Major depressive disorder (MDD) stands as the most prevalent mental illness, posing a significant challenge for public health services. It constitutes a substantial share of the worldwide disease burden (Herrman et al., 2019). The lifetime prevalence of depression in women, ranging from 20% to 25%, is about twice as likely as in men, ranging from 7% to 12% (Silverstein et al., 2017; Wang et al., 2017). Depression prevalence is generally low before puberty, and boys are more likely to be diagnosed with depression in this age group (Douglas and Scott, 2014). Following puberty, the increase in depression is more significant in girls than in boys, and this trend continues into old age (Luppa et al., 2012). Moreover, female depression patients often exhibit more atypical symptoms, such as hypersomnia and increased appetite, compared to men (Lamers et al., 2013). They are also more prone to somatic symptoms like fatigue, pain, and low energy (Silverstein et al., 2013).

During some special physiological periods, women commonly experience significant anxiety and depression symptoms, and definitions such as perinatal depression (Force et al., 2019) and perimenopausal depression (Willi and Ehlert, 2019) were gradually accepted. Middle-aged women (40–64 years old) present higher levels of sleep disturbance and psychological distress than other age groups (Huang and Wu, 2017), with many experiencing perimenopause. Importantly, they have a higher risk of experiencing anxiety and depression after hospital treatment for COVID-19 (Torjesen, 2021). Additionally, the prevalence of depression at this age is higher than at other stages in women (Huang et al., 2019). Antidepressants remain the first-line choice for treating female middle-aged depression (MAD). However, its efficacy still needs to be improved and it should take into account the possible influence of both hormone replacement therapy and menopausal status on antidepressant response (Kornstein, 2001; Strawn et al., 2023).

Extensive research offers evidence supporting the interplay of stress, sex hormones, and intrapersonal susceptibility as an explanation for the disproportionate increase in rates of female depression (Dunn et al., 2012; Slavich and Sacher, 2019). Recently, there has been considerable attention directed at the potential involvement of the malfunction of the gut-brain axis in the development of depression (Simpson et al., 2021; Thompson et al., 2023; Yuan et al., 2021). This bidirectional communication axis effectively connects stress, hormones, metabolism, and brain function (Varanoske et al., 2022). Importantly, the implication of gut microbiota dysbiosis in depression has also been extensively documented. For example, individuals with depression exhibit disruptions in the gut microbiota and its metabolites (Yang, Z.L. et al., 2020; Zheng et al., 2020). In turn, alterations in the gut microbiota induce depressive-like behaviors and reinforce the risk of depression (Kelly et al., 2016; Tillmann et al., 2019; Zhang, Y.Y. et al., 2022; Zheng et al., 2016). Correspondingly, changes in bacterial composition are also a hallmark of female depression (Chen et al., 2021; Song et al., 2022). However, information is scarce regarding the characteristics and functional changes of gut microbiota as well as its potential mechanism in female MAD. Given that changes in hormone levels and the influence of genetic factors cannot fully explain the pathogenesis of female MAD (Kuehner, 2017; Pasquali et al., 2018), exploring the gut microbiota characteristics of MAD and its potential mechanisms might provide a theoretical basis for supplemental treatment methods for female MAD.

The medium- and long-chain fatty acids (MLCFAs) play a role in the regulation of depression (Mocking et al., 2015; Shoji et al., 2022), and targeting fatty acid intake was also involved in the prevention and treatment of female MAD (Li et al., 2020a, 2020b). Importantly, the gut microbiota can regulate the brain's gut axis by influencing fatty acid metabolism (Zapata et al., 2022). Taken together, these findings strongly suggest that dysbiosis of the gut microbiota may be involved in the pathogenesis of female MAD by affecting fatty acids metabolism.

In the present study, we explored the characteristic changes in the gut microbes of female MAD and whether these changes are associated with depressive symptoms. Considering the impact of age and gender on gut microbiota in mice (Ma et al., 2020; Parker et al., 2022), we carried out a fecal microbiota transplantation (FMT) from female MAD to a microbiota-depleted antibiotic middle-aged female mice and observed alterations in the lipid metabolism function of gut microbes and changes in plasma MLCFAs in the mice.