Environmental susceptibility factors

Epidemiological studies in both Tasmania and Norway have shown that children and adolescents who are physically active outdoors have a lower risk of developing MS in adulthood. Exposure to the sun's UV rays on the skin leads to greater synthesis of vitamin D and higher levels of vitamin D in the blood. There is very little of it in our diet. Numerous studies have shown a correlation between insufficient or even deficient vitamin D levels and an increased risk of developing the disease. Thanks to Scandinavian registers of people with MS, it has also been shown that newborns with low levels of vitamin D had twice the risk of developing MS in adulthood compared with those with normal levels. Similarly, a Finnish study of a maternal cohort showed that a vitamin D deficiency during the first quarter of pregnancy resulted in a doubling of the relative risk of children developing MS in adulthood compared to pregnant women who were not deficient. The practical conclusion is therefore that vitamin D insufficiency or deficiency should be avoided in all pregnant women and in the children of MS patients.

French studies have compared the prevalence of the disease with average solar irradiation in different regions of France. The disease is more prevalent in the north and east of France (100 to 120 patients/100,000 inhabitants) than on the Atlantic coast or around the Mediterranean (50/100,000). This prevalence is significantly correlated with the average vitamin D levels in the inhabitants of these regions and with the average solar irradiation and sunshine levels recorded by meteorological statistics.

The role of sunlight and, secondarily, vitamin D levels may therefore partly explain the North-South gradient in the prevalence of the disease observed in the northern hemisphere and the South-North gradient observed in the southern hemisphere.

Vitamin D has many functions, not just an important role in calcium metabolism. It also plays an immunoregulatory role, as demonstrated in experimental autoimmune encephalitis. The question of whether people already suffering from MS should be given vitamin D supplements remains open, but the precautionary principle would dictate that at the very least, MS patients should not be vitamin D deficient.

Active smoking in adolescents and young adults is a risk factor for developing MS, and the risk is multiplied by a factor of 1.4 to 2.0 depending on the study. The longer you smoke and the more cigarettes you smoke per day, the greater the risk. Passive smoking is also a risk factor of around 1.3. A Swedish study using the national register of MS patients showed an over-representation of smokers among MS patients compared with the control group (20%). This over-representation rises to 40% in HLA-DRB1*15 positive patients who do not have the HLA-A*02 protective gene. This demonstrates the interaction between genetic and environmental factors. Combating smoking among young people is an important factor in preventing the disease.

In MS patients who continue to smoke, a second attack has been shown to occur more quickly after a first episode than in non-smokers, the total number of lesions on MRI is higher on average, and that the transition to the secondary-progressive form occurs around 10 years earlier than in non-smokers. Quitting smoking at the time of diagnosis is therefore the first "neuroprotective" treatment in MS.

Certain infections can trigger symptoms similar to those of MS. A neurotropic virus or parasite can infect the brain directly: this is primary encephalitis, for example caused by the herpes virus or by Borrelia in Lyme disease. In very rare cases, symptoms appear without the infectious agent being present in the brain because the immune system reacts abnormally to an infection causing an autoimmune disease in which the body destroys its own tissues. It is always a single episode that can occur at any age ("post-infectious acute demyelinating encephalomyelitis"). 

The fever that accompanies an infectious disease can cause an increase in pre-existing disorders in a person with MS. By definition, this is not a relapse, but the worsening of a nerve conduction block in the demyelinated plaques. However, the risk of a relapse is 3 to 5 times greater in an MS patient with a viral infection, particularly of the upper respiratory tract, in the 6 to 8 weeks surrounding the infectious episode. This observation is interpreted by the fact that the entire immune system is reactivated by the infectious agent, and in particular its autoimmune fraction.

Most vaccines pose no risk to MS patients. They may be slightly less effective in patients taking certain immunomodulatory treatments (Gilenya, Ocrevus, Kesimpta, Lemtrada...). The only exceptions are vaccines based on live attenuated viruses, in particular against yellow fever: these can cause outbreaks of the disease and cannot be administered during the treatments mentioned above.

Organic solvents are liquid products used to dissolve solid materials. They are present in paints, varnishes, dry-cleaning products, adhesives and cosmetics. They can be inhaled or absorbed by skin contact. Chronic exposure to these products could increase the risk of developing MS by a factor of 1.5. However, a recent study showed that the risk was much greater when there was simultaneously exposure to these organic solvents, smoking, the presence of the HLA -DRB1*15 susceptibility gene and the absence of the HLA-A*02 resistance gene. This 'cocktail' increased the risk of developing MS by a factor of 30 in a Swedish study. A recent meta-analysis confirmed this slight association (risk increased by a factor of 1.44), aggravated by smoking and the same genetic markers.

The role played by stress and trauma has generally not been demonstrated. It is in fact difficult to assess their influence, since stress is an integral part of every individual's life. A physical trauma could be the cause of a relapse only if there is a very close relationship in time and space (for example, trauma to the spinal column and a spinal cord relapse at the same level within a few days).

Being overweight is an additional risk factor for developing MS in adolescents. However, these people have less outdoor physical activity, lower levels of vitamin D, and possibly smoke... all of which add up to lifestyle risk factors. The role of the microbiota (all the microbes that colonise the intestines) in excess weight is well established, and the study of the microbiota in MS is a subject of intensive research.

The intestinal microbiota, formerly known as the intestinal flora, is the group of micro-organisms present in the human digestive tract. Each person has his or her own microbiota (fairly stable in healthy individuals) with a core common to all human beings and multiple associated varieties. These micro-organisms are divided into 3 main categories: archaea, bacteria and microscopic fungi. Bacteria alone account for 95% of the microbiota. There are several hundreds of species, if not thousands, but around a hundred seem to be common to all human beings. They are divided into 5 categories: the Firmicutes (over 200 strains including Clostridium and Lactobacillus), Bacteroides, Actinobacteria (including strains of Bifidobacterium), the Proteobacteria (including the well-known Escherichia coli) and the Verrucomicrobes, (including the strain Akkermansia muciniphila).

The stomach and oesophagus are relatively sterile because of their acidic pH. The duodenum, jejunum, ileum and especially the colon at the end contain more and more bacteria: 1 g of faeces contains 10 to 100 billion live or dead bacteria. The total weight of the bacteria in the intestinal microbiota is thought to amount to 1 kg (!) and the total number of intestinal bacteria to 40,000 billion, a number similar to that of all the cells in a human body! Not all of these bacteria are yet known and they are very difficult to grow in the laboratory. They are mainly detected by genetic analysis of all the DNA or RNA present in the stools (the microbiome). There are other human microbiota, but they are far less 'rich': the skin microbiota (all the micro-organisms living on our skin), the microbiota of the upper respiratory tract (oral, nasal, sinus and pharynx cavities), the urinary microbiota (urinary tract and bladder), etc.

The role of the intestinal microbiota is irreplaceable. They enable the digestion of dietary fibres and complex sugars (polysaccharides) that human cells cannot do because they lack the necessary enzymes. The microbiota also produce essential amino acids, vitamins and short-chain fatty acids, and influences fat storage.

A change in the composition of the bacterial populations in the intestine is known as dysbiosis. Altered microbiota may be associated with diseases such as type II diabetes or obesity. They could also be associated with chronic inflammatory bowel disease, the development of allergies or colorectal cancer.

The intestinal microbiota are in constant interaction with the immune system, as around 100 billion lymphocytes are located in the intestinal wall throughout the digestive tract (i.e. around a quarter of our immune system!). The digestive tract is a sea of "foreign bodies" for the human body, made up of food, its breakdown products and the microbiota. Immune monitoring of the intestinal tract is therefore of the utmost importance. We know, for example, that certain filamentous bacteria activate T17 lymphocytes, which are pro-inflammatory and potentially autoimmune, while strains of Bacteroides fragilis and Clostridium provoke the differentiation of regulatory T lymphocytes, which are anti-inflammatory.

In MS, many studies on the microbiota have already been carried out, with sometimes divergent results. Overall, however, the consensus is that microbial species belonging to the class of Firmicutes and Bacteroides are decreased, while those of Akkermansia and Streptococcus are increased. There is also a reduction in the microbiota producing short-chain fatty acids in MS, so a relative lack of these could play a role in triggering the disease. But we are still at the exploratory study stage. To give just one example, let's cite a study by the Melsbroeck Centre published in 2023: in 95 patients followed for an average of 4.4 years, 39 had worsened and 43.6% of them had stools positive for Bacteroides 2 at the start of the studies; 56 had remained stable and only 16% were carriers of this bacterium. So the presence of Bacteroides 2 is statistically linked to a poorer prognosis....

It is therefore via the immune system that the intestinal microbiota can play a role in co-triggering or aggravating MS (just like smoking...). The hope is to discover one or more intestinal bacteria that are particularly harmful in MS patients in order to detect them for prognostic purposes at an individual level, and to eliminate them from the microbiota by dietary or medicinal means. For the time being, you should stick to general dietary advice and a balanced diet, and if necessary continue your immunomodulator treatment.

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