asthma

Gut Regulation of Airway Disease

It is well known that sensing of gut microbiota can regulate mucosal immunity. However, it is unknown whether gut microbiota sensing can influence immunity in other parts of the body. A new study1 led by the first author Xin Li, DVM, PhD, senior author Dr Iliyan D. Iliev, and colleagues investigated this association in allergic airway disease.

Xin Li, DVM, PhD, is a post-doctoral associate in Dr Iliyan Iliev's lab at the Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine at Weill Cornell Medicine in New York, New York.

Consultant360 caught up with Dr Li after his presentation at the Severe Asthma, Inflammation, and Lung Repair Symposium.2

C360: Can you give us some background on your study? How did it come about?

Dr Li: We know the intact gut microbiota is essential for the maintenance of human health. The disruption of gut microbiota is associated with many disease conditions. Gut microbiota is mainly dominated by bacteria, but in addition to bacteria, there is a small percentage of fungal microbiota in the gut. Certain pathology conditions, such as with antibiotics, antimycotics, or immunosuppression, can lead to the expansion of gut commensal fungi. This process is also known as fungal dysbiosis.

Fungal dysbiosis now has been reported to be associated with local intestinal inflammatory disorders, such as inflammatory bowel diseases. Recently, increasing evidence suggests there is a strong link between the disruption of intestinal bacteria and fungi and the risk of lung diseases.3,4 Many studies have found that antibiotic use at the early stage of life increases the risk for asthma. Now, anti-fungal drugs and antibiotics are widely used. This can disrupt gut-resident fungi by affecting gut fungal populations by removing or promoting gut bacteria that coexist with the fungi.

In 2016, Iliev and colleagues5 further discovered that disruption of gut-resident fungal communities could have a similar effect—worsening intestinal inflammation worsens allergic airway disease in mice. Many groups also found the associations, but no one knows why this phenomenon occurs. Therefore, our study investigated the mechanism behind the phenomenon that gut fungal dysbiosis can affect lung diseases.

C360: Your study found that gut bacteria may play a role in airway inflammation. Can you tell us more about your findings and how they might impact clinical practice?

Dr Li: Our study found that fluconazole, the most commonly prescribed anti-fungal drug, can disrupt the fungal community through depletion of yeast fungi, such as Candida and expansion of filamentous fungi, such as Aspergillus, Epicoccum, and Wallemia. The change of gut fungal mycobiota persistently exacerbates eosinophilic asthma. This effect can be abrogated by an environmental fungi-free condition. 

We have recently shown that gut resident mononuclear phagocytes can directly sense gut fungi and be responsible for the distal effects of fungal dysbiosis on lung airway inflammation1. This is very interesting for us. It is the first time gut resident immune cells have been shown to modulate lung inflammation. Our finding also emphasizes that gut-microbiota-derived antigens might be an additional source of antigens that can activate immune cells that might amplify lung inflammation.

Specific targeting of the gut-lung axis might be useful to clinically treat asthma or severe asthma related to microbiota dysbiosis. This is an emerging field for pharmaceutical companies and clinicians. No one has thought to modulate gut microbiota to treat asthma before.

C360: What is the most common question your peers ask you regarding this research?

Dr Li: Many people asked us the role of lung mycobiome on lung diseases, such as asthma, chronic obstructive pulmonary disease, or cystic fibrosis. Patients with these diseases are frequently sensitized to environmental filamentous fungi, such as Aspergillus, Alternaria, Cladosporium, and Candida. However, we do not know too much about the role of the lung fungal mycobiome in the pathogenesis of lung diseases. We definitely want to address these questions in the future.

C360: So what’s your next step in this research? What other knowledge gaps still need to be filled?

Dr Li: We want to find a way to modulate the gut-lung crosstalk, and we are taking the next step now. Both gut microbiome and lung microbiome might share similar antigens that can activate the same circulating immune cells. As I mentioned previously, we also need to learn more about the relationship between the gut microbiome and lung microbiome. We still do not know which immune cells are circulating to recognize the antigens during the gut-lung crosstalk.

C360: What else should pulmonologists know about your study?

Dr Li: Realize that gut bacteria and fungi are also crucial players that can activate the immune system and sensitize inflammatory immune cells to amplify the lung inflammation. Some drugs, such as antibiotics and antifungals, might modulate the commensal microbiota that can bring undesired outcomes on lung diseases. Therefore, pulmonologists might need to be cautious when prescribing antibiotics or antifungal drugs to patients with lung immune disorders for long-term treatment.

References:

  1. Li X, Leonardi I, Semon A, et al. Response to fungal dysbiosis by gut-resident CX3CR1+ mononuclear phagocytes aggravates allergic airway disease. Cell Host Microbe. 2018;24(6):847-856. https://doi.org/10.1016/j.chom.2018.11.003.
  2. Li X. Sensing fungal dysbiosis by gut-resident CX3CR1+ mononuclear phagocytes aggravates allergic airway disease. Paper presented at: Severe Asthma, Inflammation, and Lung Repair Symposium; April 26, 2019; Greenwich, NY. https://www.nyas.org/events/2019/severe-asthma-novel-concepts-therapeutics/?tab=agenda.
  3. Arrieta, MC, Stiemsma, LT, Dimitriu, PA, et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med. 2015;7(307):307ra152. https://doi.org/10.1126/scitranslmed.aab2271.
  4. Fujimura KE, Sitarik AR, Havstad S, et al. Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat Med. 2016;22(10):1187-1191. https://doi.org/10.1038/nm.4176.
  5. Wheeler ML, Limon JJ, Bar AS, et al. Immunological consequences of intestinal fungal dysbiosis. Cell Host Microbe. 2016;19(6):865-873. https://doi.org/10.1016/j.chom.2016.05.003.