发育阶段、固体食物引入和停止吸吮对兔肠道微生物群和肠上皮的共成熟有不同的影响。

BACKGROUND: In mammals, the establishment around weaning of a symbiotic relationship between the gut microbiota and its host determines long-term health. OBJECTIVES: The aim of this study was to identify the factors driving the comaturation of the gut microbiota and intestinal epithelium at the suckling-to-weaning transition. We hypothesized that the developmental stage, solid food ingestion, and suckling cessation contribute to this process. METHODS: From birth to day 18, Hyplus rabbits were exclusively suckling. From day 18 to day 25, rabbits were 1) exclusively suckling; 2) suckling and ingesting solid food; or 3) exclusively ingesting solid food. The microbiota (16S amplicon sequencing), metabolome (nuclear magnetic resonance), and epithelial gene expression (high-throughput qPCR) were analyzed in the cecum at days 18 and 25. RESULTS: The microbiota structure and metabolic activity were modified with age when rabbits remained exclusively suckling. The epithelial gene expression of nutrient transporters, proliferation markers, and innate immune factors were also regulated with age (e.g., 1.5-fold decrease of TLR5). Solid food ingestion by suckling rabbits had a major effect on the gut microbiota by increasing its α diversity, remodeling its structure (e.g., 6.3-fold increase of Ruminococcaceae), and metabolic activity (e.g., 4.6-fold increase of butyrate). Solid food introduction also regulated the gene expression of nutrient transporters, differentiation markers, and innate immune factors in the epithelium (e.g., 3-fold increase of nitric oxide synthase). Suckling cessation had no effect on the microbiota, while it regulated the expression of genes involved in epithelial differentiation and immunoglobulin transport (e.g., 2.5-increase of the polymeric immunoglobulin receptor). CONCLUSIONS: In rabbits, the maturation of the microbiota at the suckling-to-weaning transition is driven by the introduction of solid food and, to a lesser extent, by the developmental stage. In contrast, the maturation of the intestinal epithelium at the suckling-to-weaning transition is under the influence of the developmental stage, solid food introduction, and suckling cessation.

背景：在哺乳动物中，肠道微生物群及其宿主之间共生关系的确立，决定了其长期健康。

目的：本研究旨在确定在哺乳到断奶过渡期促使肠道微生物群和肠上皮共同成熟的因素。我们假设发育阶段、固体食物摄入和停止哺乳会促进这一过程。

方法：从出生到第 18 天，Hyplus 兔只进行哺乳。从第 18 天到第 25 天，兔子 1）只进行哺乳；2）哺乳并摄入固体食物；或 3）只摄入固体食物。在第 18 天和第 25 天，分析盲肠中的微生物群（16S 扩增子测序）、代谢组（核磁共振）和上皮基因表达（高通量 qPCR）。

结果：当兔子只进行哺乳时，其微生物群结构和代谢活性随年龄而变化。上皮营养转运蛋白、增殖标志物和固有免疫因子的基因表达也随年龄而变化（例如 TLR5 降低 1.5 倍）。哺乳兔摄入固体食物对肠道微生物群有重大影响，增加其α多样性、重塑其结构（例如 Ruminococcaceae 增加 6.3 倍）和代谢活性（例如丁酸增加 4.6 倍）。固体食物的引入还调节了上皮的营养转运蛋白、分化标志物和固有免疫因子的基因表达（例如，一氧化氮合酶增加 3 倍）。停止哺乳对微生物群没有影响，但调节了与上皮分化和免疫球蛋白转运相关的基因表达（例如，多免疫球蛋白受体增加 2.5 倍）。

结论：在兔子中，哺乳到断奶过渡期肠道微生物群的成熟受固体食物的引入驱动，在较小程度上受发育阶段的影响。相比之下，哺乳到断奶过渡期肠上皮的成熟受发育阶段、固体食物引入和停止哺乳的影响。