By Casey R. Johnson, MD, MS, and Philip R. Fischer, MD, DTM&H

Dr. Johnson is a pediatric resident at the Mayo Clinic. Dr. Fischer is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.

Dr. Johnson and Dr. Fischer report no financial relationships relevant to this field of study.

SYNOPSIS: In a series of studies in gnotobiotic animals and malnourished children, incomplete recovery from malnutrition is associated with immature gut microbiota, and complementary foods directed to enhance microbiotal maturity improved recovery from malnutrition.

SOURCE: Gehrig JL, Venkatesh S, Chang HW, et al. Effects of microbiota-directed foods in gnotobiotic animals and undernourished children. Science 2019;365:in press. doi: 10.1126/science.aau4732.

The microbiome is a dynamic ecology of microorganisms that changes throughout the course of growth and development, especially during the weaning period. Children with acute malnutrition fail to undergo these normal patterns of change within their microbiome. Microbiota from children with severe acute malnutrition (SAM) or moderate acute malnutrition (MAM) largely reflect that of healthy but chronologically younger infants, still predominantly milk-dependent.

Current ready-to-use therapeutic foods (RUTF) and complementary foods are an important component of treatment for SAM and MAM; however, they do not afford the catch-up growth necessary to ameliorate stunting or neurocognitive delays that accompany acute malnutrition. The authors hypothesized that the microbiotal aberrations in acute malnutrition are responsible in part for failure to fully recover, and that complementary foods could be formulated to direct the microbiome toward a healthier, age-appropriate profile, further alleviating the state of persistent malnourishment and its consequences.

Stool samples from malnourished and healthy control children in Bangladesh were used to profile microbial resident communities. The authors inoculated germ-free animals with stool from children to test various formulations of microbiota-directed complementary foods (MDCF) based on culturally accepted available foods. Growth and anthropometric parameters, microbiotal changes, and plasma proteins from important signaling pathways were recorded. MDCF formulated with chickpea, soy, banana, and peanut were found to be most effective compared with controls and other formulations in aiding recovery.

Following preliminary selection of MDCF formulation, breastfeeding Bangladeshi children with persistent MAM, who previously underwent stabilization and treatment for SAM, were enrolled in a double-blind, randomized, controlled trial testing the efficacy of the MDCF prototypes. Stool samples for microbiome analysis, blood draws for plasma protein and biomarker analyses, and anthropometric data were collected routinely at set intervals. The lead MDCF identified in animal studies with chickpea, soy, banana, and peanut was again most effective at increasing levels of biomarkers and growth-signaling pathways, neurodevelopment, immune function, and bone formation.

The results of the study support the hypothesis that healthy microbiota is causally linked to healthy growth and development. The model provides a precedent for developing therapeutic foods for acute malnutrition that target healthy development of the microbiome, and provides a new platform from which microbiota-directed changes in health and development can be evaluated.

COMMENTARY

The human microbiome functions as a kind of extra-human organ, far outnumbering the cells in a human body and exceeding the number of genes in the human genome by a factor of at least 100.1,2 This coevolved ecosystem of microorganisms plays a complex role in supporting human health, capable of protecting the host from invading pathogens, stimulating the immune system, increasing availability of nutrients, stimulating bowel motility, and improving lipid levels in the body.3 However, aberrations in the gut microbiota also can contribute to disease — obesity,4,5 diabetes,6 infections,7 inflammatory bowel disease,8,9 cancer,10 and, as demonstrated in the present article, persistent malnutrition.

In their article, Gehrig and colleagues elegantly demonstrated the potential for the microbiome to be harnessed for human health improvement. Using a variety of methodologies from basic science to direct translational trials, they phenotyped the microbiome in healthy and malnourished children, established microbiota-directed prototype foods using two gnotobiotic animal models, demonstrated that the effects were dependent on having an intact microbiota, and, finally, showed physiologic and anthropomorphic superiority of their prototype foods with associated normalization of the microbiome in a double-blind, randomized, controlled trial.

The idea of using food or food ingredients to manipulate the microbiome for health benefits is an old concept that has developed more rapidly since Gibson and Roberfroid11 proposed the concept of prebiotics. Prebiotics are defined as “selectively fermented ingredients that result in specific changes, in the composition and/or activity of the gastrointestinal microbiota, thus conferring benefit(s) upon host health.” These compounds occur naturally in a wide variety of foods, including several prebiotics in foods comprising the MDCF.12,13 However, little is known about the microbiotal effects of the vast majority of foods and food ingredients globally.

Other methods directed at changing the systemic effects of the microbiota include probiotics3 and fecal transplant.14 These methods rely on introducing new species and/or increasing the quantity of resident microbial communities that are known to be associated with improved health. In the case of the former, generally a few well-known species are administered in large quantities, with randomized controlled trials showing moderate benefits for infectious diarrhea and irritable bowel syndrome.15,16 The latter employs a myriad of microbial species of various unknown concentrations, and of which little is known overall, but which is taken from a healthy human subject.

The findings presented by Gehrig and colleagues reinforce the vast amount of attention that the human microbiome has received in recent years, and their work likely will inspire many future investigations. Could microbiota-directed therapeutic foods reduce hospital-acquired infections and recurrent infections such as C. difficile? Is there a role for microbiota-directed foods in the prevention or prolongation of time to onset of neurodegenerative changes? Could similar research affect obesity in countries where childhood obesity rates have soared in recent years? As the fields of microbiology and bioinformatics continue to excel, one should expect to learn much more about such questions and many more. In the meantime, microbiota-directed complementary foods hold potential for better preventing and treating childhood malnutrition.

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