It is well established that the gut microbiome is essential for human health, since maturation and homeostasis of the immune system depends on intestinal flora. In respiratory medicine, the lung microbiome has also emerged as unique and potentially having a pivotal role in determining disease course and response to treatment. Since the seminal work of the NIH Common Fund-sponsored Human Microbiome Project (HMP) and Integrative HMP (iHMP), as well as NHLBI initiatives such as the Lung HIV Microbiome Project, we have gained vast knowledge about the microbiome composition and the dynamic associative relationships that exist with the host in the gut, skin, oral cavity, lung, and urogenital tract. Changes in microbial composition and relative abundance of the human microbiome, known as dysbiosis, have been described for a variety of autoimmune and metabolic diseases and conditions within the interest of NHLBI mission such as asthma, COPD, cystic fibrosis, diabetes and obesity, hypertension, graft versus host disease (GVHD), coronary disease, sleep disorders, and pulmonary fibrosis. Although a few areas have made progress toward showing the functional role of the microbiome, most host-microbiome studies performed to date have been largely associative, and the detailed processes by which the microbiota can influence the host remain elusive. As we are starting to understand the extent of these complex and dynamic microbe-host exchanges, research opportunities emerge to identify and characterize such microbial-host interactions, which are critical to designing microbiome-based interventions for prognostic, diagnostic and treatment purposes in a variety of diseases and conditions in which the microbiome plays a critical role.
With the vast evidence associating microbiome disturbance with disease, we can address a substantial gap in our understanding of how changes in the bacterial, viral, and fungal microbiota in the gut, lung and/or oral cavity may affect distal organ/mucosal sites directly through microbial translocation, through signaling mechanisms and/or bioactive molecules, or via crucial immune stimulation/activation of key regulatory pathways early in life . Bi-directional host signaling and environmental factors such as the timing and availability of nutrients shape microbiota composition, function, and metabolites. Recent advances indicate that irregularities in circadian-dependent host functions such as mucosal barriers, defensins, and immune cells are associated with markers of dysbiosis and the risk of disease.
The regulatory and metabolic capacity of the human microbiome may also play a fundamental role in the conversion of drugs and priming the immune system. Understanding drug transformation through microbial metabolism is increasingly necessary, and it may lead to the discovery of biomarkers that could correlate with therapeutic success or treatment outcome. Conversely, drug treatments have the potential of altering the host microbiome, which can act as a surrogate biomarker during a course of therapy leading to implementation of necessary adjustments at the individual level.
The objective of this FOA is to attract investigator-initiated multidisciplinary R01 research projects to define mechanistic interactions between the microbiome (gut/lung/oral or combinations) that influence normal physiology and pathophysiology of diseases within NHLBI’s mission (see NHLBI Strategic Vision and mission). This FOA aims to address this gap in “causation,” leveraging the use of available biospecimens from existing cohorts and biobanks, using state of the art technologies (including high throughput sequencing, transcriptomics, proteomics, metabolomics, single cell profiles) and animal models, if applicable, with the goal to further our understanding of the complex microbiome-host interactions and functions. This FOA also encourages multidisciplinary collaborations among scientists in a wide range of disciplines including those with HLBS expertise (pulmonologists, cardiologists, hematologists, sleep and circadian experts ), immunology, microbiome and microbial ecology, metabolism, genomics, other ‘-omics’ sciences, and bioinformatics.
Potential examples of the scientific questions that could be addressed in response to this FOA include, but are not limited, to the following :
- What specific microbial metabolites or microbial activated pathways contribute to poor outcomes such as immune dysfunction and disease relapse following hematopoietic stem cell transplantation?
- What specific microbial metabolites or microbial-activated pathways contribute to blood pressure regulation?
- What is the influence of the gut and/or lung microbiome on processes associated with the progression of pulmonary fibrosis (e.g., alveolar epithelial injury, fibroblast differentiation, extracellular matrix remodeling, immune cell activation)?
- What is the role of microbiota in the pathogenesis of sickle cell disease, such as patients presenting with vaso-occlusive crisis ?
- What circadian abnormalities in host and microbiota functions impair hormonal, metabolic, and immunological inter-relationships associated with HLBS pathobiology and disease?
- What host mechanisms are affected by sleep deficiency and lead to pathobiological changes in microbiota composition associated with increased risk of disease?
- What is the impact of the donor and/or recipient gut microbiome on graft survival following lung transplantation (e.g., what are the mechanistic associations between the gut microbiome and the development of lung allograft rejection)?
- What are the interactions between host and microbiome (activation pathways and molecules) that contribute to differences in clinical phenotypes and disease courses between patients?
- How does the microbiota or microbial metabolites impact hematopoiesis, the hematopoietic niche, and blood stem cell homing?
- Elucidate the networks between innate and adaptive immunity in HLBS diseases and the effect of dysbiosis in such networks.
- What role does the microbiome play in the formation of Factor VIII ( FVIII) inhibitors in patients with Hemophilia A?
Deadlines: standard dates apply (letters of intent due September 5, 2018)
Filed Under: Funding Opportunities