Gut bacteria and metabolites show depression-linked patterns in older adults

Gut bacteria and metabolites show depression-linked patterns in older adults

Researchers discover distinct microbial and metabolic signatures in the guts of older adults with depression, suggesting new avenues for personalized, microbiota-targeted mental health therapies.

A new study published in the Nature Portfolio Journal Biofilms and microbiomesshows significant changes in gut microbiota composition in older Mediterranean adults with overweight/obesity and metabolic syndrome with symptoms of depression or antidepressants. The results provide a future research path to determine 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 over a long period of time. An estimated 3.8% of the world's population experiences depression at some point in life.

Several social, psychological, lifestyle and biological factors can trigger the onset of depression. Changes 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-of metabolites in older Mediterranean adults with metabolic syndrome and depressive symptoms.

Study design

The study included 400 older Mediterranean adults (55 to 75 years old) with overweight/obesity and metabolic syndrome. Depression status was defined as a Beck Depression Inventory-II (BDI-II) score ≥ 20 (indicating symptoms of moderate to severe) or current antidepressant use.

Participants' gut microbiota composition was characterized by 16S ribosomal RNA sequencing, and fecal metabolite profiles were assessed using liquid chromatography-tandem mass spectrometry. Analyzes adjusted for diet, smoking, physical activity, and other covariates.

Study results

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. In particular, they identified eight bacterial genera, includingAcidaminococcusAndMegasphaera(enriched in depression) andChristensenellaceae R-7 group(exhausted in depression), which were differentially abundant between groups.

They performed predictive functional profiling of microbial communities and identified pathways that were significantly associated with depression. These pathways were associated with type II diabetes mellitus, bile secretion, biosynthesis of secondary metabolites, carbohydrate metabolism, and amino acid metabolism. Notably, predicted perturbations of the tryptophan metabolic pathway did not match detected fecal metabolites.

By performing metabolomic analysis of fecal samples, they identified 15 metabolites, mainly lipids, organic acids and benzenoids, that were robustly associated with depression. Some of these metabolites were significantly associated with gut microbial characteristics.

Investigate significance

This study is the first to use non-targeted 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 shows certain bacterial genera includingStreptococcusPresentAcidaminococcusAndMegasphaerawhich were significantly more common in participants with depression, whileChristensenellaceae R-7 groupand other SCFA-producing taxa were reduced.

Streptococcusis typically associated with the oral microbiota, and its presence in the gut may indicate disruptions in the oral microbial axis. IncreasedStreptococcusThe levels were associated with depressive symptoms, possibly through serotonergic signaling impairment and neuroinflammation.

The genusAcidaminococcusis associated with glutamate production, which is an important excitatory neurotransmitter in the brain. Overproduction of glutamate can lead to excitotoxicity, neuroinflammation, and the pathophysiology of depression. These observations justify the connection between this genus and depression.

The genusMegasphaerais 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 an anti-inflammatory state.

Valeric acid, a short-chain fatty acid, showed significant enrichment in depression-related metabolites identified in the study in participants with depression. In animal studies, increased valeric acid levels have been associated with changes in gut microbiota composition and changes in the gut-brain axis.

Proline metabolism, which was reduced in participants with depression, is an important precursor to glutamate. Decreased proline metabolism may limit glutamate availability and potentially impact neuronal plasticity and mood regulation. Together, these findings suggest that bacterial-derived metabolites may influence the association between gut microbiota and depression.

The study did not find significant differences in gut microbiota composition or metabolite profiles between participants who used and did not use antidepressants. These results show that antidepressants do not significantly affect the gut microbiota. Another possibility is that depression-related gut microbiota persist despite pharmacological treatment.

Limitations include the cross-sectional design, which prevents causal inferences, and the reliance on the BDI-II questionnaire, a screening tool rather than a clinical diagnosis for depression. The study also did not take into account stool consistency, which can influence microbiota composition.

As mentioned by researchers, future studies should examine the effectiveness of gut microbiota-targeted therapies in patients with depression, especially in those who are refractory to antidepressants.

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