Microbiota alterations in proline metabolism impact depression.

Area of Science:

• Neuroscience
• Microbiology
• Metabolomics

Background:

• The microbiota-gut-brain axis is a novel target for depression, a condition with limited treatment options.
• Current research is hampered by underpowered studies lacking focus on microbiome functionality and confounding factors.

Purpose of the Study:

• To investigate the role of the microbiome and its metabolites, specifically proline, in depression using a multi-omics approach.
• To explore the impact of microbial function and dietary proline on brain dynamics and depression-like behaviors.

Main Methods:

• A multi-omics approach combining pre-clinical models (mice, Drosophila) with three human cohorts (including mild depression patients).
• Analysis of microbial functions, metabolites (proline, GABA), dietary factors, whole-brain dynamics, and gene expression.
• Microbiota transplantation, RNAi-mediated knockdown, and mono-association experiments.

Main Results:

• Microbial functions and metabolites, particularly proline, were linked to depression and glutamate/GABA metabolism.
• High dietary proline intake was strongly associated with depression; proline supplementation exacerbated depression in mice.
• Human microbiota transplantation induced depression-like phenotypes and altered gene expression in mice.
• Targeting proline/GABA transporters and specific bacteria (L. plantarum) showed protective effects in Drosophila.

Conclusions:

• The gut microbiome and dietary proline significantly influence depression.
• Targeting the microbiome and proline metabolism presents a promising therapeutic strategy for depression.