Deficiency of IL-22-binding protein enhances the ability of the gut microbiota to 2 protect against enteric pathogens

Interleukin 22 (IL-22) promotes intestinal barrier integrity, stimulating epithelial cells to enact defense mechanisms against enteric infections, including production of antimicrobial peptides. IL-22 binding protein (IL-22BP) is a soluble decoy encoded by the Il22ra2 gene that decreases IL-22 bioavailability, attenuating IL-22 signaling. The impact of IL-22BP on gut microbiota composition and functioning is poorly understood. We found that Il22ra2-/- mice are better protected against Clostridioides difficile and Citrobacter rodentium infections. This protection relied on IL-22-induced antimicrobial mechanisms before the infection occurred, rather than during the infection itself. Indeed, the gut microbiota of Il22ra2-/- mice mitigated infection of WT mice when transferred via co-housing or by cecal microbiota transplantation. Indicator species analysis of WT and Il22ra2-/- mice with and without cohousing, disclosed that IL22BP deficiency yields a gut bacterial composition distinct from that of WT mice. Manipulation of dietary fiber content, measurements of intestinal short chain fatty acids, and oral treatment with acetate disclosed that resistance to Clostridioides difficile infection is related to increased production of acetate by Il22ra2-/- microbiota. Together, these findings suggest that IL-22BP represents a potential therapeutic target for those at risk for or with already manifest infection with this and perhaps other enteropathogens.

白细胞介素22（Interleukin 22，IL-22）可促进肠道屏障完整性，刺激上皮细胞启动抵御肠道感染的防御程序，包括抗菌肽的合成与分泌。白细胞介素22结合蛋白（IL-22BP）是由Il22ra2基因编码的可溶性诱饵蛋白，能够降低IL-22的生物利用度，削弱IL-22信号转导通路。目前学界对IL-22BP在肠道菌群组成与功能中的调控作用尚缺乏深入认知。本研究发现，Il22ra2基因敲除（Il22ra2-/-）小鼠对艰难梭菌（Clostridioides difficile）与鼠柠檬酸杆菌（Citrobacter rodentium）感染的抵御能力显著强于野生型（wild type，WT）小鼠。该保护效应依赖于感染发生前IL-22介导的抗菌机制，而非感染进程中发挥的作用。进一步实验证实，通过同笼饲养或盲肠菌群移植（cecal microbiota transplantation）将Il22ra2-/-小鼠的肠道菌群转移至野生型小鼠体内后，可有效缓解野生型小鼠的感染症状。对开展/未开展同笼饲养的野生型与Il22ra2-/-小鼠进行指示物种分析（Indicator species analysis）后结果显示，IL-22BP缺失会使肠道细菌群落组成与野生型小鼠呈现显著差异。通过调控膳食膳食纤维含量、检测肠道短链脂肪酸（short chain fatty acids）水平，以及口服乙酸盐（acetate）干预实验，本研究明确了抵御艰难梭菌感染的能力与Il22ra2-/-菌群的乙酸盐生成水平升高存在显著关联。综上，本研究结果表明，IL-22BP可作为此类乃至其他肠道致病菌感染高危人群或已出现感染者的潜在治疗靶点。