ena-STUDY-WASHINGTON UNIVERSITY CENTER FOR GENOME SCIENCES-13-11-2018-16:39:57:767-115
Mechanisms by which sialylated milk oligosaccharides impact bone growth in a gnotobiotic mouse model of infant undernutrition
Malnutrition 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 mechanisms. Finding that treating Bangladeshi children with severe acute malnutrition with therapeutic foods reduces plasma levels of a biomarker of osteoclastic activity but does not change biomarkers of osteoblastic activity, improve their severe stunting, or overcome their persistent impaired gut microbiota development, we turned to a gnotobiotic mouse model to characterize interactions between the microbiota, human milk oligosaccharides (HMOs), and osteoclast and osteoblast biology. Young germ-free mice were colonized with a consortium of cultured bacterial strains from a 6-month-old stunted infant and fed a diet representative of that consumed by the donor population, with or without sialylated milk oligosaccharides purified from bovine milk (S-BMO) that are also present in human milk. In colonized mice, S-BMO produced increases in femoral trabecular bone volume and cortical thickness, reductions in osteoclasts and their bone marrow myeloid progenitors, accompanying changes in regulators of osteoclastogenesis and mediators of Th2 responses, including increases in gut eosinophils, while osteoblast activity was unaffected. Comparisons of germ-free and colonized mice revealed S-BMO- and microbiota-dependent increases in cecal levels of succinate, increased numbers of small intestinal tuft cells, and accompanying changes in gene expression indicative of activation of a succinate-induced tuft cell-associated, signaling pathway that triggers a Type 2 immune response. 2'-Fucosylactose (2'-FL), a prominent fucosylated HMO, failed to elicit these effects on bone biology. Our results underscore the need to further characterize the balance between osteoclastic and osteoblastic activity in stunted infants/children, provide preclinical evidence of the gut microbiota as a determinant of bone growth in the context of undernutrition, and suggest that certain HMOs may have therapeutic utility in this setting.
Malnutrition 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 mechanisms. Finding that treating Bangladeshi children with severe acute malnutrition with therapeutic foods reduces plasma levels of a biomarker of osteoclastic activity but does not change biomarkers of osteoblastic activity, improve their severe stunting, or overcome their persistent impaired gut microbiota development, we turned to a gnotobiotic mouse model to characterize interactions between the microbiota, human milk oligosaccharides (HMOs), and osteoclast and osteoblast biology. Young germ-free mice were colonized with a consortium of cultured bacterial strains from a 6-month-old stunted infant and fed a diet representative of that consumed by the donor population, with or without sialylated milk oligosaccharides purified from bovine milk (S-BMO) that are also present in human milk. In colonized mice, S-BMO produced increases in femoral trabecular bone volume and cortical thickness, reductions in osteoclasts and their bone marrow myeloid progenitors, accompanying changes in regulators of osteoclastogenesis and mediators of Th2 responses, including increases in gut eosinophils, while osteoblast activity was unaffected. Comparisons of germ-free and colonized mice revealed S-BMO- and microbiota-dependent increases in cecal levels of succinate, increased numbers of small intestinal tuft cells, and accompanying changes in gene expression indicative of activation of a succinate-induced tuft cell-associated, signaling pathway that triggers a Type 2 immune response. 2'-Fucosylactose (2'-FL), a prominent fucosylated HMO, failed to elicit these effects on bone biology. Our results underscore the need to further characterize the balance between osteoclastic and osteoblastic activity in stunted infants/children, provide preclinical evidence of the gut microbiota as a determinant of bone growth in the context of undernutrition, and suggest that certain HMOs may have therapeutic utility in this setting.