Abstract
Deregulation of the dynamic crosstalk between the gut microbiota, intestinal epithelial cells, and immune cells is critically involved in the development of inflammatory bowel disease and the overgrowth of opportunistic pathogens, including the human opportunistic fungus Candida albicans. In the present study, we assessed the effect of N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89), a protein kinase A inhibitor, on the migration of macrophages to C. albicans through dextran sulphate sodium (DSS)-challenged Caco-2 cells. We also investigated the impact of H89 on intestinal inflammation and C. albicans clearance from the gut, and determined the diversity of the gut microbiota in a murine model of DSS-induced colitis. H89 reduced the migration of macrophages to C. albicans through DSS-challenged Caco-2 cells. In addition, H89 decreased C. albicans viability and diminished the expression of pro-inflammatory cytokines and innate immune receptors in macrophages and colonic epithelial Caco-2 cells. In mice with DSS-induced colitis, H89 attenuated the clinical and histological scores of inflammation and promoted the elimination of C. albicans from the gut. H89 administration to mice decreased the overgrowth of Escherichia coli and Enterococcus faecalis populations while Lactobacillus johnsonii populations increased significantly. Overall, H89 reduced intestinal inflammation and promoted the elimination of C. albicans from the gut.
Highlights
Candida albicans is the most common cause of nosocomial fungal infections threatening patients in intensive care units, immunocompromised patients, and patients with dysfunctional intestinal epithelial barriers [1,2]
To investigate whether H89 can modulate the expression of pro-inflammatory cytokines in Caco-2 cells treated with dextran sulphate sodium (DSS), we measured the expression of IL-8 and TNFα in this intestinal epithelium model (Figure 1)
The exact aetiology of irritable bowel disease (IBD) is not well known, it is believed that genetic susceptibility, environmental factors, a dysfunctional immune system and changes to the gut microbiota are involved in the onset and progression of this disease [33]
Summary
Candida albicans is the most common cause of nosocomial fungal infections threatening patients in intensive care units, immunocompromised patients, and patients with dysfunctional intestinal epithelial barriers [1,2]. C. albicans interacts with host cells at the level of the cell wall, which consists mainly of glycans associated with lipids and proteins [3]. The external layer of the cell wall is composed mainly of phosphopeptidomannan and phospholipomannan and the internal layer contains a dense network of polysaccharides consisting of glucans (β-1,3 and β-1,6 linked glucose) and chitin (a polymer of β-1,4-linked N-acetylglucosamine) [4]. Different clinical and experimental studies have shown that an abundance of this fungus correlates with serological markers of Crohn’s disease (CD), namely anti-Saccharomyces cerevisiae antibodies (ASCA) [5,6]. The idiopathic presence of ASCA could be correlated with an abundance of C. albicans in healthy parents of CD patients [7]. Experimental studies have shown that intestinal inflammation induced by dextran sulphate sodium (DSS) promotes C. albicans overgrowth in the gut, and, that C. albicans exacerbates intestinal inflammation in mice [6,9]
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