March of the Microbes

November 21, 2017
March of the Microbes
Source: Julio C. Valencia, NCI Center for Cancer Research

Helen Albert

We are all colonized by vast quantities of microorganisms. Until recently, there has been little focus on how these microbes can help us stay healthy. However, it has now been recognized that they can provide us with a whole array of different benefits. In contrast, disruption of these microbial communities, such as through excessive use of antibiotics, can actively contribute to disease.

The quest to try to understand the human microbiome and to discover how manipulating it in different ways could help prevent or treat disease has been taken up by the research community with enthusiasm, with advances in technology helping to power this search for knowledge.

There are several different microbiomes present in or on the human body such as that of the skin, the mouth and the urogenital tract, but the largest and most well characterized is the one found in the gut. Recent research has uncovered associations between the gut microbiome and a number of diseases including inflammatory bowel disease, diabetes, cancer, infections, and even neurologic disorders.

While a lot of this research is still at an early stage, clinicians and researchers are already finding ways to use their findings to help treat patients develop better diagnostic tools for disease; and evaluate the efficacy of different therapies based on the diversity and composition of a patient’s gut microbiome.

Conquering Clostridium difficile

An early win for gut microbiome researchers was the use of fecal transplants from healthy volunteers to treat patients with recurrent C. difficile infection—a condition that causes around 29,000 deaths per year in the United States alone.

The success of this somewhat unconventional treatment led to it cautiously being recommended for severe or reoccurring C. difficile infections by both the U.S. FDA and the U.K. National Institute for Health and Care Excellence. But, there are restrictions on its wider use due to concerns about transplant regulation and possible side effects (see “How Safe are Fecal Transplants” sidebar).

Mark Wilcox, M.D., professor, medical microbiology, University of Leeds, explained how the gut microbiome impacts on C. difficile infection: “The intact gut microbiome is hostile to C. difficile. When the gut microbiome is damaged, typically by antibiotics, this provides a niche which can be exploited by C. difficile.”

Wilcox and his colleagues advocate prevention as a way of tackling recurrent C. difficile infections. “By preventing the damage to the gut microbiome, we can potentially avoid C. difficile infection and the recurrences that typically occur in about a quarter of affected patients,” he said.

The research team has developed a laboratory gut model that allows accurate prediction of which antibiotics put patients at higher risk of developing C. difficile infection and which are most likely to be effective for treatment purposes.

The team also had success using targeted antibiotics to treat C. difficile infection. These include ridinilazole—a drug that appears to be better at preserving the gut microbiome and reducing the risk of recurrent infections than more traditional, less specific, antibiotics such as vancomycin.

Cracking Open the Cancer Microbiome

Jennifer Wargo, M.D., is associate professor of surgical oncology at University of Texas, MD Anderson Cancer Center in Houston. She first became interested in the influence that bacteria have on cancer while working at Harvard University.

“We identified bacteria within tumors that could mediate  therapeutic resistance. Specifically, in 75% of patients with pancreatic cancer you could identify bacteria within their tumors and these bacteria could actually break down chemotherapy,” she explained.

After moving to MD Anderson in 2013, Wargo and her group began to focus more on how differences in the gut microbiome could impact on cancer treatment. Working with her colleague Vancheswaran Gopalakrishnan, Ph.D., also based at MD Anderson, Wargo and her team collected oral and gut microbiome samples from more than 200 patients with metastatic melanoma both before and after treatment with anti-PD1 based immunotherapy.

“Patients who had a higher diversity of bacteria within their gut had a better response to therapy than those who did not,” explained Wargo. Adding that “component taxa also mattered.”

Gopalakrishnan continued: “Taking our findings in our human cohort forward, we understood that the data was compelling, but it was mostly correlative and so we wanted to delve into the mechanism a little more. With that in mind we planned and performed experiments in germ-free mice.”


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