microbiome of individuals with schizophrenia than the onset and development of the disorder itself. This means that future studies investigating the relationship between the gut microbiome and psychiatric disorders should also aim to collect such data.
What’s next for your research in this area?
This study informed us about key bacterial players and their functional potential in the microbiome. The next step for us is to investigate microbial metabolites within the faecal samples we collected. Preliminary analyses have suggested that the faecal metabolites in clozapine-resistant individuals are different compared to the other three groups. 
Our lab is currently working on delivering clozapine intranasally. If clozapine in fact is changing the gut microbiome, intranasal delivery could bypass the peripheral nervous system and stop the potential effects that clozapine has on the gut and the microbial environment.    
This study was published in JAMA Psychiatry.