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Systemic autistic disorders, which are the first stage to autism, result from disturbances in the gut flora, US researchers say. However, it is possible to eradicate autistic disorders with a specially tailored probiotic therapy that scientists are currently working on. In turn, an international research team found that problems in the secretion of a cytokine produced in the lymphatic organs (lymphotoxin) contribute to intestinal disorders.
A team of scientists from the California Institute Technology (Caltech) led by Prof. Sarkis K. Mazmanian dealt with the problem of autism spectrum disorder (ASD). These disorders are characterized by the repetition of often destructive behaviors, communication disorders and a reduction in the possibility of establishing social bonds.
ASD, or mirror neuron disorders
ASD is called the “first stage of autism” and its main symptom is a disorder of social functions. According to an earlier study by a team of scientists from Monash University led by Dr. Peter Enticott, the reason for such behavior may be disturbances in the mirror neurons in the brain. Enticott’s syndrome performed transcranial stimulation of the brain in healthy subjects and in ASD patients. This made it possible to measure the response of mirror neurons to stimuli with millisecond accuracy.
Scientists have found that people with ASD show extinctions of brain activity in response to stimulation of the motor cortex when, for example, they see a hand gesture. In other words, a person with ASD does not activate the mirror neuron system compared to healthy subjects. In the case of people with this condition, decreased activity of mirror neurons may be associated with an increase in social attachment disorders. So this means that disturbances in the mirror neuron system lead to impaired interpersonal communication in ASD.
As the researchers noted, this directly links brain dysfunction with systemic autistic disorders. «We do not have substantial knowledge of the role of the brain in autistic systemic disorders or of proven therapies for this condition. If we get to know the biological basis of the specific symptoms of ASD, it will lead us to the development of therapies specifically aimed at eliminating these symptoms ». Says Dr. Enticott. His team is currently looking for ways to non-invasively stimulate mirror neurons in systemic autistic disorders, which could be at least a partial therapy.
Meanwhile, scientists from Caltech noticed in their research that people with ASD often have digestive system disorders: constipation, intestinal diseases, including irritable bowel syndrome. So far, they have been attributed to neuroses, which are an integral part of autistic systemic disorders, but in other neurotic disorders such symptoms have not occurred; more – they were characteristic of ASD. Meanwhile, studies on the intestinal flora by scientists from the Karolinska Institutet in Sweden have shown that disturbances in the bacterial flora can affect behavior and emotions.
How autistic mice helped people
Due to the impossibility of more precise studies on humans, the entire series of experiments was carried out on a mouse model previously developed in Sweden and at Caltech. “Traditional research procedures have viewed autism as either a genetic disorder or a brain disorder, but these studies have shown that ASD is related to the gut flora. It seems that disturbances in the intestinal flora have effects on the functioning of the brain »- said Prof. Mazmanian.
According to the accepted hypothesis, serious viral infections in women in the first trimesters of pregnancy significantly increase the possibility of having children with autism. The Caltech scientists recreated this effect in mice by using viruses that produced generations of descendants of mice with symptoms of autism. According to the research, all these mice also showed numerous intestinal disorders. Among other things, there were “leakages” in their intestines, ie they were permeable to substances carried with food, which thus got directly into the blood. The same type of disorder has been shown in people with autism. According to Dr. Elaine Hsiao, who works on the team, this is the first evidence of the coexistence of autism with significant intestinal dysfunction. Following this discovery, scientists set out to see if reducing gut disturbance would change the behavior of the mice. To this end, they were administered Bacteroides fragilis, a bacterium used in probiotic therapy in rodents in an intestinal disorder model.
Intestinal permeability dropped significantly to normal levels after administration. Interestingly, the behavior of the mice has changed significantly. They communicated more easily with other mice, their anxiety levels dropped, and they were less likely to engage in repetitive aggressive-anxiety kicking behavior.
“Since B.fragilis treatment reduced intestinal problems in a mouse model and improved the main symptoms of autism, it means that intestinal disorders are linked to symptoms in neurodevelopmental diseases,” says Dr. Hsiao
These findings led the Caltech scientists to set the development of a probiotic therapy that could be used in humans as the next goal of their research. It will reduce the symptoms of ASD and prevent the development of autism. According to scientists, clinical trials of the new drug will begin in about 1-2 years. The therapy could be applied shortly after birth, which would prevent babies from “entering the ASD development path”, according to the researchers. The researchers emphasize that research and a lot of source work are still needed to develop an effective and reliable probiotic therapy for the treatment of human autism. This is because it is still possible in part – the discovery of intestinal disorders as the underlying ASD does not invalidate previous discoveries also concerning the genetic basis of autism. “Autism is multifactorial and the relationship between the genetic and environmental causes of the condition is probably individual for each patient. Even if the therapy with bacteria similar to B. fragilis resolves some of the symptoms associated with autism, I would be surprised if it turned out to be universal – it probably cannot be expected to work the same well in every case »- said Prof. Mazmanian.
Lymphotoxin is the key to treatment
Meanwhile, an international research team led by prof. Sergeia Nedospasova from Deutsches Rheuma-Forschungszentrum Berlin and prof. Mathias Heikenwälder from Helmholtz Zentrum München discovered that disturbances of the intestinal flora, causing such dramatic consequences, also correspond to disturbances of the human immune system. The molecule of intracellular signals – a cytokine called lymphotoxin – is responsible for the immune balance in the intestines. Lymphotoxin regulates the production of immunoglobulin A (IgA), which is found in the mucous membranes, where toxins and pathogens are rendered harmless. Basic alpha lymphotoxin (sLTa3), like membrane bound beta lymphotoxin (LTa1b2), induce IgA production and support the immune system response. They are inflammatory messengers that form immune cells that come into contact with pathogens. If there are too few lymphotoxins, the bacterial flora will change to more pathogenic, which will enable the formation of ASD. According to prof. Heikenwälder, it is very important, because the administration of drugs that stimulate the production of lymphotoxins can reduce ASD disorders and regain balance not only in the intestinal flora, but also in the immune balance.
Tekst: Marek Mejssner