a Georgetown University b Weill Cornell Medical College c Murdoch University Autoimmune disease in the era of the metagenome Amy D. Proal a , Paul J. Albert b , Trevor G. Marshall c ABSTRACT Studies of autoimmune disease have focused on the characteristics of the identifiable antibodies. But as our knowledge of the genes associated with the disease states expands, we understand that humans must be viewed as superorganisms in which a plethora of bacterial genomes – a metagenome - work in tandem with our own. The NIH has estimated that 90% of the cells in Homo sapiens are microbial and not human in origin. Some of these microbes create metabolites that interfere with the expression of genes associated with autoimmune disease. Thus, we must re-examine how human gene transcription is affected by the plethora of microbial metabolites. We can no longer assume that antibodies generated in autoimmune disease are created solely as autoantibodies to human DNA. Evidence is now emerging that the human microbiota accumulates during a lifetime, and a variety of persistence mechanisms are coming to light. In one model, obstruction of VDR nuclear-receptor-transcription prevents the innate immune system from making key antimicrobials, allowing the microbes to persist. Genes from these microbes must necessarily impact disease progression. Recent efforts to decrease this VDR-perverting microbiota in patients with autoimmune disease have resulted in reversal of autoimmune processes. As the NIH Human Microbiome Project continues to better characterize the human metagenome, new insights into autoimmune pathogenesis are beginning to emerge. This is a preprint of an article published in Autoimmunity Reviews, (C)Copyright 2009 Elsevier ARTICLE INFO This paper is a preprint. For a final copy of the original paper, please access the DOI from the publisher’s website: doi:10.1016/j.autrev.2009.02.016 Keywords: autoimmune disease metagenome vitamin D microbiota vitamin D receptor (VDR) Metabolome Contents 1. Introduction .............................................................................................. 2 2. Human microbiota ......................................................................................... 2 3. A metagenome ............................................................................................ 2 4. Bacteria alter the expression of genes that affect the progression of autoimmune disease ...................................... 2 5. Capnine and the persistence of the metagenome ................................................................... 3 6. Antibodies may be generated in response to microbial DNA ........................................................... 3 7. The human metabolome is a product of its environment .............................................................. 4 8. The microbiota can interfere with transcription and translation ......................................................... 4 9. Discussion ............................................................................................... 4 References ................................................................................................... 5 Take-home messages ........................................................................................... 6