Epithelial IL-22RA1-Mediated Fucosylation Promotes Intestinal Colonization Resistance to an Opportunistic Pathogen

Abstract

SummaryOur intestinal microbiota harbors a diverse microbial community, often containing opportunistic bacteria with virulence potential. However, mutualistic host-microbial interactions prevent disease by opportunistic pathogens through poorly understood mechanisms. We show that the epithelial interleukin-22 receptor IL-22RA1 protects against lethal Citrobacter rodentium infection and chemical-induced colitis by promoting colonization resistance against an intestinal opportunistic bacterium, Enterococcus faecalis. Susceptibility of Il22ra1−/− mice to C. rodentium was associated with preferential expansion and epithelial translocation of pathogenic E. faecalis during severe microbial dysbiosis and was ameloriated with antibiotics active against E. faecalis. RNA sequencing analyses of primary colonic organoids showed that IL-22RA1 signaling promotes intestinal fucosylation via induction of the fucosyltransferase Fut2. Additionally, administration of fucosylated oligosaccharides to C. rodentium-challenged Il22ra1−/− mice attenuated infection and promoted E. faecalis colonization resistance by restoring the diversity of anaerobic commensal symbionts. These results support a model whereby IL-22RA1 enhances host-microbiota mutualism to limit detrimental overcolonization by opportunistic pathogens.

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

“…CCR6 and IL22 ) were upregulated in colon biopsies from active UC patients compared to controls (Figure 1c). Importantly, inflamed colons developed a strong IL‐22 response32 marked by the overexpression of genes related to activation of IL‐22 receptor signaling (e.g. STAT3, REG3A, S100A8, MUC1, CXCL5 ) in active UC colons compared to inactive UC or control colons (Figure 1d).…”

“…Gene expression data were transformed into Z‐score values by genes across samples for presentation. The list of human Th17‐ or ILC3‐related genes and IL‐22 signaling (responsive) genes were retrieved from previous reports 29, 30, 31, 32…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Further studies specifically depleting LTi‐like ILC3 are needed to determine whether these findings merely reflect redundancy among IL‐22‐producing ILC3 or subset‐specific roles in the regulation of commensal bacterial species. ILC3‐derived IL‐22 also results in fucosylation of intestinal epithelial cell‐associated carbohydrate chains following colonization of the intestinal tract by commensal bacteria 85, 86, 87. Whereas, certain species of mutualistic bacteria possess the necessary machinery to use carbohydrate fucose as an energy source, many pathogenic bacteria lack this ability and are outcompeted for energy sources.…”

Escherichia coli Generate Oxidative Stress and Enhance Lipid Peroxidation in the Kidney of the Rat

“…Diseases that are produced by the normal flora in their host are called endogenous diseases. Most endogenous bacteria are opportunistic in infection [1]. Among endogenous bacteria, Escherichia coli are generally harmless for humans but some of them are parasitic and may cause life dangerous complication like a severe kidney damage function or even sepsis.…”

“…Intestinal microbes harbor a diverse microbial community, often containing opportunistic bacteria with virulence potential [1]. Both the host and bacteria are thought to derive benefit from each other.…”