It’s All in the Gut

By: Michael Ferguson
Thursday, November 14, 2013

Microbes in the human gut may prove to be the key to future therapies for much more than gastrointestinal disorders.

Since 2005, Rob Knight, PhD, Associate Professor at the BioFrontiers Institute of the University of Colorado Boulder, has been studying the various ways these microbes — communities of microbes in the body are referred to as microbiota, while their genes are the microbiome — impact human health. His findings could elevate standards of care for disease processes ranging from gastrointestinal disorders to neurodegeneration.

The widely reported case of Kaitlin Hunter — who, after surviving and recovering from a major car accident that broke all her toes, fractured her spine and lacerated her liver and colon, nearly died from a horrific Clostridium difficile infection (CDI) — illustrates the potential of gut microbiota in treatment.

Transplant What?

CDI can cause life-threatening diarrhea and colon inflammation and is one of the few bacteria that can survive antibiotic treatments — the first line of defense against the infection, Knight explains. Approximately 20 percent of CDI sufferers relapse, at which point the infection becomes more difficult to treat.

“When CDI infects your gut, it creates a radically altered microbial community that’s dominated by CDI, which is dysfunctional,” Knight says. “Typically, it’s really hard to treat with antibiotics, and, in fact, you can trigger it with antibiotics. It’s one of the few species that’s able to survive and persist in patients taking antibiotics. Basically, you have a radically altered and degraded ecosystem in the gut.”

To save Hunter’s life, physicians employed a treatment that effectively reset her microbial ecosystem and likely raised more than a few eyebrows. Physicians performed a fecal microbiota transplant (FMT), in which diluted stool from a donor is transplanted into the suffering patient via colonoscopy, depositing the donor stool and the healthy microbiota contained therein as far into the colon as possible to allow it to repopulate the recipient’s gut flora.

“It’s like taking an old trash dump and reseeding it with plants to grow into a forest,” Knight analogizes. “You’re promoting the growth of a community that’s going to be stable and restored to a high level of ecosystem functioning.”

After just one FMT treatment, Hunter’s CDI was resolved, in keeping with the procedure’s reported 90 percent success rate. When combined with an additional round of the antibiotic vancomycin, the success rate jumps to 98 percent.

Seeking Causality

Researchers’ explorations into the efficacy of bacterial therapies — the overarching treatment category to which FMT belongs — for other disease processes currently focuses on demonstrating causal relationships between gut microbiota and disease, Knight says.

“One of the problems is establishing causality,” he says. “Do microbes cause disease, or does the disease cause an alteration in the host that is also reflected in the change of microbes?”

For example, ongoing studies seek to explore and identify causal relationships between gut microbes and obesity. At Washington University, Jeff Gordon (with whom Knight frequently collaborates) uses germ-free mice with no microbes of their own to examine how microbes affect nutrient utilization. After separating the microbe-less mice into groups, Gordon introduces them to microbes from obese or lean mice and then observes their weight following microbe introduction.

“If you take the microbial community from obese or lean mice and transplant it into germ-free mice, what you see is their ability to use nutrients depends a whole lot on which mouse’s microbial community they got, and that’s how we establish causality,” Knight explains.

While gut microbiota may prove a boon in the fight against obesity, Knight relates that studies examining the relationship between gut microbiota and diabetes, non-alcoholic fatty liver disease, multiple sclerosis, colon cancer and even neurodegeneration are under way. Although results are a few years off, they may provide valuable new treatment avenues for a variety of disease and behavioral processes.

Changing the Landscape

Knight explains that breakthroughs in microbiome research are recontextualizing how seemingly unrelated disorders are seen and are reframing the way physicians think about even apparently unrelated conditions.

“A more interesting question may be, ‘In what conditions can we rule out any microbial involvement? You might think something like Down syndrome may be a good example of a genetic disorder where microbes cannot be involved, but there have been some reports that oral microbiota is substantially different between cases and controls,” Knight explains. “So microbes seem to be having all kinds of effects we never suspected on our disease susceptibility, physiology and even our behavior.”