Gut microbiota in regulation of childhood bone growth

Abstract

Childhood stunting and wasting, or decreased linear and ponderal growth associated with undernutrition, continue to be a major global public health challenge. Although many of the current therapeutic and dietary interventions have significantly reduced childhood mortality caused by undernutrition, there remain great inefficacies in improving childhood stunting. Longitudinal bone growth in children is governed by different genetic, nutritional and other environmental factors acting systemically on the endocrine system and locally at the growth plate. Recent studies have shown that this intricate interplay between nutritional and hormonal regulation of the growth plate could involve the gut microbiota, highlighting the importance of a holistic approach in tackling childhood undernutrition. In this review, I focus on the mechanistic insights provided by these recent advances in gut microbiota research and discuss ongoing development of microbiota-based therapeutics in humans, which could be the missing link in solving undernutrition and childhood stunting.

Keywords: clinical trial; insulin‐like growth factor I; microbiome; probiotics; short stature.

FIGURE 1

Regulation of bone growth by the GH/IGF‐I axis. Secretion of GH from the anterior pituitary is positively regulated by GHRH produced by the hypothalamus. Growth hormone stimulates production of IGF‐I in the liver, which then acts as an endocrine factor to stimulate bone growth at the growth plate. Growth hormone also stimulates local IGF‐I production in target tissues, such as the growth plate and the intestine, which acts as a paracrine/autocrine growth factor. Nutritional status positively regulates bone growth and maturation of the gut microbiota, which reciprocally promote nutritional intake. The gut microbiota also promotes bone growth, perhaps directly, by stimulating IGF‐I production. Possible mechanisms for such stimulation might involve SCFAs and NOD2‐mediated bacterial sensing pathways in the intestinal epithelial cells. Pointed arrows indicate stimulation; red blunted arrow indicates suppression. Abbreviations: GH, growth hormone; GHRH, growth hormone‐releasing hormone; IGF‐I, insulin‐like growth factor 1; NOD2, nucleotide‐binding oligomerization domain‐containing protein 2, SCFAs short‐chain fatty acids.

FIGURE 2

A vicious cycle of childhood stunting. Undernutrition in children could lead to gut microbiota immaturity, which itself could contribute to undernutrition and childhood stunting. This undernutrition cycle can also be intergenerational, because maternal size and maternal undernutrition are risk factors for SGA. Maternal undernutrition could also lead to maternal gut microbiota dysbiosis, which could be transmitted to the infant at birth. Improving nutritional intake by dietary intervention and microbiota‐based therapy might both be needed to escape this vicious cycle and achieve healthy childhood growth. Abbreviation: SGA, small for gestational age.

FIGURE 3

Different classes of microbiota‐based therapeutics. Probiotics are live microbes (usually in food) that contribute beneficially to the gut microbiota. Prebiotics are ingredients in food (such as fibre) that help to stimulate growth of gut microbiota. Microbiota‐directed food is specially formulated food that helps to shape or direct the growth of certain bacteria or improve microbiota maturation. Synbiotics are mixtures of probiotics and prebiotics. Postbiotics are materials left behind by probiotics, such as the bacterial cell wall. Antibiotics are antimicrobial substances that kill or inhibit microbes, which might help to reset microbiota equilibrium. Faecal microbiota transplant is a procedure that delivers mature gut microbiota from a healthy human donor stool to a recipient, such as an undernourished child with gut microbiota dysbiosis. Abbreviations: FMT, faecal microbiota transplant; MDFs, microbiota‐directed foods.