Microbial Ecology in States of Health and Disease Workshop Summary (2014) / Chapter Skim
Currently Skimming:
A19 Metagenomics and personalized medicine--Herbert W. Virgin and John A. Todd
A19 Metagenomics and personalized medicine--Herbert W. Virgin and John A. Todd
Pages 445-470
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 445... ...
A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology.
|
From page 446... ...
on autoimmune and inflammatory diseases are uncovering mechanism-based subtypes for these disorders. Applying these emerging concepts will permit a more complete understanding of the etiologies of complex diseases and underpin the development of both next-generation animal models and new therapeutic strategies for targeting personalized disease phenotypes.
|
From page 447... ...
Familial clustering is caused by a combination of inherited genetic variants from the parents to the children and shared environmental factors within the families. Susceptibility variants are being discovered rapidly by GWAS, but the environmental factors remain unknown, although numerous candidates are recognized, most particularly a role for the microbiome and infections.
|
From page 448... ...
that the interactions of individual microorganisms and their g enomes with specific host genes or pathways underpin the relationship between genotype and phenotype in these complex diseases. In this view, disease genetics may be combinatorial with different host–gene–microbial interactions, contributing to the pathogenesis of disease in subsets of patients.
|
From page 449... ...
. Importantly, many disease susceptibility loci are shared among common auto mmune i and inflammatory diseases, including T1D, Graves' disease, celiac disease, CD, UC, psoriasis, rheumatoid arthritis, alopecia areata, multiple sclerosis, and systemic lupus erythematosus (Cotsapas et al., 2011; Khor et al., 2011)
|
From page 450... ...
These very strong associations with both HLA and this autoantigen gene are not a feature of CD or UC, in which no particular antigen is known to be targeted, hence their classification as inflammatory rather than autoimmune diseases. GWAS point to several other immunologic components of T1D etiology, including IL-2 production and receptor signaling (IL-2 gene, IL-2 receptors IL2RA [CD25]
|
From page 451... ...
Here two disease subtypes are indicated for simplicity, but many such subtypes may exist, and sets of overlapping risk loci may be associated with these multiple mechanistically distinct disease phenotypes.
|
From page 452... ...
Thus, clinical diagnoses are poor phenotypes for genetic studies unless a single mechanism is responsible for the diagnosis, as in the case of a rare gene mutation in a monogenic disease. The complexity of GWAS results is consistent with the existence of multiple disease subtypes within T1D, UC, or CD, each based on a specific mechanism (Figure A19-2)
|
From page 453... ...
The concept that disease diagnoses include mechanism-based disease subtypes has many implications for interpreting human genetic studies and for under standing the relationship between the microbiome and genetic susceptibility, as discussed below. Including disease subtypes within a single diagnosis would decrease the power to define causal alleles and to detect gene-gene interactions that contribute to a single disease subtype.
|
From page 454... ...
One output would be therapeutics based on disease subtype and patient stratification into groups more likely to respond to a given therapy or preventive strategy (A)
|
From page 455... ...
. In the absence of candidate genetic mechanisms for defining disease subtypes, there is limited clinical utility in focusing on low-frequency characteristics or subtypes within a larger diagnostic category that predicts patient outcome.
|
From page 456... ...
. Further, the normal function of the innate immune system, which is critically involved in the pathogenesis of T1D, UC, and CD, is regulated by both chronic viral infections and resident bacterial communities (Barton et al., 2007; White et al., 2010; Virgin et al., 2009; Spor et al., 2011; Kau et al., 2011)
|
From page 457... ...
(A) Two recent studies analyzed the capacity of two different strains of murine norovirus, MNV strain CR6 versus MNV strain CW3, to trigger phenotypes when orally inoculated into mice with a mutation in the Crohn's disease risk gene Atg16L1 (Cadwell et al., 2008, 2010)
|
From page 458... ...
This flowchart depicts stages in the development of normal immune responses or autoimmune and inflammatory diseases at which metagenetic interactions (i.e., gene-gene and gene-microbe interactions) might play a determining role.
|
From page 459... ...
Given the continuous presence of the stimulating antigens for these Tregs in the normal intestinal microbiome, such cells could have profound effects on both intestinal and systemic immune responses, including responses
|
From page 460... ...
However, now this hypothesis needs to expand and include both nonbacterial components of the metagenome and highly specific interactions between individual bacteria or viruses and host genes, which have recently been identified as contributors to disease pathogenesis. The relative contribution of dysbiosis versus the contribution of single organisms within the microbiome to the etiology of complex inflammatory diseases is unresolved.
|
From page 461... ...
Both of these findings underline the critical importance of directly analyzing the contributions of the entire microbiome, rather than individual components, in animal models of diseases. Transmissible Colitis and Host-Gene-Metagenome Interactions Recent studies have made the striking observation that genetically determined colitis is transmissible, revealing a key role for host genes in defining the microbiome and for metagenomic contributions to enteric disease.
|
From page 462... ...
. These data raise the possibility that patterns of viral infection and specific components of the bacterial metagenome act together to influence the penetrance of UC and CD susceptibility risk alleles in humans.
|
From page 463... ...
. These events include susceptibility alleles in HLA class II genes and INS that cause increased autoreactivity against insulin, its precursors, and other islet antigens; lowered IL-2, IL-10, and IL-27 production and signaling; altered T cell receptor signaling and regulation (via, for example, susceptibility alleles in PTPN2, PTPN22, CTLA4, and IL2RA)
|
From page 464... ...
This wealth of data will set the stage for metagenetics, but meaningful and robust analyses of the complex interactions within the metagenome will require new computational tools and new conceptualizations of gene-gene and gene-microbe interactions. Conclusion: The Metagenetics of Mechanism-Based Disease Subtypes Here we have argued that two factors need to be considered as key contributors to the genetics and pathogenesis of complex inflammatory diseases, such as T1D, CD, and UC: specific host-gene-microbial interactions and the mechanistic heterogeneity of phenotypes that constitute complex diseases.
|
From page 465... ...
We, therefore, argue for the inclusion of the metagenome in human genetic studies for these diseases. We view complex diseases as "metagenetic," reflecting the contributions of both host and non-host genes within the metagenome.
|
From page 466... ...
. Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease.
|
From page 467... ...
. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells.
|
From page 468... ...
. Genome-virome interactions: examining the role of common viral infections in complex disease.
|
From page 469... ...
. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis.
|
From page 470... ...
. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.