Han Xue, Qin Yue, Guo Jielong, Huang Weidong, You Yilin, Zhan Jicheng, Yin Yue
State Key Laboratory of Vascular Homeostasis and Remodeling, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
Beijing Key Laboratory of Viticulture and Enology, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
Antibiotics (Basel). 2025 Jun 3;14(6):574. doi: 10.3390/antibiotics14060574.
Low-dose antibiotic contamination in animal feed is a persistent global food safety challenge. Transient early-life exposure to low-dose penicillin (LDP) is known to induce metabolic syndrome (MetS) in adult mice, but the underlying mechanisms are unclear. This study investigated the role of gut microbiota (GM) and intestinal immunity in mediating the long-term metabolic effects of early-life LDP exposure. Mice were exposed to LDP transiently during early life. GM composition was analyzed. Intestinal IgA responses were quantified. Bacterial encroachment, systemic and adipose tissue inflammation, and diet-induced MetS were assessed. Germ-free (GF) mice received GM transplants from LDP-exposed or control mice to test causality and persistence. Early-life LDP exposure significantly disrupted GM composition, particularly in the ileum, in 30-day-old mice. These GM alterations caused persistent suppression of intestinal IgA responses, evidenced by reduced IgA-producing cells and sIgA levels. This suppression was constrained to early-life exposure: transferring LDP-modified GM to GF mice produced only a transient reduction in fecal sIgA. The LDP-induced sIgA reduction decreased IgA binding of bacteria, leading to increased bacterial encroachment and systemic and adipose tissue inflammation. These pathological changes exacerbated diet-induced MetS. Our findings demonstrate that early-life LDP exposure induces persistent intestinal IgA deficiency through lasting GM alterations initiated in early development. This deficiency drives bacterial encroachment, inflammation, and ultimately exacerbates MetS. The exacerbation of diet-induced metabolic syndrome by early-life LDP exposure occurs through an intestinal sIgA-dependent pathway triggered by persistent GM disruption. This highlights a critical mechanism linking early-life antibiotic exposure, gut immune dysfunction, and long-term metabolic health, with significant implications for food safety.
动物饲料中的低剂量抗生素污染是一个长期存在的全球食品安全挑战。已知成年小鼠在生命早期短暂接触低剂量青霉素（LDP）会诱发代谢综合征（MetS），但其潜在机制尚不清楚。本研究调查了肠道微生物群（GM）和肠道免疫在介导生命早期LDP暴露的长期代谢影响中的作用。小鼠在生命早期短暂接触LDP。分析GM组成。量化肠道IgA反应。评估细菌侵袭、全身和脂肪组织炎症以及饮食诱导的MetS。无菌（GF）小鼠接受来自LDP暴露或对照小鼠的GM移植，以测试因果关系和持续性。生命早期LDP暴露显著破坏了30日龄小鼠的GM组成，尤其是在回肠。这些GM改变导致肠道IgA反应持续受到抑制，表现为产生IgA的细胞和分泌型IgA水平降低。这种抑制仅限于生命早期暴露：将LDP修饰的GM转移到GF小鼠中仅导致粪便分泌型IgA短暂降低。LDP诱导的分泌型IgA减少降低了细菌的IgA结合，导致细菌侵袭增加以及全身和脂肪组织炎症。这些病理变化加剧了饮食诱导的MetS。我们的研究结果表明，生命早期LDP暴露通过早期发育中引发的持久GM改变诱导持续的肠道IgA缺乏。这种缺乏导致细菌侵袭和炎症，最终加剧MetS。生命早期LDP暴露加剧饮食诱导的代谢综合征是通过持续GM破坏触发的肠道分泌型IgA依赖途径发生的。这突出了一种将生命早期抗生素暴露、肠道免疫功能障碍和长期代谢健康联系起来的关键机制，对食品安全具有重要意义。
