Gut microbiota hold keys to childhood undernutrition

ORLANDO, Fla. — Childhood undernutrition is the leading cause of death in children under age 5 years worldwide, and disturbances in the early life gut microbiota may hold clues to solving a vexing epidemic, according to a speaker here.

“A lot of epidemiological studies have been performed to try and understand the contributing factors,” Jeffrey I. Gordon, MD, director of the Center for Genome Sciences at Washington University in St. Louis, Missouri, said during the presidential plenary presentation at the Endocrine Society Annual Meeting. “We know it is not attributable to food insecurity alone, but, rather, factors that operate within and across generations.”

There have been marked improvements in the treatment of severe forms of undernutrition, particularly with the introduction of ready-to-use therapeutic foods that have been associated with a reduction in mortality, Gordon said. However, such therapies have not repaired or ameliorated the long-term sequalae of severe undernutrition, which include persistent growth stunting, impaired immune function and cognitive abnormalities.

The reason, Gordon said, is because there is an aspect to human developmental biology that occurs postnatally involving the microbial communities that needs to be addressed.

“The gut microbiota, the largest such community, has characteristic stages of development that we can identify,” Gordon said. “This community is tasked, in part, with the biotransformation of food ingredients into bioactive compounds that have many effects on post-cell biology. This program of assembly and maturation of the microbiota is disturbed and is a causal contributor to the pathogenesis of childhood undernutrition.”

A corollary hypothesis, Gordon said, is that healthy development of the microbiota is necessary for healthy growth, and the way it develops has long-term effects on physiologic, immulogic, metabolic and perhaps even neurologic phenotypes.

“We can imagine that perturbations in the assembly of this microbiota in postnatal life might have effects on the ability of enteropathogens to enter and establish themselves — that there are ‘job vacancies’ for these organisms,” Gordon said. “That there could be an impairment in the co-development of the gut mucosal immune system, which could further enhance the ability of enteropathogens to establish themselves.”

This chain reaction of events leads to the production of a variety of metabolic products that might affect various aspects of healthy growth, Gordon said.

“When this program is perturbed, effects may be felt beyond the walls of the gut in many different organ systems,” he said.

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Defining ‘normal’

A 1996-2011 national survey conducted in Bangladesh demonstrates the problem of persistent childhood undernutrition, Gordon said. In Bangladesh, Gordon said, 45% of children under age 5 years have stunted growth because of either moderate acute malnutrition or severe acute malnutrition.

Conducting studies with international collaborators in both undernourished and healthy children, researchers examined a birth cohort in an urban slum in the country. In children with healthy growth, researchers examined monthly fecal samples obtained from birth through age 6 years; culture-independent analyses of the bacterial populations in these samples was obtained by targeting the16s ribosomal RNA gene, a phylogenetic “bar code” of life. The data sets were then mined using machine learning algorithms to identify a group of age-discriminatory strains and changing patterns in the strains.

In the healthy cohort, researchers observed a “microbial signature,” Gordon said, allowing them to assign an “age” or state of maturation to samples. That age, Gordon said, correlates with chronological age in a substantial way.

“So, we have a way of defining ‘normal,’ at least in this population,” Gordon said. “The journey of people who study the human microbiome is to attain these definitions of ‘normal’ in a given population to determine whether that definition generalizes to other populations, and then to develop tools or metrics to quantify deviations from normal to determine whether those deviations are significantly correlated with disease.”

In cohorts studied in other regions of the world, these age-discriminatory strains have been identified in the “normal” gut microbiota of other children, Gordon said.

“There is something very profound about development of microbiome that is shared in children across the world,” Gordon said. “The definition of ‘normal’ generalizes.”

Cause or effect?

Gordon said researchers aim to address two big questions: Are deviations from “normal” an effect of disease, or a cause of disease? And if causality is established, what can be done?

Experiments are aiming to answer these and other questions, he said. Studies suggest that children with severe acute malnutrition have pronounced microbiota immaturity, more so than in moderate acute malnutrition, Gordon said. In a randomized trial of several therapeutic food interventions where children with severe acute malnutrition were enrolled, researchers observed that fecal microbiota in these children showed significant microbiota immaturity — and treatment did not lead to improvement.

“These children have persistent microbiota immaturity,” Gordon said. “They have a persistent developmental abnormality affecting a microbial organ. What is the meaning of that?”

Important changes

This month, Gordon said, researchers will begin their first clinical studies in Bangladesh enrolling children with moderate acute malnutrition. Microbiota will be sampled in participating children at baseline, and children will then be randomly assigned one of several microbiota-directed complementary food (MDCF) prototypes vs. standard care. The cohort will be followed for evidence of repaired microbiota immaturity and the impact on enteropathogen burden, as well as the impact on markers for bone health and immune function.

“Pause and think about this manipulation that we are attempting of postnatal developmental biology,” Gordon said. “We want to determine the extent of repair ... we want to look at short-term and long-term impact and feedback between the host and the microbiota. What happens if we are able to achieve repair?”

“We hope we can inform long-term feeding policies for women worldwide as they make choices about what types of complementary foods to give their children during this time when exclusive milk feeding stops and children move to a fully weaned state,” Gordon said. “Current recommendations are not based on features of normal gut microbiota development. We hope to change that.” – by Regina Schaffer

Reference:

Gordon JI. The Gut Microbiota and Childhood Undernutrition. Presented at: The Endocrine Society Annual Meeting; April 1-4, 2017; Orlando, Fla.

Disclosures: Gordon reports no relevant financial disclosures.