How Chronic Endometritis Hijacks the Immune System and What Doctors Can Do

Chronic endometritis affects reproductive-age women and is a leading but underrecognized driver of infertility and recurrent pregnancy loss. Unlike acute endometritis caused by classic pathogens such as Chlamydia trachomatis, CE is associated with a broader and more complex microbial picture—including Streptococcus, Enterococcus faecalis, E. coli, and Ureaplasma urealyticum—and importantly, pathogen cultures are sometimes negative, implicating multidrug-resistant organisms or non-infectious triggers.

The immunological core of CE centers on pattern recognition receptor signaling. Lipopolysaccharide (LPS) from gram-negative bacteria activates TLR4, while TLR2 responds to a wider range of microbial PAMPs and endogenous danger signals like HMGB1. These receptors engage the MyD88/NF-κB and TRIF/IRF pathways, sustaining production of IL-6, TNF-α, and CXCL8 and driving leukocyte infiltration. Pharmacological modulation—such as Epimedium glycosides inhibiting TLR4/NF-κB while activating Nrf2—demonstrates the therapeutic tractability of this axis. The NLRP3 inflammasome adds another inflammatory layer: LPS-induced endoplasmic reticulum stress activates TXNIP, which triggers NLRP3 and IL-1β release. Animal models and in vitro studies confirm this pathway, though direct evidence in human CE tissue is still lacking.

Metabolic reprogramming of immune cells further sustains CE. Pro-inflammatory M1 macrophages and effector T cells shift toward glycolysis, while anti-inflammatory Tregs and M2 macrophages rely on fatty acid oxidation. In CE, reduced TGF-β and IL-4 amplify glycolytic flux, suppressing FOXP3 expression and Treg stability, pushing the endometrial immune environment toward Th1/Th17 dominance. Additionally, miRNAs post-transcriptionally regulate IRAK1, TRAF6, and MAPK/NF-κB components, modulating cytokine output and macrophage polarization. Exosome-derived miRNAs add another layer of intercellular inflammatory crosstalk. DNA methylation changes also alter immune gene expression, compounding the chronicity of the condition.

Therapeutically, empirical antibiotics—primarily doxycycline and metronidazole—remain the first-line approach and have demonstrated histological resolution with partial improvements in IVF pregnancy and live birth rates. However, a meaningful subset of patients fails standard treatment, pointing to antibiotic resistance and immune-driven persistence as key unresolved challenges. Intrauterine infusion therapies (e.g., platelet-rich plasma, granulocyte colony-stimulating factor) and probiotic interventions targeting the endometrial microbiome are emerging as adjunctive strategies, though clinical evidence remains preliminary.

Caveats are significant: diagnostic criteria for CE are not standardized across centers; most mechanistic data on NLRP3 and metabolic reprogramming derive from animal models or in vitro systems; and the miRNA landscape has been characterized mainly at the single-cell-type level, requiring validation in human organoids and endometrial tissue. The interplay among the microbiome, immune signaling, and epigenetics in CE remains incompletely mapped.