Washington University. US: Guided by the immune system, researchers have identified types of gut
bacteria in young children in Malawi that are linked to nutritional
health and that have diagnostic and therapeutic implications for
childhood undernutrition.
The research, led by Jeffrey I. Gordon, MD, at Washington University School of Medicine
in St. Louis, is published Feb. 25 in Science Translational Medicine.
The work, funded largely by the Bill & Melinda Gates Foundation,
also involved scientists at the University of Malawi in Africa,
University of Tampere in Finland and University of California, Davis.
Tens of trillions of microbes live in the gut, where they synthesize
vitamins and process nutrients in the diet to keep the body healthy.
These microbes and their genes, collectively known as the gut
microbiota, begin to colonize the intestinal tract at birth.
Researchers long have known that a lack of food is not the sole
contributor to childhood undernutrition; infections and intestinal
problems that prevent nutrient absorption are thought to play a role.
A 2013 study
by the same group of Washington University scientists pointed to a
dysfunctional collection of gut microbes as an underlying cause of
childhood undernutrition. These children possessed communities of gut
microbes that did not mature as they grew and that couldn’t be restored
to good health even after standard treatment with nutrient-dense
therapeutic foods.
The new research, involving infants and children in Malawi, in
sub-Saharan Africa, uncovers new clues to the pathology of
undernutrition by looking at gut bacteria targeted by a key immune
system molecule, IgA (short for Immunoglobulin A).
The scientists also demonstrated that beneficial gut microbes
identified in fecal samples from healthy children could be used to treat
undernutrition in mice.
“Undernutrition robs children of achieving their full potential,”
said Gordon, the paper’s senior author and director of the Center for
Genome Sciences and Systems Biology and the Center for Gut Microbiome
and Nutrition Research at Washington University. “Many children who have
been saved with current therapies suffer from the long-term
consequences of undernutrition such as stunted growth, neurocognitive
problems and weakened immune systems. Our findings point to the
possibility of developing more effective treatments for undernutrition
using beneficial microbes – or next-generation probiotics – in addition
to therapeutic foods.”
IgA, an antibody, is secreted in large quantities in the
gastrointestinal tract, where it binds to gut microbes and food
particles, preventing them from traversing the gut lining. In essence,
IgA is part of a “wall” that separates the gut microbiota from its human
host, allowing microbial cells and human cells to peacefully co-exist.
The researchers explored gut microbes targeted by IgA in pairs of
twins in which one twin became severely undernourished during the first
three years of life and the other remained healthy. As a comparison,
they also studied pairs of healthy young twins who remained
well-nourished.
Their research shows that IgA’s interactions with several types of
gut bacteria, including Enterobacteriaceae, correlate with the
development of undernutrition. Enterobacteriaceae is a large family of
bacteria found in the gut that includes E. coli, Salmonella, Shigella
and other pathogenic species. In healthy people, such strains of
bacteria often don’t cause problems, but in undernourished children,
their effects can be devastating.
The researchers’ discovery is bolstered by additional studies in
germ-free mice raised in sterile environments. Transplanting IgA-bound
gut microbes, purified from the gut microbiota of undernourished
children, into the mice led to dramatic weight loss, rapid disruption of
the lining of the small intestine and colon, and sepsis in mice fed the
same nutrient-poor diet as the children.
The weight loss, sepsis and the breakdown of the gut lining in
undernourished mice could be prevented, however, by administering just
two IgA-targeted strains of bacteria that were well-represented in the
gut microbiota from healthy children.
The researchers also noted that the types of gut microbes targeted by
IgA shifted over time as the Malawian infants grew into toddlers, and
differed in healthy children compared with those who were
undernourished. This suggests that identifying IgA-targeted microbes may
have diagnostic value in predicting which children are likely to
develop undernutrition, even before symptoms occur.
“This study demonstrates the usefulness of mining the microbiota for
potential therapeutic agents using the lenses of the gut immune system,
specifically the IgA it produces, as a guide,” said first author Andrew
L. Kau, MD, PhD, a Washington University instructor of medicine.
“Results from the children and the mice can be used to design follow-up
clinical studies to evaluate this approach.”
Gordon added: “These beneficial microbes are important leads, but
more work is needed to determine whether they represent effective, safe
treatments in children. Nonetheless, this study provides the first
evidence that benchmark measurements of interactions between a molecule
in the gut immune system and gut microbes may predict which children are
likely to develop undernutrition as they age.
“If we can intervene early to repair the gut microbiota in
undernourished children or those at risk for the condition, we may be
able to provide new and more effective ways for achieving healthy growth
and healthy immune function.”
The research was funded by grants from the Bill & Melinda Gates
Foundation and the National Institutes of Health (NIH), grant number R01
DK30292.
Kau AL, Planer JD, Liu J, Rao S, Yatsunenko T, Trehan
I, Manary MJ, Liu T-C, Stappenbeck TS, Maleta KM, Ashorn P, Dewey KG,
Houpt ER, Hsieh C-S, Gordon JI. Functional characterization of
IgA-targeted bacterial taxa from undernourished Malawian children that
produce diet-dependent enteropathy. Science Translational Medicine. Feb.
25, 2015.