Intestinal Flora-Derived Kynurenic Acid Protects Against Intestinal Damage Caused by Candida albicans Infection via Activation of Aryl Hydrocarbon Receptor

Abstract

Colonization of the intestinal tract by Candida albicans (C. albicans) can lead to invasive candidiasis. Therefore, a functional intestinal epithelial barrier is critical for protecting against invasive C. albicans infections. We collected fecal samples from patients with Candida albicans bloodstream infection and healthy people. Through intestinal flora 16sRNA sequencing and intestinal metabolomic analysis, we found that C. albicans infection resulted in a significant decrease in the expression of the metabolite kynurenic acid (KynA). We used a repeated C. albicans intestinal infection mouse model, established following intake of 3% dextran sulfate sodium salt (DSS) for 9 days, and found that KynA, a tryptophan metabolite, inhibited inflammation, promoted expression of intestinal tight junction proteins, and protected from intestinal barrier damage caused by invasive Candida infections. We also demonstrated that KynA activated aryl hydrocarbon receptor (AHR) repressor in vivo and in vitro. Using Caco-2 cells co-cultured with C. albicans, we showed that KynA activated AHR, inhibited the myosin light chain kinase-phospho-myosin light chain (MLCK-pMLC) signaling pathway, and promoted tristetraprolin (TTP) expression to alleviate intestinal inflammation. Our findings suggest that the metabolite KynA which is differently expressed in patients with C. albicans infection and has a protective effect on the intestinal epithelium, via activating AHR, could be explored to provide new potential therapeutic strategies for invasive C. albicans infections.

Metabolic network construction reveals probiotic-specific alterations in the metabolic activity of a synthetic small intestinal community

“…Metabolites produced by the microbiota can interact with the host and improve gut integrity. For example, stimulation of GPR35 by KYNA, was shown to enhance mucosal repair and stimulate mucus secretion, which increases the integrity of the gut epithelial barrier [70, 71]. Thus, increasing microbial production of KYNA in the small intestine may indirectly increase colonization resistance.…”

A Review of the Health Benefits of Food Enriched with Kynurenic Acid

“…Similar metabolic effects of KYNA injected intraperitoneally at a dose of 5 mg/kg/day, once a day for 1 to 4 weeks, to mice on a high-fat diet were described [ 93 ]. Very recently, it was reported that KYNA administered intraperitoneally three times decreased the colonization of the intestine by fungi and ameliorated intestinal injury, i.e., inhibited inflammation, promoted the expression of intestinal tight junction proteins, and protected from intestinal barrier damage caused by invasive Candida albicans infection in mice [ 94 ] ( Table 2 ). Other data indicating multiple health-promoting effects of KYNA come from studies in which the drug was acutely injected intraperitoneally ( Table S7 ).…”

“…The Hungarian group confirmed that KYNA protects against LPS-induced sepsis in subsequent publications, in which a much lower KYNA dose of 30 mg/kg, i.p., was used [ 99 , 100 ]. Most recently, Wang et al (2022) demonstrated that intraperitoneally administered KYNA (5 mg/kg; three times at days 3, 6, and 9) reduced the mortality of mice infected with Candida albicans [ 94 ]. Hsieh et al (2011) reported that KYNA administered intravenously at doses ranging from 30–100 mg/kg attenuated multiorgan dysfunction in rats exposed to heatstroke [ 101 ].…”

“…Detailed data on the health-promoting effects of KYNA administration in animals regardless of the route of administration are presented in Table S7 [ 26 , 87 , 90 , 93 , 94 , 95 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 ].…”

Pesticides and Their Impairing Effects on Epithelial Barrier Integrity, Dysbiosis, Disruption of the AhR Signaling Pathway and Development of Immune-Mediated Inflammatory Diseases

“…AhR activation leads to maintenance of epithelial barrier integrity, preventing permeability dependent on junctional changes, but in dysbiosis, even under an astonishing quantity of AhR ligands, metabolites such as the kynurenic acid (KynA) have a protective effect on the intestinal epithelium via activating AhR [ 105 ]. Taddese et al [ 106 ] found that gut bacteria have the potential to modulate the expression of biotransformation pathways in colonic epithelial cells in an AhR-dependent manner.…”