Early weaning induces intestinal injury, leading to a series of long-term symptoms such as inflammation, malabsorption and diarrhea. In this study, we hypothesized that microbes and their metabolites modulate the host's inflammatory response to early weaning stress in a goat model. A total of 18 female Tibetan goat kids (n = 9) were weaned from their mothers at 28 d (D28) and 60 d (D60) postpartum. D60 and D28 groups were fed the same solid diet ad libitum from weaning to 75 d of age. The colonic epithelium was subject to RNA-sequencing, the caecal digesta metabolomics were assessed by liquid chromatography–tandem mass spectrometry (LC-MS/MS), and the caecal microbiota composition was analysed by 16S ribosomal RNA gene sequencing. We found that early weaning substantially increased the colonic pro-apoptotic gene expression of B-cell lymphoma associated X (Bax), caspase-9, and caspase-3, and decreased the expression of zonula occludens-1 (ZO-1) and claudin-1 (P < 0.01). In addition, a significant Bacteroides acidifaciens enrichment was observed in the hindgut of early-weaned goats (P < 0.01), which negatively correlated with lysophosphatidylcholine products. Similarly, the chemokine signaling, IL-17 signaling, and peroxisome proliferators-activated receptor (PPAR) signaling pathways were upregulated in the colonic mucosa of the early-weaned goats. By applying caecal microbiota transplantation from goats to defaunated C57/6J mice, we confirmed that caecal microbiota of D28 goat kids increased the relative abundance of B. acidifaciens and significantly up-regulated the genes of Bax, G protein–coupled receptor (GPR) 109A, GPR 43, fatty acid binding protein 6, nuclear receptor subfamily 1 group H member 3, angiotensin converting enzyme 2, and IL-6 expression (P < 0.05), and decreased ZO-1, and claudin-1 protein expression in the mice jejunum and colon (P < 0.001). These results proposed that the hindgut microbiota and metabolites mediate the barrier function weakening during early weaning, and the relative abundance of B. acidifaciens was negatively correlated with the hindgut barrier gene expression. This study demonstrates how weaning stress can affect key host–microbe interaction regulators in the hindgut, in a lysophosphatidylcholine dependent and independent manner. Furthermore, based on our mice data, these results are transferable to other mammal species.

过早断奶会导致肠道损伤，导致一系列长期症状，如炎症、吸收不良和腹泻。在这项研究中，我们假设微生物及其代谢物在山羊模型中调节宿主对早期断奶应激的炎症反应。共 18 只雌性藏山羊（n = 9) 在产后 28 天 (D28) 和 60 天 (D60) 断奶。D60和D28组从断奶到75日龄随意饲喂相同的固体饲料。对结肠上皮进行 RNA 测序，通过液相色谱-串联质谱 (LC-MS/MS) 评估盲肠食糜代谢组学，通过 16S 核糖体 RNA 基因测序分析盲肠微生物群组成。我们发现早期断奶显着增加了 B 细胞淋巴瘤相关 X ( Bax )、caspase-9 和 caspase-3 的结肠促凋亡基因表达，并降低了 zonula occludens-1 ( ZO-1 ) 和 claudin的表达-1 ( P  < 0.01)。此外，一种显着的酸拟杆菌早期断奶山羊后肠富集（P  < 0.01），与溶血磷脂酰胆碱产物呈负相关。同样，在早期断奶山羊的结肠粘膜中，趋化因子信号、 IL-17信号和过氧化物酶体增殖物激活受体 ( PPAR ) 信号通路上调。通过将山羊的盲肠微生物群移植到丧失功能的 C57/6J 小鼠，我们证实 D28 山羊孩子的盲肠微生物群增加了酸杆菌的相对丰度并显着上调了Bax、G 蛋白偶联受体 ( GPR ) 109A的基因,探地雷达 43、脂肪酸结合蛋白 6、核受体亚家族 1 组 H 成员 3、血管紧张素转换酶 2、IL-6表达（P  < 0.05），并降低小鼠空肠和结肠中ZO-1和 Claudin-1 蛋白的表达( P  < 0.001)。这些结果表明，后肠微生物群和代谢物介导了早期断奶期间屏障功能的减弱，以及B. acidifaciens的相对丰度。与后肠屏障基因表达呈负相关。这项研究证明了断奶压力如何以溶血磷脂酰胆碱依赖和独立的方式影响后肠中关键的宿主-微生物相互作用调节剂。此外，根据我们的小鼠数据，这些结果可以转移到其他哺乳动物物种。