Project lead
| Prof. ZHENG Xiao | |
Deputy director, State Key Laboratory of Natural Medicine, China Pharmaceutical University |
Exploring the Sex Differences in the Role of Gut Microbiota in the Pathogenesis of Depression
Depression, a leading cause of disability worldwide, exhibits significant sex disparities: the prevalence in women is approximately twice that in men, with an earlier onset and a higher tendency for chronicity. The severity and manifestation of symptoms also differ between sexes; female patients are more prone to comorbid symptoms such as binge eating, anxiety, and hypersomnia, whereas male patients more frequently exhibit co-occurring alcohol or substance abuse. Furthermore, the efficacy of widely used antidepressant drugs varies between men and women, underscoring sex-specific differences in the underlying mechanisms of depression. Despite the higher burden of depression among women, most neurobiological research has been conducted predominantly in male animal models, resulting in a critical knowledge gap regarding the pathogenesis of depression in females. To improve therapeutic outcomes, it is essential to develop disease models applicable to both sexes and to investigate both shared and distinct mechanisms and treatments.
Current treatments for depression primarily target the central nervous system, focusing on dysfunctions of specific neurotransmitters (e.g., serotonin, norepinephrine, and dopamine). However, centrally acting drugs are often limited by slow onset, significant side effects, and insufficient efficacy. In recent years, the gut microbiota, recognized as a second brain, has gained increasing attention. It participates in the regulation of host mood via metabolites, immune modulation, and neural pathways, forming the gut microbiota–gut–brain axis. The sexually dimorphic composition of the gut microbiota may play a key role in susceptibility to depression. Studies have shown that the gut microbiota of patients with major depressive disorder (MDD) exhibits sex-specific differences, with the most differentially abundant bacterial taxa in female and male MDD patients belonging to the phyla Actinobacteria and Bacteroidetes, respectively. Therefore, this study aims to systematically elucidate the role of the gut microbiota in the sex-specific susceptibility to depression and differential treatment responses.
This research plans to investigate the role of gut microbiota in the pathogenesis of depression under sex differences through the following four aspects:
1. Conduct metagenomic sequencing and metabolomic analyses of fecal samples from female and male MDD patients to identify sex-specific differential microbial communities and their metabolite profiles, and to screen for functional microbiota significantly correlated with depression severity.
2. Utilize gut–brain organoid-on-a-chip technology, incorporating patient-derived gut microbiota and neural organoids, to establish an in vitro co-culture system with a sex hormone microenvironment, simulating gut microbiota–gut–neuron interactions under different hormonal contexts (female vs. male).
3. Establish a depression mouse model applicable to both sexes to further analyze sex-specific differential microbiota. This will be combined with fecal microbiota transplantation (FMT) and behavioral assessments to validate the effects of key bacterial strains on depression-like behaviors at the animal level.
4. Based on the above experimental findings, proceed to clinical trials by recruiting a sex-balanced cohort of depressed patients for individualized FMT intervention studies. Integrated with dynamic multi-omics monitoring, this will assess sex differences in treatment response and further validate the efficacy and precision of gut microbiota-targeted interventions in antidepressant therapy for both sexes.
