(Illustration by Wesley Bedrosian)

Study Offers New Insight into the Causes of GERD

Scientists have long thought of the esophagus as a desolate path connecting two hubs of activity: the mouth and the stomach. But new research by Zhiheng Pei, MD, PhD, assistant professor of pathology and medicine, paints a very different picture—one of a highway teeming with millions of bacteria, harmful and beneficial alike. Which particular type dominates and polices the esophageal highway tips the scales toward disease or health, he has discovered.

Dr. Pei’s research could help explain why rates of esophageal cancer have soared 600 percent in the past 30 years, and why gastroesophageal reflux disease (GERD) now afflicts a record 50 million Americans. “Since human genetics don’t change that fast,” Dr. Pei explains, “we’re looking at the esophagus’s microbial environment to see if changes could help explain these high rates of GERD and cancer.”

This massive collection of bacterial inhabitants, which outnumbers human cells by 10 to 1, is called the esophageal microbiome. Dr. Pei is one of a number of scientists studying the microbiome to better understand certain diseases. His work is supported by a large national effort, the Human Microbiome Project, which the National Institutes of Health began in 2007 to study microbiomes in the digestive tract, skin, and other organs.

As early as 2004, Dr. Pei and Martin Blaser, MD, the Frederick H. King Professor of Internal Medicine, chairman of the Department of Medicine, and professor of microbiology, challenged conventional wisdom that the esophagus is inhospitable to bacteria and so had little to reveal about disease. They proved that the esophagus is, in fact, home to a vast, diverse collection of microbes. Building on that observation, Dr. Pei analyzed the microbiome of the esophagi of 34 men and has now identified two distinct microbiome patterns. One is characteristic of a healthy esophagus, and the other, of tissue damage and inflammation.

In a study published in August in the journal Gastroenterology, Dr. Pei, using endoscopy to take biopsies, found that in patients with normal, healthy esophageal tissue, gram-positive bacteria known as Streptococci, commonly found in the mouth, dominated. The healthy, Streptococci-dominated microbiome, which is not associated with inflammation or damage, Dr. Pei dubbed type I.

Patients with abnormal, inflamed esophagi had a much more diverse microbiome—dubbed type II by Dr. Pei—which is comprised largely of gram-negative, anaerobic bacteria. These bacteria have cell membrane composed of large molecules known as lipopolysaccharides, which can trigger inflammation and cell damage. Dr. Pei found that patients with GERD or with precancerous changes called Barrett’s esophagus, which GERD can cause, had the type II microbiome.

“We can now say that the type II microbiome is the strongest of all known environmental factors associated with abnormal changes related to GERD,” says Dr. Pei. “We think that type II bacteria cause GERD by producing inflammation in the lower esophagus, which relaxes a muscle located there and allows acidic stomach contents to flow backward up the esophagus, causing further inflammation and damage.” Alternatively, GERD may change the microbiome from type I to II. Either way, a shift from type I to type II could be an essential step in esophageal damage and, ultimately, cancer.

Next, Dr. Pei will extend his microbiome research to the entire esophagus, oral cavity, and stomach in women and men with GERD and esophageal cancer. After establishing the link between change in microbiome and disease, he will shift his focus to determine whether the type II microbiome actually causes GERD. If so, he believes it might be possible to design better treatments to restore the normal microbiome using antibiotics and probiotics.