Researchers uncover distinct microbial and metabolic signatures in the guts of older adults with depression, pointing to new avenues for personalized, microbiota-targeted mental health therapies.
Study: Multi-omics approach identifies gut microbiota variations associated with depression. Image Credit: Tatiana Shepeleva / Shutterstock
A new study published in the Nature Portfolio Journal Biofilms and Microbiomes reveals significant alterations in gut microbiota composition in older Mediterranean adults with overweight/obesity and metabolic syndrome who have depression symptoms or antidepressant use. The findings provide a future research path for determining whether gut microbiota influences the pathophysiology of depression.
Background
Depression is a serious mental disorder characterized by a feeling of sadness and a lack of interest in activities for a prolonged period of time. An estimated 3.8% of the global population experiences depression at some point in life.
Several social, psychological, lifestyle, and biological factors can trigger the onset of depression. Alterations in gut microbiota composition have also been observed in patients with major depressive disorders.
The gut microbiota has been found to influence physical and mental health through the gut-brain axis, a complex bidirectional network of neural, endocrine, immune, and metabolic pathways.
The brain’s vagus nerve sends signals to the gut, and the gut microbiota processes these signals and responds through multiple pathways, including vagal activation, immune modulation, and production of inflammatory mediators and microbial metabolites. Both inflammatory mediators and microbial metabolites can cross the blood-brain barrier and modulate brain functions.
Given the potential link between gut microbiota and the development of depression, the current study aimed to characterize the gut microbial composition and the fecal profile of gut microbiota-derived metabolites in older Mediterranean adults with metabolic syndrome and depressive symptoms.
Study Design
The study included 400 older Mediterranean adults (aged 55–75) with overweight/obesity and metabolic syndrome. Depression status was defined as having a Beck Depression Inventory-II (BDI-II) score ≥20 (indicating moderate-to-severe symptoms) or current antidepressant use.
The gut microbiota composition of participants was characterized through 16S ribosomal RNA sequencing, and fecal metabolite profiles were assessed using liquid chromatography-tandem mass spectrometry. Analyses adjusted for diet, smoking, physical activity, and other covariates.
Study Findings
The researchers classified 69 participants into the depression group (DG) and 331 into the reference group (RG).
They observed significant differences in gut microbiota richness and diversity between the depression and reference groups. Specifically, they identified eight bacterial genera, including Acidaminococcus and Megasphaera (enriched in depression) and Christensenellaceae R-7 group (depleted in depression), which were differentially abundant between the groups.
They conducted predictive functional profiling of microbial communities and identified pathways that were significantly associated with depression. These pathways were related to type II diabetes mellitus, bile secretion, biosynthesis of secondary metabolites, carbohydrate metabolism, and amino acid metabolism. Notably, predicted disruptions in tryptophan metabolism pathways did not align with detected fecal metabolites.
By conducting metabolomic analysis of fecal samples, they identified 15 metabolites, primarily lipids, organic acids, and benzenoids, which were robustly associated with depression. Some of these metabolites were significantly associated with the gut microbial characteristics.
Study Significance
This study is the first to utilize untargeted fecal metabolomics and microbial ribosomal RNA sequencing simultaneously to determine the association between gut microbiota and depression.
The study identifies eight bacterial genera and 15 fecal metabolites that are significantly associated with depression. It reveals specific bacterial genera, including Streptococcus, Acidaminococcus, and Megasphaera, which were significantly more abundant in participants with depression, whereas Christensenellaceae R-7 group and other SCFA-producing taxa were reduced.
Streptococcus is typically associated with the oral microbiota, and its presence in the gut may indicate disruptions in the oral-gut microbial axis. Elevated Streptococcus levels were associated with depressive symptoms, potentially via serotonergic signaling disruption and neuroinflammation.
The genus Acidaminococcus is associated with glutamate production, which is a key excitatory neurotransmitter in the brain. An overproduction of glutamate can lead to excitotoxicity, neuroinflammation, and the pathophysiology of depression. These observations justify the link between this genus and depression.
The genus Megasphaera is associated with propionate production, and overproduction of this short-chain fatty acid is known to disrupt the gut-brain axis by altering signaling pathways and promoting a pro-inflammatory state.
Among depression-related metabolites identified in the study, valeric acid, a short-chain fatty acid, exhibited significant enrichment in participants with depression. In animal studies, elevated valeric acid levels have been linked to changes in gut microbiota composition and alterations in the gut-brain axis.
Proline metabolism, which was reduced in participants with depression, is a key precursor of glutamate. Reduced proline metabolism may limit glutamate availability, potentially impacting neural plasticity and mood regulation. These findings collectively indicate that bacteria-derived metabolites can influence the association between gut microbiota and depression.
The study could not find significant differences in gut microbiota composition or metabolite profiles between participants who consumed and did not consume antidepressants. These findings indicate that antidepressants do not significantly influence the gut microbiota. Another possibility is that depression-related gut microbiota changes persist despite pharmacological treatment.
Limitations include the cross-sectional design, which prevents causal conclusions, and reliance on the BDI-II questionnaire, a screening tool rather than a clinical diagnosis for depression. The study also did not account for stool consistency, which may influence microbiota composition.
As mentioned by researchers, future studies should explore the efficacy of gut microbiota-targeted therapies in patients with depression, especially those who do not respond to antidepressants.