Are those the gut microbes of an unhealthy person, or a pregnant one?

By Ed Yong | August 2, 2012 12:00 pm

A pregnant woman isn’t just eating for one, but for trillions. Aside from her baby, she’s also home to a multitude of bacteria and other microbes. They have been part of her life since she herself emerged from a womb, and they have influenced her health ever since. Now, as she enters her third trimester, her microbe community is radically changing.

The diversity of species is falling, while certain groups are rising to the fore. Oddly enough, the whole community starts to resemble the microbes of someone with metabolic syndrome – a collection of symptoms that increase the risk of diabetes and heart disease, such as obesity, high blood sugar levels, and inflammation. It’s a good reminder that context matters. These “unhealthy” changes in our gut microbes are actually normal in a different setting, and might even be necessary for a healthy pregnancy.

In the last decade, it has become abundantly clear that we are not so much humans as colonies of microbes in human-shaped sacks. These passengers and their genes, collectively known as the microbiome, are a hot area of research. Scientists have studied the microbiomes of infants and old people, hunter-gatherers and city-dwellers, healthy people and cancer patients. But a new study by Omry Koren from Cornell University is the first to show how the microbiome changes over the course of a pregnancy.

Koren’s research is a powerful reminder that our knowledge of the microbiome is still a work in progress. There’s a lot of optimism around using these microscopic partners to diagnose diseases or predict the risk of illness. After all, the microbiome can apparently predict the risk of type 2 diabetes better than usual measures like body-mass index or waist-to-hip ratio. But if such readouts can’t yet distinguish between someone in poor health, and someone with child, they clearly still have a long way to go.

The connection between pregnancy and metabolic syndrome was apparent long before the microbiome became part of the zeitgeist. Pregnant women pack on more fat, become less sensitive to the hormone insulin, and develop higher sugar levels in their blood. In some cases, these changes are severe enough to be classified as “gestational diabetes”. They would be considered unhealthy in men or women who aren’t pregnant. But in expecting mothers, they help to store energy in fat and maintain a constantly supply of sugar – two traits that help to steadily nourish a growing foetus.

Koren discovered the microbiome’s role in these changes by collecting stool samples from 91 Finnish women who had signed up for another study of nutrition during pregnancy. By sequencing the microbial genes within them, he found that the volunteers’ gut microbes were very similar to those of other normal healthy women in the first trimester of pregnancy.

By the third trimester, things had changed considerably. Each woman’s microbiome had genetically gentrified, and lost much of its original diversity. For the same reason, the differences between the individual microbiomes had increased. These changes were largely unpredictable: they didn’t correlate with the women’s health, diets, or first trimester results. They were, however, similar to what happens in the guts of someone with metabolic syndrome. “This was a surprise,” says Ruth Ley, who led the study. “We didn’t realize that metabolic changes during pregnancy were similar to metabolic syndrome until we saw the similarities between the microbiota associated with both.”

There were other similarities. Two groups of bacteria – the Proteobacteria and Actinobacteria – became more common in the third trimester, by four and two times respectively. That’s normally not a good sign. For example, many studies have found that Proteobacteria are more common in people with inflammatory bowel disease. And sure enough, the volunteers had higher levels of inflammatory chemicals (cytokines) in their blood in the third trimester than in the first.

To see if the changing microbes were causing inflammation, or if inflammation was changing the microbes, Koren transplanted gut bacteria from the pregnant women into germ-free mice that lacked any microbiome of their own. Two weeks later, the mice that had been loaded with third-trimester microbes had put on more weight than those who were given first-trimester sets, even though all of them had eaten the same food. They also had higher levels of sugar and inflammatory chemicals in their blood. Again, these are exactly the same changes you’d expect to see if you transplanted the microbiome of an obese mouse into the germ-free ones.

The third-trimester microbiome certainly seems superficially similar to an obese one, but Koren found important differences too. For example, the microbiomes of obese and lean individuals differ mainly in the balance of two bacterial groups: Bacteroidetes and Firmicutes. Bacteroidetes tends to rule the skinny gut, while Firmicutes takes over in the fat one. But over the course of a pregnancy, the balance between these groups stays the same and neither cedes territory to the other.

It’s still unclear why the microbiome change so dramatically during pregnancy, but the team suspects that it starts with the mother. “There are significant immune changes that occur in pregnancy, particularly at the placenta, so that the fetus is not rejected,” says Ley. She suspects that the immune environment also changes in the lining of the gut, including a low level of inflammation. The local microbes respond to these changes, and they drive even more inflammation.

You could view this chain of events as an adaptation on the part of the mother. By manipulating her gut bacteria during pregnancy, she triggers the metabolic changes that will best support her growing foetus. “This study shows that some of these interactions between immunity, metabolism, and the microbiota that we think of as unhealthy may just be normal in [a different] context,” says Ley.

Reference: Koren, Goodrich, Cullender, Spor, Laitinen, Backhed, Gonzalez, Werner, Angenent, Knight, Backhed, Isolauri, Salminen & Ley. 2012. Host Remodeling of the Gut Microbiome and Metabolic Changes during Pregnancy. Cell http://dx.doi.org/10.1016/j.cell.2012.07.008

Image by Ken Hammond (USDA)

An introduction to the microbiome


CATEGORIZED UNDER: Bacteria, Microbiome, Select

Comments (9)

  1. Bob

    That is scary. I wonder when the microbiome has returned to its original state? Is some of the diversity lost forever?

  2. QoB

    Interesting. I’d love to see research on the same women after pregnancy; on women who developed GD during pregnancy; and on women who had diabetes or metabolic syndrom pre-pregnancy.

  3. Please. Readers. let’s agitate potential investors to fund this research. Micro, it appears, is mightier than Macro has ever suspected. THIS is basic science.

  4. I have now seen articles that suggest the microbiome impacts diabetes, heart disease, cancer and all autoimmune diseases. It also may give us the ability to draw nutrients from most of the food we eat and be the reason we developed the most sophisticated part of our immune system. And now child birth. It’s astounding how deeply we depend on bacteria.

  5. As to what happens after pregnancy, I asked Ley. They only took samples for the women one month after birth, and the microbes were still like they were in the third trimester. However, she says “But it does go back to normal, because for many of these women this was not their first child, and they were all normal at the first trimester.”

    @Jan – Don’t worry. I think the microbiome people do a pretty good job of raising funds for this work. It’s clearly a growth area.

    @Greg – Yes. Yes it is.

  6. I can’t help but wonder how much our modern obsession with cleanliness (spreading bleach, alcohol and other antimicrobial agents everywhere in our homes, on our bodies, etc.) has to do with the increase in diseases such as allergies, asthma, obesity, cancer, and whatever else. It’s not pleasant to think about, but there’s only one route into our intestines for these bacteria.

    I’ve read that in Europe C. Difficile infections are being successfully treated with fecal transplants, but so far the eww-factor has kept that treatment out of North America. In fact, a Canadian doctor was forced by the regulatory body to halt a trial of the procedure, even though it was clearly saving lives.

  7. E. McCoy

    Interesting work.
    @Jan – yes – more funding needs to go to basic research. It’s a shame that NIH and NSF funding continues to be cut each year when there is still so much left to learn.

  8. John Obenauer

    “But if such readouts can’t yet distinguish between someone in poor health, and someone with child, they clearly still have a long way to go.”

    You’re not giving Koren’s research enough credit. It is very easy to tell if a woman is pregnant after a quick trip to the drugstore. If she’s not, and still has the third-trimester-like gut microflora, then she has a metabolic disorder.

  9. Ed your writing is fascinating again! And cool discussion. As for fecal transplants – I believe they were pioneered at the University of Calgary, but I should check. They are still done here but most often in patients’ homes to avoid the administrative hassle http://www.cmaj.ca/content/183/5/541.full. And not only is the microbiome important for digestion and immunity but also mood, and may be implicated in some cases of regressive autism http://www.ncbi.nlm.nih.gov/pubmed/22202440. And yeah, kids that grow up around farm animals or even household pets tend to have fewer autoimmune diseases, so stop with the antibacterials!

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