Microbial Infection and Dysbiosis: All Part of the Same Process

 

by Dr. William Chamberlin

Western culture tends to emphasize the importance of the individual more as an independent entity whereas Asian philosophy stresses the individual’s role as a component within a greater society. Both perspectives are valid; they are just different ways of conceptualizing what one is observing. 

A similar phenomenon occurs with conceptual models of Crohn’s disease. Conceptual models, the official term being “paradigms”, are pre-existing mindsets through which we interpret and give meaning to what we observe around us. Equally logical people viewing data through different paradigms may arrive at differing explanations for what is observed. Since there is only one reality, we must strive to understand what is really important.

Over the past 50 years, the three dominant paradigms through which we think about Crohn’s disease are the following:

• Autoimmune Theory: This theory assumes that that the adaptive arm of the immune network driven by T-cells target self-antigens resulting in chronic inflammation.

• Dysbiosis Theory: The Dysbiosis Hypothesis assumes that observed imbalances of the intestinal microbial ecosystem cause dysregulation of the mucosal immune network resulting in chronic inflammation of the intestinal wall.

• Infectious Disease Theory: The more traditional Infectious Disease model proposes that specific pathogenic bacteria infect cells of dendritic cell/macrophage lineage resulting in dysregulation of the immune network, persistent infection and chronic inflammation. It is the chronic bowel inflammation caused by a pathogenic microbe(s) that causes alterations of the gut microbiota.

Gene mutations identified in the Genome Wide Association Studies predispose to infections and hint at which microbial species may be involved.

It should be noted that the Autoimmune Theory has been largely abandoned by researchers in the field and that the Dysbiosis and Infectious Disease Theories are related in that they both involve interactions of different bacterial species with the immune system. The Dysbiosis Theory implies that the cause (etiology) of Crohn’s disease lies within the altered microbiome. The Infectious Disease Theory implies that the etiology is an infection with a specific pathogenic bacteria and the altered gut microbiome should be considered as part of the pathogenesis of the disease process.

The Dysbiosis Theory emphasizes imbalances of the microbial ecosystem as a whole without implicating a specific microbial species whereas the pathogenic microbe/infectious disease theory places emphasis on a specific microbial species that elicits an ineffectual and damaging inflammatory response resulting in imbalances of the microbial ecosystem.

Complexity Theory, the science of the study of complex adaptive systems, does an admirable job of integrating the two theories. Complexity Science studies complex adaptive systems by studying the inter-relationships of the components of a system and graphing them as nodes with interconnecting lines. Some nodes are more important than others and may have profound effects on the behavior of the system as a whole. Such nodes are termed “major influence agents.”  Clearly, biological systems are complex adaptive systems… and specifically the interacting network of intestinal bacteria interacting with cells and molecules of the host immune network form a complex adaptive system and as such can be described using the insights of Complexity Theory.

In the terminology of Complexity Science, a pathogenic microbe that is described as an etiologic agent in the Infectious Disease paradigm would be a “major influence agent” and its influence throughout the immune network and intestinal microbial ecosystem would be instantly recognized. The secondary ripples of a major influence agent throughout the complex adaptive system would be recognized as the “pathogenesis” of a disease in traditional terms.

Thus, we submit that the Dysbiosis Theory and the Infectious Disease Theory of Crohn’s disease do not differ substantially from one another; the apparent differences are generated by our lack of appropriate terms to fully communicate the dynamic effects of an adapting and continually changing system.  Communicating the effects of introducing a new microbe into the complex network involving the gut microbiome and host immune network is best accomplished by adopting the paradigm and terminology of the science developed to handle such complex adaptive systems…Complexity Science.

We propose employing the paradigm and terminology of Complexity Science to describe the complex relationships involved in microbial interactions with their hosts. Such interactions were traditionally termed commensal, symbiotic, parasitic, benign or pathogenic. Influencing factors such as the presence of other microbes, prior state of the immune system, genetic background, hormonal background etc. can best be contemplated by adopting the paradigm of Complexity Science.

With the above as a clarifying introduction, we present evidence that Mycobacterium avium paratuberculosis (MAP) is a major influence agent that infects dendritic cells and macrophages in predisposed individuals and through its effects on these key cells of the immune network disrupts immune homeostasis. The ensuing chronic inflammatory processes cause imbalances in the intestinal bacterial ecosystem. The process is a dynamic process and restoration of immune homeostasis to its non-inflammatory state is desirable.

MAP is but one component of an unfathomably complex system, but it is a very important one. How important is MAP as a “major influence agent” to the global system of the host and microbiota? The common term is that it is a CAUSAL AGENT. In short, Mycobacterium paratuberculosis is a cause of the Crohn’s disease syndrome.  The observed “dysbiosis” of the enteric microbiota is a result of a MAP infection.

To clarify, traditional terminology defines etiology as a causal agent. The secondary effects of a causal agent observed in a disease process are considered to be part of the pathogenesis of the disease.

Disease models using Complexity Theory would term an etiologic agent as a major influence agent. A major influence agent both influences and is influenced by all the other entities that compose the network in which it exists. The dynamic ripples that occur throughout the complex adaptive system are synonymous with the pathogenesis of a disease process.

This short paper is offered in an attempt to illustrate that the dysbiosis theory and the infectious theory of Crohn’s disease are not mutually exclusive.