Programmbereich Chronische Lungenerkrankungen

Medical need

Chronic inflammatory lung diseases such as asthma represent a huge global economic and social burden but curative or preventative measures are not in sight. To reduce this burden, biomedical research has so far focused on the identification of molecular signatures of the host, such as biologicals targeting cytokines or their receptors. However, to date they failed to cure asthma and are restricted to insufficiently defined subsets of patients.

In the past decade, the host´s microbiome emerged as novel “target organ” since its composition and metabolic activity are essential for respiratory health (1,2). Environmentally- or disease-induced changes in the microbiota will therefore also alter metabolite profiles eventually leading to a breakdown of immune tolerance as seen in asthma, i.e. “healthy” microbiome will release a different set of metabolites as compared to “diseased” microbiome (Fig. 1). The knowledge which metabolite/metabolites correlate positively with the beneficial effects of a “healthy” microbiome can open possibilities for preventive (3) and/or therapeutic (4) strategies towards asthma, and other chronic lung diseases. Preclinical studies indicated that application of physico-chemically defined metabolites improves dysbiosis and lung health (5). Additionally, novel findings showing that fatty acids metabolism of gut bacteria influences fatty acid composition of the host have been reported (6). In this context, the concept of a gut-lung axis (7) is of high clinical relevance, as it offers the possibility of modulation of the lung microbiome and lung function in the future by means of tailored nutritive strategies.

Aim:

The knowledge on protective metabolites in the field of lung chronic diseases is sparse. Therefore, there is a need for further identification of novel, protective metabolites in a non-targeted screening approach that can be transfer to clinical phase I.

 

 

 

Fig. 1. Metabolites of the “healthy” microbiome as potential protective/therapeutic agents for allergic asthma.

 

Project:

The prototypic bacterial metabolites are short chain fatty acids (SCFAs), such as acetate, butyrate and propionate, that have been shown to protect mice against allergic inflammation indirectly confirming the gut-lung axis (4,5). However, one can envisage that other still unknown small bacterial molecules can act on the lung milieu through the gut-lung axis. Going even one step further it is plausible that such metabolites reaching lung via bloodstream may affect inflammatory status of the lung influencing the content and production of selective pro-resolving mediators (Fig. 3) – Current project with coop. Markus Weckmann, Isabel Ricklefs, UKSH Lübeck.

 

Fig. 3 Hypothesized connection between metabolites produced by gut bacteria and inflammatory status in the lung. Bacterial metabolites reach lung immune cells via bloodstream and active receptors, such as PPARg or G-protein-coupled receptors that recognize metabolites triggering anti-inflammatory cascade on macrophages and other innate immune cells responsible for the production of selective pro-resolving mediators and doing so contribute to resolution of lung inflammation and restoration of “healthy” microbiome.

The overarching goal is creation a workflow bringing prioritized bioactive metabolites into phase 1 clinical trials in a cooperative approach with other FGs at Research Center Borstel, UKSH in Lübeck and CAU in Kiel.

References:

1. Man WH, de Steenhuijsen Piters WAA, Bogaert D. The microbiota of the respiratory tract: gatekeeper to respiratory health. Nat Rev Microbiol (2017) 15:259–270. doi:10.1038/nrmicro.2017.14
2. Wypych TP, Wickramasinghe LC, Marsland BJ. The influence of the microbiome on respiratory health. Nat Immunol (2019) 20:1279–1290. doi:10.1038/s41590-019-0451-9
3. Kepert I, Fonseca J, Müller C, Milger K, Hochwind K, Kostric M, Fedoseeva M, Ohnmacht C, Dehmel S, Nathan P, et al. D-tryptophan from probiotic bacteria influences the gut microbiome and allergic airway disease. J Allergy Clin Immunol (2017) 139:1525–1535. doi:10.1016/j.jaci.2016.09.003
4. Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, Blanchard C, Junt T, Nicod LP, Harris NL, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med (2014) 20:159–166. doi:10.1038/nm.3444
5. Dang AT, Marsland BJ. Microbes, metabolites, and the gut–lung axis. Mucosal Immunol (2019) 12:843–850. doi:10.1038/s41385-019-0160-6
6. Kishino S, Takeuchi M, Park S-B, Hirata A, Kitamura N, Kunisawa J, Kiyono H, Iwamoto R, Isobe Y, Arita M, et al. Polyunsaturated fatty acid saturation by gut lactic acid bacteria affecting host lipid composition. Proc Natl Acad Sci (2013) 110:17808–17813. doi:10.1073/pnas.1312937110
7. He Y, Wen Q, Yao F, Xu D, Huang Y, Wang J. Gut–lung axis: The microbial contributions and clinical implications. Crit Rev Microbiol (2017) 43:81–95. doi:10.1080/1040841X.2016.117698