Session Topic: The Emerging Role of the Human Microbiome in Inflammatory and Autoimmune Diseases
The microbiome concept denotes the totality of microbes, their genomes, and their interactions within defined environments such as the human body. This concept, together with the advances in DNA sequencing technologies, has created a new field of research, called metagenomics, allowing comprehensive examination of microbial communities, even those comprised of predominantly uncultivable organisms. It has been estimated that 20% to 60% of the human microbiome cannot be cultivated. Recent investigations on the role of the human microbiome in health and disease have led to new paradigms that the microbiome plays an important role in maintaining a healthy state, as well as contributing to the etiopathogenesis of diseases including inflammatory and autoimmune diseases. To maintain a healthy state, our normal microflora is likely involved in keeping pathogenic organisms under control. In addition, the gut microbiome plays a role in human energy homeostasis and may contribute to the pathogenesis of obesity. Conversely, substantial alterations of the microbiome have been observed in patients suffering from conditions such as psoriasis, atopic dermatitis and rheumatoid arthritis. However, the molecular mechanisms by which the microbiome influences innate and adaptive immunity are not fully understood. Better understanding of the mechanisms of action hold promise to change how we diagnose, treat and, ultimately prevent many health conditions.
The Human Microbiome Project (HMP) was launched in 2007 as part of the NIH Roadmap for Medical Research in order to accelerate human microbiome research. This is a community resource generating project that will use metagenomics to survey the human microbiome at five body sites (skin, gastrointestinal, urogenital, oral and nasal), sequence reference genomes, develop new methodologies and bioinformatics tools, and address ethical, legal, and social issues. In addition, fifteen demonstration projects have been funded to study the relationship between the human microbiome and human health and disease. Several skin-related demonstration projects from the HMP are within the mission of NIAMS, including the studies on psoriasis, acne, and atopic dermatitis. Most recently, an ARRA RC2 grant co-funded by the NIH OD and NIAMS proposes to investigate the role of the microbiome in rheumatoid arthritis. These emerging studies keep the Institute at the cutting edge of this new frontier of genomics, and we expect that, in the near future, the microbiome research will expand into additional disease areas which are of interest to NIAMS.
The purpose of this session is to discuss the state-of-the-art of human microbiome research, especially as it relates to diseases and conditions of interest to NIAMS. The important role that the microbiome plays in homeostasis will be discussed, as well as potential roles in both disease prevention and pathogenesis. Current NIAMS-related microbiome projects on skin and rheumatoid arthritis, their possible outcomes, and contributions to advancing the fields will be covered. Finally, we will assess future scientific opportunities and needs, as well as the role of NIAMS in sustaining human microbiome research post HMP and ARRA funding.
Microbiome and Health:
- What is the human microbiome and why is it important for NIAMS to study?
- Is there a core human microbiome? What is the variation in the human microbiome between individuals and across time?
- What are the important roles of the human microbiome in maintaining a healthy state? What are the host-microbe and microbe-microbe interactions at play? How are the human proteome and metabolome complemented by that of our microbiota?
Host-microbe Interactions and Immunity:
- How do skin pathogens and commensal microbes interact with the epidermis of the skin? What are the possible outcomes of such interactions? What are the key molecular factors regulating such interactions?
- What properties of the host-microbe interaction distinguish commensal microbes from pathogens?
- How is the human immune system shaped by the microbiome? Is the immune system of pathogen-free mice less developed? Is the activation and/or function of specific subsets of lymphocytes (e.g., TH17/Tregs) regulated by the gut microbiome?
Role of Microbiome in Skin and Rheumatic Diseases:
- What skin diseases are correlated with changes in the microbiome? Are there pathogenic mechanisms that link changes in the microbiome with disease?
- Do specific microbiota dispose us to the development of rheumatic diseases such as rheumatoid arthritis and lupus? What can we learn from animal models of arthritis in which disease does not develop in a germ free environment?
- How is the host-microbe interaction, as well as the human microbiome, influenced by the genetics of the host?
- Can we use microbial profiles as a biomarker for clinical diagnoses and treatment decisions?
- What are the effects of widespread use of antibiotics and antimicrobial agents (e.g., in soaps and hand sanitizers) and vaccines on the human microbiome? Do alterations of the microbiome with antibiotics affect host immune responses, disease prevalence, flares, etc.?
- Can we develop new non-antimicrobial drug treatments that target the host-microbiome interaction?
- What is the potential role for probiotics, both in the maintenance of health and in treatment of disease?
Role of NIAMS in Microbiome Research:
- What are the roadblocks associated with microbiome research? How can NIAMS/NIH engage the larger scientific and lay communities, including the private sector and foundations, to promote microbiome research beyond what is currently supported by the NIH Roadmap and ARRA?
Expected Session Outcomes
NIAMS staff will gain a better understanding of the role of the human microbiome in health and disease, especially as it relates to NIAMS interests. Staff will also gain knowledge of the many challenges faced by microbiome researchers as well as the resources generated by the HMP that can help address these challenges. This session will help position NIAMS to both assess and respond to future scientific opportunities in microbiome research.
- The NIH Human Microbiome Project
NIH HMP Working Group, Peterson J, Garges S, Giovanni M, McInnes P, Wang L, Schloss JA, Bonazzi V, McEwen JE, Wetterstrand KA, Deal C, Baker CC, Di Francesco V, Howcroft TK, Karp RW, Lunsford RD, Wellington CR, Belachew T, Wright M, Giblin C, David H, Mills M, Salomon R, Mullins C, Akolkar B, Begg L, Davis C, Grandison L, Humble M, Khalsa J, Little AR, Peavy H, Pontzer C, Portnoy M, Sayre MH, Starke-Reed P, Zakhari S, Read J, Watson B, Guyer M. Genome Res. 2009 Dec;19(12):2317-23. Epub 2009 Oct 9.
- PMID: 19819907 [PubMed - in process]
- What are the consequences of the disappearing human microbiota?
Blaser MJ, Falkow S. Nat Rev Microbiol. 2009 Dec;7(12):887-94. Epub 2009 Nov 9.
PMID: 19898491 [PubMed - indexed for MEDLINE]
- Human Skin Microbiota: A New Investigation of Commensal Bacteria. Kong, HH and Segre, JA Chapter 176, General Considerations of Bacterial Disease, Fitzpatrick's Dermatology in General Medicine, 7th edition online. Edited by Klaus Wolff, Lowell A. Goldsmith, Stephen I. Katz, Barbara A. Gilchrest, Amy S. Paller, David J. Leffell.
- The gut microbiota shapes intestinal immune responses during health and disease. Round JL, Mazmanian SK. Nat Rev Immunol. 2009 May;9(5):313-23. Review. Erratum in: Nat Rev Immunol. 2009 Aug;9(8):600.
PMID: 19343057 [PubMed - indexed for MEDLINE]