Diallyl disulfide (DADS), a garlic extract also known as allicin, has been reported to have numerous biological activities, including anticancer, antifungal, and inflammation-inhibiting activities, among others. Although many studies have assessed whether DADS can treat Candida albicans infection in vitro, its in vivo function and the underlying mechanism are still not clear. Accumulated evidence has implicated the gut microbiota as an important factor in the colonization and invasion of C. albicans. Thus, this study aimed to identify the mechanism by which DADS ameliorates dextran sulfate (DSS)-induced intestinal C. albicans infection based on the systematic analysis of the gut microbiota and metabolomics in mice. Here, we determined the body weight, survival, colon length, histological score, and inflammatory cytokine levels in the serum and intestines of experimental mice. Fecal samples were collected for gut microbiota and metabolite analysis by 16S rRNA gene sequencing and LC–MS metabolomics, respectively. DADS significantly alleviated DSS-induced intestinal C. albicans infection and altered the gut microbial community structure and metabolic profile in the mice. The abundances of some pathogenic bacteria, such as Proteobacteria, Escherichia–Shigella, and Streptococcus, were notably decreased after treatment with DADS. In contrast, SCFA-producing bacteria, namely, Ruminiclostridium, Oscillibacter, and Ruminococcaceae_UCG−013, greatly increased in number. The perturbance of metabolites in infectious mice was improved by DADS, with increases in secondary bile acids, arachidonic acid, indoles and their derivatives, which were highly related to the multiple differentially altered metabolic pathways, namely, bile secretion, arachidonic acid metabolism, and tryptophan metabolism. This study indicated that DADS could modulate gut microbiota and metabolites and protect the gut barrier to alleviate DSS-induced intestinal C. albicans infection in mice. Moreover, this work might also provide novel insight into the treatment of C. albicans infection using DADS.

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.

Background: Invasive candidiasis may be caused by Candida albicans (C. albicans) colonisation of the intestinal tract. Therefore, protection against invasive C. albicansinfections requires a functional intestinal epithelial barrier. Mice infected with Candida albicans in the gut and healthy mice were sampled for faecal analysis. After C. albicans infection, we found significant changes in tryptophan metabolites-kynurenic acid (KynA) and indole acrylate (IA)compared with healthy mice. Results: We identify the mechanism by which KynA and IA ameliorate dextran sulphate sodium (DSS)-induced intestinal C. albicansinfection, based on a systematic analysis of the gut microbiota, metabolomics and transcriptome sequencing in mice. KynA and IA suppress inflammation, upregulate the expression of intestinal tight junctions and reduce IL-22 secretion of colonic lamina propria ILC3 in response of invasive Candida infection. Furthermore, we demonstrated that the gut barrier protection and ILC3 regulation mediated by KynA and IA were dependent on gut microbiota modification by transplanting faecal microbiota into ABX-treated C57BL/6J mice. Conclusion: Our study provides microbiome-to-metabolite alterations in C. albicans gut infection and identifies gut microbiome regulation and IL-22 derived from colonic lamina propria ILC3 as novel targets for C. albicans gut infection therapies.

Background: Aromatic hydrocarbon receptors (AHR) are widely expressed in the intestinal barrier and play a regulatory role in intestinal inflammation and immunity. Objectives: In this study, a dextran sulfate (DSS)-induced colitis mouse model was established to detect the effects of AHR activation on the intestinal barrier, flora, and metabolites. Design: The mice were randomly divided into three groups: Control group, DSS group, and DSS- formylindole (3,2-b) carbazole (FICZ) group. The Control group accepted sterile distilled water, the DSS group received 3%DSS, and the DSS-FICZ group were provided 3% of DSS and intraperitoneal injection of FICZ (1ug / mouse / day). Methods: The mental state and the fecal traits were observed, the basic living characteristic occult blood and inflammatory cytokine levels in the serum were detected. Fecal samples were collected for gut microbiota and metabolite analysis by 16S rRNA gene sequencing and LC–MS metabolomics. Results: AHR activation significantly improved the degree of colon shortening in DSS-induced colitis mice, reduced the degree of intestinal mucosal barrier damage, the production of inflammatory factors, and the intestinal epithelial permeability, and increased the tight junction protein expression. The results of 16S rRNA gene sequencing found that, compared with the DSS group, the abundance of Desulfobacterota was up-regulated in the DSS-FICZ group, and the abundance of Proteobacteria was down-regulated at the phylum level. At the genus level, Escherichia-Shigella was down-regulated, Clostridia _ UCG-014, Alistipes, andParabacteroides were up-regulated. At the species level, Escherichia _ coli _ g _ Escherichia-Shigella，Bacteroides _ sartorii _ g _ Bacteroides，Paeniclostridium _ sordellii _ g _ Paeniclostridium and Clostridium _ perfringens _ g _ Clostridium _ sensu _ stricto _ 1 were down-regulated; Bacteroides _ dorei _ g _ Bacteroides was up-regulated, Helicobacter _ hepaticus _ g _ Helicobacter, and Bacteroides _ caecimuris _ g _ Bacteroides was up-regulated, Parabacteroides _ distasonis _ g _ Parabacteroides were down-regulated. LC-MS metabolomics detection revealed that there were differences in a variety of intestinal contents between DSS group and DSS-FICZ group, which was mainly related to histidine metabolism, arginine biosynthesis, lysine degradation, and steroid biosynthesis. Conclusion: The activation of AHR can protect against intestinal injury in mice with DSS-induced colitis by regulating intestinal flora and metabolism.