Gut microbiota dysbiosis contributes to depression-like behaviors via hippocampal NLRP3-mediated neuroinflammation in a postpartum depression mouse model

Xu Q; Sun L; Chen Q; Jiao C; Wang Y; Hatherley Li; Xie J; Zhu F; Wang J; Zhang, De Wei; Liangzhen Xie; Hsin-Hung Wu; Zuo Z; Chen X

doi:10.1016/j.bbi.2024.04.002

Postpartum · Mental Health

Gut microbiota dysbiosis contributes to depression-like behaviors via hippocampal NLRP3-mediated neuroinflammation in a postpartum depression mouse model

Xu Q, Sun L, Chen Q, Jiao C, Wang Y, Li H, Xie J, Zhu F, Wang J, Zhang W, Xie L, Wu H, Zuo Z, Chen X

Published July 2024 Brain, behavior, and immunity, 119, 220-235

DOI 10.1016/j.bbi.2024.04.002 PMID 38599497

Abstract

Postpartum depression (PPD) is a severe mental disorder that affects approximately 10---20% of women after childbirth. The precise mechanism underlying PPD pathogenesis remains elusive, thus limiting the development of therapeutics. Gut microbiota dysbiosis is considered to contribute to major depressive disorder. However, the associations between gut microbiota and PPD remain unanswered. Here, we established a mouse PPD model by sudden ovarian steroid withdrawal after hormone-simulated pseudopregnancy-human (HSP-H) in ovariectomy (OVX) mouse. Ovarian hormone withdrawal induced depression-like and anxiety-like behaviors and an altered gut microbiota composition. Fecal microbiota transplantation (FMT) from PPD mice to antibiotic cocktail-treated mice induced depression-like and anxiety-like behaviors and neuropathological changes in the hippocampus of the recipient mice. FMT from healthy mice to PPD mice attenuated the depression-like and anxiety-like behaviors as well as the inflammation mediated by the NOD-like receptor protein (NLRP)-3/caspase-1 signaling pathway both in the gut and the hippocampus, increased fecal short-chain fatty acids (SCFAs) levels and alleviated gut dysbiosis with increased SCFA-producing bacteria and reduced Akkermansia in the PPD mice. Also, downregulation of NLRP3 in the hippocampus mitigated depression-like behaviors in PPD mice and overexpression of NLRP3 in the hippocampal dentate gyrus induced depression-like behaviors in naïve female mice. Intriguingly, FMT from healthy mice failed to alleviate depression-like behaviors in PPD mice with NLRP3 overexpression in the hippocampus. Our results highlighted the NLRP3 inflammasome as a key component within the microbiota-gut-brain axis, suggesting that targeting the gut microbiota may be a therapeutic strategy for PPD.

Topics

Postpartum Mental Health Postpartum Depression

By this author

Reproductive Aging · Ovarian Aging

Impacts of fetal/infant and adolescent exposure to famine on age at menopause in Chinese women

Wang H et al., 2025 Maturitas

Early-life nutritional deprivation may influence lifelong health, but its role in the broader process of reproductive aging remains underexplored. Guided by the Developmental Origins of Health and Disease framework, this study investigates the impacts of fetal/infant and adolescent exposure to famine on age at natural menopause, a key indicator of reproductive aging. The study sample comprised 4256 women from the China Health and Retirement Longitudinal Study. Participants were categorized into fetal/infant (1959-1962 births) or adolescent (1942-1946 births) famine-exposed cohorts and non-exposed controls. Multivariable linear and logistic regression models were used to assess associations between famine exposure and age at natural menopause or early menopause, adjusting for sociodemographic, economic, and behavioral covariates. Famine exposure was associated with an earlier age at natural menopause: 1.16 years earlier for fetal/infant exposure (β = -0.12, p = 0.002), and 0.72 years earlier for adolescent exposure (β = -0.07, p = 0.014); it was also associated with increased odds of early menopause (odds ratio [OR] = 1.05, 95 % confidence interval [CI] 1.01-1.10). No significant association with premature menopause was observed. Nutritional deprivation during critical developmental windows-particularly adolescence-has distinct, long-term effects on the trajectory of reproductive aging. These observational findings, which cannot establish causality, underscore the importance of early-life nutrition in shaping female reproductive health and are consistent with the Developmental Origins of Health and Disease framework in reproductive health.

Outcomes and Effectiveness · Live Birth Rates

Paternal age does not jeopardize the live birth rate and perinatal outcomes after in vitro fertilization: an analysis based on 56,113 frozen embryo transfer cycles

Liao M et al., 2024 American journal of obstetrics and gynecology

The global trend of delaying childbearing has led to an increasing number of couples seeking in vitro fertilization. The adverse effects of advanced maternal age on pregnancy and perinatal outcomes are well documented, regardless of the conception method. In addition, advanced paternal age may contribute to poor reproductive potential because of high levels of sperm DNA fragmentation. However, it remains challenging to guide older men regarding the effect of paternal age on pregnancy and birth outcomes in the field of assisted reproduction. This study aimed to investigate the association of paternal age with live birth and perinatal outcomes following in vitro fertilization-frozen embryo transfer. A retrospective study was performed at a university-affiliated fertility center, involving women who were younger than 36 years and had undergone frozen embryo transfer from January 2011 to June 2021. Subjects were categorized into 6 groups based on paternal age: <25, 25 to 29, 30 to 34, 35 to 39, 40 to 44, and ≥45 years. A generalized estimating equation logistic regression model was used to account for the clustered nature of data and to adjust for confounders. Paternal age between 25 and 29 years served as the reference group in the logistic regression models. A total of 56,113 cycles who met the inclusion criteria were included in the final analysis. On unadjusted analyses, the reproductive outcome parameters showed a considerable decline with increasing male age. The live birth rate decreased from 47.9% for men aged 25 to 29 years to 40.3% among men aged ≥40 years. Similarly, the clinical pregnancy rate decreased from 54.4% in the reference group to 47.8% in the ≥40 years age group. Conversely, the miscarriage rate increased as male age increased, from 10.2% among men aged 25 to 29 years to 13.5% among men aged ≥45 years. However, the differences in the reproductive outcomes mentioned above were no longer significant in the multivariable models. Compared with the younger controls, advanced paternal age was not associated with a lower chance of live birth (males aged 40-44 years: adjusted odds ratio, 0.94; 95% confidence interval, 0.85-1.04; males aged ≥45 years: adjusted odds ratio, 0.93; 95% confidence interval, 0.79-1.10). In addition, the rates of clinical pregnancy (males aged 40-44 years: adjusted odds ratio, 0.95; 95% confidence interval, 0.85-1.05; males aged ≥45 years: adjusted odds ratio, 0.94; 95% confidence interval, 0.79-1.12) and miscarriage (males aged 40-44 years: adjusted odds ratio, 1.05; 95% confidence interval, 0.85-1.31; males aged ≥45 years: adjusted odds ratio, 1.07; 95% confidence interval, 0.77-1.50) were comparable between the reference and advanced paternal age groups. Furthermore, men in the youngest age group (<25 years) did not have worse pregnancy outcomes than those in the reference group. Regarding perinatal outcomes, there was no difference among the study cohorts in terms of preterm birth, low birthweight, macrosomia, small for gestational age, and large for gestational age, both in the unadjusted and confounder-adjusted models. This study did not demonstrate a significant association between paternal age and live birth and perinatal outcomes after in vitro fertilization-frozen embryo transfer when the female partners were younger than 36 years. With the global trend toward delaying childbirth, our findings provide useful information for counseling patients that increasing paternal age may not adversely affect pregnancy and perinatal outcomes in assisted reproduction.

Environmental Exposures · Endocrine Disrupting Chemicals

Multi-source exposure and health risks of phthalates among university students in Northeastern China

Zhu H et al., 2024 Science of The Total Environment

The endocrine disruptor phthalates (PAEs) are widely used as important chemical additives in a variety of areas around the globe. PAEs are toxic to reproduction and development and may adversely affect the health of adolescents. Risk assessments of exposure to PAEs from different sources are more reflective of actual exposure than single-source assessments. We used personal exposure parameters to estimate the dose of PAEs to 107 university students from six media (including dormitory dust, dormitory air, clothing, food, disposable food containers, and personal care products (PCPs)) and three exposure routes (including ingestion, inhalation, and dermal absorption). Individual factors and lifestyles may affect PAE exposure to varying degrees. Based on a positive matrix factorization (PMF) model, the results indicated that the main sources of PAEs in dust were indoor building materials and plastics, while PCPs and adhesives were the major sources of airborne PAEs. The relative contribution of each source to PAE exposure showed that food and air were the primary sources of dimethyl phthalate (DMP) and dibutyl phthalate (DBP). Air source contributed the most to diethyl phthalate (DEP) exposure, followed by PCPs. Food was the most significant source of diisobutyl phthalate (DiBP), benzyl butyl phthalate (BBP), and bis(2-ethylhexyl) phthalate (DEHP) exposure. Additionally, the exposure of DEHP to dust was not negligible. The ingestion pathway was the most dominant among the three exposure pathways, followed by dermal absorption. The non-carcinogenic risk of PAEs from the six sources was within acceptable limits. DEHP exhibits a low carcinogenic risk. We suggest university students maintain good hygienic and living habits to minimize exposure to PAEs.

Environmental Exposures · Endocrine Disrupting Chemicals

Characteristics and health risks of population exposure to phthalates via the use of face towels

Zhang W et al., 2023 Journal of Environmental Sciences

The production of face towels is growing at an annual rate of about 4% in China, reaching 1.13 million tons by 2021. Phthalates (PAEs) are widely used in textiles, and face towels, as an important household textile, may expose people to PAEs via the skin, further leading to health risks. We collected new face towels and analyzed the distribution characterization of PAEs in them. The changes of PAEs were explored in a face towel use experiment and a simulated laundry experiment. Based on the use of face towels by 24 volunteers, we calculated the estimated daily intake (EDI) and comprehensively assessed the hazard quotient (HQ), hazard index (HI), and dermal cancer risk (DCR) of PAEs exposure in the population. PAEs were present in new face towels at total concentrations of <MDL-2388 ng/g, with a median of 173.2 ng/g, which was a lower contamination level compared with other textiles. PAE contents in used face towels were significantly higher than in new face towels. The concentrations of PAEs in coral velvet were significantly higher than those in cotton. Water washing removed some PAEs, while detergent washing increased the PAE content on face towels. Gender, weight, use time, and material were the main factors affecting EDI. The HQ and HI were less than 1, which proved PAEs had no significant non-carcinogenic health risks. Among the five target PAEs studied, DEHP was the only carcinogenic PAE and may cause potential health risks after long-term exposure. Therefore, we should pay more attention to DEHP.

Related research

Mental Health · Postpartum Depression

Effect of Lactobacillus rhamnosus HN001 in Pregnancy on Postpartum Symptoms of Depression and Anxiety: A Randomised Double-blind Placebo-controlled Trial

Slykerman RF et al., 2017 EBioMedicine Free full text on PubMed Central

Probiotics may help to prevent symptoms of anxiety and depression through several putative mechanisms. The aim of this study was to evaluate the effect of Lactobacillus rhamnosus HN001 (HN001) given in pregnancy and postpartum on symptoms of maternal depression and anxiety in the postpartum period. This was a secondary outcome, the primary outcome being eczema in the offspring at 12 months of age. Design, Setting, A randomised, double-blind, placebo-controlled trial of the effect of HN001 on postnatal mood was conducted in 423 women in Auckland and Wellington, New Zealand. Women were recruited at 14–16 weeks gestation. Women were randomised to receive either placebo or HN001 daily from enrolment until 6 months postpartum if breastfeeding. Modified versions of the Edinburgh Postnatal Depression Scale and State Trait Anxiety Inventory were used to assess symptoms of depression and anxiety postpartum. Australia NZ Clinical Trials Registry: ACTRN12612000196842. Findings: 423 women were recruited between December 2012 and November 2014. 212 women were randomised to HN001 and 211 to placebo. 380 women (89.8%) completed the questionnaire on psychological outcomes, 193 (91.0%) in the treatment group and 187 (88.6%) in the placebo group. Mothers in the probiotic treatment group reported significantly lower depression scores (HN001 mean = 7·7 (SD = 5·4), placebo 9·0 (6·0); effect size -1·2, (95% CI -2·3, -0·1), p = 0·037) and anxiety scores (HN001 12·0 (4·0), placebo 13·0 (4·0); effect size -1·0 (-1·9, -0·2), p = 0·014) than those in the placebo group. Rates of clinically relevant anxiety on screening (score > 15) were significantly lower in the HN001 treated mothers (OR = 0·44 (0·26, 0·73), p = 0·002). Interpretation: Women who received HN001 had significantly lower depression and anxiety scores in the postpartum period. This probiotic may be useful for the prevention or treatment of symptoms of depression and anxiety postpartum.

Mental Health · Postpartum Depression

Is Postpartum Depression a Disease of Modern Civilization?

Hahn-Holbrook J et al., 2014 Current directions in psychological science Free full text on PubMed Central

Access to calorie-dense foods, medicine, and other comforts has made modern humans healthier than our prehistoric ancestors in many respects. However, the epidemics of obesity, diabetes, and cardiovascular disease suggest that there are also drawbacks to modern living. Here, we address the question of whether the dramatic cultural changes that have occurred over the past century have inflated rates of postpartum depression, adding postpartum depression to the list of "diseases of modern civilization." We review evidence from cross-cultural, epidemiological, and experimental studies documenting associations between postpartum depression and modern patterns of early weaning, diets deficient in essential fatty acids, low levels of physical activity, low levels of sun exposure, and isolation from kin support networks, all of which mark significant divergences from lifestyles believed to have been typical throughout human evolutionary history. This "mismatch hypothesis" of postpartum depression integrates research across diverse research areas and generates novel predictions.

Beyond the gut: decoding the gut–immune–brain axis in health and disease

Park JC et al., 2025 Cell Mol Immunol Free full text on PubMed Central

Emerging research underscores the pivotal role of the gut–immune–brain axis, a dynamic bidirectional communication system involving intricate interactions between the gut microbiota, immune responses, and the central nervous system. Gut microbes and their metabolites have profound effects on immune and neurological homeostasis, influencing the development and function of multiple physiological systems. Disruption of the composition of the gut microbiota and barrier integrity has been implicated in various neurological and psychiatric disorders, including autism spectrum disorder, Alzheimer’s disease, Parkinson’s disease, depression, and anxiety. Most insights into these host–microbiota interactions come from preclinical models, revealing both the complexity and potential therapeutic opportunities of the gut–brain communication pathways. This review synthesizes the current understanding of these intricate interactions, exploring how microbiota-driven modulation of the gut and brain barriers, immune signaling, and neuronal pathways, such as those through the vagus nerve, contributes to health and disease. We further explore therapeutic implications, including personalized precision microbiota interventions, microbiome-derived biomarkers, and barrier-strengthening strategies. Advancing this field offers transformative potential for developing innovative, personalized therapies tailored to individual microbiomes and immune profiles, ultimately redefining clinical approaches to neurological and immune-mediated diseases.

Ovarian Hormones · Androgens

Gut microbiota: a hidden player in polycystic ovary syndrome

Senthilkumar H et al., 2025 Journal of translational medicine Free full text on PubMed Central

Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects reproductive-aged women worldwide, causing hormonal imbalances and ovarian dysfunction. PCOS affects metabolic health and increases the risk of obesity, insulin resistance, and cardiovascular disease, in addition to infertility. This review delves deeper into the connections of gut microbiota with PCOS pathophysiology, particularly into its impact on hormone metabolism, obesity, inflammation, and insulin resistance by way of short-chain fatty acids, lipopolysaccharides, and gut-brain axis. Studies also show that changes in the metabolic processes and immune responses are seen in changes in the gut microbiota in PCOS subjects, such as changes in the Bacteroidetes and Firmicutes groups. Some bacteria, like Escherichia and Shigella, have been associated with dysbiosis in patients with PCOS, leading to systemic inflammation and changed hormone levels, which further worsen the clinical symptoms. Therapeutic interventions targeting the gut microbiota comprise probiotics, prebiotics, and fecal microbiota transplantation; these have potential to alleviate the symptoms of PCOS. Other precision microbiome-based therapies include postbiotics, and CRISPR-Cas9 genome editing, which are relatively new avenues toward precision treatment. This complex interlink of gut microbiota and PCOS pathophysiology will open the avenues for possible treatments for hormonal imbalances and metabolic problems that characterize these complex disorders. The review here focuses on the requirement of further studies to be able to elucidate the specific pathways relating gut microbiota dysregulation to PCOS and, thus, improve microbiome-based therapies for better clinical outcomes in affected individuals.

Postpartum › Mental Health › Postpartum Depression

Liangzhen Xie

L Xie

PMID 38599497 38599497 DOI 10.1016/j.bbi.2024.04.002 10.1016/j.bbi.2024.04.002 Xu et al. 2024, Xu 2024

Cite this article

Xu, Q., Sun, L., Chen, Q., Jiao, C., Wang, Y., Li, H., Xie, J., Zhu, F., Wang, J., Zhang, W., Xie, L., Wu, H., Zuo, Z., & Chen, X. (2024). Gut microbiota dysbiosis contributes to depression-like behaviors via hippocampal NLRP3-mediated neuroinflammation in a postpartum depression mouse model. Brain, behavior, and immunity, 119, 220-235. https://doi.org/10.1016/j.bbi.2024.04.002

Keywords

Fecal microbiota transplantation, Gut microbiota, Ovarian hormone withdrawal, Postpartum depression