For malnourished children, a new type of microbiome-directed food boosts growth – Washington University School of Medicine in St. Louis

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New foods are said to promote healthy gut microbes

International Center for Diarrheal Diseases

A new type of therapeutic food specifically designed to repair the gut microbiome of malnourished children is superior to standard growth-promoting therapy, according to a proof-of-concept clinical study conducted in Bangladesh.

The study, conducted by an interdisciplinary team of researchers from Washington University School of Medicine in St. Louis and the International Center for Diarrheal Diseases in Dhaka, Bangladesh (icddr, b), aimed to supplement the diet of malnourished children with a formulation that is locally available, Contains culturally acceptable foods selected based on the ability of the ingredients to promote key growth-promoting gut microbes. The work supports the notion that healthy growth in infants and children is closely related to the healthy development of their gut microbial communities – or microbiomes – after birth.

The results of the study will be published online April 7th in the New England Journal of Medicine.

According to the World Health Organization, child malnutrition is a major global health challenge affecting over 150 million children under the age of 5 worldwide. In southern Asia and sub-Saharan Africa the effects are disproportionate. The ongoing COVID-19 pandemic only exacerbates this problem. Numerous studies have shown that malnutrition is not solely due to food insecurity, but reflects a combination of factors, including an important role in the gut microbiome, which does not develop properly in malnourished children during the first two years of life.

“Malnutrition has proven extremely difficult to treat. Standard high-calorie foods have been shown to prevent the death of malnourished children, but fail to effectively overcome stunted growth and other harmful effects of malnutrition, including impaired brain development, bone growth and immunity, “said senior author Jeffrey I. Gordon, MD, who respected university professor of Dr. Robert J. Glaser and Director of the Edison Family Center for Genomic Science and Systems Biology at the School of Medicine. “To address this problem, we are investigating whether repairing the poorly developed microbial communities of malnourished children affects their growth. This is the first time a microbiome-driven therapeutic food has been compared to standard therapy for malnourished children. In addition, it resulted in a superior rate of weight gain, the study’s key clinical finding. “

An earlier one-month pilot clinical study conducted by the team in Bangladesh had provided evidence of the benefits of the microbiome-driven therapeutic food in a small number of children who received it. However, the study wasn’t large enough or long enough to confirm the new food’s effects on growth. The current three-month clinical study, supervised by Tahmeed Ahmed, MBBS, PhD, managing director of icddr, b, enrolled 118 children aged 12 to 18 months who lived in an urban slum called Mirpur in Dhaka, Bangladesh . All of these children have been diagnosed with acute malnutrition, a condition in which the body depletes its fat stores and muscles, leading to waste or weight loss. The immune system is also weakened, making these children more susceptible to other diseases.

“This work is based on our studies that have shown that a disorder in the gut microbiome is responsible for malnutrition in children,” said Ahmed. “We have successfully used a food made from local ingredients to repair the disrupted gut microbiome and thereby improve the growth of the children who receive the food. At a time when we unfortunately still have a staggering number of children suffering from malnutrition and dying, our discovery of microbiome-driven food supplements can make a difference. “

Half of the children in the current study were randomly given the microbiome-driven therapeutic food and the other half were given a standard therapeutic food that was not intended to repair the gut microbiome. The new microbiome-driven food contains, among other things, a mix of chickpeas, soy, bananas and peanuts that the group discovered in previous pre-clinical models for repairing the gut microbiome. The therapeutic standard food is based on rice and lentils and contains around 20% more calories per serving than the microbiome-controlled food.

The children received 25 grams of their assigned therapeutic foods twice a day for three months. The height, weight and girth of the middle upper arm of the children were measured at regular intervals throughout the intervention period and for one month after the end of treatment. Blood and stool samples were also drawn at various times to assess changes in the levels of nearly 5,000 proteins in the blood and to quantify the effects of therapies on the display of specific beneficial microbes in stool samples.

The researchers found that the rate of change in the children’s weight and girth in the middle upper arm area was significantly higher in the group that received the microbiome-controlled diet compared to the standard therapeutic diet. This growth superiority also persisted for a month after the children stopped receiving the diet-related intervention. This is the last point in time that has been analyzed so far.

“If we look at the standard clinical measure used to assess acute malnutrition – the weight-for-length Z score – the difference between the two treatment groups was even more significant one month after stopping treatment,” said co-lead author Robert Chen. a graduate student in Gordon’s lab. “If this rate of growth is maintained for a year, we estimate an improvement in the weight-for-length Z-score of almost a full standard deviation.

“Children with acute malnutrition typically have a decreasing or, at best, stable weight. If this extrapolation continues, it would be a significant clinically relevant improvement in growth outcomes,” added Chen.

Co-first author Ishita Mostafa, a research fellow at the International Center for Diarrhea, said, “We continue to monitor and collect samples from these children. This is important to determine whether the effects of this new treatment will actually last for an extended period of time or whether the intervention will need to be sustained for longer periods of time. “

The researchers also found that a group of 23 strains of bacteria found in stool samples correlated with the increased rate of weight gain seen in the children who received the microbiome-controlled food. Twenty-one strains were positively correlated – meaning more of these gut bacteria were associated with increased growth. And two strains were negatively correlated – meaning fewer of these gut bacteria were associated with increased growth. The microbiome-targeted food was found to increase levels of the 21 positively correlated strains and decrease levels of the two negatively correlated strains.

The researchers also found 70 proteins in the blood samples that correlated positively with increased weight, with greater improvements in their levels after the microbiome-directed treatment compared to the standard intervention.

“These proteins are key regulators in bone biology, neurodevelopment and immune function,” said Gordon. “We found that this food can promote and expand the abundance of beneficial microbes while increasing the levels of beneficial proteins in their human hosts, which has an impact on growth.

“The rate of weight gain of the children given the new therapeutic food, which was developed with healthy gut microbes in mind, was significantly higher, even though its calorie density was 20% lower than the standard food,” added Gordon. “This suggests that repairing the gut microbiome, rather than just adding calories, is key to healthy growth in these children.”

The teams led by Gordon and Ahmed, funded by the Bill & Melinda Gates Foundation, plan to continue studying whether therapeutic foods that promote beneficial gut microbes can help malnourished children in other parts of the world. This includes a program to develop microbiome-driven foods that contain diverse but functionally “biosimilar” ingredients that are readily available, affordable and culturally acceptable to parents and children in these other countries. In addition, Gordon and colleagues plan to investigate whether repairing dysfunctional gut microbial communities could have an even greater impact in younger years and over longer periods of time.

“After the World Health Organization recommended six months of breastfeeding, we believe there may be an early window for the adoption of these types of microbiome-directed therapeutic foods that may have greater effects,” said co-author Michael J. Barratt, PhD, Associate Professor for Pathology and Immunology and Executive Director of the Center for Gut Microbiome and Nutritional Research at Washington University.

Researchers are also planning studies to examine the benefits of microbiome-driven therapeutic foods during pregnancy to see if they can not only improve the gut microbiome of malnourished mothers, but also promote the transmission of healthy gut microbial communities to their infants, helping to break the devastating one intergenerational cycle of malnutrition.

Gordon added, “We are also exploring the possibility of offering a clinical trial of this new therapeutic food to children who would benefit from nutritional intervention here in St. Louis. We are in the earliest stages of this process and are beginning to connect with members of the local community. We cannot begin any of these exams without making sure that community leaders, community members, parents, and caregivers are fully involved in the process. “

This work was supported by the Bill & Melinda Gates Foundation and the National Institutes of Health (NIH) grant numbers DK30292, F30DK124967, and GM007200.

Chen RY et al. A microbiota-driven food intervention for malnourished children. The New England Journal of Medicine. April 7, 2021.

The 1,500 faculty physicians at Washington University School of Medicine are also medical staff at Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, teaching and patient care and is consistently one of the best medical schools in the country according to the US News & World Report. The School of Medicine is affiliated with BJC HealthCare through its connections with the Barnes-Jewish and St. Louis Children’s Hospitals.

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