Targeted delivery of galectin-1 via lactococcus lactis: a novel therapeutic strategy for inflammatory bowel diseases

CUTINE, A; MOROSI, L; BLANCATO, VS; PÉREZ-SÁEZ, J; MORALES, R; MANSELLE-COCCO, M; MASSARO, M; PAPA-GOBBI, R; TOSCANO, M; MAGNI, C; MARIÑO, K; RABINOVICH, G

San Luis

Congreso; LXXI REUNIÓN CIENTÍFICA ANUAL DE LA SOCIEDAD ARGENTINA DE INMUNOLOGÍA (SAI); 2023

SOCIEDAD ARGENTINA DE INMUNOLOGÍA

Inflammatory bowel diseases (IBD) are chronic and progressive diseases that severely affect quality of life, with ulcerative colitis and Crohn´s disease being the most frequent in adults. IBD arises from a combination of genetic and environmental factors leading to exuberant inflammation and pathologic activation of the immune system. Although introduction of TNF-α-neutralizing monoclonal antibodies revolutionized IBD therapy, a third of patients do not respond to this treatment. Thus, the search for new therapeutics is of great importance in IBD. In this regard, development of genetic engineering has given rise to genetically modified probiotics for delivery of therapeutic mediators. Recently, we reported the dysregulation of galectin-1 (Gal1), an immunomodulatory β-galactoside-binding protein in mucosal tissue of patients with IBD and validated its therapeutic potential in experimental colitis. These results prompted us to investigate a selective delivery method of Gal1 through the oral route. Particularly, we used Lactococcus lactis (L. lactis) genetically engineered to deliver Gal1 as a new therapeutic approach for intestinal inflammation. We generated a novel construct for Gal1 recombinant expression in L. lactis producing higher amounts of bioactive human Gal1, as evidenced by Western-blot, ELISA and a glycan binding assay. The anti-inflammatory effect of Gal1-secreting L. lactis was first evaluated in the 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced model of colitis in Gal1-deficient (Lgals1-/-) mice. Daily intragastric administration of 1 x 109 CFU of Gal1-secreting L. lactis led to active delivery of Gal1 at the ileum and colon, measured by ELISA of tissue homogenates from Lgals1-/- TNBS-treated mice. Remarkably, treatment with Gal1-secreting L. lactis significantly decreased weight-loss (p