Gut’s role in multiple sclerosis
Multiple Sclerosis (MS) is commonly considered an autoimmune disease, depending on an auto-antibody attack against myelin. Though its antigens are unknown, specific biological markers (1) have not yet been identified, as well as pathognomonic symptoms and paraclinical tests that allow for a safe diagnosis (2). Diagnosis is not easy at all, due to the heterogeneity of symptoms: many of them are not typical of multiple sclerosis. (3)
Although axonal damages that were already described in 1865 (5,6) have been reported (4), demyelination is considered MS’s main feature, even if it has been reported as a possible epiphenomenon (7), since it is present in other neurological pathologies, and there is not correlation between symptoms and plaques distribution (8), but above all because plaques have been incidentally found in autopsies of people who had never shown any neurological symptoms (9,10). These evidences led to define an atypical and silent MS, but they are confirming the epiphenomenon aspect, otherwise we can define all the people with plaques and no neurological problems throughout their life, who are suffering from a silent form of one or more neurological pathologies featuring plaques.
On the other hand, dDemyelinating plaques on the other hand are the main features of the experimental model used for MS, the model of autoimmune encephalomyelitis (EAE) (11)., But even if it is controversial to use EAE model as a MS model (12): because there are clinical differences (13, 14) between them, and it is reported as for the lacking of correlation between the progression of plaques and those of symptoms. Moreover few agents have translated from efficacy in EAE to the treatment of human disease, carried out according to the clinical view that “everything stops EAE (Phosphate buffer saline, too), nothing cures MS (15). In factagreement with this, the actual therapies, based on autoimmune components are reported not to be very effective: IFNb can slow down MS conversion in the first 2-3 years’ treatment (16) but after 5 years there have been no gains in disabilities (17, 18), while acetate gladitiramer does not even slow down the disease’s initial steps. (19).
However both of them are ineffective throughout the pathology’s progressive phase (20).
Dr. Paolo Mainardi, Dinogmi Univeristà di Genova and Kolfarma Srl
Meanwhile the incidence of multiple sclerosis is reported to be increasingon the up, and it is the cause of death in two thirds of cases (21, 22). Thisis results from the retrospective studies on hospital-based records, since there is a discrepancy on the disease severity between results of retrospective studies and those reported by clinical studies (23), reporting that MS does not modify life expectancy (24) and it is also easily curable.
Recently, iIt has been proved that one of the characteristics of autoimmune pathologies is an high intestinal permeability that precedes symptoms. An high intestinal pPermeability corresponds to an inflammatory state of intestine. As marker of intestinal permeability, Alessio Fasano had recently proposeds the plasmatic level determination of zonulin as marker of intestinal permeability, since an high level correspond to an high permeability. To confirm the role of intestinal permeability in autoimmune pathologies, he determines zonuline in different pathologies. In MS he reports that 29% of his patients has a double than average level of zonulin. These results are reported by Fasano asand they confirming the autoimmune component in MS, but on the contrary they highlight that the autoimmune component is not frequent in MS. Autoimmune component are reported in several Similarly to what is reported for other neurological pathologies, also those that are considered to be not auto-immune diseases, such as for instance epilepsy, where in 20% of cases, auto-antibodies towards protein complexes involved in the pathology have been discovered.
If it is not autoimmune, what are its causes?
Many symptoms reported in MS, that are not typical of MS, could be linked toare caused by a brain serotonin and melatonin deficit. In 1979 Monaco et al. report in MS patients low plasmatic levels of tryptophan (Trp) (25) an essential amino-acid, brain precursor of serotonin that on its turn is precursor of melatonin. Depending on these plasmatic levels, a poor brain synthesis of serotonin and thus of melatonin (26) is assessable.
Serotonin brain deficit is confirmed by low depressed monoamine catabolite levels of its CSFs catabolites, as well as HVA and 5-HIAA , in MS patients (27, 28). Monoamine theory of depression, that has led to the development of SSRIs drugs, began (PROPRIO) on the basis of identical results reported on depressed patients . Instead depression in MS has been little considered (29), though in MS a high incidence of suicides has been reported (30, 31, 32), showing a high level of depression (33). Not only depression in MS is usually not remarked and treated, although MS patients seem to be more responsive to SSRI drugs than depressed patients. (34).
Low brain levels of serotonin correspond to a scarce melatonin synthesis, in fact low levels of melatonin have been reported in MS patients (35-36). The subsequent melatonin deficit may be responsible for vision problems that are often reported in MS, since this neurotransmitter is widely used in vision processes. Melatonin deficit may also be responsible for sleep and fatigue disorders, that are often reported by MS patients. That is not all: cognitive deficits as well, that are oftenalso reported in MS (39) can be linked connected with melatonin (40, 41) and serotonin (42) deficit ,too.
Recently, a chronic cerebrospinal venous insufficiency (CCSVI) theory as well, that has been recently reported proposed by Zamboni (43) in MS patients and suggested as cause of MS. But, in agreement with the evidence of a serotonin deficit, it could be considered finds an explanation as a possible symptom of MS. In fact,, not a cause, since the name ‘serotonin’ originates precisely from its plasmatic action of control of the tone of blood vessel. A high homocystiniura has been considered responsible for blood vessels’ stenosis (44) and while high levels of homocysteine have been reported in MS (45), confirming the possibility of blood vessels’ stenosis in MS patients .
The highest serotonin and melatonin brain synthesis occurs in the pineal gland (46) that is usually atrophied in MS. (47). Pineal aAtrophy may depend on the lack of chemical substratum, tryptophan ,that makes it inactive, according to the well-known rule: “use it or loose it” (48).
The pineal gland is well known to have shows an high susceptibility to magnetic fields, this explains the clinical results reported in MS through the application of weak pulsed magnetic fields (49, 50) since the weak pulsed magnetic field (µutesla) can interact with it (51). To consider the role of melatonin and serotonin in MS allow us to understand theThis way also SM’s silent phase, hallmark of this pathology is explained, that it. The latter can be hardly explained on the basis of the autoimmune component. I, while it could be due to to an initial self-regeneration capabilityself-capability to regenerate of the atrophied serotinergical serotonergic and melatonergic fibres (52). Then, the silent phase is likely to depends on the capability of the central nervous system to self-repair, thus causing the full disappearance of symptoms in the initial phase. The lacking of this capacity, as well as the non resolution of pathogenic causes, are responsible of the re-apparing of make sure that, when symptoms re-appear, and progressive phase of MS is difficult to be treated.
Moreover melatonin has been recently associated with the brain’s capability of managing inflammatory processes (53) that are linked with and thus withthe brain’s skill to self-repair (54).
A valuable therapeutic strategy consists in keeping the self-repairing endogen systems active, restoring a correct chemical feeding of the pineal gland, that needs tryptophan, simultaneously stimulating it through weak pulsed magnetic fields.
The best way to recover tryptophan’s correct blood levels lies in reducing intestinal dyisbiosis (see dyisbiosis, tryptophan dyisbiosis) that is responsible for its excessive decarboxylation. This can be done through an appropriate prebiotic diet, that by decreasing intestinal inflammation sinflammates gut, reducing its permeability and restore symbiotic intestinal flora.