Increasing breast milk betaine modulates Akkermansia abundance in mammalian neonates and improves long-term metabolic health

Accelerated postnatal growth is a 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 breast milk and found an inverse association between milk betaine content and infant growth. This association was replicated in an independent and geographically distinct cohort. To determine the potential role of milk betaine in modulating offspring obesity risk, we performed maternal betaine supplementation experiments in mice. Higher betaine intake during lactation increased milk betaine content in dams and led to lower adiposity and improved glucose homeostasis throughout adulthood in mouse offspring. These effects were accompanied by a transient increase in Akkermansia spp. abundance in the gut during early life and a long-lasting increase in intestinal goblet cell number. The link between breast milk betaine and Akkermansia abundance in the gut was also observed in humans, as infants exposed to higher milk betaine content during breastfeeding showed higher fecal Akkermansia muciniphila abundance. Furthermore, administration of A. muciniphila to mouse pups during the lactation period partially replicated the effects of maternal breast milk betaine, including increased intestinal goblet cell number, lower adiposity, and improved glucose homeostasis during adulthood. These data demonstrate a link between breast milk betaine content and long-term metabolic health of offspring.
This work was supported by grants from Ajinomoto Innovation Alliance Program (Ajinomoto 2015-2017) to CL, EFSD/Lilly programme to C.L., and the Spanish Government (SAF-2017-88005-R to C.L. and BFU2017-89336-R to M.V.). D.S.-I. and J.C.J.-C. are Miguel Servet investigators (Carlos III National Institute of Health, Spain). The MILK Study is supported by NIH grant R01-HD080444 to D.A.F. and E.W.D. Mead Johnson Nutrition provided financial support to D.A.F. for breast milk collection, but had no role in study design, study results, or manuscript content. M.C.C. and I.G.-M. acknowledge support from European Research Council under the European Union’s Horizon 2020 research and innovation programme (ERC Starting Grant 639226).