Oral administration of Bifidobacterium longum ES1 reduces endometrial inflammation in women with recurrent pregnancy loss.

BACKGROUND: Over-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. METHODS: We 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)-1ß 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®. RESULTS: RLP 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-1ß (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-1ß (p < 0.001), and IL-18 (p < 0.01) concentrations in endometrial fluids of RPL women. CONCLUSIONS: RPL 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.

Synthetic PreImplantation Factor (sPIF) reduces inflammation and prevents preterm birth.

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality and spontaneous PTB is a major contributor. The preceding inflammation/infection contributes not only to spontaneous PTB but is associated with neonatal morbidities including impaired brain development. Therefore, control of exaggerated immune response during pregnancy is an attractive strategy. A potential candidate is synthetic PreImplantation Factor (sPIF) as sPIF prevents inflammatory induced fetal loss and has neuroprotective properties. Here, we tested maternal sPIF prophylaxis in pregnant mice subjected to a lipopolysaccharides (LPS) insult, which results in PTB. Additionally, we evaluated sPIF effects in placental and microglial cell lines. Maternal sPIF application reduced the LPS induced PTB rate significantly. Consequently, sPIF reduced microglial activation (Iba-1 positive cells) and preserved neuronal migration (Cux-2 positive cells) in fetal brains. In fetal brain lysates sPIF decreased IL-6 and INFγ concentrations. In-vitro, sPIF reduced Iba1 and TNFα expression in microglial cells and reduced the expression of pro-apoptotic (Bad and Bax) and inflammatory (IL-6 and NLRP4) genes in placental cell lines. Together, maternal sPIF prophylaxis prevents PTB in part by controlling exaggerated immune response. Given the sPIF`FDA Fast Track approval in non-pregnant subjects, we envision sPIF therapy in pregnancy.