Advancing Gut-Lung Axis Research

Trillions of microorganisms that live in the human gut may hold the key to healing some serious or chronic lung conditions. It is theorized that the community in the intestines — or gut microbiota — has bidirectional communication with the respiratory system in the concept known as the gut-lung axis.

The connection between respiratory infections, chronic diseases like asthma, and the role of the gut microbiome in immune regulation drives researchers to uncover exactly how the two systems interact, with the ultimate goal that untangling these connections could lead to more effective, targeted treatments for chronic or acute lung diseases.

‘The Bugs Make the Drugs’

The human intestinal microbiota, more commonly referred to as the gut microbiome, is a complex ecosystem, surpassing even the human body in terms of genetic diversity, explained Joseph H. Skalski, MD, Pulmonary and Critical Care Medicine at Mayo Clinic in Rochester, Minnesota.

It consists of an array of microbes that coexist and compete within the intestinal lumen, a 25-foot tube that absorbs nutrients, and is home to immune cells that react to microbial activities — playing a role in the body’s overall health.

Once thought to be systems which operated wholly separately, researchers have discovered changes in this gut microbial composition can influence lung disease. Lungs are affected by the gut through the immune system when it detects these microbes and triggers a cytokine response. Additionally, some microbes can produce byproducts that, once absorbed into the bloodstream, have the potential to directly affect lung function.

“There are several examples where the bugs make the drugs — intestinal microbes release substances that are absorbed into circulation and transmitted through the bloodstream to the lungs,” said Skalski, adding that both the lungs and the gut have mucosal immune systems.

To date, researchers have demonstrated a possible association between the gut microbiome and outcomes with chronic or serious lung conditions, such as asthma. Dysbiosis, an imbalance in these microbial communities, can silently affect lung diseases without symptoms.

Skalski is exploring the connection between intestinal fungal dysbiosis and respiratory conditions like asthma and chronic obstructive pulmonary disease (COPD). In a research article published in PLOS Pathogens, Skalski and colleagues found that an imbalance in intestinal fungi can exacerbate asthma, even without fungi being present in the lungs.

Other studies have found a similar association. In a study published in Gut, researchers found associations between gut microbiota composition, levels of cytokines, and inflammatory markers in patients with COVID-19. This association suggests that the gut microbiome influences “the magnitude of COVID-19 severity, possibly via modulating host immune responses.” In Respiratory Research, Li and colleagues observed significant differences in the gut microbiome between patients with COPD and healthy individuals, with patients with COPD having a unique microbial diversity and a prevalence of Prevotella. Interestingly, fecal transplants from patients with COPD to mice resulted in increased lung inflammation.

To advance gut-lung axis research, Skalski advocates for expansive human studies involving more than 4000 participants and collaboration across various laboratories. Today, his team is using sequencing techniques to understand the impact of intestinal microbiota on obstructive lung diseases with the help of animal models. By profiling the intestinal microbiota, he aims to understand the complex interactions between microbial communities and respiratory health. As knowledge expands, it may lead to targeted treatments that can correct dysbiosis and improve patient outcomes, he said.

Establishing Clinical Significance

While researchers have established an association between intestinal microbiome and lung health, the extent to which it is clinically significant has yet to be determined, according to Robert Dickson, MD, pulmonologist, professor, and researcher with University of Michigan Health, Ann Arbor, Michigan.

Dickson and his lab at the University of Michigan have studied this relationship among patients with acute respiratory distress syndrome (ARDS) in the critical care setting. Recently, they found that among mechanically ventilated patients, depletion of gut anaerobes due to antibiotics is associated with an increase in in-hospital mortality.

“The gut microbiome is an ‘organ’ that plays important roles in the body’s metabolic and immunologic processes,” said Dickson in an interview. “What we’re learning is that disrupting the microbiome causes a kind of ‘organ failure,’ and this contributes to unfavorable clinical outcomes.”

A challenge in understanding the gut microbiome’s influence on systemic health is the complexity of the mechanisms involved. In one mechanism, the gut microbiome generates metabolites, including the fatty acid butyrate, which can be protective in models of acute lung injury. But antibiotics, especially broad-spectrum, can disrupt this ecosystem. And in critically ill patients, the gut’s ability to be a barrier becomes compromised, and the “leaky gut” phenomenon can occur. As a result, bacteria from the intestines can migrate to the lungs, increasing inflammation in the air sacs and exacerbating the patient’s condition.

Adding to the research challenge is making sense of the biodiverse organisms with multiple external variables. “The tools we use in microbiome research are taken from the microbial ecology field,” Dickson said. “Whereas we used to study individual species, we now need to study complex, dynamic communities of bacteria.”

Driving Toward Precision Medicine

One of the largest knowledge gaps is the specific species that predispose patients to chronic lung diseases and make treatment less effective, said Rachel Scheraga, MD, pulmonologist and researcher with the Cleveland Clinic, Cleveland. “A more thorough understanding of the gut-lung axis in human health will help define the specific perturbations that cause chronic inflammatory lung diseases.”

To advance gut-lung axis research, a combination of germ-free and antibiotic-treated animal models and human samples is needed. “Select patients with chronic lung diseases such as asthma and COPD are the most difficult to treat despite advances in therapy,” Scheraga said. “Understanding the gut-lung axis in these chronic lung diseases will advance the field if we are able to identify subsets of patients that would respond to therapy.”

Scheraga also sees potential in gut-lung axis research to treat ARDS. “Currently there is no therapy to treat ARDS that frequently occurs after bacterial pneumonia, hence designing a specific therapy for this syndrome would advance the field.” In terms of the gut-lung axis, when a patient is critically ill with ARDS, “there is enhanced crosstalk between the lung and the intestines as patients are frequently on ventilators and develop aspiration,” she explained.

“As we develop animal model tools to study the gut-lung axis, I am excited about potential targets and/or identifying subphenotypes of patients that may respond to certain therapy,” she said. “But I am concerned that it will take a while to fully understand the impact of the gut-lung crosstalk.”

Emerging Therapeutic Strategies

That leaves another research question: What might precision medicine or other therapies look like? The answer may lie in the gut itself. In a study published in the Journal of Microbiology and Biotechnology, Shin and colleagues reported probiotics, prebiotics, short-chain fatty acids, and fecal microbial transplant hold promise as therapeutic agents for COPD.

Gregor Reid, PhD, MBA, FRSC, the distinguished professor emeritus at Western University, London, Ontario, Canada, is an internationally renowned expert on probiotics and overall health. He said strains of commonly used species, such as Lactobacillus, Bifidobacterium, and Saccharomyces, are shown to be safe and effective, while lesser-known strains of Roseburia spp., Akkermansia spp., Propionibacterium spp., and Faecalibacterium spp. have potential. Similarly, well-known prebiotics like glucans and fructans are joined by emerging ones derived from various natural substances, showing a promising future for gut health.

As he wrote in his book, “Probiotics: A story about hope,” it is critical to select organisms for properties desired for the result, then perform clinical studies to see if they are effective.

“Unfortunately, often researchers just take a commercial product and test it hoping it works,” he said. “More physicians need to push for doing studies in combination with scientists, even on small sample sizes at the beginning. Without a rationale, careful strain selection and delivery methods and properly designed clinical studies, the field of gut-lung-brain will remain interesting but hypothetical.”

Scheraga, Dickson, and Skalski reported no relevant conflicts of interest. Reid consults for Seed, a company selling probiotics not discussed in this article interview.