Muscular atrophic lateral sclerosis, abbreviated as ALS in English, is a frightening disease. As the motor neurons that control the muscles gradually die, the patient will slowly lose control of the muscles, accompanied by muscle atrophy. As the disease progresses, the patient will be trapped in a wheelchair, completely lose the ability to take care of themselves, and eventually die because of the loss of the ability to breathe independently. After the patient is sick, it is like being slowly frozen, so ALS patients are also called “gradually frozen people.”
The most famous ALS patient is Stephen Hawking, a British theoretical physicist. Hawking’s disease progressed relatively slowly, so he continued to live for several decades after his onset, and made important physics discoveries during this period. Another well-known “Frozen Man” is the German Marshal Borus, who commanded the Nazi German army to attack Stalingrad during the Second World War, but failed and was captured. After being released back to East Germany in 1953, Borus served as the director of the East German Institute of Military History. In 1956, he suffered from ALS, and his condition deteriorated rapidly, and he died in early 1957.
The very different fate of mutant mice
The reason why people get ALS is unclear. Studies have found that mutations in some genes increase the probability of ALS. Among them, an important disease-causing gene is named C9ORF72. At present, the mainstream view in the scientific community is that the C9ORF72 gene may be related to the normal immune response. Therefore, the mutation of this gene may cause the body to produce some excessive inflammatory response, thereby damaging the nervous system. Some studies have confirmed that ALS patients with mutations in the C9ORF72 gene are more likely to have autoimmune diseases.
However, scientists still face a very important problem-C9ORF72 gene mutation does not 100% cause disease. For example, in mice that knock out the gene, some will develop severe inflammation and cause death, while others are very normal. These conflicting results are documented in many scientific literature.
What is the reason for this? A more reasonable explanation is that the environment has an important influence on this disease. Recently, a study published in the journal “Nature” better explained the impact of environmental factors on neurodegenerative diseases. The researchers compared two groups of C9ORF72 knockout mice raised at Harvard University and the Broad Institute. It was found that the life span of mice raised by Harvard University was significantly shorter than that of wild-type mice (i.e. mice with normal C9ORF72 gene). At the same time, these mice were also accompanied by abnormal exercise capacity, indicating that mutations in this gene would indeed Cause nerve damage. However, unlike the situation at Harvard University, the C9ORF72 knockout mice of the Broad Institute have little difference in lifespan and exercise capacity from those of wild-type mice. Not only that, scientists found that compared with wild-type mice, the level of inflammation in Harvard University mice was significantly increased, indicating that after the loss of the function of the C9ORF72 gene, the immune system of the mice was abnormal. However, the level of inflammation in the Broad Institute mice was not much different from that of wild-type mice. So, why do mice behave differently if the same gene is knocked out, just in different feeding locations?
Changing the intestinal flora can cure the patient
Because the intestinal flora has a very important impact on the immune system of animals, researchers hypothesized that the two groups of mice may have different intestinal flora due to different feeding environments. Studies have shown that there are indeed differences in the composition of the intestinal flora of mice bred in the two scientific research institutions. For example, there are more bacteria of the genus Spirochetes in the intestines of mice at Harvard University. Such bacteria often have the effect of promoting inflammation. The most surprising thing is that if the mice of Harvard University are treated with a lifelong broad-spectrum antibiotic, all the symptoms related to the C9ORF72 gene defect (such as shortened lifespan, inflammation, abnormal movement, etc.) will disappear. That is, only by taking broad-spectrum antibiotics, a serious neurodegenerative disease caused by this gene in mice can be “cured”. A similar “treatment” effect can also be achieved by fecal bacteria transplantation, that is, transplanting bacteria from the feces of mice from the Broad Institute into mice at Harvard University.
The above research illustrates a possibility that the activity of intestinal flora may affect the progression of neurodegenerative diseases. Some people may have a certain genetic risk (such as C9ORF72 gene defect), but genetic risk factors alone are not enough to develop the disease. In this case, as an important environmental factor, the intestinal flora plays an important role in neurodegenerative diseases. At present, scientists in this area have found that in addition to ALS, Parkinson’s disease and Alzheimer’s disease may have a certain relationship with the intestinal flora.
Gut and Parkinson’s disease
In terms of the relationship between intestinal flora and neurodegenerative diseases, Parkinson’s disease is currently more thoroughly studied. Parkinson’s disease is a type of degenerative disease that involves the substantia nigra and striatum of the brain, and produces symptoms such as tremor, muscle rigidity, and decreased movement. Among the elderly over 65, the incidence of Parkinson’s disease can reach 1.7%. The cause of most Parkinson’s disease patients is difficult to confirm, and may be related to factors such as genetics, environment, aging, and oxidative stress. Among them, the accumulation of α-synuclein (α-Syn, a protein for short) caused by protein misfolding is considered to be related to the pathogenesis of Parkinson’s disease.
At present, studies have found that the intestinal tract has a very direct relationship with Parkinson’s disease. First of all, many Parkinson’s disease patients have intestinal symptoms (such as constipation) before neurological symptoms, and the accumulation of α-Syn is often the first to be found in the enteric nervous system and the vagus nerve. The vagus nerve is the main neuron that establishes the connection between the brain and the intestine. Therefore, scientists put forward the “intestinal origin hypothesis” of Parkinson’s disease.
This hypothesis is that a certain inflammatory response in the intestine can lead to the initial Parkinson’s disease (such as the formation of α-Syn accumulation), and then the disease will gradually spread along the vagus nerve to the brain, and when it finally spreads to the substantia nigra or striatum After the body, the typical symptoms of Parkinson’s disease will appear.
As evidence to support this hypothesis, the researchers found that the intestinal flora of Parkinson’s disease patients is quite different from that of normal people. For example, they have more bacteria in the Enterobacteriaceae family in their intestines. In some cases, the increase of Enterobacteriaceae is positively correlated with the severity of Parkinson’s disease, that is, the more bacteria, the more serious the disease. In addition, members of the Enterobacteriaceae family are also associated with intestinal inflammation, especially Crohn’s disease. Crohn’s disease patients also have a higher risk of Parkinson’s disease.
Further evidence comes from animal experiments. Scientists use a certain type of mice that can produce Parkinson’s disease symptoms as experimental materials. They found that if these mice are artificially made to produce intestinal infections, their Parkinson’s disease symptoms will be more severe. In turn, the use of antibiotics to eliminate the intestinal flora of these mice can alleviate the symptoms of Parkinson’s disease in mice. This result is actually very similar to the aforementioned antibiotic treatment of ALS symptoms.
Therefore, current scientific research has proved that the inflammatory response caused by the intestinal flora may increase the risk of people suffering from neurodegenerative diseases. This is even more obvious in some people who have genetic risks themselves. So, can antibiotic treatment or fecal bacteria transplantation be used to reduce the risk of developing neurodegenerative diseases? Animal experiments show that this idea is worth trying.
However, we need to be aware that because the physiological structure of mice is quite different from that of humans, the results obtained from animal experiments cannot be automatically extended to humans. Therefore, although this idea is feasible, there is still a long way to go to develop an effective method that can treat neurodegenerative diseases by intervening in the intestinal flora.
