The review included a total of (n=780) subjects from case-controlled studies in China and (n=1104) subjects from a retrospective cohort study in Germany. Among the case-control studies, (n=239) female and (n=125) male subjects with MDD were compared to (n=261) female and (n=155) male healthy controls. Notably, one study by Li et al. (33) involved subjects with Bipolar disorder (BD) (n=166) experiencing a depressive episode, whose data were excluded from this review’s analysis ( Table 1.1 ).

Alpha diversity remained unchanged in MDD subjects across three studies (32–34), while one study (35) reported a reduction. Beta diversity analysis revealed significant differences in both male and female MDD groups compared to matched healthy controls (HCs) in studies by Chen and Li (32, 33). In the female-only study by Chen et al. (34), alterations in beta diversity were observed only at the species level in female MDD subjects. Notably, Li et al. (33) found that while alpha diversity was significantly higher in female healthy controls compared to male healthy controls, this difference was not evident in the context of depression. Table 1.2 provides an overview of the key findings.

All case-control studies (32–34), highlighted notable differences in gut microbiota between individuals with major depressive disorder (MDD) and the respective control groups. These distinctions were particularly pronounced when comparing male and female cohorts. Further details can be found in Table 1.3 . Upon examining studies encompassing both male and female subjects, females with MDD exhibited a higher relative abundance of Actinobacteria, Firmicutes, and Bacteroidetes compared to the control group (32, 33). In male MDD patients, an increase and decrease in Bacteroidetes clusters, along with an increase in Firmicutes clusters, was observed. In the study conducted by Chen et al. (34) focusing on female MDD patients, an increase in Bacteroidetes, Proteobacteria, Fusobacteria, and Verruomicrobia, and a decrease in Firmicutes and Actinobacteria was reported. Notably, only two studies (34, 35) investigated the microbiome at the species level, revealing significant changes at the family, genus, and species levels.

Four studies examined the relationship between the severity of depression symptoms and specific bacterial taxa at the genus level (32–35). Among female MDD subjects, three genera (Anaerotruncus, Parabacteroides, and Anaeroglobus) exhibited associations with increased depressive symptoms, whereas five genera (Clostridium XIVa, Erysipelotrichaceae incertae sedis, Streptococcus, Romboutsia, and Fusicatenibacter) were linked to reduced depressive symptoms. In male MDD subjects, two distinct genera (Collinsella, Veillonella) were found to be correlated with depression symptoms (refer to Table 1.4 ).

Two studies (33, 34) examined the accuracy of microbial markers in diagnosing MDD, identified sex-specific gut microbiota signatures, and evaluated diagnostic performance using the area under the receiver operating characteristic curve (AUC). Analysis of the diagnostic performance sensitivity of these microbial signatures showed area under the curve (AUC) values ranging from 0.79 to 0.92 for females and 0.79 for males with MDD. An additional study (19) investigated the risk of developing MDD within five years following an initial dysbiosis diagnosis and found a stronger association between dysbiosis and MDD diagnosis in males (HR:3.54, 95% CI: 1.75–7.14) compared to females HR:2.61 (95% CI: 1.74 – 3.92). (Refer to Table 1.5 ).

Our review results are consistent with existing literature, emphasizing notable differences in the gut microbiota composition between individuals diagnosed with MDD and controls (9–18). These differences primarily involve microbial diversity and the prevalence of specific bacterial taxa. Four separate studies highlighted discernible variations in microbial diversity in both male and female MDD patients compared to their healthy counterparts (32–35). Notably, one study observed no significant difference in microbial diversity between male and female MDD patients (32). Most case-control studies found no alterations in alpha diversity among female MDD subjects compared to female healthy controls, while one study (35) reported reduced alpha diversity in female MDD subjects relative to healthy controls, mirroring a similar trend observed in male MDD subjects.

All studies examining beta diversity identified significant differences between female MDD patients and healthy controls (32–34), with two studies also noting distinct variations in beta diversity between male MDD patients and healthy controls (32, 33). One study focusing solely on females revealed alterations in beta diversity at the species level in female MDD subjects (34). Despite observing higher alpha diversity in healthy females compared to healthy males, this distinction was not observed in the depressed state (33).

These findings suggest gender-specific differences in the gut microbiome that may be influenced by various factors, such as the menstrual cycle stage, diet, age, and environmental factors. Overall, the results emphasize distinct beta diversity in both female and male MDD patients compared to healthy controls (32–34), with potential discrepancies in alpha diversity stemming from methodological variations in assessing microbiome diversity and the influence of confounding factors. Further clinical studies are warranted to comprehensively investigate the role of the gut microbiome in both male and female MDD patients, considering the potential implications for other diseases prevalent in females. The studies used various techniques, including 16S rRNA gene sequencing and shotgun metagenomic sequencing (SMG), to assess the microbiome. However, discrepancies in the methodologies employed suggest the need for standardized approaches in future research.

The current study reveals notable differences in the gut microbiome profiles of females with MDD in comparison to both healthy controls (HCs) and males with MDD. Analyzing data from four cross-sectional studies (32–35), we identified several differential abundances in bacterial clusters in both female and male MDD groups relative to HCs. These alterations primarily involved Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, Fusobacteria, and Verrucomicrobia, which represent the dominant bacterial phyla in the human gut (29) Notably, despite previous literature suggesting Bacteroides as a signature gut microbe of MDD (17), our review unveiled inconsistent directions of compositional changes, which may be partly attributed to variations in the severity of depression. Hu et al. (35) also highlighted the influence of depression severity on gut microbiome alterations. Furthermore, a recent review on MDD and the gut microbiome by Knuesel and Mohajeri (22) identified disparities across studies, suggesting potential variations arising from different underlying causes and manifestations of depression across different age groups. Notably, the influence of confounding factors, such as the stage of the menstrual cycle, dietary patterns, physical activity, and environmental factors (28, 36) may contribute to the discrepancies observed in the findings. The current body of literature, however, lacks a sufficient number of studies investigating sex-specific differences in the gut microbiome concerning MDD.

Several studies have indicated associations between specific bacterial taxa and the severity of depressive symptoms in individuals with MDD, as observed in the works of recent studies (19, 32–35). Notably, certain genera, including Anaerotruncus, Parabacteroides, and Anaeroglobus, were linked to increased depressive symptoms, whereas the presence of Clostridium XIVa, Erysipelotrichaceae incertae sedis, Streptococcus, Romboutsia, and Fusicatenibacter was associated with reduced symptoms. Despite Chen et al. (32) documenting correlations in males with MDD, the literature remains relatively limited and heterogeneous. A comprehensive review by Knuesel and Mohajeri (22) emphasized a negative correlation between Faecalibacterium and depressive symptoms, coupled with a positive correlation in cases of remission and improved quality of life. Similarly, Jiang et al. (9) demonstrated a negative association between Faecalibacterium prausnitzii (FP) and the severity of depressive symptoms. Likewise, Hu et al. (35) utilized shotgun sequencing, revealing a negative correlation between Faecalibacterium and depressive symptoms in a mixed-sex group of MDD patients with moderate depression. However, this correlation was not observed in the subgroup with severe depression, suggesting the potential confounding impact of depression severity. While the reviewed studies did not definitively establish the specific link between Faecalibacterium and the severity of depressive symptoms in females with MDD, they reported varying levels of Faecalibacterium in females with MDD compared to HCs. Despite existing disparities, Faecalibacterium remains a critical bacterial taxon of interest, previously associated with gut health and overall host well-being (37). Further exploration through improved methodological approaches, including controlling for sex as a biological factor and considering depression severity, is warranted to clarify the precise contribution of specific bacterial taxa to disease development or their status as a consequence of the disease.

The evaluation of the diagnostic efficacy of microbial markers in females with MDD is still in its preliminary stages. Two separate studies have identified sex-specific gut microbial markers capable of distinguishing between males with MDD, females with MDD, and HCs (33, 34). Examination of how well these microbial signatures perform diagnostically showed that the area under the curve (AUC) values ranged from 0.79 to 0.92 for females and 0.79 for males diagnosed with MDD. Although these findings are limited due to sparse data and disparate methodologies, the identification of sex-specific microbial panels with potential diagnostic capabilities highlights the significance of sex stratification in MDD case-control studies. Additionally, this discovery provides crucial insights into the divergent pathophysiological mechanisms and prognostic variances between male and female MDD patients. Moreover, a study by Chung et al. (19) observed sex-specific disparities in the risk of developing MDD within five years following an initial dysbiosis diagnosis, with a notably stronger association among males compared to females. While specific microbial markers were not identified, this observation, in conjunction with existing evidence indicating the presence of sex-specific gut microbial profiles in MDD, emphasizes the potential for comprehensive characterization of sex-specific risk factors and the formulation of non-invasive gut microbial-based screening or diagnostic tools for MDD.

Include the heterogeneity in measurement and reporting methods, as well as the use of limited sample sizes and study designs, which impose certain restrictions on the interpretability of the results. However, these findings provide critical insights into the potential role of the gut microbiome in the context of MDD, especially concerning sex-specific differences. Future research should emphasize the inclusion of sex as a biological factor, conduct longitudinal studies to understand microbiome changes in response to clinical variations better, and carefully control for confounding factors to establish a more comprehensive understanding of the complex interplay between the gut microbiome and MDD.