Diambra, L.

The gut microbiome is a key regulator of host immunity; however, microbial factors defining basal immune homeostasis remain poorly understood. While large-scale multi-omics have mapped microbial influences on stimulated immune responses, the fundamental dialogue maintaining resting inflammatory tone is often obscured by systemic confounders. In this study, we demonstrate that failing to account for sex leads to a Simpson's paradox. Using a multivariate framework, we reveal a profound sexual dimorphism in the gut-immune homeostatic axis. In women not using oral contraceptives, we identified consistent homeostatic anchors, including Bacteroides ovatus, Faecalitalea cylindroides, and Firmicutes bacterium CAG:83, which correlate negatively with TNF-alpha and IL-1beta levels. This regulatory network is virtually abolished in women using oral contraceptives, revealing an associative silencing where exogenous synthetic hormones uncouple the microbiome from host immune sentinels. Furthermore, taxa such as Butyricimonas virosa exhibit sign reversals in cytokine associations depending on hormonal context, highlighting the plasticity of microbial immunomodulation. Our findings establish that basal immune homeostasis is a sex-specific construct and underscore the need for endocrine stratification to accurately decipher the regulatory architecture.