Sialic acid-based probiotic intervention in lactating mothers improves the neonatal gut microbiota and immune responses by regulating sialylated milk oligosaccharide synthesis via the gut–breast axis

ABSTRACT

Human milk oligosaccharides (HMOs) are vital milk carbohydrates that help promote the microbiota-dependent growth and immunity of infants. Sialic acid (SA) is a crucial component of sialylated milk oligosaccharides (S-MOs); however, the effects of SA supplementation in lactating mothers on S-MO biosynthesis and their breastfed infants are unknown. Probiotic intervention during pregnancy or lactation demonstrates promise for modulating the milk glycobiome. Here, we evaluated whether SA and a probiotic (Pro) mixture could increase S-MO synthesis in lactating mothers and promote the microbiota development of their breastfed neonates. The results showed that SA+Pro intervention modulated the gut microbiota and 6’-SL contents in milk of maternal rats more than the SA intervention, which promoted Lactobacillus reuteri colonization in neonates and immune development. Deficient 6’-SL in the maternal rat milk of St6gal1 knockouts (St6gal1^−/−) disturbed intestinal microbial structures in their offspring, thereby impeding immune tolerance development. SA+Pro intervention in lactating St6gal1^± rats compromised the allergic responses of neonates by promoting 6′-SL synthesis and the neonatal gut microbiota. Our findings from human mammary epithelial cells (MCF-10A) indicated that the GPR41-PI3K-Akt-PPAR pathway helped regulate 6′-SL synthesis in mammary glands after SA+Pro intervention through the gut – breast axis. We further validated our findings using a human-cohort study, confirming that providing SA+Pro to lactating Chinese mothers increased S-MO contents in their breast milk and promoted gut Bifidobacterium spp. and Lactobacillus spp. colonization in infants, which may help enhance immune responses. Collectively, our findings may help alter the routine supplementation practices of lactating mothers to modulate milk HMOs and promote the development of early-life gut microbiota and immunity.

KEYWORDS:

• Sialic acid
• probiotic
• milk oligosaccharide
• infant
• gut microbiota
• immune response
• gut–breast axis

Acknowledgments

We sincerely thank all the volunteers who participated in this study. We express our gratitude to the Dalian Women and Children Medical Center for their help in sample collection. We also thank Dr. Namarta for constructive comments on this manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

YSW, BQR and XLZ wrote the first draft version of the manuscript, analyzed data, and generated the figures. XLZ, ML and YJD contributed to the design of the experiments. YSW and BQR performed most animal experiments. DY, ZL and YJD collected the clinical samples and analyzed the data. YHL and JYY performed experiments to detect milk oligosaccharides. YX, YJL, XXN, ZJL, LL and XGZ performed the literature search and the cellular experiments. LXW, ZL, YX, JLY, WZL, XGZ and JYY revised the manuscript and improved the quality of the language in the manuscript. ML, YJD and JYY contributed to revising the manuscript and were in charge of the final version of the manuscript. All authors were involved in the conception and preparation of the manuscript. All authors read the final version of the manuscript and approved it before submission.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2334967

Additional information

Funding

This work was supported by the National Natural Science Foundation of China under Grant numbers 32371335, 22074143, and 21934005; the Nature Science Foundation of Liaoning Province, China, under Grant number 2023-MS-260; and the BYHEALTH Nutrition and Health Research Foundation under Grant number TY0191117. This work was also supported by the Liaoning Provincial Program for Top Discipline of Basic Medical Sciences, China.