Asthma and the Gastrointestinal Microbiome: Is There a Causative Link?

A recent editorial published in Journal of Allergy and Clinical Immunology examined the results of several studies analyzing the relationship between the respiratory tract and the gastrointestinal (GI) tract.¹ The authors of the editorial concluded that more research is needed to rule out false positives and correlation between different microbial variables. However, these studies provide intriguing supports for theories that physical processes in the gut may be causally related to asthma.

The Potential Link Between Asthma and the GI Tract

It has long been acknowledged by the medical community that there is some link between asthma and GI symptoms.² Many individuals with asthma report digestive issues, particularly gastroesophageal reflux disease.³ Historically, however, researchers have  been uncertain as to whether these 2 sets of symptoms stem from the same root cause or if GI processes themselves might cause respiratory symptoms.

Most medical providers are aware that acid in the esophagus can cause coughing, yet acid suppression treatments often fail to improve asthma symptoms in humans.⁴ Thus, the link between GI disorders and asthma symptoms has remained unclear. Researchers have also struggled to identify effective preventive measures for asthma.

At present, known interventions for preventing the development of asthma include:¹

· Prolonged breastfeeding

· Delayed weaning of infants

· Elimination of common food allergens during infancy

Delaying exposure to food allergens until after the first year of life decreases a child’s lifetime risk of developing asthma.⁵ Findings on this topic are of particular interest, as they suggest that ingesting certain substances may trigger asthma. It is thus possible that exposure to allergens through the GI tract may cause asthma.

Logistical Challenges to Interpreting Study Results

Longitudinal studies are on this topic are essential for a deeper understanding of the gut microbiome. However, recruitment biases, small sample sizes, and loss of follow-up can confound the results.¹

In addition, the gut microbiome can fluctuate significantly throughout participants’ lives. The relationships between different microbes and their hosts are complex, and multiple samples must be collected. Improper timing of sample collection may skew results, and countless other variables can also affect the state of the gut microbiome.¹ It can be difficult for researchers to determine the primary cause of various changes.

Study parameters can also be a significant challenge. As the editorial notes, there is currently no gold standard definition of asthma; different studies may use differing parameters, further confusing the issue.¹

The Role of Bacteria in Asthma

Despite these difficulties, the editorial acknowledges that researchers have collected a wealth useful data on the role of bacteria in asthma symptoms. For example, individuals who are asymptomatic nasopharyngeal carriers of certain bacteria appear to be at an increased lifetime risk for asthma.⁶

Gut bacteria may also contribute to asthma development through lower airway bacterial colonization. These bacteria appear to trigger atopy or cross talk between different areas of the immune system.¹ Over time, this communication could contribute to the development of asthma or other undesired immune responses.

Improving the Quality of Clinical Studies

To work toward better understanding the link between bacterial colonization and asthma, the editorial notes that many research-related challenges can be overcome¹ by exploring biological mechanisms to identify direct causation between gut microbes and the host, relying on longitudinal studies to ensure that data is collected consistently, and analyzing microbial signals to identify objective disease markers and the correlation between disease flare-ups and treatments.

The editorial identifies 3 landmark studies that demonstrate the importance of these approaches for collecting reliable data regarding the link between the gut microbiome and asthma. 

Previous Studies on Asthma and the GI Tract

One study by Arrieta et al on microbial alterations during early infancy identified 5 GI tract key bacterial genera found in a significant number of children with asthma. In addition, the identified bacteria were associated with lower incidences of atrophy and wheeze in infants.⁷

In this study, the link between bacteria and protection against asthma was clearly observed through a careful examination of the biological mechanisms within the gut microbiome, but the precise mechanism of protection was not identified.¹

Another study by Quince et al examined longitudinal changes in the microbiome in individuals with Crohn disease.⁸ Samples were collected before and after exclusive enteral nutrition. By analyzing the effect exclusive enteral nutrition had on the gut microbiome, researchers were able to document the relationship between different microbes and host cells.

An analysis by Lee-Sarwar et al also explored the relationship between GI tract microbiome and fecal metabolome.⁹ Most significantly, a cross-sectional analysis found associations between asthma symptoms and an increased presence of Christensenellaceae family bacteria in stools.⁹

These studies indicate that communication between mucosa in the large intestinal and respiratory tract may lead to similar bacterial communities in both sites.¹ Intestinal bacteria may also influence bacterial in lower airways, possibly through fecal-oral transmission. The gut metabolome then determines an individual’s predisposition to asthma.

The Limitations of Recent Studies

The editorial acknowledges that the analysis by Lee-Sarwar et al provides essential evidence that biological mechanisms within the gut play a role in asthma symptoms. However, the researchers relied on multiple correlations in their data sets, which may have obscured results.¹

Lee-Sarwar’s analysis also raises many questions that are not fully answered with the study’s parameters, particularly on the topic of breastfeeding. It is unclear whether historical breastfeeding can have a significant effect on older children’s asthma symptoms or if the effects of breastfeeding on the gut microbiome are temporary.¹ In addition, researchers are currently unsure whether key metabolites originate from the gut microbes, host, or diet. These mechanisms are not yet fully understood, which limits the abilities of current research to influence clinical practice.

Nevertheless, the editorial acknowledges that these studies provide a deeper understanding of the link between the gut microbiome and asthma symptoms.¹ These analyses must be replicated in other populations to rule out false-positive results.¹

Summary and Clinical Applicability

The link between physical processes within the human body and communicable bacteria is not yet fully understood. However, new scientific studies may prove that bacteria may cause many diseases that were historically considered noncommunicable.

References

1. Hansen R, Gerasimidis K, Turner S. Asthma causation and the gastrointestinal microbiome and metabolome: might there be a signal, or is it just noise? [published online May 10, 2019]. J Allergy Clin Immunol.  doi:10.1016/j.jaci.2019.04.026

2. Vieira WA, Pretorius E. The impact of asthma on the gastrointestinal tract (GIT). J Asthma Allergy. 2010;3:123-130.

3. Mastronarde JG. Is there a relationship between GERD and asthma? Gastroenterol Hepatol. 2012;8(6):401-403.

4. Writing Committee for the American Lung Association Asthma Clinical Research Centers, Holbrook JT, Wise RA, et al. Lansoprazole for children with poorly controlled asthma: A randomized controlled trial. JAMA. 2012;307(4):373-380.

5. Scott M, Roberts G, Kurukulaaratchy RJ, Matthews S, Nove A, Arshad SH. Multifaceted allergen avoidance during infancy reduces asthma during childhood with the effect persisting until age 18 years. Thorax. 2012;67(12):1046-1051.

6. Bisgaard H, Hermansen MN, Buchvald F, et al. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med. 2007;357(15):1487-1495.

7. Arrieta M-C, Stiemsma LT, Dimitriu PA, et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med. 2015;7(307):307ra152.

8. Quince C, Ijaz UZ, Loman N, et al. Extensive modulation of the fecal metagenome in children with Crohn’s disease during exclusive enteral nutrition. Am J Gastroenterol. 2015;110(12):1718-1729.

9. Lee-Sarwar K, Kelly R, Lasky-Su J, et al. Integrative analysis of the intestinal metabolome of childhood asthma [published online March 23, 2019]. J Allergy Clin Immunol. doi:10.1016/j.jaci.2019.02.032