Spontaneous abortion (SA) is a challenging and frustrating obstetric complication. Immune dysregulation at the mother–fetal interface has long been recognized as a threat to pregnancy maintenance. Decidual macrophages are key gatekeepers for immune homeostasis at the mother–fetal interface, characterized by their heterogeneity and high plasticity. Abnormalities in their number, function, and phenotype are strongly associated with pregnancy loss. However, the specific regulation mechanisms remain elusive. Here, we outline the origin and identity of the endometrial macrophages and review their diverse changes in phenotypes and functions to pregnancy initiation. More importantly, we highlight the underlying mechanisms mediating aberrant changes in macrophage polarization and functions in the context of SA, involving epigenetic landscape dysregulation, metabolic reprogramming, and aberrant communication between macrophages and other component cells at the maternal–fetal interface. Altogether, these provide a clear framework for understanding the crucial roles and prospective therapeutic targets of macrophages in SA.

Previous studies to date have demonstrated a significant relationship between spontaneous abortion (SA) and rheumatoid arthritis (RA). Moreover, positive links between gut microbiota and SA, RA have been discussed in observational studies. However, observational studies are prone to bias and result in the causality between gut microbiota and the comorbidity of SA and RA remaining unclear. We therefore aimed to investigate this using a two-sample Mendelian randomization study. A total gut microbiota-related sample size of 18,340 participants from genome-wide association studies was obtained. The summary statistics data for SA (98,453 subjects) and RA (1,53,457 subjects) were obtained from the MRC integrative epidemiology unit genome-wide association studies database as the outcome of gut microbiota. Inverse variance weighted, weighted median, weighted mode, MR-Egger and simple mode were used to assess the causal effects. Sensitivity analyses were applied using the Cochran’s Q -statistic, MR-Egger, the leave-one-out analysis, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO). In addition, the statistical power was calculated to evaluate the cause-and-effect. We identified genus Alloprevotella as a shared protective factor for both SA (odds ratio [OR] = 0.903, 95% CI: 0.817–0.997, P = .043) and RA (OR = 0.826, 95% CI: 0.722–0.945, P = .005). In addition, increased abundance of genera Actinomyces (OR = 1.213, 95% CI: 1.025–1.435, P = .025), Subdoligranulum (OR = 1.208, 95% CI: 1.036–1.408, P = .016), and Veillonella (OR = 1.167, 95% CI: 1.003–1.358, P = .046) was causally associated with a higher risk of SA. For RA, decreased abundance of genera ChristensenellaceaeR (OR = 0.736, 95% CI: 0.570–0.950, P = .018), Enterorhabdus (OR = 0.806, 95% CI: 0.684–0.950, P = .010), Prevotella7 (OR = 0.895, 95% CI: 0.808–0.991, P = .032) and Hungatella (OR = 0.818, 95% CI: 0.691–0.970, P = .021), along with increased abundance of the Ruminococcus gauvreauii group (OR = 1.406, 95% CI: 1.112–1.777, P = .004), was linked to elevated disease risk. Sensitivity analyses, including MR-PRESSO, MR-Egger, and Cochran’s Q -statistic, revealed no evidence of heterogeneity or pleiotropy. Furthermore, leave-one-out analysis confirmed the robustness of the causal estimates. Our study identified several gut microbiota genera with putative causal effects on SA (4 genera) and RA (6 genera). Notably, Alloprevotella emerged as a shared protective factor for both conditions. These findings suggest that gut microbiota, particularly Alloprevotella , may play a causal, protective role in the shared etiology of SA and RA, highlighting a potential common therapeutic target for future research and clinical management.