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

Carrie A. Cowardin, Philip P. Ahern, Vanderlene L. Kung, Matthew C. Hibberd, Jiye Cheng, Janaki L. Guruge, Vinaik Sundaresan, Richard D. Head, Daniela Barile, David A. Mills, Michael J. Barratt, Sayeeda Huq, Tahmeed Ahmed, Jeffrey I. Gordon

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)11988-11996
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number24
DOIs
StatePublished - Jun 11 2019
Externally publishedYes

Keywords

  • Bone growth
  • Breast milk oligosaccharides
  • Childhood undernutrition
  • Gut microbiota
  • Stunting

ASJC Scopus subject areas

  • General

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