The intestinal microbial ecosystem is actively regulated by Paneth cell–derived antimicrobial peptides such as α-defensins. Various disorders, including graft-versus-host disease (GVHD), disrupt Paneth cell functions, resulting in unfavorably altered intestinal microbiota (dysbiosis), which further accelerates the underlying diseases. Current strategies to restore the gut ecosystem are bacteriotherapy such as fecal microbiota transplantation and probiotics, and no physiological approach has been developed so far. In this study, we demonstrate a novel approach to restore gut microbial ecology by Wnt agonist R-Spondin1 (R-Spo1) or recombinant α-defensin in mice. R-Spo1 stimulates intestinal stem cells to differentiate to Paneth cells and enhances luminal secretion of α-defensins. Administration of R-Spo1 or recombinant α-defensin prevents GVHD-mediated dysbiosis, thus representing a novel and physiological approach at modifying the gut ecosystem to restore intestinal homeostasis and host–microbiota cross talk toward therapeutic benefits.

肠道微生物生态系统受到Paneth细胞衍生的抗菌肽（例如α-防御素）的积极调控。包括移植物抗宿主病（GVHD）在内的各种疾病破坏Paneth细胞功能，导致肠道菌群发生不利变化（营养不良），从而进一步加剧了潜在疾病。当前恢复肠道生态系统的策略是细菌治疗，例如粪便微生物群移植和益生菌，并且迄今为止尚未开发出生理学方法。在这项研究中，我们证明了Wnt激动剂R-Spondin1（R-Spo1）或重组α-防御素在小鼠中恢复肠道微生物生态的新方法。R-Spo1刺激肠道干细胞分化为Paneth细胞，并增强α-防御素的腔分泌。