Not that long ago, physicians believed that healthy sinuses were sterile environments. Scientific advances have since revealed that the sinuses, like other parts of the body, are home to vast numbers of microbes. These microbes live in distinct communities, called microbiomes, which may be the key to understanding and developing effective treatments for chronic rhinosinusitis and other ailments.
Explore This IssueMarch 2019
“We have some evidence that the population of the microbiome does contribute to disease and inflammation within the nose and sinuses,” said Eugene Chang, MD, vice chair of the department of otolaryngology and director of rhinology and skull base surgery at the University of Arizona in Tucson. However, Dr. Chang and others say it will probably be years before microbiome research alters treatment paradigms.
“We’re still a long way from knowing if we can manipulate the microbiome and if it truly presents opportunity as a new therapy,” said Vijay Ramakrishnan, MD, associate professor of otolaryngology at the University of Colorado in Denver. “There’s a phenomenon that happens whenever new major discoveries happen in science and new tools are available to researchers. Take genomics, for instance. Everyone gets excited. We thought genes were going to be the answer to everything.”
In reality, there are still many questions to be answered about the microbiome and its role in otolaryngology. Here’s what we know so far.
Dysbiosis Associated with Chronic Rhinosinusitis
The sinus microbiome varies widely among individuals. “If you look at 10 different people, the difference between one person and the next would be so large that it’s hard to know if differences are the cause of disease or if they are related to symptoms or past treatment,” Dr. Ramakrishnan said.
However, a number of research studies to date have linked decreased microbial diversity with chronic rhinosinusitis (CRS). A 2017 study that compared 59 CRS patients with 10 healthy participants found that the bacterial burden was similar for both groups. The patients with CRS, however, “exhibited significantly lower microbiota richness, evenness, and diversity.” Researchers also noted that alpha diversity in CRS patients was more pronounced in those with concomitant lower airway disease (Microbiome. 2017; 5:53).
“One overall theme we see is dysbiosis in the community,” said Emily Cope, PhD, co-author of the study and assistant director at The Pathogen and Microbiome Institute at Northern Arizona University in Flagstaff. Dysbiosis can take different forms, Dr. Cope said. Sometimes, there is overrepresentation of certain pathogenic bacteria. Other times, there’s an overall decrease in microbial diversity. Still other studies have shown fragmentation of ecological networks.
Interestingly, studies done so far have not revealed any consistent differences in the microbiomes of people with CRS with polyps vs. CRS without polyps. “We expected to see a difference, but two studies now have shown that’s not the case,” Dr. Ramakrishnan said. Given that clinicians typically treat CRS with polyps differently than CRS without polyps, the lack of significant differences in the microbiome may mean that these two presentations of CRS have more in common than not and should perhaps be handled similarly. Or, Dr. Ramakrishnan said, “it could mean that the microbial differences we’re observing are kind of irrelevant.”
The key question that has not yet been answered is, “Do alterations in the microbiome cause disease, or are they a side effect of the disease process?” Dr. Chang said that, “ideally, if you wanted to look at that question, you would wipe a subject clean of their microbiome and then insert a microbiome that’s dominated by pathogens to see if that causes diseases. You’d also want to find somebody with chronic sinus disease, completely deplete the microbiome, and observe what repopulates over a period of time.”
A 2012 animal study by Susan Lynch, PhD, director of the Colitis and Crohn’s Disease Microbiome Research Core at the University of California–San Francisco, demonstrated that altering the sinus microbiome may indeed contribute to the presence or absence of disease. Her team used antibiotics to deplete the sinus microbiome of mice. Corynebacterium tuberculostearicum, a bacterium that has been noted in abundance in the microbiome of CRS patients, was instilled into the sinus cavities of some mice; Lactobacillus sakei, a bacterium that’s abundant in the healthy sinus mucosal samples, was instilled into the sinuses of other mice. Mice who received C. tuberculostearicum developed evidence of sinus infection, including mucin hypersecretion. The mice who received L. sakei remained healthy. (Sci Transl Med. 2012; 4:151ra124).
At present, though, it’s not possible to do such studies with human participants.
We’re still a long way from knowing if we can manipulate the microbiome and if it truly presents opportunity as a new therapy. —Vijay Ramakrishnan, MD
Certain Bacteria May Be More Common in Disease States
Research suggests that particular strains of bacteria are more likely to be found in the microbiomes of patients with diseased sinuses. According to a 2016 review by Dr. Ramakrishnan and others, S. aureus, Prevotella, Fusobacterium, Bacteroides spp. and Peptostreptococcus spp. are more abundant in the microbiota of patients with CRS than in patients with healthy sinuses. (Curr Opin Otolaryngol Head Neck Surg. 2016;24:20–25). A 2017 study by Dr. Cope, Dr. Lynch, and others identified four distinct subgroups among patients with CRS. The microbiome of each subgroup was dominated by a different pathogenic family: Streptococcaceae, Pseudomonadaceae, Corynebacteriaceae, or Staphylococcaceae. The authors speculate that these different states “represent a gradient of pathogenic microbial co-colonizations that are related to patient treatment history and/or disease progression”
Indeed, it’s possible that past treatment has altered the microbiomes of many CRS patients. “People with chronic rhinosinusitis have generally already been treated with lots of antibiotics and steroids and sprays,” Dr. Ramakrishnan said. “The challenge is teasing apart whether the microbiota differences are an innocent observation–something that just happens to be different but doesn’t really have a role in anything–or an active driver of inflammation and disease.”
Dr. Cope and her team are looking for answers. “I’m interested in how microbes interact with each other in the sinuses,” she said. “If we see certain species of bacteria and fungi in our sequence data, I want to take them out into the lab and see how they play together. Is the combination causing more virulence? Could they be beneficial together?” At present, her team is using animal models to study the interplay of microbes.
Microbiome May Contribute to Asthma Development
Evidence strongly suggests that the microbiome of the lower airways may play a role in the development of asthma. Compared to people without asthma, the microbiota of people with asthma is commonly enriched for members of Proteobacteria. People with asthma also typically have a high bacterial burden and bacterial diversity in the lower airways. While no studies have yet demonstrated a direct causal link between microbial changes and the development of asthma, the composition of the airway microbiome is highly correlated with the degree of bronchial hyper-responsiveness. There’s also evidence to suggest that alterations to the oral microbiome may be associated with the development of childhood asthma. (Cell Host Microbe. 2015;17:592–602.)
“Some of these early microbial exposures during this important window of opportunity may be important in preventing asthma,” Dr. Cope said.
The gut microbiome may play a role in airway health
Scientists have noted links between gut microbiome composition and digestion, weight, and digestive diseases such as irritable bowel syndrome, and proven that manipulating the gut microbiome via fecal transplants is a highly effective treatment for recurrent Clostridium difficile infection. (Gastroenterol Hepatol (N Y). 2012;8:191–194; Infect Dis Clin North Am. 2015;29:109–122.)
Evidence also suggests that the gut microbiome may play a role in the health and function of the heart, brain, and airways. “We don’t know yet how much the gut microbiome matters for chronic rhinosinusitis or airway inflammatory diseases,” Dr. Ramakrishnan said. “One possibility is that the gut, which houses the vast majority of the microbes on our insides, could be a spot where systemic immune priming occurs. This adds another wrinkle to the whole question of, should we be looking at the sinuses, the gut, or both?”
Microbiome-Based Treatments Won’t Be Available Soon
Despite widespread desire for more effective treatments for sinus and airway disease, researchers say it will likely be years before microbiome research leads to new clinical treatments.
“I absolutely expect it will be three to five, or even more, years into the future,” Dr. Cope said. “There’s a lot of potential here; I don’t think we’ve really cracked it yet. But we’re still working on addressing core questions like, how do these altered microbial communities interact with the host system in the sinuses?”
Additional research is needed to determine why (and how) microbial disturbances occur, and to uncover the mechanisms by which changes in the microbiome might trigger inflammation and disease. “I think these mechanisms are really going to be the key to finding targeted interventions,” Dr. Chang said. Research may also teach clinicians how to safely tweak the sinus, oral, and upper and lower airway microbiomes.
“The microbiome isn’t a magic bullet; we can’t simply alter it in one manner and then everyone’s disease-free,” Dr. Cope said. “There’s a lot of basic research that’s still needs to be done to understand how to alter microbiota properly for specific groups of patients, and if doing so will help at all.”
Jennifer Fink is a freelance medical writer based in Wisconsin.