TLR4 genetic variants in the interface between gut-brain axis and Natalizumab response in Multiple Sclerosis patients.

Background: Multiple Sclerosis (MS) is an inflammatory, demyelinating and degenerative disease that affects Central Nervous System (CNS). Recent researches indicate that Disease-Modifying Therapies (DMTs) used for treating MS, aside from their immunomodulatory effects, could also influence the intestinal microbiota, thereby contributing to the modulation of the immune response. In this sense, Natalizumab (NTZ) is a monoclonal antibody (mAb), safe and efficacious for MS treatment responsible for the inhibition of leukocyte migration in CNS, thus attenuating inflammatory processes. Due to Natalizumab's ability to reduce T cell trafficking in the intestinal mucosa, our hypothesis investigates whether genetic variants in TLR4 can influence therapeutic response. Methods: A total of 104 blood samples were collected from patients admitted to two university hospitals in Rio de Janeiro, with approval from the ethics committee (CAAE 5,782,087). Genomic DNA was extracted from leukocytes for subsequent rs10759931 genotyping by TaqMan^® PCR assay. TLR4 rs10759931 functional assay was conducted on monocytes isolated from the peripheral blood of healthy volunteers, followed by mRNA expression assessment. Results: Among the patients, 9 confirmed therapeutic failure to NTZ treatment. A higher frequency of the AA genotype was observed in the good response group (p>0,0002) associated with the decrease of TLR4 mRNA expression, suggesting a possible protective role. Conclusions: Given to the genetic diversity of the Brazilian population, our preliminary findings suggest the necessity to investigate the role of TLR4 rs10759931 as a potential pharmacogenetic predictor for MS patients' response to NTZ. Currently, our research into the rs273719 polymorphism in the TLR4 gene is ongoing. Regarding the importance of the gut-brain axis in the mechanisms related to the therapeutic effect of Natalizumab, our preliminary data show a possible biomarker of the good response of the AA genotype.