Goal 1: Promote Human Health

Microbiome and hypertension

What is the connection between the gut microbiome and the development of hypertension?

Submitted by (@nhlbiforumadministrator1)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Help understand the normal and pathophysiology of human hypertension and related disorders, such as metabolic syndrome, diabetes, obesity, and stroke.

Feasibility and challenges of addressing this CQ or CC :

Yes., this is feasible.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 1: Promote Human Health

Lung Microbiome and Innate Immunity

How does the lung microbiome shape its innate immunity? Is there a commensal immune system in the lung? Is the lung microbiome metabolically active?

Submitted by (@nhlbiforumadministrator1)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 2: Reduce Human Disease

Inflammation: what is the role of the blood microbiome?

Blood is not continuously sterile. Data from dental studies, blood donors, and random blood cultures document that "normal" human blood often harbors microbes. Sepsis only occurs when immunological regulatory systems fail. Growing evidence link subclinical, potentially transient bacteremia to cardiovascular and other diseases. Could many of the diseases associated with inflammatory markers represent either continuous ...more »

Submitted by (@kevinfiscella)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

A central scientific question is whether the blood microbiome has immunologic significance or not. Does it represent a largely incidental, trivial finding or does it represent an important source for immunologic activity?

 

This change in scientific paradigm could have major implications for research including providing a unifying explanation for unexplained phenomena including potential mechanisms related to disparate conditions including CVD, HTN, preterm births, CNS disorders, auto-immune diseases, etc. For example, the inflammation associated with obesity may result from differences in not only the micriobiome of the GI tract but also blood. Transient bacteremia might also explain effects of psychologic stress, smoking, and diet via permeability effects via other microbiomes.

 

Historically, transient, subclinical bacteremia has been regarded as an incidental finding of little consequence outside of selected conditions e.g. bacterial endocarditis and severe immune suppression. The concept that subclinical, transient bacteremia (and potentially very low level viremia) have both beneficial (adaptive immunity) and harmful (inflammatory) significance creates new directions for research and ultimately new targets for intervention including regulators of permeability on various barriers between different microbiomes. e.g blood and GI tract, or blood and oral cavity etc.

Feasibility and challenges of addressing this CQ or CC :

One challenge is methodologic. Standard blood cultures miss low level and/or transient bacteremia. New approaches, e.g. 16 rDNA PCR etc offer promise but advances in methods are needed to capture potentially intermittent phenomena.

 

Another challenge is that the blood microbiome is likely polymicrobial and potentially dynamic with bursts of different microbes resulting from different sources e.g. oral cavity,skin, GI tract, UG tract, lung etc. Like other microbiomes, it is probably more of an ecological system embedded within other micorbiome systems. Methods need to account for for the potential large diversity in blood microbes with likely differing significance including potential competition and synergy between different microbes whether intra or extracellular.

 

A third challenge relates to the potential longitudinal and developmental implications. Potentially blood microbiome effects are relatively small, but cumulative and developmentally sensitive.This will require longitudinal studies in humans (and animal models) including studies done during pregnancy and other critical developmental periods.

 

A final challenge is modeling. This includes disentangling effects from established human microbiomes from the blood and establishing directions of effects between blood microbiomes and immune activity. Methods applicable to complex adaptive systems with non-linear, time dependent effects are likely required.

Name of idea submitter and other team members who worked on this idea : Kevin Fiscella, MD, MPH

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Goal 1: Promote Human Health

Microbiome, immunity and health

What is the influence of the microbiome on the immune system and other development processes across the normal human lifespan?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

There is a potential of microbiome-based therapeutics to treat human disease. A deep understanding of the mechanisms governing the interactions between microbiomes, immune development and metabolic networks are key to improve health outcomes. New therapeutic approaches including personalized pre- and probiotics and nutritional interventions, narrow spectrum antibiotics and fecal transplantation therapies may provide an avenue for safer alternatives to traditional clinical interventions for chronic diseases.

Feasibility and challenges of addressing this CQ or CC :

Through the Human Microbiome Project investigators have started to characterize and analyze the microbial communities in the body. Today metagenomics tools and other technologies developed through these projects are available to the broader scientific community. Such tools and standardized protocols can be applied and improved in future research to address functional and mechanistic consequences of host-microbiome interactions and their influence in human health.

Bacterial communities colonize the human host from birth, giving rise to a highly adapted microbiota that is established, but dynamic, in healthy individuals though life. Growing evidence suggests that this complex symbiotic relationship between microbiome and its host fulfills critical physiological roles, immune maturation, and diverse metabolic functions. Immune maturity and balance is conquered and maintained partly due to the influential interaction among the resident gut microbiota and host mucosal immune system. In addition, the immune system is continuously stimulated by chronic systemic viruses; the human virome is considered one of the drivers of idiopathic systemic inflammation that has been linked to many of the most severe public health threats, including cardiovascular diseases. In depth understanding of the underlying mechanisms that control homeostasis and dysbiosis (microbial imbalance) of the gut, lung and/or other host microbiota are vital for our ability to potentially manipulate the microbiota to achieve positive clinical outcomes for systemic diseases.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 2: Reduce Human Disease

Influence of the Gut Microbiome on Pulmonary Immunity in HIV-Infected Individuals

It has become increasingly clear that gut microbiota have a tremendous impact on human health and disease. While it is well known that commensal gut bacteria are crucial in maintaining immune homeostasis in the intestine, there is also evidence of indirect effects on the lung. Multiple studies have shown that alterations in gut microbiota can lead to severe defects in pulmonary immune responses and reduced ability to ...more »

Submitted by (@brent.palmer)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

HIV-infected individuals are at significant risk of developing and dying from infectious and non-infectious pulmonary complications. Alteration of gut microbiota have been shown to have dramatic effects on pulmonary immunity and severity of lung infections. For instance, multiple studies have indicated that probiotic treatment with certain Lactobacillus and Bifidobacterium strains results in reduced incidence and severity of upper respiratory tract infections in children. Similarly, a recent study showed that treatment with the minimally absorbed antibiotic neomycin was associated with alterations in gut microbiota composition and concomitant reduced pulmonary immunity and the inability to control Influenza infection in mice. It was recently described that HIV infection is associated with a dramatic alteration in gut microbiota and that these changes persist with antiretroviral therapy (ART). Thus, it is important to understand how these alterations may effect lung immunity, since the majority of HIV-infected individuals develop pulmonary infections. Furthermore, gut microbiota contribute to development of non-infectious complications such as atherosclerosis, metabolic disease, obesity and diabetes. It is thus highly plausible that the gut microbiota may also play a role in the development of non-infectious complications of the lung such as Chronic Obstructive Pulmonary Disease and Pulmonary Hypertension, the rates of which are elevated in HIV-infected individuals.

Feasibility and challenges of addressing this CQ or CC :

A better understanding of how alterations in gut microbiota associated with HIV infection affects pulmonary infectious and noninfectious complication could lead to therapies to protect this “at risk” group. Furthermore, manipulation of the gut microbiota in HIV-infected individuals using pro- and/or pre-biotics, antibiotics or diet modification to a composition that is associated with increased pulmonary immunity, reduced infections and lung complications are all low risk therapeutic strategies that could substantially improve lung heath in these individuals.

Name of idea submitter and other team members who worked on this idea : Brent Palmer (NHLBI-INHALD group member) and Catherine Lozupone

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Goal 2: Reduce Human Disease

The Importance of the Microbiome in Recovery after Hematopoietic Stem Cell Transplantation

Do modifications in the recipient gut or lung microbiome affect development of tolerance and immunologic recovery after allogeneic hematopoietic stem cell transplantation (HCT) and can re-institution of a more normal microbiome lead to improved outcomes?

Submitted by (@marymh)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

HCT leads to profound changes in the host microbiome. Some small studies indicate that differential recovery of the gut microbiome is associated with differential outcomes, including graft-versus-host disease and mortality. Less is known about the pulmonary microbiome. Better understanding of the role of the microbiome in facilitating posttransplant recovery could lead to easily administered interventions and provide important insights into the role of different subpopulations of the microbiome on the health of all people.

Feasibility and challenges of addressing this CQ or CC :

Preclinical and clinical studies of this area would be greatly facilitated by a microbiome repository linked to high quality clinical data and would provide opportunity for insight into the role of the microbiome in health and disease.

Name of idea submitter and other team members who worked on this idea : Mary Horowitz

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