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Proc Natl Acad Sci U S A. 2019 Jun 11;116(24):11988-11996. doi: 10.1073/pnas.1821770116. Epub 2019 May 28.

Mechanisms by which sialylated milk oligosaccharides impact bone biology in a gnotobiotic mouse model of infant undernutrition.

Author information

1
Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110.
2
Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, St. Louis, MO 63110.
3
Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.
4
Genome Technology Access Center, Washington University School of Medicine, St. Louis, MO 63110.
5
Foods for Health Institute, University of California, Davis, CA 95616.
6
Department of Food Science and Technology, University of California, Davis, CA 95616.
7
International Centre for Diarrhoeal Disease Research, 1212 Dhaka, Bangladesh.
8
Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110; jgordon@wustl.edu.

Abstract

Undernutrition in children is a pressing global health problem, manifested in part by impaired linear growth (stunting). Current nutritional interventions have been largely ineffective in overcoming stunting, emphasizing the need to obtain better understanding of its underlying causes. Treating Bangladeshi children with severe acute malnutrition with therapeutic foods reduced plasma levels of a biomarker of osteoclastic activity without affecting biomarkers of osteoblastic activity or improving their severe stunting. To characterize interactions among the gut microbiota, human milk oligosaccharides (HMOs), and osteoclast and osteoblast biology, young germ-free mice were colonized with cultured bacterial strains from a 6-mo-old stunted infant and fed a diet mimicking that consumed by the donor population. Adding purified bovine sialylated milk oligosaccharides (S-BMO) with structures similar to those in human milk to this diet increased femoral trabecular bone volume and cortical thickness, reduced osteoclasts and their bone marrow progenitors, and altered regulators of osteoclastogenesis and mediators of Th2 responses. Comparisons of germ-free and colonized mice revealed S-BMO-dependent and microbiota-dependent increases in cecal levels of succinate, increased numbers of small intestinal tuft cells, and evidence for activation of a succinate-induced tuft cell signaling pathway linked to Th2 immune responses. A prominent fucosylated HMO, 2'-fucosyllactose, failed to elicit these changes in bone biology, highlighting the structural specificity of the S-BMO effects. These results underscore the need to further characterize the balance between, and determinants of, osteoclastic and osteoblastic activity in stunted infants/children, and suggest that certain milk oligosaccharides may have therapeutic utility in this setting.

KEYWORDS:

bone growth; breast milk oligosaccharides; childhood undernutrition; gut microbiota; stunting

Conflict of interest statement

Conflict of interest statement: D.B. and D.A.M. are cofounders of Evolve Biosystems, a company focused on diet-based manipulation of the gut microbiota. J.I.G. is a cofounder of Matatu, Inc., a company characterizing the role of diet-by-microbiota interactions in animal health.

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