At the recent Cambridge Immunology Network seminar, Dr. Benjamin Marsland explained how the metabolism of dietary fiber by gut microbiota influences allergic inflammation in the respiratory tract and causes alterations in bone marrow hematopoiesis1. There also appears to be a crucial window during early development where microbial diversity in the lung can result in tolerance to airborne allergens later in life2.
The role of the microbiota in maintaining good health has been in the scientific and mainstream media for a number of years now. This has been heavily focussed on gut health and there has been little or no information around how gut microbiota might affect peripheral tissues like the lung.
Until relatively recently the lung was regarded as a sterile environment, but we know now that healthy lungs contain as many as 100 bacterial cells per 1,000 human cells3. First contact with this complex mix of microbial life might actually begin in utero4 before becoming established in other tissues.
Fiber, fatty acids and allergy
The food we eat affects the metabolism of the gut microbiota, which in turn can affect other tissues and processes. When the gut microbiota metabolizes fermentable dietary fiber for example, it produces short chain fatty acids (SCFAs). Experiments with mice fed a high-fiber diet result in elevated levels of circulating levels of SCFAs compared to control animals1. Mice on a high-fiber diet also have improved airway hyper-reactivity and a population of dendritic cells with lowered activity (demonstrated by reduced surface expression of CD40, CD80, PD-L1 and PD-L2).
These changes translate into protection against allergic inflammation in the lung, as seen by reduced levels of IL-4, IL-5, IL-13, IL-17 and total IgE in the lungs following exposure to house dust mite extract. Interestingly, SCFAs were not detected in the in the lung itself, implicating a more indirect means of exerting these effects.
SCFAs in circulation, specifically propionate, are able to enhance the hematopoiesis of macrophage and dendritic cell precursors in the bone marrow. The lungs are subsequently repopulated by dendritic cells characterized by a high phagocytic capacity but an impaired ability to drive T helper type 2 (Th2) cell effector functions. This allows allergic airway inflammation to be resolved quickly. SCFAs from dietary fiber effectively ameliorate the allergic responsiveness via a gut-bone marrow axis.
Window of opportunity
There is a rapid increase in intestinal microbiota within the first few weeks after birth in mice5 and the first few months in humans6. The resulting microbial diversity is important as it can help to avoid allergic asthma later on: children with asthma have a lower intestinal microbial diversity in the first month after birth compared with children who do not have asthma7.
Dr. Marsland highlighted recent work in mice, in which a low diversity and low load of microorganisms in the airways are associated with an immature immune response and susceptibility to allergic inflammation2. Through a series of experiments exposing mice at three days (neonate), 15 days (preweanling) or 60 days (adult) of age to house dust mite allergens, it was shown that neonates have a window of two weeks to set the level of their allergic immune response.
During this time, any exaggerated or decreased responsiveness toward aeroallergens that develops is maintained through to adulthood. The stabilization of both the load and composition of lung microbiota is essential for inducing T regulatory (Treg) cells and a programmed cell death 1 ligand 1 (PD-L1)-mediated mechanism of tolerance to aeroallergens during this critical window.
The microbes in our gut are capable of having a regulatory effect on peripheral tissues and are critical in defining the trajectory of an individual’s risk of allergic disorders later in life. It no longer makes sense to think of tissues in isolation, but instead we must consider them in terms of their wider environment and diverse microbial inhabitants.
Future research is needed to better understand the crosstalk between different tissue-specific microbiota and their metabolites, as well as characterizing the immunoprotection that this symbiosis confers to an individual.
1. Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159–66 (2014).
2. Gollwitzer, E. S. et al. Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat. Med. 20, 642–7 (2014).
3. Sze, M. A. et al. The lung tissue microbiome in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 185, 1073–1080 (2012).
4. Marsland, B. J. & Salami, O. Microbiome influences on allergy in mice and humans. Curr. Opin. Immunol. 36, 94–100 (2015).
5. Deshmukh, H. S. et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat. Med. 20, 524–30 (2014).
6. Turnbaugh, P. J. et al. Human gut microbiome viewed across age and geography. Nature 457, 222–227 (2009).
7. Abrahamsson, T. R. et al. Low gut microbiota diversity in early infancy precedes asthma at school age. Clin. Exp. Allergy 44, 842–850 (2014).