AbstractBackgroundOver‐activation of endometrial inflammasome NALP‐3 (Nod‐like receptor family pyrin domain containing 3) can be found in recurrent pregnancy loss (RPL) women probably due to leaky gut and passage into circulation of lipopolysaccharides (LPS). Leaky gut can be caused by exposure to gluten in RPL women genetically predisposed to celiac disease, positive for Human Leukocyte Antigen (HLA)‐DQ2/DQ8 haplotype. Oral administration of Bifidobacterium longum ES1 (GliadinES®) can inactivate gluten peptides toxicity to epithelial gut cells and improve gut barrier.MethodsWe investigated by enzyme‐linked immunoassay: (a) serum levels of LPS and zonuline (a marker of leaky gut); (b) LPS, NALP‐3, caspase‐1, interleukine (IL)‐1β and IL‐18 concentration in endometrial fluids, in untreated women with uncomplicated pregnancies (negative HLA‐DQ2/DQ8 haplotype) (n = 22) and in women with unexplained RPL, HLA‐DQ2/DQ8 positive (n = 22), before and after daily oral administration for 3 months of GliadinES®.ResultsRLP women showed higher serum levels of LPS (p < 0.0001) and higher concentration of LPS (p < 0.0001), NALP‐3 (p < 0.01); Caspase‐1 (p < 0.0001), IL‐1β (p < 0.0001), and IL‐18 (p < 0.0001) in endometrial fluids compared to controls. GliadinES® treatment significantly reduced serum levels of both LPS (p < 0.0001) and zonuline (p < 0.01), as well as LPS (p < 0.5), NALP‐3 (p < 0.01), Caspase‐1 (p < 0.001), IL‐1β (p < 0.001), and IL‐18 (p < 0.01) concentrations in endometrial fluids of RPL women.ConclusionsRPL women positive for HLA‐DQ2/DQ8 haplotype show increased circulating and endometrial levels of LPS and endometrial inflammasome NALP‐3 over‐activation. Oral administration of GliadinES® can reduce gut permeability, decrease serum levels of LPS and, contextually, improve endometrial inflammation in this specific subset of RPL women.