The female immune system operates within an evolutionary stability-plasticity trade-off, where the physiological demands of pregnancy necessitate a considerable degree of regulatory T cell (Treg) plasticity. This essential flexibility, however, inherently lowers the threshold for autoimmune dysregulation. Recent mechanistic evidence has identified Xist ribonucleoprotein complexes as female-specific autoantigens that constitutively sensitize innate sensors, thereby establishing an intrinsic state of autoimmune priming. This review introduces the Metabolic Calibration Hypothesis, proposing that commensal microbiota-derived metabolites function as essential extrinsic stabilizers specifically required to maintain female immune homeostasis. Beyond canonical short-chain fatty acid signaling, we synthesize emerging evidence regarding host-microbiota metabolic integration, emphasizing the roles of histone lactylation in the reproductive tract and the ligand-specific activation of nuclear receptors by secondary bile acids in orchestrating Treg fate. We posit that female immune pathologies, ranging from systemic autoimmunity to gynecologic malignancies, represent a context-dependent dysregulation or co-option of this metabolic calibration. Ultimately, we discuss the clinical necessity of transitioning from generic biotic interventions toward Sexual Dimorphic Metabotyping, providing a precision framework to restore physiological tolerance and manage sex-biased immune pathologies.
Huang et al. (Tue,) studied this question.