Differences in gut microbiome composition between persons with chronic schizophrenia and healthy comparison subjects
Introduction
Recent years have seen a rapid growth of interest in the human gut microbiome in the pathophysiology of human health and disease. The microbiome is a dynamic ecological community of microorganisms that inhabit the human body. The gut microbiome has a pivotal role in regulating inflammatory and metabolic pathways across a number of physical diseases, including gastrointestinal (GI) disorders, such as inflammatory bowel disease (Kostic et al., 2014), obesity and metabolic diseases (Bouter et al., 2017; Hartstra et al., 2015), cancer (Schwabe and Jobin, 2013), and chronic pulmonary diseases (Budden et al., 2017; O'Dwyer et al., 2016). There is also an emerging body of empirical support for the view that the gut microbiome can impact brain and behavior (Collins et al., 2012; Cryan and Dinan, 2012; Mayer, 2011). A number of animal studies suggest that the alterations in gut microbiota can induce physiological and behavioral features that resemble psychiatric disorders (e.g., Sudo et al., 2004; Zheng et al., 2016). However, human studies in this area have been few, particularly in schizophrenia (Nguyen et al., 2018).
Converging evidence suggests that schizophrenia and other serious mental illnesses are associated with chronic systemic and gastrointestinal inflammation, oxidative stress, and metabolic dysfunction (Nguyen et al., 2018). Some studies have found that schizophrenia is associated with elevated serological biomarkers of microbial translocation (Severance et al., 2012; Severance et al., 2016; Severance et al., 2013), suggesting increased permeability of the intestinal lumen, which may be a mechanism by which intestinal dysbiosis impacts systemic physiological functioning. Additionally, gut and digestive disturbances, including irritable bowel syndrome, colitis, and celiac disease, are highly prevalent comorbidities in persons with schizophrenia (Severance et al., 2015). Gastrointestinal diseases are the third leading cause of natural deaths in schizophrenia (Saha et al., 2007). Considering that microbial colonization of the gut is crucial for optimal function of the immune system (Kamada et al., 2013; Round and Mazmanian, 2009), inflammation, oxidative stress, and other physiological dysfunctions implicated in schizophrenia might be, at least in part, associated with changes in the microbiome.
The number of empirical studies of the gut microbiome in persons with schizophrenia is very limited (Nguyen et al., 2018). The four published studies of the gut microbiome in psychotic disorders include a study of individuals at high-risk and ultra-high-risk for schizophrenia (He et al., 2018), two investigations of patients with first-episode psychosis (Schwarz et al., 2018; Yuan et al., 2018), and a report on persons with schizophrenia of <10 years' duration (Shen et al., 2018). These studies revealed that the species composition within the gut microbiomes of individual with or at risk for psychotic disorders is different from that of non-psychiatric comparison subjects (NCs), with varying bacterial taxa driving community separation in each study. Only one of these studies investigated the relationship between gut bacteria and clinical characteristics; first-episode patients with the greatest abnormalities in microbiota composition had more severe psychotic symptoms and worse global functioning at hospitalization and a lower rate of disease remission at one-year follow-up (Schwarz et al., 2018).
These studies focused on psychosis at earlier stages in the disease process and were conducted on European and Chinese subjects. Microbial composition varies across individuals with different countries of residence (McDonald et al., 2018). One study (Shen et al., 2018) excluded individuals with any chronic disease that may affect the stability of gut microbiota, including hypertension and diabetes, which are common in schizophrenia. To our knowledge, the present report is the first investigation of gut microbiome in US-based patients with chronic schizophrenia.
Our objective was to characterize gut microbiome in patients with schizophrenia, with duration of >10 years (range 12–56 years). We hypothesized that gut microbial composition would differ between schizophrenia subjects and NCs. We also sought to explore relationships of microbial composition differences with clinical and disease characteristics, specifically with psychiatric symptomatology, smoking, physical comorbidity, and antipsychotic medications.
Section snippets
Participants
Fifty subjects, including 25 outpatients with schizophrenia or schizoaffective disorder (hereafter referred to collectively as schizophrenia) and 25 demographically matched NCs, between the ages of 30 and 76 years, participated in this study. The diagnosis of schizophrenia was made based on the Structured Clinical Interview for the DSM-IV-TR (SCID) (First et al., 2002). Twenty-one patients were on antipsychotic medication at the time of the study. NC participants were recruited through multiple
Results
Demographic and clinical characteristics for groups are presented in Table 1. Schizophrenia and NC groups did not differ on age, gender, or race. As expected, persons with schizophrenia had worse psychiatric symptoms, higher depression and anxiety levels, lower levels of physical well-being, higher rates of smoking, and greater medical comorbidity. Comparing exact BMI values, persons with schizophrenia had higher BMI than NCs; however, in terms of BMI classification, there were no significant
Discussion
Consistent with our hypothesis, this study found several significant differences in the overall composition and levels of specific bacterial taxa in the gut microbiome in persons with schizophrenia compared to NCs. To our knowledge, this investigation is the first to provide evidence for altered gut microbiota in a sample of chronically ill patients with schizophrenia living in the US. Notably, most of these differences remained significant after controlling for demographic and clinical factors
Funding
This work was supported, in part, by National Institute of Mental Health (grant numbers 2R01 MH094151-06 and 5T32 MH019934-24 to DVJ), UC San Diego Stein Institute for Research on Aging, and UC San Diego Center for Microbiome Innovation.
Contributors
Study concept and design: Tanya T. Nguyen, Tomasz Kosciolek, Dilip V. Jeste
Acquisition of data: Yadira Maldonado, Rebecca E. Daly, Averria Sirkin Martin
Literature review and drafting of the manuscript: Tanya T. Nguyen, Tomasz Kosciolek
Statistical analysis: Tomasz Kosciolek
Critical revision of the manuscript for important content: Tanya T. Nguyen, Tomasz Kosciolek, Dilip V. Jeste, Rob Knight
Obtained funding: Dilip V. Jeste, Rob Knight
Study Supervision: Tanya T. Nguyen, Tomasz Kosciolek, Dilip V.
Conflict of interest
The authors have declared that there are no conflicts of interest in relation to the subject of this study.
Acknowledgements
The authors would like to express their sincere gratitude to all of the participants who participated in this study and to the staff at the UC San Diego Stein Institute for Research on Aging and UC San Diego Center for Microbiome Innovation.
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