Inflammatory Disease and the Human Microbiome
Authors: Amy D Proal , Paul J Albert, Trevor G Marshall
Institution: Autoimmunity Research Foundation
The human body is a superorganism in which the human genome continually interacts with the millions of microbial genes from the microbiome. Pathogens have now been identified in tissue and blood previously considered sterile. Those capable of persisting inside the nucleated cells can directly alter cellular transcription, translation, and DNA repair mechanisms. Dysregulation of VDR nuclear receptor activity by a number of prominent pathogens can slow innate immune activity to the point where microbiome composition shifts away from a state of homeostasis. Under these conditions, a person may develop an inflammatory disease, the nature of which varies depending upon many factors. These include the location and virulence of the pathogens they acquire and the semi-infinite number of ways in which the proteins and metabolites created by these pathogens can cause dysfunction by dysregulating the body’s metabolic pathways.
The comorbidities so frequently observed among patients with a wide range of both physical and neurological conditions support the possibility that different inflammatory conditions may develop from common underlying mechanisms. Babies begin to harbor a microbiome just weeks after birth, the composition of which reflects the microbiome of their parents and even those of extended relatives. Thus, the familial aggregation characteristic of inflammatory disease may well result when components of the microbiome are inherited.
The theory of autoimmunity was developed at a time when the human body was believed to be largely sterile. However, as the thousands of species within the microbiome are increasingly characterized, it is more likely that the autoantibodies detected in patients with autoimmune disease are generated in response to pathogens rather than “self.”
Immunosuppressive therapies for inflammatory disease may provide short-term relief by slowing the cytokine and chemokine release associated with a healthy immune response towards acquired pathogens. However, pathogens are able to spread with much greater ease over the long term, leading to relapse and instability. Indeed, during the period that immunosuppressive therapies have become the standard of care in the United States, the incidence of nearly every chronic disease has increased. The secosteroid vitamin D has immunosuppressive properties, and should subsequently be evaluated in this context.
It is urgent that we re-evaluate the long-term efficacy of immunosuppressive therapies. In lieu of slowing the innate immune response in patients with inflammatory disease, it seems we should seek to activate it, so that chronic pathogens might be successfully targeted. However, patients on an immunostimulative therapy will inevitably experience immunopathology as toxins and debris generated from microbial death enter the bloodstream. While the resulting symptoms may be difficult to manage, the root cause of the disease is being addressed.
There is a pressing need for researchers to focus on developing tests that might better characterize and measure immunopathology in a clinical setting. Additionally, the current standard of care prioritizes symptom palliation. This means that physicians have few guidelines with which to evaluate the symptom and metabolite fluctuations characteristic of immunopathology. Development of techniques that might help patients better manage the reaction must also become a priority.