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Jennifer Fettweis (Photo by Sarah Walor)
When Jennifer Fettweis stepped on the stage at The Byrd Theatre for a TEDxRVA talk in October, she had news that may have left some in the sold-out crowd squirming.
The message? You’re not entirely human.
Rather, our bodies are host to a complex network of bacteria, fungi and viruses — trillions of them. These micro-organisms and their products, which are known as the human microbiome, play an important part in bodily functions, from digesting food to warding off infection. Researchers say they may also hold the key to better understanding many diseases.
Research into these microbes and their impact on our health has exploded in the last decade. While traditionally the study of microbes has considered their role as pathogens — disease promoting organisms — the focus of this new research is more holistic.
At her lab at Virginia Commonwealth University’s School of Medicine, Fettweis explains that this trend has been facilitated in part by technology — particularly the decreased cost of DNA sequencing. Researchers studying microbes used to have one option: To culture one strain of bacteria or other microbe in the lab. While this method yielded important insights, it only allowed researchers to consider organisms in isolation. Sequence a subject’s DNA sample, though, and you have a fuller picture of what is there, and how it operates together.
Researchers have found that microbial communities look and behave differently depending on where they’re located. “If you think of microbial communities as ecosystems, there are different habitats on the human body,” Fettweis explains. “The microbes that live in the skin are different than the microbes that live in the mouth, they’re different from the microbes that live in the gut, and for women, those that live in the vagina.”
A microscopic view of a vaginal smear with human vaginal epithelial cells (nuclei in blue) and bacteria in green
The vaginal microbiome has been the focus of research for Fettweis, who, along with Gregory Buck, leads VCU’s Vaginal Microbiome Consortium. Together with their team, they have been analyzing microbial samples from nearly 5,000 women, looking for markers that may be associated with particular health outcomes.
One finding is that the vaginal microbiome seems to shift significantly once a woman becomes pregnant. “Pregnant women tend to have vaginal flora dominated by lactobacilli,” Fettweis says. And this change may be for good reason: “We now think that’s a mechanism to keep out other species that may cause ascending infection.”
Those results led to a second project looking for patterns within the microbiome associated with pregnancy complications, including preterm labor, gestational diabetes and pre-eclampsia.
The team has also been collecting samples from babies born to study participants to learn how a mother’s microbiome influences the health of her newborn. She notes there have been studies showing babies born via cesarean section and babies born vaginally have different microbes, at least in the first year of life — though more research is needed to know what that means in the long-run.
Dr. Jasmohan Bajaj in the lab (Photo by Sarah Walor)
Researchers are also looking at the impact that microbes in one part of the body may have on functions in another. Some of the most promising research in this area is happening around the ways gut health may affect our brains.
“There is a very robust gut-brain axis that helps us live our lives the way we’re supposed to live it,” explains Dr. Jasmohan Bajaj, a gastroenterologist and liver specialist at Hunter Holmes McGuire VA Medical Center and VCU School of Medicine, where he also teaches. “If that gets disrupted, bad things happen.”
Just think of the classic “nervous stomach,” says Bajaj — how quickly under duress our stomachs manifest what’s going on in our heads, and vice versa. That’s because our digestive tract is connected to the rest of our body through a vast system of nerves and blood vessels. When changes happen to the microbial communities in our gut, that can alter what’s being produced there, and those products have a direct line to our brains via our bloodstream and nervous system.
Bajaj has been studying this “gut-brain axis” and what it means for patients with liver damage from cirrhosis. When the liver is compromised as a result of hepatitis, diabetes, alcohol abuse, or other factors, it triggers mechanisms that produce an imbalance of micro-organisms in the gut, says Bajaj. This imbalance can contribute to hepatic encephalopathy, a potentially fatal brain disease.
Bajaj offers an analogy: “If you think of [the gut microbiome] like a rain forest, or any other ecosystem — if it gets diseased, the number of different organisms that were present before collapses.” This diminished diversity then allows potentially disease-inducing bacteria, fungi and viruses to proliferate, the way an invasive plant species might gain footing in a damaged environment.
Fortunately, our microbial communities tend to sort themselves out once we recover from illness. But in the case of chronic diseases like cirrhosis, the body never gets to hit this reset button, and, as Bajaj explains, the result is a “vicious cycle” in which liver disease promotes inflammation in the gut, which drives further inflammation in the liver, which then worsens the situation in the gut and throughout the body.
“If you think of [the gut microbiome] like a rain forest, or any other ecosystem — if it gets diseased, the number of different organisms that were present before collapses.” —Dr. Jasmohan Bajaj
Bajaj and other researchers hope that by better understanding the mechanisms through which microbial imbalances in the gut trigger inflammation, they’ll be able to develop more effective treatment, as well as better predict which cirrhosis patients are at risk for developing hepatic encephalopathy, a condition in which liver damage leads to ineffective removal of blood toxins, which causes impaired brain function.
To do so, they’ve enlisted the help of peculiar animals that have become important tools in understanding the role of microbes in disease: mice that have no microbiome at all. These “germ-free” mice are born via cesarean section (in mice, like humans, passage through the birth canal is the first source of microbial contact) and raised in sterile conditions.
Because they have no bacteria, viruses or fungi, these mice allow Bajaj and his research partners to study how cirrhosis might progress in the absence of microbial actors. Their findings suggest that not only are particular microbes complicit in the development of cirrhosis (the germ-free mice took longer to develop the disease than their conventional counterparts under the same induction methods) — microbes were also essential for triggering the systemic inflammation that leads to hepatic encephalopathy. The researchers were even able to isolate particular bacterial groups that proved especially pro-inflammatory.
Bajaj cautions there’s no way to run the same experiments on humans. But a study looking at the microbes of cirrhotic patients with and without hepatic encephalopathy has lent credence to their findings.
The only permanent cure for cirrhosis is a liver transplant. But because the disease is the 12th-leading cause of death in the United States, demand far outpaces supply. Current treatments for patients with hepatic encephalopathy — usually a combination of laxatives and antibiotics — are not always effective, especially when the condition is advanced. They can also be expensive or come with a host of side effects. “Like killing an ant with a cannon” is how Bajaj describes these treatments, which target microbes in the gut indiscriminately.
Bajaj hopes his research will lead to treatments that are “more targeted, less injurious to the patient, and more likely to cause lasting benefit.”
Fettweis foresees a future where a better understanding of microbial communities yields more targeted treatments. “Our microbes are really something that constitute an organ that we haven’t appreciated before,” she says.
The best way to look after your microbes is to look after your overall health. It’s not flashy advice, Bajaj admits, but he’s sticking by it: “Eat a healthy, varied diet, with plenty of vegetables.”
