Our guts are home to a cast of billions: bacteria, viruses, and fungi all congregate and collectively make up our microbiome. This vast gastrointestinal tribe shapes the onset, incidence, and treatment of a startling number of diseases including inflammatory bowel disease and cancer. In the past 20 years since the field took off, much has been discovered about how this unseen ecosystem interacts with all aspects of human life, and the rate of discoveries shows no signs of slowing.
As a recent STAT News article noted, it’s academic centers like the PennCHOP Microbiome Program that “play an outsize role in pushing microbiome therapeutics forward.”
“The field is expanding in many directions,” said Rick Bushman, PhD, chair of Microbiology. “Understanding the microbiome is helping to sort out the intricacies of diet, chronobiology, cancer treatment, and more. One area with exciting new work centers on how the microbiome develops in infants and how it affects their birth and health in the first few days outside the womb.”
A related study, published last month by Michal Elovitz, MD, a professor of Obstetrics & Gynecology, found that seven types of bacteria and certain immune factors in a woman’s vagina and cervix may be responsible for increasing the risk of spontaneous preterm birth or protect against it. In the future, Elovitz hopes this knowledge will provide ways to target bad bacteria or increase protective bacteria to keep babies from being born too early.
Weighing in on Microbes’ Role
The past century has seen remarkable changes in lifestyle, from new patterns in what and when we eat to irregular and often insufficient sleep schedules. In addition to causing a host of negative feelings like sleepiness and hunger, these behaviors of everyday life also increase the risk of diseases such as type 2 diabetes and cardiovascular disease, and shape the composition of gut microbes, which researchers are discovering predispose us to weight gain and metabolic disorders.
Christoph Thaiss, PhD, an assistant professor of Microbiology, is all too familiar with the daily rotating cast of characters that makes up the gut microbiome and is at the forefront of uncovering how these changes affect overall health.
“We study the interaction of three factors – diet, daily cycles, and gut bacteria – that are tightly connected with our modern lifestyle,” he said. Over the course of a day, intestinal microbes change composition, activity, and location in the gut. Disruption to the normal patterns, Thaiss explains, can change the microbe community to one that predisposes an individual to obesity and high blood sugar.
Using mouse models, Thaiss has shown that weight gain can have a long-lasting effect on the composition of the microbiome. For example, his team noted that the microbiomes in once-obese mice did not change after the animals lost weight. Compared to control mice, the once-obese mice were particularly susceptible to regaining the weight they had lost. Thaiss discovered that it was the loss of flavonoids—nutrients found in almost all fruits and vegetables—in the obese mice that caused fat cells to slow down and burn fewer calories, causing the weight regain. However, when the flavonoids were restored to the microbiomes of the obese mice, the fat cells resumed their normal activity levels and the weight regain stopped.
High blood sugar also affects the way the gut interacts with beneficial microbes. Normally, cells lining the gut form a tight wall that keeps intestinal microbes where they belong instead of wandering throughout the rest of the body. High blood sugar levels make that barrier leaky. Last year, Maayan Levy, PhD, an assistant professor of Microbiology, reported in Science that mice with a Salmonella-like infection had high blood sugar and that chemically inhibiting sugar metabolism restored barrier function to the cells lining the intestines, keeping gut bacteria in their proper place. With this in mind, Levy, who was recently named a 2019 Searle Scholar, is now working to understand how keeping microbes in their correct home can reduce inflammation and how this anti-inflammatory process can potentially be imitated to treat such metabolic disorders as diabetes.
The C. diff Difference
Sorting out the tangled intricacies of diet, chronobiology, and gut bacteria is what keeps microbiome researchers so excited.
One twist on helpful bacteria turning harmful is the case of fecal transplantation for combating Clostridium difficile (also known as C. diff), the difficult-to-treat scourge of hospital-borne infections. Inflammatory bowel disease and obesity top the list of other diseases that fecal transplantation might be able to help, and there’s some evidence to suggest that others such as cancer may follow. In fact, earlier this month, oncologists from the United States and Israel presented results from two studies suggesting that tumors in some patients, who initially did not benefit from PD-1 cancer immunotherapy drugs, stopped growing or shrank after a transplant from the stools of patients’ in which PD-1 did work.
In current research that looks at C. diff’s biology from the perspective of what humans ingest, Joe Zackular, PhD, an assistant professor of Pathology and Laboratory Medicine, recently found that nonsteroidal anti-inflammatory drugs, commonly called NSAIDs, actually aggravated C. diff infections in mice, including instabilities in the gut microbiome and a breakdown of the cell barrier of the gut lining that Levy also studies.
“Engineering the microbiome is a very promising area for long-term research,” Bushman said. “The effectiveness of microbiome fecal transplants for relapsing C. diff infection, for example, is a perfect example of the promise the field holds.” In fact, a search on the National Institutes of Health clinicaltrials.gov database comes up with 47 trials related to C. diff. Penn Medicine was a site for one of the studies—the first prospective, multi-center, double-blinded, randomized controlled study of fecal transplants to treat C. diff infection. The first publication from this trial recommends that two doses of the transplant was superior to placebo, which provides information needed to design a larger phase 3 trial.
Given this momentum, Bushman said that in the next few years he expects several of these exciting advances on mechanisms in mouse studies to make their way into the clinic.