May 23, 2016

It happens to even the most experienced and diligent surgeons. When a surgeon resects a portion of diseased intestine, continuity is reestablished by carefully suturing or stapling the remaining ends together, a connection termed “anastomosis.” No surgeon, no matter how much experience and training, is immune from this problem. If the anastomosis leaks, bacteria and toxins can seep out and cause peritonitis, sepsis and even death.

Surprisingly, such an event is not rare and has dogged gastrointestinal surgeons for decades. Although the mortality rate from anastomotic leak has gone down, the 12.1 percent incidence of leaks hasn’t changed, amounting to a $500-million burden on our healthcare system every year.

So, why do leaks occur, even when the anastomoses are performed perfectly? Researchers at the University of Chicago have been fervently investigating this very question and believe they may be on the cusp of uncovering the major role intestinal microbes play in the process of anastomotic leak. Such a discovery would pave the way to evidence-based protocols that could drastically lower the risk of anastomotic leaks forever.

Setting the stage in research
Leading the charge on this research is John C. Alverdy, MD, Sarah and Harold Lincoln Thompson professor of Surgery and executive vice chair of the Department of Surgery at the University of Chicago Medicine. He has partnered with experts in colorectal surgery (Neil Hyman, MD, chief of Colon & Rectal Surgery, and Konstantin Umanskiy, MD, associate professor of surgery), microbiology (Jack Gilbert, PhD, and Olga Zaborina, PhD), biostatistics (Theodore Karrison, PhD) and research informatics (Samuel Volcenboum, MD, PhD).

Pulling the brightest minds from each of these disciplines is a critical component to this research, Dr. Alverdy says. “Anastomotic leaks continue to plague the most experienced and expertly trained surgeons and the human suffering is incalculable,” he says. “It is time to apply next-generation sequencing and precision medicine to understand and solve this devastating complication, which can lead to life-threatening infection, cancer recurrence and permanent colostomy.”

Over the last 15 years, Dr. Alverdy’s laboratory has been studying how intestinal bacteria shift their behavior to express enhanced virulence (harmfulness) when they “sense” factors released by host tissues during surgical injury. By understanding this process at the molecular level, they have developed novel, nonantibiotic compounds that can inhibit this process without disturbing the overall microbial ecology, thus preserving the health-promoting probiotic microbiota.
Using this line of reasoning, the Alverdy lab identified a species of intestinal bacteria that appears to play a direct role in the process of leakage, Enterococcus faecalis. Interestingly, this bacteria is normally present in the human intestine but behaves like a symbiont, meaning it shares resources and does not express harmfulness against its host.

Yet the lab demonstrated that this normal symbiont can turn into pathogenic bacteria (pathobiont) when it “senses” injury and stress and can shift its behavior from essentially a pacifist to an aggressive bacteria by activating genes that make the flesh-eating enzyme collagenase. This enzyme can then drill through healthy healing tissues and cause a leak.

“While we know that many of our socalled ‘normal microbiota’ can turn on us and cause harm, understanding this process at the species and molecular levels now equips us to think about strategies to interfere with the activating signals as opposed to simply taking a ‘shoot first, ask questions later’ approach with broad spectrum antibiotics,” Dr. Alverdy says. “This becomes especially important when we realize that many of the patients we operate on harbor antibiotic-resistant bacteria due to the promiscuous use of antibiotics. Understanding how and why these bacteria then become cued to cause harm during surgery is the key to prevention.”

Knowledge that leads to change
Armed with this new knowledge, Dr. Alverdy and his team are conducting preliminary clinical research — which is part of the larger multi-center trial called “Serial Endoscopic Surveillance & Direct Topical Antibiotics” (SES-DTA). In this trial, patients will undergo serial endoscopic examination of their anastomosis over three weeks with microbiologic sample analysis to examine which microbes are present in anastomotic tissues in order to determine how they behave over the course of healing.

In this preliminary research phase, the clinical team will enroll patients who are at the highest risk of experiencing anastomotic leak: patients undergoing low anterior colorectal resection where the anastomosis is 10 cm or less from the anal verge and a diverting loop ileostomy is performed.

The serial endoscopic surveillance will be performed three times, once in the operating room at the time of resection and twice in an inpatient endoscopy suite. Several important questions can be addressed by directly visualizing and examining anastomotic tissues for their microbial content and enzyme production.

  • Are there flesh-eating microbes present on anastomotic tissues that have escaped the antibiotics routinely used by surgeons?
  • How dangerous are these microbes, and what is their capacity to produce destructive enzymes?
  • Are there molecules in the tissues that provoke these bacteria to produce tissue-destructive enzymes?
  • Can antibiotics be locally applied to anastomotic tissues to keep them sterile without destroying all the normal bacteria by giving systemic or oral antibiotics in a manner that might actually aid the healing process?
  • Can serial endoscopic surveillance and the development of biomarkers of bacterial enzyme production allow surgeons to predict which patients will leak?
  • Can serial endoscopic surveillance be used to preemptively strike against an impending anastomotic catastrophe?

Dr. Alverdy and Dr. Hyman are performing this preliminary research in patients through a start-up grant from the American Society of Colorectal Surgeons to gain preliminary data for the larger SES-DTA multi-center trial.

So far, the results are highly encouraging that the procedure is safe and highly indicative of impending problems. Ultimately, the results from this initial planning phase of SES-DTA will allow Dr. Alverdy and Dr. Hyman to apply for R01 grant funding. This trial will be the largest of its kind in the department and a major benchmark for many more such trials in the future.