A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia

Abstract

The emerging understanding of gut microbiota as 'metabolic machinery' influencing many aspects of physiology has gained substantial attention in the field of psychiatry. This is largely due to the many overlapping pathophysiological mechanisms associated with both the potential functionality of the gut microbiota and the biological mechanisms thought to be underpinning mental disorders. In this systematic review, we synthesised the current literature investigating differences in gut microbiota composition in people with the major psychiatric disorders, major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ), compared to 'healthy' controls. We also explored gut microbiota composition across disorders in an attempt to elucidate potential commonalities in the microbial signatures associated with these mental disorders. Following the PRISMA guidelines, databases were searched from inception through to December 2021. We identified 44 studies (including a total of 2510 psychiatric cases and 2407 controls) that met inclusion criteria, of which 24 investigated gut microbiota composition in MDD, seven investigated gut microbiota composition in BD, and 15 investigated gut microbiota composition in SZ. Our syntheses provide no strong evidence for a difference in the number or distribution (α-diversity) of bacteria in those with a mental disorder compared to controls. However, studies were relatively consistent in reporting differences in overall community composition (β-diversity) in people with and without mental disorders. Our syntheses also identified specific bacterial taxa commonly associated with mental disorders, including lower levels of bacterial genera that produce short-chain fatty acids (e.g. butyrate), higher levels of lactic acid-producing bacteria, and higher levels of bacteria associated with glutamate and GABA metabolism. We also observed substantial heterogeneity across studies with regards to methodologies and reporting. Further prospective and experimental research using new tools and robust guidelines hold promise for improving our understanding of the role of the gut microbiota in mental and brain health and the development of interventions based on modification of gut microbiota.

Fig. 1. PRISMA flowchart.

PRISMA flowchart and decision-making process for the inclusion of studies.

Fig. 2. Differences in gut microbiota α- and β-diversity in cases compared to controls across studies of MDD, BD and SZ.

A Testing of differences in α-diversity across comparison groups in MDD (N = 27), BD (N = 7), and SZ (N = 18). Purple indicates no reported difference in α-diversity, dark blue indicates lower α-diversity and light blue indicates higher α-diversity. B Testing of differences in β-diversity across comparison groups in MDD (N = 18), BD (N = 6) and SZ (N = 13). Light blue indicates reported differences in β-diversity, dark blue indicates no reported difference in β-diversity.

Fig. 3. Bacterial genera that were commonly higher or lower in mental disorders compared to controls.

Bacterial genera that were differentially abundant or discriminatory in equal to or >20% (N = 9) of the included studies that reported differences at the genus level were collated. The purple circle indicates genera that were different in SZ cases compared to controls, the blue circle indicates genera that were different in BD cases compared to controls, and the yellow circle indicates bacterial genera that were different in MDD cases compared to controls. Genera within overlapping sections indicate where differences in the abundance of that genus was a shared feature between two disorders. The centre overlap indicates genera that were commonly different in cases compared to controls across all three mental disorders. MDD Major depressive disorder, BD Bipolar disorder, SZ Schizophrenia, GABA γ-aminobutyric acid. ^ indicates butyrate-producing genera; # indicated lactic acid-producing and utilising genera; * indicates bacteria that influence glutamate and GABA metabolism. Created with BioRender.com.

Fig. 4. Potential functional implications of bacterial genera implicated as different in mental disorders in this review.

Bacterial genera belonging to the human gut microbiota that were commonly different or discriminatory in people with mental disorders compared to controls. The functional potential of these bacteria to (1) produce and utilise lactic acid, (2) produce butyrate, and (3) influence the metabolism of glutamate and GABA, may be mechanistic pathways through which differences in these bacteria may influence their human host and contribute to mental disorder pathophysiology. Created with BioRender.com.