Abstract
Clostridioides difficile is a major cause of diarrhea in patients with antibiotic administration. Lacticaseibacillus casei T21, isolated from a human gastric biopsy, was tested in a murine C. difficile infection (CDI) model and colonic epithelial cells (Caco-2 and HT-29). Daily administration of L. casei T21 [1 × 108 colony forming units (CFU)/dose] for 4 days starting at 1 day before C. difficile challenge attenuated CDI as demonstrated by a reduction in mortality rate, weight loss, diarrhea, gut leakage, gut dysbiosis, intestinal pathology changes, and levels of pro-inflammatory cytokines [interleukin (IL)-1β, tumor necrosis factor (TNF)-α, macrophage inflammatory protein 2 (MIP-2), and keratinocyte chemoattractant (KC)] in the intestinal tissue and serum. Conditioned media from L. casei T21 exerted biological activities that fight against C. difficile as demonstrated in colonic epithelial cells by the following: (i) suppression of gene expression and production of IL-8, an important chemokine involved in C. difficile pathogenesis, (ii) reduction in the expression of SLC11A1 (solute carrier family 11 member 1) and HuR (human antigen R), important genes for the lethality of C. difficile toxin B, (iii) augmentation of intestinal integrity, and (iv) up-regulation of MUC2, a mucosal protective gene. These results supported the therapeutic potential of L. casei T21 for CDI and the need for further study on the intervention capabilities of CDI.
Highlights
Clostridioides difficile, an anaerobic Gram-positive spore-forming bacillus (Kachrimanidou and Malisiovas, 2011), is one of the important causative organisms of diarrhea in hospitalized patients who receive antibiotics (Kelly et al, 1994b; Bartlett, 2002; Aslam et al, 2005)
After the second oral gavage on day 1, C. difficile infection (CDI) symptoms became worse on day 2, and mice were moribund on day 3 with maximum weight loss (Figure 1B) and significant diarrhea as compared with the ATB uninfected group (Figure 1C)
C. difficile damaged intestinal integrity as demonstrated by the increased serum FITC-dextran levels (Figure 1E), causing gut leakage-induced bacteremia (Figure 1F) that enhanced the production of systemic inflammatory cytokines (Figures 1G–J)
Summary
Clostridioides difficile, an anaerobic Gram-positive spore-forming bacillus (Kachrimanidou and Malisiovas, 2011), is one of the important causative organisms of diarrhea in hospitalized patients who receive antibiotics (Kelly et al, 1994b; Bartlett, 2002; Aslam et al, 2005). Binding of TcdA and TcdB to specific receptors on the surface of intestinal epithelial cells stimulates the secretion of several pro-inflammatory cytokines and chemokines (Hodges and Gill, 2010) Both toxins cause the loss of intestinal epithelial barrier function (gut leakage) by glucosylating Rho GTPases, which causes actin cytoskeleton rearrangement, tight junction disruption, and enterocyte cell death (Pothoulakis, 2000; Aktories and Barbieri, 2005; Jank and Aktories, 2008; Kuehne et al, 2011; Chen et al, 2015). Binary toxin (C. difficile transferase, CDT) is observed in some C. difficile strains that cause severe CDI This toxin is an ADPribosyltransferase that causes depolymerization of F-actin and rearrangement of the actin cytoskeleton (Gerding et al, 2014; Aktories et al, 2018)
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