Depression-associated gut microbes, metabolites and clinical trials

Abstract

Depression is one of the most prevalent mental disorders today. Over the past decade, there has been considerable attention given to the field of gut microbiota associated with depression. A substantial body of research indicates a bidirectional communication pathway between gut microbiota and the brain. In this review, we extensively detail the correlation between gut microbiota, including Lactobacillus acidophilus and Bifidobacterium longum, and metabolites such as short-chain fatty acids (SCFAs) and 5-hydroxytryptamine (5-HT) concerning depression. Furthermore, we delve into the potential health benefits of microbiome-targeted therapies, encompassing probiotics, prebiotics, and synbiotics, in alleviating depression. Lastly, we underscore the importance of employing a constraint-based modeling framework in the era of systems medicine to contextualize metabolomic measurements and integrate multi-omics data. This approach can offer valuable insights into the complex metabolic host-microbiota interactions, enabling personalized recommendations for potential biomarkers, novel drugs, and treatments for depression.

Keywords: clinical trials; depression; gut microbiota; metabolites; pathogenesis.

Figure 1

Geographical locations and sample metadata of different animal studies related to depression.

Figure 2

Depression-associated metabolic pathways. Gut microbiota regulates the levels of 5-HT to influence depression. Through dietary or drug interventions, it upregulates the expression of tryptophan hydroxylase 1 (TPH1) in enterochromaffin cells (ECCs), enhancing the production of 5-HT. SCFAs have been shown to affect the production of 5-HT in the gut. An increase in dietary tryptophan induces the synthesis of SCFAs by gut microbiota, leading to an increase in 5-HT production and release in ECCs. Gut microbiota has the ability to increase γ-aminobutyric acid (GABA) levels in the central nervous system (CNS) of mice. GABA crosses the intestinal barrier and is sensed by the vagus nerve, transmitting signals to paraventricular nucleus (PVN) neurons, thereby initiating hypothalamic–pituitary–adrenal (HPA) axis activity and producing an antidepressant effect. In the human body, choline positively influences emotions through promoting SAM-dependent DNA methylation. However, oral choline increases the concentration of acetylcholine in the brain, promoting depression-like behavior. Choline deficiency or excess may both affect depression, highlighting the complexity of the relationship between choline metabolism and depressive behavior. Lactic acid can pass through the blood–brain barrier, and studies in rodents and humans have found a connection between depression and lactic acid abnormalities. About one-third of depression patients exhibit folate deficiency. Folate supplementation has demonstrated its antidepressant effects, but clinical trials have not yet provided strong evidence to support folate as an advantageous adjunctive strategy for depression. The signaling pathway of bile acid metabolism within the gut–liver axis (not depicted in the figure), subject to structural modifications by the gut microbiota, can elicit either severe depression or manifest antidepressant effects based on the specific receptors involved. Created with BioRender.com.

Figure 3

Geographical locations and sample metadata of different clinical trials related to depression.

Figure 4

The occurrence of different probiotics across various studies. The left bar in the Upset Plot indicating the number of studies related to each microbe. Higher bars signify stronger evidence linking the microbe to depression. The upper bar displays the number of studies in which several connected microbes simultaneously used. A higher bar indicates that these microbes are found in a greater number of studies.