From metabolome to asthma therapy

How new therapy options can be obtained from the complex pathophysiology of allergies was also the subject of EAACI 2019 in Lisbon.

Finding new options from a complex set of factors

The pathophysiology of allergies is very complex. They are influenced, among other things, by genetics, nutrition, age, epigenetics, as well as by "omics", such as metabolomics, microbiomics or exposomics, which have recently been the subject of more and more intensive research. How new therapy options can be derived from this was also the subject of EAACI 2019 in Lisbon.

Metabolome and exposome offer modern allergology innovative starting points for future treatment strategies. The metabolome comprises all metabolic processes, e.g. within the immune cells, but can usually be reduced to the fatty acid metabolism, which plays a very important role in inflammatory reactions.

On the other side is the exposome, which summarizes the allergy causes outside the body. These include, for example, allergens or a number of environmental particles that can cause reactions, particularly in the respiratory tract.

Eicosanoids, Inflammation, and Asthma

Eicosanoids are a major factor in the development of allergies and allergy-related asthma. These signal molecules based on fatty acids promote inflammatory reactions and can be found in excess especially in allergy sufferers and asthmatics.

In the meantime, studies have also clarified where these eicosanoids come from and what triggers their overproduction. For example, allergy sufferers often found fragmented hyaluronic acid, which in turn stimulates the production of arachidonic acid. This stimulates eicosanoid synthesis in certain immune cells such as macrophages.

This relationship was also confirmed in a smaller feasibility study (source 1) on metabolome and transcriptome in asthma patients published in 2017. There the scientists led by Milena Sokolowska proved that asthmatics produce more arachidonic acid and that consequently the antiviral immune response in people with asthma is also reduced (source 1).

Such studies show that the risk of asthma increases with the degree of dysregulation in fatty acid metabolism. The underlying mechanism is currently being discussed as follows: A genetic predisposition leads to the development of more fragmented hyaluronic acid. This stimulates the production of arachidonic acid, resulting in an excess of eicosanoids, among other things. The metabolism of the immune cells, e.g. the macrophages, is thereby altered and the immune response suffers. The immune cells, especially macrophages, can no longer induce a sufficient antiviral and/or antibacterial immune response.

Cell metabolism determines cell function

In another omics study (source 2) from 2019, data from transcriptome and metabolome analyses were evaluated in combination. The researchers found that the lungs of diseased animals in the mouse model had clearly different expression patterns for mucins and tight-junction proteins.

These different expression patterns favored causally inflammatory reactions in the lungs. The proportion of mucins increased with the degree of inflammation, while tight-junction proteins decreased in expression. The epithelial cells thus became more permeable (source 2).

In addition, a previously unpublished study shows that lung biopsies of asthmatics showed more abnormal glucose and fatty acid levels than those of non-asthmatics. Cell metabolism, therefore, influences cell function and in the end, even suggests a disease phenotype. According to the researchers, this would probably lead to a more "individualized" immunotherapy in the future.

1. Sokolowska M et al, J Allergy Clin Immunol 2017; 139(4): 1379-1383
2. Tan HT et al., Allergy 2019;74(2): 294-30; doi: 10,1111/all,13619
3. PL 3 "Fueling the immunity: From immunometabolism to novel treatment strategies": Sokolowska M, "Translating novel concepts in metabolomics into allergy interventions", EAACI Congress 2019, Lisbon (Portugal)