Lactobacillus delbrueckii CIDCA 133 Ameliorates Chemotherapy-Induced Mucositis by Modulating Epithelial Barrier and TLR2/4/Myd88/NF-κB Signaling Pathway

Abstract

Intestinal mucositis promoted by the use of anticancer drugs is characterized by ulcerative inflammation of the intestinal mucosa, a debilitating side effect in cancer patients undergoing treatment. Probiotics are a potential therapeutic option to alleviate intestinal mucositis due to their effects on epithelial barrier integrity and anti-inflammatory modulation. This study investigated the health-promoting impact of Lactobacillus delbrueckii CIDCA 133 in modulating inflammatory and epithelial barrier markers to protect the intestinal mucosa from 5-fluorouracil-induced epithelial damage. L. delbrueckii CIDCA 133 consumption ameliorated small intestine shortening, inflammatory cell infiltration, intestinal permeability, villus atrophy, and goblet cell count, improving the intestinal mucosa architecture and its function in treated mice. Upregulation of Muc2, Cldn1, Hp, F11r, and Il10, and downregulation of markers involved in NF-κB signaling pathway activation (Tlr2, Tlr4, Nfkb1, Il6, and Il1b) were observed at the mRNA level. This work suggests a beneficial role of L. delbrueckii strain CIDCA 133 on intestinal damage induced by 5-FU chemotherapy through modulation of inflammatory pathways and improvement of epithelial barrier function.

Paraprobiotics and Postbiotics of Lactobacillus delbrueckii CIDCA 133 Mitigate 5-FU-Induced Intestinal Inflammation

“…The reduction in mRNA expression of mucin 2 and tight junction proteins zonulin, claudin 1, and claudin 2 observed in the inflamed mice was attenuated by both heat-killed and cell-free supernatants of L. delbrueckii CIDCA 133. These results are consistent with data obtained by De Jesus et al [ 29 ] and Barroso et al [ 30 ], who demonstrated that viable L. delbrueckii CIDCA 133 reduced intestinal permeability and goblet cell degeneration and upregulated the gene expression of tight junction proteins ( Cldn1, Fr11, Hp ) altered by 5-FU chemotherapy, thus being essential to reduce the translocation of toxins and pathogenic bacteria, and consequently the inflammation amplification process in the intestinal mucosa [ 45 ].…”

“…The anti-inflammatory properties of viable L. delbrueckii CIDCA 133 have been previously reported [ 29 , 30 , 31 ]. This study evaluated the anti-inflammatory properties of the bacterial inactivation or secreted bioactive products derived from this strain in a 5-Fluorouracil drug-induced mouse intestinal inflammation model.…”

“…Increased TGFβ levels were observed in the 5-FU-induced inflammation model [ 50 , 51 , 52 ]. On the other hand, IL10 cytokine levels were reduced [ 30 , 53 , 54 , 55 ]. Evidence shows that in the absence/reduction of IL10 cytokine in the intestinal inflammation context, levels of TGFβ1 are increased [ 19 , 56 ].…”

“…We believe that these results can be linked to extracellular molecules and cell surface-associated components (e.g., LtaS, SLAP, HtrA, MucBP, and PrtB) identified in the strain genome [ 31 ] since these genetic factors interacted the most with human immune protein receptors associated with NF-κB signaling pathway regulation, including NFKB1 protein. These molecular markers were also associated as possibly genetic factors of viable CIDCA 133 involved with its anti-inflammatory properties through the upregulation of immunoregulatory Tgfb1 and Il10 cytokines and downregulation of Nfkb1 gene expression in vivo [ 30 , 31 ].…”

“…lactis CIDCA 133 in a murine model of 5-FU-induced mucositis was previously demonstrated by our research group [ 29 ]. Ameliorative effects promoted by this strain were mainly associated with the reduction of inflammatory cells, improvement in mucus-producing goblet cell count, secretory IgA levels and intestinal permeability reduction, modulation of markers involved in NF-κB signaling pathway activation ( Tlr2 , Nfkb1 , Il6 , and Il1b ), and regulation of tight junction protein expression [ 29 , 30 ]. Additionally, a probiogenomics study of this strain showed that its anti-inflammatory profile could be related to genes encoding secreted and membrane surface proteins able to interact with immune proteins involved in the NF-κB signaling pathway [ 31 ].…”