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Childhood undernutrition, the gut microbiota, and microbiota-directed therapeutics

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Science  24 Jun 2016:
Vol. 352, Issue 6293, pp. 1533
DOI: 10.1126/science.aad9359

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Gut microbiota and undernutrition

Poor nutrition during the early years of life can have severe consequences for subsequent skeletal, immunological, and intellectual development. Blanton et al. review the evidence showing that undernutrition is not caused by food insecurity alone. Other factors range from the length of the breastfeeding period and the availability of milk oligosaccharides, enteropathogen exposure, and enteric dysfunction marked by villus atrophy and loss of gut barrier function. Unfortunately, the current practice of nutritional restoration with or without antibiotic treatment may not be effective in the longer term. Differences in the succession of microbial establishment and maturity might contribute to family discordances in nutritional status. Thus, microbiota-directed therapeutics could be a promising route to nutritional restoration in these children.

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Structured Abstract

BACKGROUND

Childhood undernutrition is a global health challenge. Undernutrition in early life is associated with a number of adverse outcomes, including persistent stunting, immune dysfunction, and neurocognitive deficits. Current approaches to treatment have only modest effects in correcting these long-term sequelae, suggesting that certain features of host biology are not being adequately repaired. This has led to the hypothesis that healthy growth is dependent, in part, on normal postnatal development of the gut microbiota and that perturbations in its development are causally related to undernutrition. Testing this hypothesis illustrates a number of the challenges that human microbial ecology research faces: (i) defining “normal,” both in terms of community structure and expressed functions; (ii) determining whether normal in one population generalizes to other populations; (iii) ascertaining whether deviations from normal correlate with disease and are a cause rather than an effect of pathology; (iv) determining whether abnormal microbial community configurations can be repaired in a sustained fashion, and what route and time course are optimal for such repair; (v) deciphering the short- and long-term effects and safety of repair; and (vi) proactively addressing the ethical, regulatory, and other societal implications of microbiota-directed food and/or microbial interventions designed to deliberately manipulate this facet of postnatal human development.

ADVANCES

Culture-independent studies of the gut microbiota of members of birth cohorts with healthy growth phenotypes have identified a program of community assembly (“maturation”) defined by the changing representation of a group of age-discriminatory bacterial taxa. Features of this program are shared across individuals living in several low-income countries. Applying metrics for defining deviations from this program (microbiota-for-age Z score) has disclosed that children with severe acute malnutrition have gut microbial communities that appear younger than would be expected on the basis of their chronological age. The resulting microbiota “immaturity” is not repaired by current therapeutic food interventions. Compared with healthy children, microbiota from undernourished children transmit impaired growth phenotypes to recipient gnotobiotic mice fed diets representative of those of the human donors; moreover, some of the transplanted age-discriminatory strains are growth-discriminatory. These findings provide early preclinical proof-of-concept that gut microbiota immaturity is causally related to a number of the manifestations of childhood undernutrition.

OUTLOOK

Gnotobiotic animal models can be used to test a number of concepts. Gut microbiota immaturity, increased enteropathogen burden, and gut barrier dysfunction are interrelated factors that affect disease risk and pathogenesis. Microbiota development is linked to maturation of the gut mucosal immune system, metabolic function in multiple host tissues, plus musculoskeletal and brain development. Age- and growth-discriminatory bacterial strains identified in the normally developing microbiota represent therapeutic targets in children with undernutrition. The representation of these strains provides a way not only for defining the efficacy of these therapeutic interventions but also for assessing the effects of various parameters postulated to contribute to disease risk and pathogenesis (such as maternal health status, breast milk composition, history and quality of complementary feeding, poor sanitation and enteropathogen burden, and antibiotic exposures). Microbiota-directed strategies for treating and ultimately preventing childhood undernutrition raise intriguing questions about the mechanisms that define human development. They also highlight the need to add a microbial dimension to our conceptualization of human biological immaturity and its associated adaptations and compensations, and to consider whether interventions that promote healthy microbiota development can spawn a form of preventative medicine that has lifelong benefits.

The concept that impaired postnatal gut microbiota development (maturation) is causally related to childhood undernutrition.

The representation of age-discriminatory bacterial taxa defines a program of normal gut microbiota development. Disrupting the coordinated functional codevelopment of microbiota and host affects multiple biological regulatory systems through largely unknown mechanisms. Developing effective strategies for sustained repair of microbiota immaturity though food or microbial interventions requires preclinical studies of these mechanisms and modeling of the effects of different rates and routes of repair.

Abstract

Childhood undernutrition is a major global health challenge. Although current therapeutic approaches have reduced mortality in individuals with severe disease, they have had limited efficacy in ameliorating long-term sequelae, notably stunting, immune dysfunction, and neurocognitive deficits. Recent work is providing insights about the role of impaired development of the human gut microbiota in disease pathogenesis, leading to new concepts for treatment and prevention. These findings raise intriguing basic questions about the mechanisms that direct normal gut microbial community assembly and functional maturation. Designing and implementing new microbiota-directed therapeutics for undernutrition highlights the need to simultaneously consider a variety of features of human biology as well as broader societal issues.

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