PORTEFEUILLE

In western societies there has been a striking increase in the incidence of inflammatory diseases such as asthma, autoimmunity and inflammatory bowel disease over recent decades. The general consensus in the field is that major underlying causes of this increase are changes in lifestyle, diet and hygiene. A commonality between all of these factors is shifts in the constituents of the microbiota. Accordingly, there has been a surge of interest in trying to manipulate the microbiota with bacterial pre- or pro-biotics, for example, as a means of improving human health. Based upon preliminary data, we propose that bacteria are only one aspect of this phenomenon, and that fungi represent an untapped resource for shaping the microbiome and consequently disease susceptibility and development. In this project proposal we aim to identify which fungi in mice and humans are responsible for influencing inflammatory diseases, such as asthma. We aim to decipher the mechanisms through which fungi impact upon disease and to perform preclinical efficacy studies to establish which fungi hold the greatest promise for further development as novel future therapeutics. To achieve these goals, we plan to take an interdisciplinary approach incorporating preclinical immunology, computational modeling and a clinical cohort. Our hypotheses are based upon preliminary data and we have established the required models and collaborations in order to achieve our goals. Therapeutic targeting of the fungal ‘mycobiome’ could be the step-change needed to reduce inflammatory diseases, improve human health and lower the burden that these diseases place upon society and healthcare systems.

This is a highly innovative and unique project addressing a new concept in microbiome research–harnessing fungi for their therapeutic potential. The approach is interdisciplinary, with a cross-over between immunology, clinical studies and computational modeling approaches.

We validated the core premise of our grant by showing anti-fungal treatment allowed certain fungi to bloom and that supplementing the microbiome with this fungi (e.g. Candida) led to an enhanced asthma response. We developed a bioinformatics pipeline allowing better identification of bacteria within the microbiome and a new high throughput fungal sequencing pipeline. However, utilizing these new tools and deploying them on a series of different studies revealed that although depleting fungi led to an exacerbation of asthma, there was no single fungi that could be attributed to this effect. We conclude that fungi are opportunistic members of the microbiome, and do not represent a targetable microbial community for therapeutic interventions. Rather, future studies should be focused on the bacterial constituents of the microbiome.