In 2008, the National Institutes of Health funded the Human Microbiome Project—an ambitious project, similar to the Human Genome Project—aimed at characterizing the incredibly complex microbes that live in and on each of us. Six years later, the program expanded to become the integrative Human Microbiome Project (iHMP), with a goal of understanding how the microbiome in different parts of the body changes overtime and in various states of health such as pregnancy or disease.
Three studies from the iHMP, published today (May 29) in Nature and Nature Medicine, connect microbial composition to type 2 diabetes, pregnancy, and inflammatory bowel disease (IBD). Each study included data from thousands of blood samples, biopsies, and microbial swabs taken repeatedly from patients over time.
The main finding of all three studies, says Curtis Huttenhower, a computational biologist at Harvard University and the senior author of the IBD study, is that “everything is interconnected. Everything changes at once, and when the bugs change, you can see the human respond, and vice versa.”
Prediabetes and infection
One of the studies hit close to home for Michael Snyder, a geneticist at Stanford University who had shifted his research to focus on type 2 diabetes when he was diagnosed with the disease. Many patients, like Snyder, are diagnosed with diabetes following viral infections, but scientists don’t understand the connection between infections and insulin. He and his team wondered if people with diabetes or prediabetes respond differently to infections than those with healthy insulin function.
They followed 106 participants over four years (83 of which agreed to make their data open-access). Half of the volunteers had prediabetes, a condition in which blood sugar levels are elevated, but not quite to the point of type 2 diabetes. When the patients said they were healthy (not experiencing acute illnesses), the scientists took blood, stool, and nasal samples every three months. They used the samples to monitor the patients’ blood sugar and run deep genome sequencing to characterize the makeup of the gut microbiome and observe changes over time.
Everything changes at once, and when the bugs change, you can see the human respond, and vice versa.—Curtis Huttenhower, Harvard University
“We sequenced the genome from the host, the transcriptome, the proteome, and metabolome,” Snyder tells The Scientist, “and microbiome as well, obviously.”
If the patients reported that they’d gotten sick, had an immunization, gained weight, or experienced other significant life stresses such as colonoscopies, the researchers asked them to come in more frequently to give samples. Thirty-two patients had respiratory infections during the study.
They found that patients with prediabetes or dysfunctional insulin receptor signaling had impaired and delayed responses to respiratory viral infections, which the authors suggest can lead to extended, low-level inflammation, known to exacerbate diseases such as diabetes. The nasal and gut microbiomes changed differently in response to an infection than those of patients with healthy receptor signaling.
More importantly though, the difference in microbial makeup from person to person was greater than the difference within one person when he was sick or healthy. This means that “it’s really, really important that you capture someone’s profile when they’re healthy so when they get disease you can see [any changes] at the earliest time,” says Snyder.
Inflammatory bowel disease
Huttenhower and his colleagues found a similar idiosyncratic phenomenon in their sample of patients with IBD. “The exact ways in which the disease’s flares manifest differ from person to person,” he says. “One of the surprising outcomes there is just really how different everyone is.”
The group followed 132 patients for a year each. Patients used home collection kits and mailed a stool sample to the investigators every two weeks. The researchers also analyzed quarterly blood samples and biopsies from the patients’ colonoscopies.
IBD is an autoimmune disease, but the samples showed that it’s not just the immune system that’s disrupted. The known biomarkers of Crohn’s and colitis, two types of IBD, are antibodies in the blood, but these are only present when there are also changes in the gut microbiome.
“It’s not just that the immune system is generally disrupted during Crohn’s disease or ulcerative colitis, it’s very specifically during periods of disease activity. When there are microbial and biochemical changes in the gut, you can also see the immune system respond throughout the body with changes in which antibodies are present,” says Huttenhower.
Pregnancy and prematurity
The final study in the trio didn’t track disease, but changes in microbial diversity as they related to pregnancy—especially in those that end with preterm deliveries.
Scientists have made enormous progress in supporting preterm babies after they are born, but there is still no way to predict when it is likely to happen.
In the United States, women of African ancestry are more likely than any other women to give birth prematurely. In hopes of better understanding the issue in this population, Greg Buck, a microbiologist and immunologist at Virginia Commonwealth University, and his team analyzed a subset of samples from the 1,527 women involved in the Multi-Omic Microbiome Study-Pregnancy Initiative (MOMS-PI). The subset of pregnant women was mostly of African descent and ended up including 45 who had preterm births (defined as pregnancies lasting less than 37 weeks), and 90 who went to term.
Until these microbiome studies create actionable outcomes and test hypotheses, we won’t know if they are high impact or just expensive association studies.—Gregor Reid, Western University
“The question was, could we identify any microbial signatures or multi-omic signatures that would give us some idea of how to either predict risk of preterm birth or give us some idea of the mechanisms by which bacteria [cause preterm birth]?” says Buck.
The team collected samples of the vaginal microbiome from the women at every appointment throughout their pregnancies. Like the other studies, they studied these samples in the context of the rest of the body, also collecting cord blood and placenta tissues at birth, and other microbial specimens.
The group identified certain bacterial taxa associated with preterm birth. Most surprising, says Buck, was that the signals seemed to be greatest early in the pregnancy, instead of as the women approached labor. Previous studies had shown that during the first trimester, the vaginal microbiome is very diverse, but throughout pregnancy that decreases, and the microbial community becomes dominated by Lactobacillus. In the current study, the signs of potential preterm delivery disappeared along with microbial diversity.
David Sela, a nutritional microbiologist at the University of Massachusetts who was not involved in the study, called the work “expansive” and “well executed,” and added that the identification of microbes tied to preterm birth could one day help inform interventions.
However, Buck and his colleagues are not yet ready to take the leap of claiming that they can predict which moms will deliver early. And it’s unclear how much practical utility the massive scientific undertaking of the integrative Human Microbiome Project will have.
Gregor Reid, a microbiologist and immunologist at Western University who was not involved in any of the studies, says, “Until these microbiome studies create actionable outcomes and test hypotheses, we won’t know if they are high impact or just expensive association studies. . . . We need to go beyond following people and not testing interventions.”
W. Zhou et al., “Longitudinal multi-omics of host- microbe dynamics in pre-diabetes,” Nature, doi:10.1038/s41586-019-1236-x, 2019.
J. Lloyd-Price et al., “Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases,” Nature, doi:10.1038/s41586-019-1237-9, 2019.
J. Fettweis et al., “The vaginal microbiome and preterm birth,” Nature Medicine, doi:10.1038/s41591-019-0450-2, 2019.