Undernourished children exhibit impaired gut microbiota development. Transplanting microbiota from 6- and 18-month old healthy or undernourished Malawian donors into young germ-free mice fed a Malawian diet revealed that immature microbiota from undernourished infants/children transmit impaired growth phenotypes. The representation of several age-discriminatory taxa in recipient animals correlated with lean body mass gain, liver, muscle, and brain metabolism, plus bone morphology. Co-housing mice shortly after receiving microbiota from healthy (H) or severely stunted/underweight (Un) infants demonstrated that invasion of age-/growth-discriminatory taxa from H to Un cagemates’ microbiota ameliorates growth faltering. Adding two invasive species, Ruminococcus gnavus and Clostridium symbiosum, to the Un microbiota also ameliorated growth and metabolic abnormalities. These results provide evidence that microbiota immaturity is causally related to undernutrition, and reveal potential therapeutic targets and agents.

Summary Identifying interventions that more effectively promote healthy growth of children with undernutrition is a pressing global health goal. Analysis of human milk oligosaccharides (HMOs) from 6-month postpartum mothers in two Malawian birth-cohorts revealed that sialylated HMOs are significantly less abundant in mothers with severely stunted infants. To explore this association, we colonized young germ-free mice with a consortium of bacterial strains cultured from the fecal microbiota of a 6-month old stunted Malawian infant and fed recipient animals a prototypic Malawian diet with or without purified sialylated bovine milk oligosaccharides (S-BMO). S-BMO produced a microbiota-dependent augmentation of lean body mass gain, changed bone morphology and altered liver, muscle and brain metabolism in ways indicative of a greater ability to utilize nutrients for anabolism. These effects were also documented in gnotobiotic piglets using the same consortium and Malawian diet. These preclinical models indicate a causal, microbiota-dependent relationship between S-BMO and growth promotion.

The bacterial component of the human gut microbiota undergoes a definable program of postnatal development. Evidence is accumulating that this program is disrupted in children with severe acute malnutrition (SAM) and that their persistent gut microbiota immaturity, which is not durably repaired with current ready-to-use therapeutic food (RUTF) interventions, is causally related to disease pathogenesis. To further characterize gut microbial community development in healthy versus malnourished infants/children, we performed a time-series metagenomic study of DNA isolated from virus-like particles (VLPs) recovered from fecal samples collected during the first 30 mo of postnatal life from eight pairs of monoand dizygotic Malawian twins concordant for healthy growth and 12 twin pairs discordant for SAM. Both members of discordant pairs were sampled just before, during, and after treatment with a peanut-based RUTF. Using Random Forests and a dataset of 17,676 viral contigs assembled from shotgun sequencing reads of VLP DNAs, we identified viruses that distinguish different stages in the assembly of the gut microbiota in the concordant healthy twin pairs. This developmental program is impaired in both members of SAM discordant pairs and not repaired with RUTF. Phage plus members of the Anelloviridae and Circoviridae families of eukaryotic viruses discriminate discordant from concordant healthy pairs. These results disclose that apparently healthy cotwins in discordant pairs have viromes associated with, although not necessarily mediators, of SAM; as such, they provide a human model for delineating normal versus perturbed postnatal acquisition and retention of the gut microbiota's viral component in populations at risk for malnutrition.assembly of the human gut DNA virome | childhood malnutrition | age/disease-discriminatory phage and eukaryotic viruses | gnotobiotic mice | epidemiology M alnutrition (undernutrition) is a leading cause of child mortality worldwide (1). Severe acute malnutrition (SAM) can manifest itself as progressive wasting (marasmus) or as a more abrupt onset syndrome characterized by generalized edema, hepatic steatosis, skin rashes and ulcerations, and anorexia (kwashiorkor). The configuration of the bacterial component of the gut microbiota of healthy infants evolves to an adult-like configuration during the first 2-3 y of life (2, 3). Normal postnatal maturation of the gut microbial community is perturbed in SAM; children with SAM living in Malawi and in Bangladesh have gut microbiota with bacterial configurations that appear younger (more immature) than the microbiota of chronologically age-matched individuals with healthy growth phenotypes (3, 4). Moreover, this immaturity is only transiently improved with current ready-to-use therapeutic food (RUTF) interventions (3, 4). These children can be viewed as having a persistent developmental abnormality-one that affects a microbial "organ" whose key functions include the biosynthesis of vitamins and the biotransformation of dietary components into p...

Immunoglobulin A (IgA), the major class of antibody secreted by the gut mucosa, is an important contributor to gut barrier function1–3. The repertoire of IgA bound to gut bacteria reflects both T cell-dependent and -independent pathways4,5, plus glycans present on the antibody’s secretory component6. Human gut bacterial taxa targeted by IgA in the setting of intestinal barrier dysfunction are capable of producing intestinal pathology when isolated and transferred to gnotobiotic mice7,8. A complex reorientation of gut immunity occurs as infants transition from passively acquired IgA present in breast milk to host-derived IgA9–11. How IgA responses co-develop with assembly of the microbiota during this period remains poorly understood. Here, we (i) identify a set of age-discriminatory bacterial taxa whose representations define a program of microbiota assembly/maturation during the first 2 postnatal years that is shared across 40 healthy USA twin pairs; (ii) describe a pattern of progression of gut mucosal IgA responses to bacterial members of the microbiota that is highly distinctive for family members (twin pairs) during the first several postnatal months then generalizes across pairs in the second year; and (iii) assess the effects of zygosity, birth mode and breast feeding. Age-associated differences in these IgA responses can be recapitulated in young germ-free mice, colonized with fecal microbiota obtained from two twin pairs at 6 and 18 months of age, and fed a sequence of human diets that simulate the transition from milk feeding to complementary foods. The majority of these responses were robust to diet suggesting that ‘intrinsic’ properties of community members play a dominant role in dictating IgA responses. The approach described can be used to define gut mucosal immune development in health and disease states and help discover ways for repairing or preventing perturbations in this facet of host immunity.

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.

Preface Most people think of human development only in terms of ‘human’ cells and organs. Here, we discuss another facet involving human-associated microbial communities. A microbial perspective of human development provides opportunities to refine our definitions of healthy pre- and postnatal growth and to develop new strategies for disease prevention and treatment. Considering the dramatic changes in lifestyles and disease patterns that are occurring with globalization, we issue a call for human microbial observatory programs designed to examine microbial community development in birth cohorts representing populations with diverse anthropologic characteristics, including those undergoing rapid change.

SUMMARY To understand how different diets, the consumers’ gut microbiota and the enteric nervous system (ENS) interact to regulate gut motility, we developed a gnotobiotic mouse model that mimics short-term dietary changes that happen when humans are traveling to places with different culinary traditions. Studying animals transplanted with the microbiota from humans representing each cuisine and fed a sequence of diets representing those of all donors, we find that correlations between bacterial species abundances and transit times are diet-dependent. However, the levels of unconjugated bile acids - reflecting microbial bile salt hydrolase activity - correlate with faster transit across diets, including a Bangladeshi diet. Mice harboring a consortium of sequenced bacterial strains from the Bangladeshi donor’s microbiota and fed a Bangladeshi diet revealed that the commonly used spice, turmeric, slows transit times. Turmeric affects gut motility via bacterial bile acid deconjugation and modulation of Ret signaling in the ENS. These results demonstrate how a single food ingredient interacts with a functional microbiota trait to regulate host physiology.

Microbiota assembly is perturbed in children with undernutrition, resulting in persistent microbiota immaturity that is not rescued by current nutritional interventions. Evidence is accumulating that this immaturity is causally related to the pathogenesis of undernutrition and its lingering sequelae. Preclinical models in which human gut communities are replicated in gnotobiotic mice have provided an opportunity to identify and predict the effects of different dietary ingredients on microbiota structure, expressed functions, and host biology. This capacity sets the stage for proof-of-concept tests designed to deliberately shape the developmental trajectory and configurations of microbiota in children representing different geographies, cultural traditions, and states of health. Developing these capabilities for microbial stewardship is timely given the global health burden of childhood undernutrition, the effects of changing eating practices brought about by globalization, and the realization that affordable nutritious foods need to be developed to enhance our capacity to cultivate healthier microbiota in populations at risk for poor nutrition.