The proliferation of research pertaining to the human gut microbiome has produced numerous findings that point to its role in a range of illnesses, including gastrointestinal, metabolic, and psychiatric diseases.1,2 In addition, emerging evidence suggests that the gut microbiome may contribute to the pathogenesis of atopy and asthma.

“There are exciting data that implicate the composition of the gut microbiome in early life — the first 1000 days — to the development of asthma, although the evidence to date remains correlative,” Cathryn R Nagler, PhD, the Bunning Food Allergy Professor and professor of pathology, medicine, pediatrics, and the college at the University of Chicago, told Pulmonology Advisor.

Some study results suggest that maternal-fetal microbiota transfer may be initiated in utero, with further bacterial transfer occurring during vaginal delivery and breastfeeding.3 Birth cohort studies have found that dysbiosis of the gut microbiota in the first years of life is associated with the subsequent development of asthma and allergy, including a 2018 prospective study (n=690) linking the composition of the gut microbiome at age 1 year with an increased risk for asthma at age 5 years.4

Such findings are “supported by work in mouse models that show age-dependent regulation of immunoglobulin E production by the gut microbiota and a potential direct role for specific bacteria, such as Lachnospira, Veillonella, Faecalibacterium, and Rothia, in mitigating asthma development during the first 100 days of life,” according to a recent review published in the Annals of Allergy, Asthma & Immunology.5 These bacteria were found to be reduced in children at risk for asthma. Meanwhile, when researchers inoculated germ-free mice with these specific taxa, airway inflammation decreased.6

Among the potential mechanisms driving the relationship between gut microbiota and asthma pathogenesis are altered levels of short-chain fatty acids “produced by fermentation of fiber by specific gut bacteria.” This may lead to an increased risk for asthma, according to murine and human studies.5 Other potential mediators include histamine and tryptophan metabolites.5

These observations suggest that interventions targeting the gut microbiome may ultimately prove useful in asthma management. “Microbiome-modulating therapeutics could be administered as both preventive or therapeutic modalities,” said Dr Nagler. While these therapies are not currently available for clinical use, many research scientists and biotechnology start-up companies are working to develop such strategies. “Much more work needs to be done to examine how bacteria and other microbes impact the host at the cellular and molecular level in both health and disease,” Dr Nagler said.

To gain additional insights regarding the “gut-airway axis,” Pulmonology Advisor interviewed Yvonne J Huang, MD, assistant professor of internal medicine in the division of pulmonary and critical care medicine at the University of Michigan Ann Arbor, who coauthored the 2019 review5 mentioned, and Tara F Carr, MD, associate professor of medicine and otolaryngology in the division of pulmonary, allergy, critical care and sleep medicine at the University of Arizona in Tucson.

Editor’s note: These interviews were lightly edited for length and clarity.

Pulmonology Advisor: What is known thus far about the connection between the gut microbiome and asthma?

Dr Carr: Recent studies have supported that the connection between the gut microbiome and risk [for] asthma may start in very early life, even prenatally. For example, differences in microbiota present in the meconium and infant stool can predict children at high risk for allergic diseases and asthma.7 Protective characteristics of infant stool microbiota include richness and diversity of the bacterial colonies. This is supported by various epidemiologic studies showing that early life microbial exposures — such as to pets, farming environments, vaginal flora, and daycare — may be protective against asthma development.7 One pathway through which microbiota influence immune development and asthma risk may be through different metabolic functions of the microbiota, which lead to differential levels of proinflammatory molecules. Another way may be through direct contact of microbiota with immune cells.7

The gut microbiome also differs between patients who have asthma and those who do not have asthma, and seems to relate to asthma characteristics such as lung function. The effect of asthma and allergy medications on the microbiome in these studies is less well understood, so the relationship of gut microbiome to asthma in patients with established asthma is still unclear.

Dr Huang: An enormous amount of research has found connections between risk [for asthma] developing in childhood and the gut microbiome. In infancy, it is known that how the gut microbiome develops — that is, the types of microbes that take up residence and how they interact — has an important impact on how the developing immune system is trained. A lot of work to date has focused on determining early life factors that shape the gut microbiome and the mechanisms by which a different pattern of microbes associated with asthma risk actually lead to that outcome.1

In contrast, far less attention has been paid to exploring similar connections in adults who have established asthma or [who have] the disease later in life. Persistent asthma presents and behaves in many different ways, and this variability in phenotype is well recognized in adults. We know a lot about airway inflammation patterns and how they vary among patients. What we do not fully understand are the factors driving different inflammation patterns and, in turn, different response to treatments.

In light of the broader literature, there are plausible links between functional consequences of an altered gut microbiota and certain phenotypes of asthma. This aspect is what we explored in a pilot study using stool samples we collected from adult patients with asthma participating in a long-term study.8

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Pulmonology Advisor: What are the current and potential treatment implications for clinicians?

Dr Carr: The mechanism through which the gut microbiome affects asthma risk is an important area of investigation, so we can fully understand the implications of influencing the microbiome through treatments or other exposure interventions. Trials of probiotic supplementation for asthma treatment have not consistently shown benefit for asthma or other atopic diseases, so this is not currently recommended.7 An oral supplement of lyophilized bacterial extract is widely used in European countries for treatment of respiratory diseases and is postulated to function through modulation of gut microbiome.

Dr Huang: Looking at the gut microbiota data, we started by asking basic questions: Is there a relationship between variation in gut bacterial composition and allergic sensitization to aeroallergens and lung function measures?5 In pediatric studies, there is strong evidence linking the gut microbiome to allergy risk and even degree of allergen sensitization, but this has not really been studied in adults nor in relationship to lung function. We found a strong association between these clinical markers related to asthma phenotype and differences in the collective composition of gut bacteria between patients. We next took an agnostic approach to clinical phenotype, looking at how the composition of gut microbes naturally segregate in adults with asthma and then comparing clinical and immunologic features to see what characteristics differed among the microbiome-defined clusters of patients.5

This revealed some interesting trends that align with known differences in adult asthma phenotype. Even in our small study, 3 patient clusters were found. One [group] seemed to have obesity-associated asthma, and the other 2 groups were composed of nonobese patients who differed in levels of sputum and blood inflammatory cytokines, such as IL-8 and IL-1-β, and had lower lung function than the patients in our obese asthma group.8 Given that these patients all had noneosinophilic asthma, and hence are unlikely to benefit from the newer therapies targeting type 2 cytokine pathways, we think these early observations are provocative and should inform further study of gut-related factors that drive forms of noneosinophilic asthma.

Pulmonology Advisor: What are remaining needs in this area in terms of research or otherwise?

Dr Carr: This is an exciting field of study that offers profound implications for asthma prevention or treatment. We may be able to use infant microbiome characteristics to identify individuals at high risk for asthma. We need to understand the mechanisms through which the gut microbiome affects asthma risk and asthma symptoms/severity. We also need to develop more effective ways of modulating the gut microbiota such that healthy/protective characteristics are long lasting.

Dr Huang: With growing evidence implicating differences in the microbiome with distinct features of asthma, there is a critical need to better understand mechanisms of how microbiota functionally shape host responses. Conversely, there is also a need to understand how host-specific factors potentially shape the behavior of resident microbes. These interactions almost certainly are bidirectional and dynamic, the latter depending on patient-specific exposures and events. Much research to date in the microbiome-respiratory disease context has been cross-sectional in nature. Given the dynamism of lifetime events, understanding longitudinal patterns of associations in human cohorts and impact on clinical outcomes is important.

References

  1. Bull MJ, Plummer NT. Part 1: The human gut microbiome in health and disease. Integr Med (Encinitas). 2014;13(6):17-22.
  2. Malan-Muller S, Valles-Colomer M, Raes J, Lowry CA, Seedat S, Hemmings SMJ. The gut microbiome and mental health: implications for anxiety- and trauma-related disorders. OMICS. 2018;22(2):90-107.
  3. Fujimura KE, Lynch SV. Microbiota in allergy and asthma and the emerging relationship with the gut microbiome. Cell Host Microbe. 2015;17(5):592-602.
  4. Stokholm J, Blaser MJ, Thorsen J, et al. Publisher correction: Maturation of the gut microbiome and risk of asthma in childhood Nat Commun. 2018;9(1):704.
  5. Kozik AJ, Huang YJ. The microbiome in asthma: role in pathogenesis, phenotype, and response to treatment. Ann Allergy Asthma Immunol. 2019;122(3):270-275.
  6. 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.
  7. Carr TF, Alkatib R, Kraft M. Microbiome in mechanisms of asthma. Clin Chest Med. 2019;40(1):87-96.
  8. Begley L, Madapoosi S, Opron K, et al. Gut microbiota relationships to lung function and adult asthma phenotype: a pilot study. BMJ Open Respir Res. 2018;5(1):e000324.

This article originally appeared on Pulmonology Advisor