Latitude, Vitamin D, Melatonin, and Gut Microbiota Act in Concert to Initiate Multiple Sclerosis: A New Mechanistic Pathway

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). While the etiology of MS is still largely unknown, scientists believe that the interaction of several endogenous and exogenous factors may be involved in this disease. Epidemiologists have seen an increased prevalence of MS in countries at high latitudes, where the sunlight is limited and where the populations have vitamin D deficiency and high melatonin levels. Although the functions and synthesis of vitamin D and melatonin are contrary to each other, both are involved in the immune system. While melatonin synthesis is affected by light, vitamin D deficiency may be involved in melatonin secretion. On the other hand, vitamin D deficiency reduces intestinal calcium absorption leading to gut stasis and subsequently increasing gut permeability. The latter allows gut microbiota to transfer more endotoxins such as lipopolysaccharides (LPS) into the blood. LPS stimulates the production of inflammatory cytokines within the CNS, especially the pineal gland. This review summarizes the current findings on the correlation between latitude, sunlight and vitamin D, and details their effects on intestinal calcium absorption, gut microbiota and neuroinflammatory mediators in MS. We also propose a new mechanistic pathway for the initiation of MS.

Keywords: gut microbiota; latitude; melatonin; multiple sclerosis; sunlight; vitamin D.

Figure 1

Schematic representation correlating various factors such as light, eye, melanopsin, pineal gland, vitamin D, intestinal calcium, and gut microbiota to neuroinflammation and MS. (A) Adequate exposure to sunlight; (1) Long days and adequate exposure to sunlight suppresses the melatonin secretion and (2) leads to activation of melanopsin, generated by RGCs. (3) Activated melanopsin by sunlight sends an inhibitory signal to pineal gland to decreases the melatonin secretion. (Red numbered rectangle). (B) Inadequate exposure to sunlight; (1) Long nights and/or inadequate exposure to sunlight increase the level of melatonin (black arrow), (2) causes melanopsin inactivation and. (3) Promotion in level of inactivated melanopsin by darkness leads to sending a stimulatory signal to pineal gland to cause a further increase in melatonin levels. (4) On the other hand, darkness leads to Vitamin D deficiency. (5) Vitamin D deficiency causes injury to RGCs, (6) reducing melanopsin secretion (dashed black arrow). (7) Vitamin D deficiency also causes disruption in intestinal calcium absorption, which (8) leads to a reduction in smooth muscles of the intestine and subsequently gut stasis. (9) The latter increases gut permeability and LPS translocation toward the CNS. (10) LPS activates CD14/TLR4/MD2 complex which (11) increases the proinflammatory mediators in the brain such as TNF-α. (12) CD14 and TLR4 receptors in the pineal gland respond to LPS by (13) TNF secretion and (14) suppression of melatonin synthesis. (15) Eventually, secreted proinflammatory mediators and activated NF-kB pathway leads to neuroinflammation and possible demyelination at the long term. (Green numbered rectangle).