Lingering problem found in gut microbe communities of malnourished children

​New research may help explain why millions of malnourished children suffer from stunted growth and fail to thrive after treatment with nutrient-rich therapeutic foods.

Studying healthy and malnourished young children in Bangladesh, a team at Washington University School of Medicine in St. Louis found that malnutrition has persistent detrimental effects on the vast community of microbes living in the gut. These “friendly” microbes typically aid in extracting nutrients and calories from food, and perform many other vital functions.

The study’s results suggest that the long-term consequences of childhood malnutrition, such as stunted growth, cognitive problems and weakened immune systems, may be rooted in lingering, underdeveloped collections of gut microbes that can’t fully harvest energy and calories from food, said the study’s senior author, Jeffrey I. Gordon, MD, director of Washington University’s Center for Genome Sciences & Systems Biology.

In healthy children, the researchers identified features associated with normal development of the gut’s community of microbes. In comparison, they noted that malnourished children carried communities of gut microbes that did not mature along a normal trajectory. Moreover, these immature bacterial collections could not be restored to good health with standard treatments of therapeutic foods.

The research, conducted in collaboration with colleagues at the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh, is published online June 4 in the journal Nature.

“Although therapeutic food-based interventions have resulted in a significant decline in deaths from malnutrition, many children never fully recover,” said first author Sathish Subramanian, a Washington University MD/PhD student. “We found that children who were malnourished had gut microbial communities that were not consistent with their chronological ages. Moreover, the severity of a child’s malnourishment was tied closely with the degree of immaturity of his or her gut microbial community, and this immaturity could not be durably repaired with standard treatments.”

The researchers are following up their research in animal models colonized with immature gut microbe communities from malnourished children. They are seeking to determine whether giving therapeutic foods for longer periods of time or administering beneficial mixtures of naturally occurring human gut microbes can repair this immaturity and improve health.

Severe acute malnutrition affects about 20 million children worldwide, according to the World Health Organization. Moderate acute malnutrition, a less serious form of the disease, is more prevalent in South Central Asia, where it affects 30 million children. Both conditions are problematic in Bangladesh, where more than 40 percent of children under age 5 are afflicted by stunted growth.

“Treatment of malnutrition is challenging in a developing country like Bangladesh, where more than half a million children under 5 years of age suffer from severe acute malnutrition and close to 2 million from moderate acute malnutrition,” said co-author Tahmeed Ahmed, MBBS, PhD, who treats malnourished children and heads the Nutrition Program at the International Centre for Diarrhoeal Disease Research in Bangladesh. “This research has contributed immensely to what we know about the mechanisms operating in acute malnutrition. I believe it will open up new vistas for simplifying treatment of this dreadful condition that affects millions of children globally.”

In recent years, scientists have come to learn that severe childhood malnutrition is not due to a lack of food alone. Rather, the condition is far more complex and may involve other factors including a breakdown in the way gut microbes process various components of the diet.

Gordon’s earlier research in Malawi involving sets of twins, in which one in the pair was healthy and the other was severely malnourished, indicated that a dysfunctional gut microbial community is an underlying cause of a severe form of childhood malnutrition.

“Tens of trillions of microbes, primarily bacteria, live in the gut,” Gordon explained. “They break down components of our diets that otherwise would pass right through our bodies and also harvest energy from food, synthesize vitamins, regulate our metabolism and shape our immune systems. You can think of the collection of microbes in your gut as an organ within an organ, but one that is composed of microbial cells rather than human cells.”

To understand the relationship between gut microbes and childhood malnutrition, Gordon and his team first needed a clearer picture of the process by which the community of microbes normally assembles in the gut. The researchers analyzed collections of gut microbes captured in fecal samples collected monthly from healthy children, including twins, from birth to age 2. All of the children in the study lived in the slums of Dhaka, the capital of Bangladesh.

Studying these children, they identified groups of microbes that assemble in the gut during the first two years of life. “Using this microbial signature of normal gut microbial community maturation, we evaluated the gut microbial communities of 64 severely malnourished children before, during and after they received standard food-based interventions,” Gordon explained.

The children ranged in age from 6-20 months and were randomly assigned to receive one of two therapeutic foods: Plumpy’Nut, an enriched peanut-based food that is the mainstay treatment for severe malnutrition worldwide, or Khichuri-Halwa, which is produced in Bangladesh and has rice and lentils as its main ingredients. Both types of food include milk powder and micronutrients, such as iron.

Fecal samples were obtained from the children before they received the therapeutic foods and every three days while they were being treated for malnutrition. Most children received the therapeutic foods for about two weeks, until they had reached certain weight milestones, as is the standard of care. After treatment ended, the children were followed for four months, and fecal samples were collected monthly.

All the children gained weight on the therapeutic foods, and no significant difference existed in the rate of weight gain based on the type of food a child received. But the therapeutic foods only had a transient improvement on the maturity of a child’s gut microbe community. Once the therapeutic food was discontinued, the gut microbe communities regressed to a more immature state.

“These children, although they gained weight, remained severely stunted and severely underweight, and their health was not fully restored,” Gordon said.

In a separate group of children with moderate acute malnutrition, the researchers also noted a similar immaturity in gut microbe communities.

“These new measuring tools for defining the maturation of the gut microbial community ‘organ’ expand our view of human development following birth, provide a new way of classifying malnourished states, establish a new measure for determining the effects of current therapies, and catalyze thinking about new forms of therapy. This could include new therapeutic foods and the possibility for safely administering naturally occurring human gut microbes that could promote healthy maturation of the gut microbial community,” Gordon said.

The researchers also are asking whether the signature of gut microbe maturation they identified in healthy Bangladeshi children applies to children living in other areas of the world where malnutrition is pervasive but people consume different diets. They are actively pursuing an answer to that question in locations around the world.

“We want to know whether and how this immaturity is linked to the long-term consequences of malnutrition such as stunted growth, impaired immunity and neurodevelopmental abnormalities,” Gordon added.

The research is funded by the Bill & Melinda Gates Foundation, the International Atomic Energy Agency, and the National Institutes of Health (AI043596).

Subramanian S, Huq S, Yatsunenko T, Haque R, Mahfuz M, Alam MA, Benezra A, DeStefano J, Meier MF, Muegge BD, Barratt MJ, VanArendonk LG, Zhang Q, Province MA, Petri WA, Ahmed T and Gordon JI. Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature, June 4, 2014.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.