One of the more perplexing aspects of COVID-19 is the heterogeneity of clinical manifestations of SARS- CoV-2 infection. A variety of factors, including body mass index, age, comorbidities, genetics, and (epi)genetics, are likely involved in the diversity and severity of COVID-19 symptoms. Like all respiratory viruses, SARS-CoV-2 enters the body via the upper respiratory tract, and progression to severe disease accompanies the migration of the virus to the lower respiratory tract. By contrast, some COVID-19 patients have absent-to-mild respiratory symptoms and, instead, present with moderate to severe gastrointestinal (GI) symptoms. GI complications of respiratory infections have been observed for other pathogens. Influenza, for example, has been associated with abdominal pain, nausea, vomiting, and diarrhea, despite the apparent absence of influenza virus in the gut.

The gut-lung axis refers to the two-way exchange of microbiota and microbial-associated small molecules between the digestive system and the respiratory system. This floral link between the two systems is one of the internal microbial axes thought to play a critical role in maintaining health and fighting disease (other examples include the gut-brain and gut-bone axes). Intriguingly, some have suggested that the influence of the microbiome on human health and disease may be just as strong as the influence of other personal factors, like genetics.^[1]

A better understanding of the gut-lung axis could offer promising and simple protective, prophylactic, and therapeutic strategies to mitigate the severity of respiratory diseases, like COVID-19. However, to inform any microbiome-based disease prevention or mitigation strategy, it is crucial to have deep knowledge of the diversity and density of human microbial symbionts at the organ level and how these communities interact at a human systems level. Although profiling the gut microbiome is becoming increasingly popular in personalized medicine, non-invasive and accessible approaches to profiling the lung microbiome, or techniques to assess its health, is an area of opportunity for innovation in pulmonary medicine, diagnostics, and future pandemic preparedness.

One approach to assessing the health of the lung microbiome may be to use the oral microbiome as a surrogate. The mouth is the entry point for both the respiratory and digestive systems, and the oral microbiome is likely connected with both of its downstream neighbors. Dysbiosis of the oral microbiome is linked to lung diseases such as pneumonia, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and lung cancer.^[2] Secondary bacterial pneumonia is a common complication and leading cause of mortality during influenza pandemics, and the oral cavity is a known reservoir for these pathogens. An altered oral microbiome has also recently been linked to long COVID.^[3] Further exploration of the relationship between the oral, gut, and lung microbiomes is warranted and could show promise as an early health status indicator or diagnostic tool.

Since the gut-lung axis appears to play an important role in respiratory health, which interventions designed to modulate and strengthen these microbial communities have the potential to ward off infectious disease?

Perhaps one approach is (re-)introducing microbes into the gut through probiotics (consumed, live microorganisms). Some scientists now are referring to probiotics as “immunobiotics” due to their immunomodulatory activity, or their capacity to reduce virus infectivity.^[4] Probiotics demonstrate antiviral activity by competing with pathogens for adhesion sites and nutritional sources, secreting antimicrobial substances, inactivating toxins, and stimulating the immune system to enhance protection and response mechanisms.^[5]

Another approach is creating an ideal internal environment for microbiota through diet (prebiotics) and exercise. However, although there is promising research on the positive effects of pre- and probiotics and on human health, there is still much to be studied and understood.^[6]

An alternative approach to creating and supporting healthy microbial communities is to “do-what-they- do” in activating robust immune responses. For example, if the metabolites produced by a healthy microbial community are responsible for immunomodulation along the gut-lung axis, can those metabolites be provided as a type of host-based prophylactic or therapeutic?

Although scientific attention to the human microbiome and its relationship with disease has significantly increased in recent years, attracting so much buzz that Forbes dubbed the last decade, “the decade of the microbiome,”^[7] the microbiome’s role in promoting health security has yet to be fully explored. BARDA recognizes the importance of the microbiome and has started investing in products that support the gut-lung axis as tools for pandemic preparedness. Probiotic and other microbiome-based approaches could address the critical need for pathogen-agnostic medical countermeasures against “the next big one,” and could be an immense help in combating the annual flu, too.

[1] Carney SM, Clemente JC, Cox MJ, et al. Methods in lung microbiome research. Am J Respir Cell Mol Biol. 2020;62(3):283-299. doi:10.1165/rcmb.2019-0273TR

[2] Pu CY, Seshadri M, Manuballa S, Yendamuri S. The oral microbiome and lung disease. Curr Oral Health Rep. 2020;7:79-86. doi: 10.1007/s40496-020-00259-1

[3] Haran JP, Bradley E, Zeamer AL, et al. Inflammation-type dysbiosis of the oral microbiome associates with the duration of COVID-19 symptoms and long COVID. JCI Insight. 2021;6(20):e152346. doi:10.1172/jci.insight.152346

[4} Kitazawa H, Villena J, Alvarez S. Probiotics: Immunobiotics and immunogenics. New York, USA: CRC Press; 2013.

[5] Al Kassaa I. Antiviral probiotics: A new concept in medical sciences. New Insights on Antiviral Properties. 2017; 1-46. doi: 10.1007/978-3-319-49688-7_1

[6] National Center for Complementary and Integrative Health. Probiotics: What You Need to Know. Updated August 2019. Accessed 11/30/2021.https://doi.org/10.1016/bs.pmbts.2018.03.003

[7] Cat LA. The decade of the microbiome. Forbes. Published December 31, 2019. https://www.forbes.com/sites/linhanhcat/2019/12/31/decade-of-the- microbiome/?sh=403bab2a9961/