Background: Alterations in gut microbiota, coupled to increased gut permeability
are now widely recognized as having a role in the etiology, course and treatment of many
medical conditions, including autoimmune and neurodegenerative disorders.
Methods: In this review, the role that such gut changes play over the course of multiple
sclerosis (MS) is detailed.
Results: Given the wide array of biological factors and processes that have been shown to
be altered in MS, including changes in the gut, this allows for a better integration of the
diverse array of pathophysiological processes linked to MS. Such pathophysiological processes
include increases in oxidative and nitrosative stress, pro-inflammatory immune responses,
especially T helper (Th)17 cell proliferation and activation, tryptophan catabolites,
pain, fatigue and increased levels of depression. By raising levels of immune activation,
increased gut permeability and alterations in gut microbiota impact on all of these MS-associated processes. Alterations
in the regulation of local melatonergic pathway activation is proposed to be an important hub for such
pathophysiological processes in MS, allowing for the increased frequency of depression that may be prodromal in
MS, both in the first episode as well as in relapses, to become more intimately associated with the etiology and
course of MS. We propose this occurs by decreasing serotonin availability as a precursor for the melatoninergic
Conclusion: Changes in the gut are evident in the early stages of MS, including in paediatric MS, and may interact
with pro-inflammatory genetic susceptibility genes to drive the biological underpinnings of MS. Such a conceptualization
of the biological underpinnings of MS also has treatment implications.