The Microbiome: Friend or Foe?

NYUCI Scientists Study Inflammation, Bacteria, and Cancer

Unless you’re a pro at oral hygiene, you’ve probably been told more than once that you need to floss more. Here’s another reason: Chronic gum disease may raise your risk of stomach cancer and cancers of the head and neck.

That’s just one area of research at the NYU Cancer Institute aiming to scrutinize the link between inflammation, microbes (such as bacteria), and cancer. Such studies are under way in numerous laboratories and in epidemiological programs — those that examine cancer determinants in populations. The goal is to learn more about how inflammation, the microbiome — the bacteria, viruses, and fungi residing in our bodies — and cancer are related, and ultimately to use this information to prevent or treat the disease.

Here’s the rub: Your body contains trillions of “friendly” bacteria that we need and use for normal processes, such as digestion. But we don’t yet know friend from foe. Making that distinction is a goal of many researchers in the microbiome field.

“This is a relatively recent area of inquiry, taking off in the last decade or so. New technologies have opened new areas of scientific study,” explains Richard Hayes, DDS, PhD, Professor and Director of the Division of Epidemiology in the Departments of Population Health and Environmental Medicine. “We used to culture only one bacterium at a time. Now we use novel computer-based methods which make it more efficient and less expensive to analyze hundreds of bacteria at once, propelling this research forward. A solid story has yet to emerge, but this is just the beginning.”

 

Plenty to Go Around

The microbiome is a hot area of study.

To be sure, there’s no shortage of microbes for researchers to analyze. Our bodies are home to over 100 trillion of these microscopic organisms, most of which live in peaceful coexistence with us. But scientists are learning that the introduction of more “hostile” species, such as H. pylori bacteria, can have dire consequences in some individuals, but not others.

There are numerous ways in which microbes may influence cancer risk. They may cause inflammation when put in direct contact with tissue (such as the lining of the mouth or esophagus), or they may make tissue more susceptible to the cancer-causing effects of carcinogens (such as tobacco and alcohol). Studies have already established H. pylori bacteria as a cause of stomach cancer and human papillomavirus (HPV) as an instigator of cervical and oropharynx cancers. Now scientists are digging deeper to link other microbes to cancer and to study the mechanisms underlying the association.

 

A Mouthful of Trouble?

Alcohol is a known cause of oral cancers. Bacteria in the mouth are capable of metabolizing alcohol into a cancer-causing form, called acetaldehyde, which may react with the tissue lining the mouth and pharynx, possibly through inflammation.

Dr. Hayes and Zhiheng Pei, MD, PhD, Associate Professor of Pathology and Medicine, are conducting a National Cancer Institute (NCI)-supported prospective study of 70,000 individuals. The researchers are comparing bacterial profiles in oral wash samples of people who developed head and neck cancers with the samples from people who didn’t develop cancer to see if they can identify a bacterial “signature” that could be used to predict head and neck cancer risk.

Jiyoung Ahn, PhD, Assistant Professor of Population Health and Environmental Medicine, found that individuals with periodontitis had more than double the risk of cancers of the oral cavity and digestive tract. Cancer risk rose with increasing periodontitis severity and was specifically associated with an oral bacterium called P. gingivalis, which the scientists suggest may serve as a biomarker for microbe-associated digestive cancers.

Dr. Ahn is also exploring the relationship between the mouth microbiome and pancreatic cancer. From a study of 75,000 people who contributed oral wash samples and who agreed to be monitored for ten years, she is comparing 300 people who subsequently developed pancreatic cancer and 300 who did not, to see how their oral microbiome data differ. “We want to clarify what caused what,” she says. “Did the bacteria cause the pancreatic cancer, or did the cancer change the oral microbiome?”

Yu Chen, PhD, Associate Professor of Population Health and Environmental Medicine, has been studying the link between oral health conditions and precancerous lesions of the stomach. She is collaborating with Fritz Francois, MD, Assistant Professor of Medicine; Martin Blaser, MD, Frederick H. King Professor of Internal Medicine and Chair of the Department of Medicine; Dr. Pei; and colleagues at the NYU College of Dentistry, including Yihong Li, DDS, PhD, Ananda Dasanayake, BDS, PhD, and Patricia Corby, DDS. Dr. Chen invited individuals who were scheduled for upper endoscopy at Bellevue Hospital Center to undergo a comprehensive oral examination at the Bluestone Center for Clinical Research, which is part of NYU College of Dentistry. The researchers found that people with precancerous lesions in the stomach were nearly three times as likely as healthy individuals not to floss and to have a higher percentage of tooth sites with gingival (gum) bleeding — factors related to active gingivitis and periodontitis.

“These data suggest that oral conditions related to periodontal disease may be predisposing factors for stomach cancer, which is consistent with literature supporting the positive association between tooth loss and stomach cancer mortality,” says Dr. Chen. The next step is to study these patients’ oral microbiomes in hopes of finding specific bacteria that may explain this association.

 

 

Building on History

H. pylori remains the major cause of stomach cancer around the world. Dr. Blaser and his colleagues established this association in the mid-1990s, and have been exploring the different strains of the bacterium and their ability to cause stomach cancer.

Until 1930, stomach cancer was the most common cancer in America. But as H. pylori infection rates have declined (due to increased use of antibiotics, among other causes), so has stomach cancer. Interestingly, however, other cancers are on the rise. Cancer of the junction between the esophagus and the stomach is the fastest growing cancer in the United States, notes Dr. Blaser. “H. pylori is part of the human microbiome, and it is disappearing,” he says. “It causes stomach cancer, but seems to have a protective effect on the esophagus.”

Dr. Pei is trying to find out more about this association. He and his colleagues have studied the microbiomes of people with esophageal cancer and found a higher population of Gram-negative bacteria, which are usually found in the acidic environment of the stomach. But when acid from the stomach bubbles up into the esophagus (a condition called reflux), those bacteria can enter the esophagus and may cause chronic inflammation (esophagitis). This may explain the link that has been established between chronic reflux and esophageal cancer. “Bacteria are an essential component of chronic inflammation and cancer in the digestive tract,” Dr. Pei concludes.

He and his colleagues are now doing studies to further define the strains of Gram-negative bacteria that may raise esophageal cancer risk. Once identified, scientists could introduce these strains into laboratory animals to see if they induce cancer. They could also assess the potential value of anti-inflammatory drugs for reducing cancer risk.

 

A Gut Reaction

Some intestinal bacteria may metabolize food components that enter the gut. Dr. Ahn and Liying Yang, Research Assistant Professor, are conducting an NCI-funded study comparing the intestinal microbiome between people with colorectal cancer and healthy individuals. With NYUCI funding, Dr. Ahn is also conducting the Human Microbiome and Colorectal Tumors Study, in which information on usual dietary intake and stool samples for microbiome analysis are collected from people who have had normal colonoscopy results. Study participants are being followed over time to see which specific gut bacterial profiles are associated with the subsequent development of colorectal tumors, and to assess the influence of dietary factors.

Bacteria in the intestine may also be implicated in cancers outside the digestive tract. In work led by Claudia Plottel, MD, Clinical Associate Professor of Medicine, researchers found that estrogen metabolism takes place in the gut and is highly dependent on the actions of gut bacteria. If all goes as it should, estrogen in the gut is excreted from the body. But if the bacteria are not functioning normally, estrogen is reabsorbed into the body, potentially raising the risk of estrogen-related cancers such as breast cancer. Drs. Plottel and Blaser are now studying this association in animal studies.

The intestinal microbiome may also play a role in pancreatic cancer. George Miller, MD, Assistant Professor of Surgery and Cell Biology, is analyzing a group of proteins called toll-like receptors (TLRs), which become activated by byproducts of inflammation and microbes. Bacteria in the digestive tract can migrate to the pancreas, produce TLRs, and stimulate inflammation.

“The pancreatic tumor environment is full of inflammatory cells that provide feedback to cancer cells,” Dr. Miller explains. “Once TLRs are activated, it starts a vicious cycle of inflammation that contributes to the cancer, and then more inflammation results.” He and colleagues from other labs are studying the intestinal microbiomes of patients with pancreatic cancer to see how they differ from those of people without the disease.

One potential target is a family of proteins on immune cells called “pattern recognition receptors” (PRRs), which are stimulated by byproducts of yeast and fungi and may be linked to pancreatic cancer. “We think the key is to modulate or block these receptors on immune cells,” Dr. Miller contends.

Dafna Bar-Sagi, PhD, Professor of Biochemistry and Molecular Pharmacology, Senior Vice President and Vice Dean for Science, and Chief Scientific Officer, adds that the inflammatory response in pancreatic cancer has a significant impact on the body’s immune response, making it possible for cancer cells to evade detection by the immune system. Therapies that stimulate the immune system to recognize and attack pancreatic cancer may therefore be a possible treatment.

Cancer cells also instigate an inflammatory response that repeatedly injures pancreatic tissue. The tissue does not have an opportunity to recover, and this chronic inflammatory state exacerbates the development of cancer. “By going haywire, the cancer cells not only affect their own growth, but also disrupt the well-being of the normal pancreatic tissue that surrounds them,” Dr. Bar-Sagi says. The result is the vicious cycle of inflammation and cancer development.

 

Putting It All Together

What could come of the findings generated by the studies of cancer researchers investigating the microbiome and inflammation? “This is an exciting field,” concludes Dr. Ahn. “With a link between bacteria and cancer, there is the potential to use probiotics or antibiotics to reduce a person’s risk of developing the disease by altering the microbiome.”

“It’s not likely that you’ll be able to eat a cup of yogurt and change your microbiome enough to alter your cancer risk,” Dr. Hayes adds. “We know there’s a link between the microbiome and cancer, but it may or may not turn out to be through inflammation. Only time and research will tell.”