Growth differentiation factor 11 delivered by dairy Lactococcus lactis strains modulates inflammation and prevents mucosal damage in a mice model of intestinal mucositis

Abstract

Mucositis is an inflammation of the gastrointestinal mucosa that debilitate the quality of life of patients undergoing chemotherapy treatments. In this context, antineoplastic drugs, such as 5-fluorouracil, provokes ulcerations in the intestinal mucosa that lead to the secretion of pro-inflammatory cytokines by activating the NF-κB pathway. Alternative approaches to treat the disease using probiotic strains show promising results, and thereafter, treatments that target the site of inflammation could be further explored. Recently, studies reported that the protein GDF11 has an anti-inflammatory role in several diseases, including in vitro and in vivo results in different experimental models. Hence, this study evaluated the anti-inflammatory effect of GDF11 delivered by Lactococcus lactis strains NCDO2118 and MG1363 in a murine model of intestinal mucositis induced by 5-FU. Our results showed that mice treated with the recombinant lactococci strains presented improved histopathological scores of intestinal damage and a reduction of goblet cell degeneration in the mucosa. It was also observed a significant reduction of neutrophil infiltration in the tissue in comparison to positive control group. Moreover, we observed immunomodulation of inflammatory markers Nfkb1, Nlrp3, Tnf, and upregulation of Il10 in mRNA expression levels in groups treated with recombinant strains that help to partially explain the ameliorative effect in the mucosa. Therefore, the results found in this study suggest that the use of recombinant L. lactis (pExu:gdf11) could offer a potential gene therapy for intestinal mucositis induced by 5-FU.

Comprehensive Probiogenomics Analysis of the Commensal Escherichia Coli CEC15 as a Potential Probiotic Strain

“…Likewise, no signi cant variation in microbiota composition, richness and diversity was observed following probiotic administration, even though the microbiota of CEC15-treated mice seemed closer to that of control mice than those treated with strain EcN. As expected, 5-FU administration led to a consistent in ammatory process in the ileum which was characterized by excessive weight loss, increase in intestinal permeability, neutrophils in ltration, and an accentuated destruction of ileal epithelial structure, as it has been reported by many studies before [106, 107,110]. No strain was able to prevent weight loss, a result that is not surprising given the aggressive nature of the 5-FU therapy.…”

“…Nevertheless, CEC15, yet not EcN, partially prevented the weight loss, and such protection is known to depend on the probiotic strain, as has been observed with many other probiotics [108,110,[116][117][118][119][120][121].…”

“…To assess and compare their health effects, CEC15 and EcN strains were also tested in a mice 5-FU mucositis model. The reason for selecting this model is its high severity, which would enable the observation of notable protective effects promoted by any potential probiotic strains [4,104,105] and the fact that it is a well-established model [106][107][108][109][110]. Furthermore, it is crucial to emphasize the absence of studies assessing the impact of both EcN and CEC15 on the 5-FU-induced intestinal mucositis model, with the exception of two studies evaluating the effects of EcN supernatant [111,112].…”

Recombinant probiotic Lactococcus lactis delivering P62 mitigates moderate colitis in mice

“…Another study used a DSS-induced IBD mouse model to compare the effects of the NCDO2118 wild-type strain and a recombinant strain producing 15-lipoxygenase-1 (Carvalho, 2016). Finally, cloning of the Growth Differentiation Factor 11(GDF11) protein in this strain enhanced its anti-inflammatory against mucositis compared to the wild-type strain (Américo et al, 2023). However, this work was carried out in a different inflammation context, i.e., mucositis, an inflammation of the mucous membranes of patients undergoing chemotherapy.…”