Microbiome study. 16S Mus musculus cecum. Increasing breast milk betaine content modulates offspring Akkermansia abundance during early life and improves long-term metabolic health

Accelerated postnatal growth is a strong and potentially modifiable risk factor for future obesity. To study how specific breast milk components contribute to early growth and obesity risk, we quantified one-carbon metabolism-related metabolites in human milk and found an inverse association between milk betaine content and infant growth. Notably, this association was replicated in an independent and geographically distinct cohort. To determine the potential role of milk betaine in programming offspring obesity risk, we performed maternal betaine supplementation experiments in mice. Higher betaine intake during lactation increased milk betaine content and led to lower offspring adiposity and improved glucose homeostasis throughout adulthood. These effects were accompanied by a transient increase of Akkermansia spp. abundance during early life and a long-lasting increase in intestinal goblet cell number. Akkermansia muciniphila levels in infants were also linked to milk betaine content in the human cohort. Furthermore, administration of Akkermansia muciniphila to pups during the lactation period partially replicated maternal betaine effects, including long-term improvements in adiposity and glucose homeostasis. Together, our data demonstrate a link between breast milk betaine content and offspring long-term metabolic health, and indicate that betaine may be a target for early interventions aimed at childhood obesity prevention.

产后加速生长是未来肥胖发生的一项强且具有潜在可干预性的风险因素。为探究特定母乳成分如何影响早期生长与肥胖风险，我们对人乳中的一碳代谢相关代谢物进行了定量分析，发现母乳甜菜碱含量与婴儿生长速率呈负相关关联。值得注意的是，该关联在另一独立且地理分布不同的队列中得到了重复验证。为明确母乳甜菜碱在子代肥胖风险程序化调控中的潜在作用，我们在小鼠中开展了母鼠甜菜碱补充干预实验。母鼠在泌乳期摄入更高剂量的甜菜碱，可提升母乳中的甜菜碱含量，并使子代成年后的体脂水平更低、葡萄糖稳态更健康。上述效应伴随有子代早期生命阶段嗜黏蛋白阿克曼氏菌（Akkermansia spp.）丰度的一过性升高，以及肠道杯状细胞数量的持续性增加。在人类队列中，婴儿体内的嗜黏蛋白阿克曼氏菌（Akkermansia muciniphila）水平同样与母乳甜菜碱含量相关。此外，在泌乳期给幼鼠灌胃嗜黏蛋白阿克曼氏菌，可部分复刻母鼠甜菜碱补充的干预效果，包括长期改善子代体脂水平与葡萄糖稳态。综上，本研究数据证实了母乳甜菜碱含量与子代长期代谢健康之间存在关联，并提示甜菜碱或可成为预防儿童肥胖的早期干预靶点。