The Gut-Brain Axis in Multiple Sclerosis. Is Its Dysfunction a Pathological Trigger or a Consequence of the Disease?

Abstract

A large and expending body of evidence indicates that the gut-brain axis likely plays a crucial role in neurological diseases, including multiple sclerosis (MS). As a whole, the gut-brain axis can be considered as a bi-directional multi-crosstalk pathway that governs the interaction between the gut microbiota and the organism. Perturbation in the commensal microbial population, referred to as dysbiosis, is frequently associated with an increased intestinal permeability, or “leaky gut”, which allows the entrance of exogeneous molecules, in particular bacterial products and metabolites, that can disrupt tissue homeostasis and induce inflammation, promoting both local and systemic immune responses. An altered gut microbiota could therefore have significant repercussions not only on immune responses in the gut but also in distal effector immune sites such as the CNS. Indeed, the dysregulation of this bi-directional communication as a consequence of dysbiosis has been implicated as playing a possible role in the pathogenesis of neurological diseases. In multiple sclerosis (MS), the gut-brain axis is increasingly being considered as playing a crucial role in its pathogenesis, with a major focus on specific gut microbiota alterations associated with the disease. In both MS and its purported murine model, experimental autoimmune encephalomyelitis (EAE), gastrointestinal symptoms and/or an altered gut microbiota have been reported together with increased intestinal permeability. In both EAE and MS, specific components of the microbiota have been shown to modulate both effector and regulatory T-cell responses and therefore disease progression, and EAE experiments with germ-free and specific pathogen-free mice transferred with microbiota associated or not with disease have clearly demonstrated the possible role of the microbiota in disease pathogenesis and/or progression. Here, we review the evidence that can point to two possible consequences of the gut-brain axis dysfunction in MS and EAE: 1. A pro-inflammatory intestinal environment and “leaky” gut induced by dysbiosis could lead to an altered communication with the CNS through the cholinergic afferent fibers, thereby contributing to CNS inflammation and disease pathogenesis; and 2. Neuroinflammation affecting efferent cholinergic transmission could result in intestinal inflammation as disease progresses.

Thinking outside the box: non-canonical targets in multiple sclerosis

“…Endogenous bile acid supplementation is neuroprotective, ameliorates disease severity in an EAE model and is currently being evaluated in a phase 1 clinical trial 158 . Although not within the scope of this Review, there is an evolving understanding of the interaction between the gut microbiome and the pathophysiology of MS; influencing the gut microbiota might be another therapeutic avenue (reviewed elsewhere 160 – 163 ).…”

The Enclosed Intestinal Microbiome: Semiochemical Signals from the Precambrian and Their Disruption by Heavy Metal Pollution

“…Although the exact details remain elusive, a problem with the microbiota-gut-brain axis is reported to be connected to the development of obesity [55]. Needless to say, disruption of the enclosed intestinal microbiome is also associated with immune-system problems, as illustrated by a recent article on multiple sclerosis, asking the question about the causative relationship between immune-system disease on the one hand and a malfunctioning gut-brain axis on the other [56]. The microbiome-function deficiency hypothesis described in the present and previous articles [1] suggests that the two exist in parallel, albeit initiated by microbiome dysfunction during early childhood.…”

Unveiling the gut-brain axis: structural and functional analogies between the gut and the choroid plexus vascular and immune barriers

“…These data suggest that CNS microorganism invasion and immune recruitment could be mediated by the blood-CSF barrier rather than by the BBB [ 141 – 144 ] and that the choroid plexus vascular barrier could play an important role in mediating CNS invasion and inflammation. Thus, several disorders, including the metabolic syndrome and neurological degeneration [ 145 , 146 ], may be related to an impairment of the GVB-PVB axis which could become a new target for treatment and prevention. It will be particularly important to switch the interest from the affected organ to the gut in order to reestablish barrier properties.…”