Gut microbes might keep malnourished children from growing

Long-term malnutrition might at first seem like a medical condition with an easy fix: access to a wholesome diet rich in calories and nutrients.

But many of the children on the receiving end of such interventions still struggle to grow. Even when given enough to eat, they end up shorter than their peers and are saddled with cognitive deficits, weakened immune systems and other long-term consequences that tax their brains and bodies alike. The result is a paradox that continues to vex researchers worldwide.

Some 150 million children under the age of 5 have stunted growth. “It’s perhaps the single most common nutritional problem that we see all over the world, and there is no single intervention that has worked,” said Tahmeed Ahmed, senior director of the nutrition and clinical services division of the International Center for Diarrheal Disease Research, Bangladesh.

With so many children imperilled by poor sanitation and food insecurity, it is unlikely that researchers will ever uncover a simple root cause for stunting, Ahmed said. But in a paper published Wednesday in The New England Journal of Medicine, a team led by Ahmed and Jeff Gordon, a microbiologist at Washington University in St. Louis, may have taken a crucial step toward understanding one driver behind the debilitating condition: the bacteria that reside within the small intestine, where most nutrients are absorbed.

Certain members of this microbial community, the researchers found, may cause a cascade of inflammation in the gut that makes it harder for children to get the most out of their meals. Treatments that target these microbes for elimination — or perhaps foster friendlier strains — might someday help physicians rebuild the health of malnourished children.

“The only way to cure malnutrition is with nutrition,” said Maria Gloria Dominguez Bello, a microbiologist at Rutgers University who was not involved in the study. But for children in whom dietary changes alone are not enough, she added, “what you want is to break that resilience.” She said that the findings suggested this could be accomplished through interventions that alter the microbiota, the population of microbes in the gut.

Data tying intestinal microbes to malnutrition are not new. As a part of a decadelong collaboration, Ahmed and Gordon have produced several studies showing that nurturing the gut’s microscopic tenants can spur healthy growth in young children, and may even aid recovery after periods of severe weight loss.

But a role for gut bacteria in stunting, a condition that results from repeated bouts of undernourishment, has been far less obvious, although a couple of studies have pointed to the possibility in the past. To complicate matters further, some forms of stunting may have origins in persistent inflammation in the small intestine, a disorder called environmental enteric dysfunction, or EED, which can strip away the gut’s absorptive lining and stymie its ability to sponge up nutrients.

In reality, these three factors — gut microbes, EED and stunting — might all be intricately linked. But researchers have had trouble establishing these relationships in part because the small bowel is so inaccessible. Whereas the contents of the colon can be studied by simply sifting through faeces, understanding the upper gut often requires snaking a camera down the throat and through the stomach, an invasive procedure that can be especially risky for very young patients.

Still, that may be a risk worth taking for children with stunting who are not helped by diet alone, Ahmed said.

To identify this population, the researchers recruited more than 500 children from an urban district in Dhaka, Bangladesh, from 2016 to 2018; all were around 18 months old and at high risk of stunting. For three months, each child was given eggs, milk, vitamins and minerals, as well as antiparasitic medications to purge unwanted infections from their gut.

Most of the children in the study gained weight and grew, but just over one-fifth of them stayed obstinately small. Most of their small intestines showed signs of inflammation, the researchers found, a possible indicator of EED.

An analysis of their gut contents also revealed that many of the children harbored several of the same types of bacteria in their small intestines. None of the microbial members of this “core group” of bugs was “what you’d call a classic pathogen,” Gordon said. And yet, “the more of these bacterial strains you had, the worse the stunting,” he said. “That to us was an amazing surprise.”

The team then transferred a subset of these bacteria into germ-free mice, each one bred without gut microbes of its own. Shortly after the microbes set up shop in the animals’ small intestines, the tissues began to deteriorate — an apparent mimicry of the inflammatory friendly fire seen in many children with signs of stunting.

That bacteria alone can give mice gut inflammation is “huge, in my mind,” said Honorine Ward, a microbiologist and immunologist at Tufts University who was not involved in the study.

Although it is still unclear whether these dynamics will play out the same way in people, “this is very convincing, and a really good start,” said Ana Maria Porras, a microbiologist and tissue engineer at Cornell University who also was not a part of the research team.

And there is more for researchers to learn. For ethical reasons, they analysed the gut tissues and microbes only of children with signs of stunting, and for whom diet made little difference. “You can’t biopsy healthy children for no reason at all,” Ward said.

That leaves the portrait of a healthy microbial community in the small intestine ill-defined — something of a terra incognita, Gordon said.

Without that knowledge, the researchers cannot determine which has a greater influence on gut inflammation, the microbes that are present or the microbes that are absent, said Arianna Celis Luna, a microbiologist at Stanford University who was not involved in the study. Perhaps bad actors are seeding destruction in the gut, or maybe this intestinal community lacks benign bacteria that could counteract these harmful effects. Finding a humane way to transfer bacteria from healthy children, or from children who can recover from malnutrition through diet alone, into mice may help tease apart those differences, Dominguez Bello said.

There is almost certainly more to the picture, Gordon said. In the study, children with more inflammation did not experience more stunting. “So we’re missing something,” he said. And what’s true of malnourished children in Bangladesh won’t necessarily apply to populations in other parts of the world, Ahmed added.

But the study’s findings still hold a great deal of promise for global health, Ward said. Perhaps future interventions might include treatments that bolster the well-being of not just the human cells in our bodies but the bacterial ones, too. Combating malnutrition may be just as much about feeding our microbes as it is about feeding ourselves.

“We’re still a long way from devising those microbiota-based interventions, or even understanding what microbes to use,” Ward said. “But this opens the door to that.”

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