Credit: Mark Knobil
Credit: Mark Knobil

Does Your Microbiological Age Match Your Biological One?

By the time babies are two months old, they start to smile.  By five months, they usually start picking up objects. By 12 months, they’ve probably said their first word. By 18 months, they’re walking. These milestones are familiar, but growing up isn’t just about moving, speaking and thinking.

It’s also about microbes.

When we are born, our mothers seed us with our first bacteria. As we grow up, these microbes—the microbiota—behave like an extra organ. They help us to digest our food, they shape the development of our gut and our nervous systems, and they train our immune systems to deal with threatening infections.

They also change. If you watch a newborn island, or perhaps a landscape scoured by fire or lava, you’ll see that living things colonise the land in predictable stages. Simple pioneering plants like lichens and mosses arrive first. Grasses and small shrubs come next, followed eventually by taller trees. Ecologists call this succession, and it happens in an infant’s gut too. A newborn’s bowels are first dominated by bacteria that digest substances in breast milk and produce important vitamins. Over time, these communities diversify to include those that can break down the more complex carbohydrates in plants, preparing us for an adult diet.

Over the past decade, scientists have documented these successional changes, often by studying their own kids. But Sathish Subramanian from Washington University in St Louis has gone one step further—he has developed ways of measuring the maturity of an infant’s microbes. He then used those measures to work out how malnourishment in early life affects the growth of our bacterial partners, and whether we can do anything about it.

“It’s a more comprehensive way of looking at human development,” says Jeffrey Gordon, who led the study. It’s about looking at a child not just as an individual, but also as an ecosystem.

Last year, Gordon’s team showed that Malawian children with a severe type of malnutrition called kwashiorkor had very different gut bacteria to their unaffected peers. When the researchers transplanted these microbes into mice, the rodents lost weight.

Once these unusual microbial communities set in, they were hard to shift. When the team fed the starving children with ready-to-use therapeutic food (RUTF)— special fortified meals that are routinely used to treat malnutrition—their gut microbes changed a bit but soon boomeranged to their impoverished state. These results might explain why RUTFs save many lives but don’t fix common problems in malnourished kids like stunted growth, weak immune systems, and developmental disorders.

Gordon wanted to know why RUTFs weren’t good enough, and how exactly malnutrition changes gut microbes. To do that, he needed two things: a group of healthy children living in an area with lots of malnutrition; and a way of measuring the succession of their gut microbes. He found both in Bangladesh.

With help from local scientist Tahmeed Ahmed, Gordon’s team collected monthly stool samples from 50 healthy Bangladeshi children over their first two years of life, and identified the bacteria within. Using data from 12 children, Subramanian put together a roll call of 24 species that best discriminated between kids of different ages. By creating a mathematical model using these 24 species, he could predict the age of the other 38 children with about 70 percent accuracy, just by studying their gut bacteria.

Using this model, Subramanian created a metric that measures the maturity of a child’s microbiota compared to healthy kids of the same age. If a baby is one year old but has the microbes of a 6-month-old, that community is immature. The baby’s microbiological age doesn’t match her biological one.

Next, the team applied their metric to 64 severely ill and malnourished children, aged 6 to 20 months, who were being treated at Ahmed’s hospital. The children were taking part in a trial that compared two types of therapeutic food: a French peanut-based brand (Plumpy’Nut), and a cheaper, local, rice-and-lentil-based one (Khichuri-Halwa). They ate these meals for one or two weeks and Gordon’s team collected their stool samples before, during, and after.

Their gut microbes, predictably, were very immature at the study, but improved significantly in the month after they ate the special meals.  But these improvements were short-lived. Four months later, when they had reverted back to their old diets, their microbial maturity scores had plummeted again—not quite as far as the old lows, but not far off either. And the kids’ physical changes mirrored their microbial ones—for each kilogram they weighed, they put on an extra 10 grams a day, but they still ended up underweight and stunted.

So why can’t the RUTFs fix the immature microbe communities in the long run? If might be that the kids aren’t eating the meals for long enough, or that the team didn’t track their health for long enough after the trial. Gordon’s team are now testing both of these explanations.

But in an accompanying editorial, Elizabeth Costello and David Relman from Stanford University, raised another possibility: that “degraded ecosystems are notoriously difficult to restore”. You can’t just fix a bleached coral reef or a fallow meadow by adding the right species. You might also need to remove invasive species too or change the flow of nutrients. The same holds for our guts, which are complex worlds in their own right. If they don’t develop correctly, they can be very hard to fix. “Thus, an ounce of prevention is likely to be worth a pound of cure and,” they write. “As with other types of developmental delays, early intervention may be crucial.”

Subramanian’s microbiota-age metric might help with that. They found that children with milder forms of malnutrition also had signs of slightly immature gut microbes. “If we could use these measurement tools to detect the development of immaturity early on, before disease becomes apparent, perhaps earlier intervention would produce more durable repair,” says Gordon.

The team also found that their 24-species model can also accurately predict the age of children in Malawi, even though it was developed in Bangladesh. That’s encouraging. It suggests that the same measure can be used to check the gut health of children all over the world—something that the team is now actively checking in infants from India, South Africa, Peru, Brazil, and the USA.

The challenges, according to Herbert Tilg from Innsbruck Medical University, are to work out whether the malnutrition changes the gut communities or vice versa, and to define any strains that are responsible for the children’s clinical symptoms. “It’s a fascinating topic with huge potential,” he says.

Perhaps in the future, just as we ask whether babies are walking and talking at the right time, we’ll be able to tell if their microbe partners are developing correctly.

Reference: Subramanian, Huq, Yatsunenko, Haque, Mahfuz, Alam, Benezra, DeStefano, Meier, Muegge, Barratt, VanArendonk, Zhang, Province, Petri Jr, Ahmed & Gordon. 2014 Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature

Correction: The piece originally said that the kids put on 10 kilograms a day, which is obviously ridiculous. Er, sorry.

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