Systemic autistic disorder, which is the first step to autism, is due to disorders in the gut flora, say US researchers. However, it is possible to eradicate autistic disorders with a specially tailored probiotic therapy, which researchers are currently working on. An international research team, on the other hand, discovered that problems in the secretion of a cytokine produced in the lymphoid organs (lymphotoxin) contribute to intestinal disorders.
A team of researchers from the California Institute Technology (Caltech) led by Professor Sarkis K. Mazmanian addressed the problem of systemic autism spectrum disorder (ASD). These disorders are characterised by repetitive behaviours that are often destructive, impaired communication and reduced ability to form social bonds.
ASD, or mirror neuron disorder
ASD is referred to as ‘first-degree autism’, and its main symptom is precisely the impairment of social functions. According to an earlier study by a team of researchers from Monash University, led by Dr Peter Enticott, the reason for such behaviour could be a disorder of mirror neurons in the brain. Enticott’s team performed transcranial brain stimulation in healthy individuals and in ASD patients. This allowed them to measure the response of mirror neurons to stimuli with millisecond accuracy.
The researchers found that people with ASD show extinctions of brain activity in response to motor cortex stimulation when they see a hand gesture, for example. In other words, there is no activation of the mirror neuron system in a person with ASD, compared to the healthy subjects studied. In the case of people with this condition, the reduced activity of mirror neurons can be linked to an increase in social bonding disorders. This means, therefore, that disturbances in the mirror neuron system lead to impaired interpersonal communication in ASD.
This directly links brain dysfunction to systemic autistic disorders, the researchers noted. “We do not have significant knowledge about the role of the brain in systemic autistic disorders or validated therapies for this condition. If we learn more about the biological basis of the specific symptoms of ASD, this will lead us to the development of therapies specifically directed at eradicating these symptoms,” – states Dr Enticott. His team is currently looking for ways to non-invasively stimulate mirror neurons in systemic autistic disorder, which could provide at least a partial therapy.
Meanwhile, Caltech researchers noted in their study that people with ASD often have disorders of the digestive system: constipation, intestinal disorders headed by irritable bowel syndrome. Until now, these were attributed to neuroses, which are an integral part of systemic autistic disorders, but in other neurotic disorders such symptoms were not present; moreover, they were specific to ASD. Meanwhile, research on the gut flora by scientists at Karolinska Institutet in Sweden, has shown that disruption of the gut flora can affect behaviour and emotions.
How mice with autism helped humans
Due to the impossibility of more thorough human studies, the entire series of experiments was conducted on a mouse model previously developed in Sweden and at Caltech. “Traditional research procedures have seen autism as a genetic disorder or a brain disorder, meanwhile this research has shown that ASD is linked to the gut flora. Disorders in the gut flora appear to have effects on brain function,” said Prof Mazmanian.
According to the accepted hypothesis, severe viral infections in women during the first trimesters of pregnancy, significantly increase the possibility of children being born with autism. Caltech scientists replicated this effect in mice in the laboratory using viruses that produced generations of offspring mice with autism symptoms. According to the study, all of these mice exhibited multiple intestinal disorders at the same time. Among other things, there were ‘leaks’ in their intestines, i.e. they were permeable to substances carried with food, which thus entered directly into the blood. Abnormalities of the same type have been shown in people with autism. According to Dr Elaine Hsiao, who worked in the team, this is the first evidence of the coexistence of autism with a significant intestinal dysfunction. Following this discovery, the researchers decided to test whether a reduction in intestinal dysfunction would bring about a change in the behaviour of the mice. To do so, they administered Bacteroides fragilis, a bacterium used in probiotic therapy in rodents in a model of intestinal disorders.
After administration, intestinal permeability dropped significantly, to normal levels. Interestingly, the behaviour of the mice changed significantly. They communicated more easily with other mice, their anxiety levels dropped and they engaged in repetitive aggressive-anxiety digging behaviour less frequently.
“Since B.fragilis therapy reduced intestinal problems in the mouse model and resulted in improvements in the main symptoms of autism, this means that intestinal disorders are linked to symptoms in neurodevelopmental diseases,” – states Dr Hsiao
These findings have led the Caltech researchers to set as their next research goal the development of a probiotic therapy that could be applied to humans. It would reduce the symptoms of ASD and prevent the development of autism. According to the researchers, clinical trials of the new drug will begin in about one to two years. The therapy could be applied immediately after birth, which would prevent infants from “entering the developmental pathway of ASD”, according to the researchers. The researchers emphasise 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 underlying ASD does not invalidate previous discoveries about the genetic basis of autism as well. “Autism has a multifactorial basis and the relationship between genetic and environmental causes of the disorder is likely to be individual for each patient. Even if B. fragilis-like bacteria therapy abolishes some of the symptoms associated with autism, I would be surprised if it proves to be universal – it probably cannot be expected to work equally well in every case,” Prof Mazmanian said.
Lymphotoxin key to treatment
Meanwhile, an international research team led by Prof. Sergei Nedospasov of the Deutsches Rheuma-Forschungszentrum Berlin and Prof. Mathias Heikenwälder of the Helmholtz Zentrum München has discovered that disorders of the bacterial flora in the gut, which cause such dramatic effects, are also responsible for disorders of the human immune system. This is because an intracellular signalling molecule, a cytokine called lymphotoxin, is responsible for the immune balance in the gut. Lymphotoxin regulates the production of immunoglobulin A (IgA), which is found in the mucous membranes where toxins and pathogens are inactivated. The basic lymphotoxin alpha (sLTa3), as well as the membrane-bound lymphotoxin beta (LTa1b2), induce IgA production and promote the immune system response. This is because they are inflammatory messengers that form immune cells that come into contact with pathogens. If there are too few lymphotoxins then the bacterial flora will change to a more pathogenic flora, allowing ASD to form. According to Prof. Heikenwälder, this is very important, because the administration of drugs that stimulate the production of lymphotoxins can mean a reduction in ASD and, at the same time, a restoration of balance not only in the intestinal flora, but also in the immune balance.
Source
- https://www.medonet.pl/zdrowie/diety,autyzm-moze-miec-poczatek-w-jelitach,artykul,1694220.html
