The Gut–Brain Connection

Triggering of Brain Autoimmune Disease by Commensal Gut Bacteria

Hartmut Wekerle

Disclosures

Rheumatology. 2016;55(S2):ii68-ii75. 

In This Article

Abstract and Introduction

Abstract

In a transgenic model of spontaneous experimental autoimmune encephalomyelitis, autoimmune attack against the CNS requires the presence of an intact commensal gut flora. Extending this observation to human autoimmune disease, such as multiple sclerosis, we postulate that the pathogenic reaction requires the coincidence of at least three factors: a permissive genetic disposition, a pro-inflammatory intestinal microbial profile, and the accumulation of autoreactive T cells in the gut-associated lymphatic tissue. This concept may offer new approaches to diagnostic markers and non-invasive therapies.

Introduction

The world we are living in is less clean than we would like it to be. In fact, throughout our existence, we are diving literally through a sea of microbes, some of which seemingly just to wait for an opportunity to invade, decompose and digest our organism. However, this does not happen as evolution has developed a dual strategy. First, our body is sealed by largely impermeable surfaces (skin and mucous membranes) that prevent most outside microorganisms from entering. Second, those few bugs that yet may have made it into our tissues are spotted, pursued and neutralized from inside by our immune system.

Immunology has been termed the science of self/nonself discrimination.[1] Indeed, the immune system's cardinal mission is to distinguish the body's own components (self) from any foreign structure (non-self) intruded into the body. Self-structures must be tolerated, whereas non-self material, which includes infectious agents, must be eliminated. This seemingly clear-cut confrontation is blurred by a third, most powerful player in the field: the universe of our microbiota, the commensal microbes colonizing our body's outer surfaces, as well as the linings of our caves, most importantly the gut.[2] To appreciate their power, it is worthwhile to remember that we carry in our bowels ~100 trillion bacteria, densely packed within the intestinal lumen.[3]

Naturally, the gut microbiota are our welcome partners, vitally involved in helping us digest our diet. But quite unexpectedly, it now turns out that, way beyond this, these microbes profoundly influence the body's functions on a global level. Microbial dialogues with the immune system are indispensable in helping develop and maintain the system's full functionality. However, there is a downside to this partnership: in particular circumstances, our commensals can trigger autoimmune responses. In this article, we specifically discuss the ignition of brain autoimmunity by the seemingly healthy gut flora. We examine whether our experimental observations can be extended to clinical brain autoimmunity, most pertinently to human multiple sclerosis. We also propose that our observations made with brain autoimmune models may be extended further to other organ-specific autoimmune conditions, including RA.

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