Paper - Autoimmune disease in the era of the metagenome

Type: Paper
Authors: Amy D. Proal, Paul J. Albert, Trevor Marshall PhD
Publication: Autoimmunity reviews
Citation: Proal AD, Albert PJ, Marshall T. Autoimmune disease in the era of the metagenome. Autoimmun Rev. 2009 Jul;8(8):677-81. doi: 10.1016/j.autrev.2009.02.016. Epub 2009 Feb 13.
[PMID: 19393196] [DOI: 10.1016/j.autrev.2009.02.016]

See also: Preprint (full text)
Notes: Paper based on presentation given at 6th International Congress on Autoimmunity, Porto, Portugal, September 2008

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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 microbiotaThe bacterial community in the human body. Many species in the microbiota contribute to the development of chronic disease. 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 microbiotaThe bacterial community which causes chronic diseases - one which almost certainly includes multiple species and bacterial forms. 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.

Appraisal by Faculty of 1000 Medicine

Dr. Steven Witkin writing in the prestigious literary awareness tool, Faculty of 1000 rated the Proal et al. paper a “must read,” saying in part:

The clear message of this article is that molecular genetic studies of diseases must include analysis of resident bacterial genomes and not focus solely on the human genome. The observations presented in this review are thought-provoking and offer new ways of thinking about the origin of diseases and possible novel treatments.

The essence of this eye-opening article is that 90% of the cells in the human body are bacterial, that bacterial genomes are expressed in humans and that they have profound positive or negative influences on health. Compelling evidence is presented that humans are “superorganisms” whose molecular functions result from the sum of interactions between the human genome and a multitude of microbial genomes. The advantages of bacterial colonization and its profound influence on the diversity of the human metagenome are emphasized. The human genome is composed of about 30,000 genes, while the endogenous microbial flora contribute millions of genes. In addition, transcription of the human genome is altered by the presence or absence of bacterial products. Differences in bacterial colonization account for individual variations in gene expression. Lastly, the potential pivotal role of endogenous microbial genomes on the induction and persistence of autoimmune disease is emphasized.

Dr. Steven Witkin, Weill Cornell Medical College

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