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MicrobiomeThe human body is colonized by a vast number of microbes and microbial colonies gain many advantages by parasitizing immune cells and altering nuclear receptor activity. Tissue invasion provides a privileged niche with access to host protein and iron, sequestration from immune response, and a means for persistence. [1] Macrophage microbicidal mechanisms are thought to be responsible for the control and elimination of intracellular pathogens; 1,25(OH)2D production and action in macrophages activates toll-like receptors to increase expression of the AMP cathelicidin and kill the infectious invaders. [2, 3] Consequently, when immune defenses are stimulated Th17 cells mobilize host immunity and contribute to the development of harmful chronic inflammatory conditions. [4, 5]

The Human Microbiome project, which is cataloguing all the microorganisms associated with mankind, has revealed that over 90% of the cells in the human body are not human in origin. The millions of genes carried in the human microbiota greatly outnumber the 23,000 genes in the human genome. When host conditions are favorable, non-pathogenic bacteria in the microbiome may become pathogenic using a panoply of tactics to cause interferences within host cells. Intracellular pathogens are described as often entering an unusual biologic state designated "persistence" and in this form have been associated with engendering several chronic diseases. [6-8] Phagocyte-inflicted tissue damage plays an important role in many chronic diseases. [9] In the arms race of host-microbe co-evolution, successful microbial pathogens have evolved innovative strategies to evade host immune responses and persist in intracellular cytoplasm. For example, 'crosstalkmanipulation' (the proactive microbial interference strategies that instigate, subvert or disrupt the molecular signaling crosstalk between receptors of the innate immune system) undermines host defenses and contributes to microbial adaptive fitness. [10, 11]

Pathogenic microbes also induce stress responses which protect the cell from lethal factors, express proteases that degrade AMPs, use biofilms as a shield, modulate host cell motility to facilitate establishment of an infection, and secrete substances that block the VDR. [12-16] Genetic foreign and host protein interactions alter gene transcription and translation mechanisms and many species survive by horizontal gene transfer. [6, 17, 18] Autoimmune patients acquire a distinct pathogenic microbiota and multi-morbidity often results. [19, 20]Intracellular bacteria modulate cytokine production; and in monocytes and macrophages, cytokine activation markedly inhibits 1,25(OH)2D/VDR gene transcription. [21, 22] When the immune system is fighting a persistent microbe, it continually releases inflammatory molecules in an effort to kill the pathogen. [23] This dysfunctional immunological response produces low-grade inflammation which is a component of many chronic and autoimmune diseases.


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3. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. Mar 2006;311(5768):1770-3.
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17. Goodacre R. Metabolomics of a superorganism. J Nutr. Jan 2007;137(1 Suppl):259S-266S.
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21. Wang KX, Chen L. Helicobacter pylori L-form and patients with chronic gastritis. World J Gastroenterol. May 2004;10(9):1306-9.
22. Jones G, Prosser DE, Kaufman M. 25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): Its important role in the degradation of vitamin D. Arch Biochem Biophys. Jul 2012;523(1)(9-18):9-18.
23. Allie N, Alexopoulou L, Quesniaux VJ, et al. Protective role of membrane tumour necrosis factor in the host's resistance to mycobacterial infection. Immunology. Dec 2008;125(4):522-34.

Created June 16, 2014