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Schizophrenia, Depression Studies Suggest Gut Microbiome May Influence Mental Health

NEW YORK (GenomeWeb) – Two new studies in schizophrenia and depression boost a growing collection of evidence that the gut microbiome, and compounds it produces, may play a role in mental health conditions.

In a paper published online today in Sciences Advances, researchers from Chongqing Medical University and Sun Yat-sen University in China, SUNY Upstate Medical University, and elsewhere used 16S ribosomal RNA gene sequencing to compare the composition of gut microbe communities in dozens of medicated and unmedicated schizophrenia patients as well as healthy controls.

Overall, the team found lower-than-usual bacterial diversity and other alterations in the gut microbiomes of individuals with schizophrenia. The researchers narrowed in on specific microbial taxa with apparent ties to schizophrenia and schizophrenic symptom severity — results the group explored further by gauging central nervous system and peripheral metabolites, along with metagenomic gut microbe sequences, in germ-free mice that received fecal transplants from schizophrenia patients.

"Together, our findings suggest that the [schizophrenia] microbiome itself can alter neurochemistry and neurologic function in ways that may be relevant to [schizophrenia] pathology," co-senior and co-corresponding authors Peng Xie, Hong Wei, and Julio Licinio and their colleagues wrote, noting that prior studies have implicated the gut microbiome and the microbiota-gut-brain axis in conditions ranging from anxiety to memory and cognition.

The team used Illumina 16S V3 and V4 region rRNA sequencing to profile gut microbial community members in fresh frozen fecal samples from 58 schizophrenia patients who were receiving one or more antipsychotic drugs but were still experiencing disease symptoms, as well as five non-medicated individuals with schizophrenia and 69 unaffected controls.

Among the 864 operational taxonomic units (OTUs) the researchers identified with these reads, they noted that 56 turned up exclusively in individuals with schizophrenia, while 64 appeared to be unique to the unaffected healthy controls. The schizophrenia patients tended to have enhanced levels of OTUs from Veillonellaceae, Prevotellaceae, Bacteroidaceae, and Coriobacteriaceae bacterial families, they reported, despite decreased alpha-phylogenetic diversity and microbial richness in general.

In a series of follow-up experiments, the team focused in on a refined set of microbes that distinguished schizophrenia cases from controls, identified microbes associated with symptom severity, and demonstrated that gut microbes from the schizophrenia patients could prompt behavior changes, as well as shifts in hippocampus, blood, and fecal metabolites, in mice.

The authors suggested that their metabolic and subsequent metagenomic findings in the microbe-treated mice "suggest that alterations in gut microbiota may be associated with [schizophrenia] pathophysiology through [microbiota-gut-brain] amino acid and lipid metabolic pathways."

Indeed, an independent team led by Jeroen Raes, a microbiology and immunology researcher affiliated with the University of Leuven and the VIB Center for Microbiology in Belgium, wrote that the "relationship between gut microbial metabolism and mental health is one of the most intriguing and controversial topics in microbiome research."

For a related analysis published in Nature Microbiology earlier this week, Raes and his colleagues used 16S rRNA and metagenomic sequencing to assess gut microbiomes in the context of mental quality of life and depression.

That team focused on 1,054 participants in the Flemish Gut Flora Project who had completed quality of life surveys addressing both mental and physical health questions, uncovering quality of life- and depression-related gut microbiome shifts that they went on to validate in another 1,063 individuals from the Dutch LifeLines DEEP project.

In particular, the researchers found that individuals with higher quality of life scores tended to have enhanced gut community levels of bacteria from the Faecalibacterium and Coprococcus genera, which are known for producing butyrate. On the other hand, microbes from the Dialister and Coprococcus species appeared to decline in gut microbiomes from depression-prone individuals.

"Analysis of a large fecal microbiome population study and validation of several public and newly sequenced data sets allowed us to establish significant co-variation of gut microbiota composition with [quality of life] indicators as well as depression status," the authors wrote.

The team explored potential ties between the gut microbiome and the brain in more detail with a network approach aimed at uncovering gut-brain modules — a search that highlighted microbial products with potential activity in the human brain.

"Gut-brain module analysis of fecal metagenomes identified the microbial synthesis potential of the dopamine metabolite 3,4-dihydroxyphenylacetic acid as corresponding positively with mental quality of life and indicated a potential role of microbial gamma-aminobutyric acid production in depression," the authors wrote, though they cautioned that the current analysis "does not allow testing for causality nor directionality of microbiota-gut-brain axis interactions."