Health disparities are significantly influenced by social disadvantage (SD) and psychosocial stressors (PS), particularly when exposure begins prenatally. The mechanisms linking these factors to adverse health outcomes remain unclear. Systemic chronic inflammation is often associated with SD/PS-related morbidities. The gut microbiome (GM), known to modulate the immune system and influence systemic inflammation, presents a potential mechanistic pathway. While the intersection between GM and psychosocial inequities is increasingly recognized, few studies have examined their perinatal impact on human gut microbial community structure and function, especially considering both maternal and infant GM and inflammatory phenotypes. This study uses a prospective birth cohort to identify the distinct association of exposure to SD and PS on GM structure and function in mothers and their infants, aiming to understand the dynamic interaction between the GM and social determinants of health for potential interventions.

Existing literature has primarily focused on either maternal psychological state or socioeconomic status's impact on the gut microbiome during pregnancy, but not both. Many studies have employed 16S rRNA analysis, limiting taxonomic and metabolic profiling. Furthermore, few studies have examined paired maternal and infant biologic transfer of bacteria and inflammatory phenotypes. Studies exploring the relationship between socioeconomic status and the gut microbiome in infants and children have revealed correlations, but the specific mechanisms and the combined effects of SD and PS remain largely unexplored. Animal models and smaller human studies have shown an impact of stress on the gut microbiome and inflammatory responses, creating a context for the current research.

This prospective case-control study used data from the Early Life Adversity Biological Embedding and Risk for Developmental Precursors of Mental Disorders Study (eLABE). 121 mother-child dyads were included, with available maternal prenatal 3rd trimester and infant 4-month fecal samples. SD and PS latent factor variables were calculated using previously published methods. Targeted bacterial 16S rRNA gene sequencing was performed for all 121 dyads. Whole metagenomic shotgun (WMS) sequencing was conducted on 89 dyads. Maternal prenatal circulating cytokines (IL-6, IL-8, IL-10, and TNFα) were also measured. Data analysis included alpha and beta diversity analyses (Faith phylogenetic diversity, UniFrac distance, Bray-Curtis distance, Aitchison distance), Dirichlet Multinomial Mixtures (DMM) clustering, Random Forest machine learning, linear discriminant analysis effect size (LEfSe), and ANCOM-BC analysis to identify discriminatory taxa and pathways associated with SD and PS. The study adhered to ethical regulations and STROBE guidelines.

Social disadvantage and psychosocial stress scores were significantly, but only moderately correlated. In children, alpha diversity was significantly positively correlated with SD and PS, possibly due to lower breastfeeding rates among high-SD mothers. Beta diversity between mother-child GMs showed significant negative correlations with SD and PS. DMM clustering revealed distinct GM profiles in children based on high/low SD and PS, but not in mothers. High-SD mothers had significantly more variable GMs than low-SD mothers. WMS sequencing identified discriminatory bacterial species associated with SD and PS in mothers and children. In mothers, *Lawsonibacter asaccharolyticus* was associated with low SD, while several *Bifidobacterium* species were associated with high SD and high PS. In children, *Enterobacter nimipressuralis* and *Klebsiella pneumoniae* were associated with high SD, and *B. infantis* with low SD. Metabolic pathway analysis revealed that carbohydrate degradation pathways were associated with high SD in mothers, and L-glutamate and L-glutamine synthesis with high SD in children. A significant association was observed between infant GM and maternal prenatal IL-6, with some overlapping taxa and pathways identified in the SD/PS analysis.

This study provides the first human evidence separating the effects of SD and PS on the gut microbiome, revealing distinct taxonomic and functional features. The higher predictive accuracy for SD compared to PS suggests unique underlying mechanisms for each. The significant association between infant GM and maternal IL-6 highlights the potential link between prenatal inflammation and early-life microbiome development. The findings support the concept of early-life programming and potential long-term health consequences associated with SD and PS, offering opportunities for interventions to modify the gut microbiome and improve health outcomes. The overlap between specific taxa and pathways associated with low maternal IL-6 and high maternal SD suggests a possible interconnected pathway affecting health inequities.

This study identified distinct gut microbiome features associated with prenatal social disadvantage and psychosocial stress in mothers and their infants, suggesting unique mechanistic pathways for each. The findings highlight the potential for interventions targeting the gut microbiome to mitigate health inequities. Future research should focus on longitudinal studies to determine the long-term stability of these microbiome signatures and their causal relationship with health outcomes.

The study's findings are associations and cannot establish causality. The study population is geographically limited, and results may not be generalizable to other populations. The smaller sample size for cytokine analysis necessitates validation in larger cohorts. The high degree of collinearity between race and SD limited exploration of race as a separate variable. Longitudinal studies are needed to fully understand the long-term impacts of these microbiome changes.