TWO ARTICLES ESTABLISH THE LINK BETWEEN IN UTERO DEVELOPMENT, INFLAMMATION, MICROBIOTA AND AUTISM

Since the classical work of the late Paul Patterson, it is known that the activation of the immune system during the intrauterine period produces an autistic syndrome by activating the immune system and causing the release of inflammatory molecules such as interleukins which will impact the cerebral maturation. It is also known that in rodents as in non-human primates, there are cortical malformations suggesting migratory disorders – which are incidentally the cause of many forms of infantile epilepsy. These malformations, which have also been observed in autistic patients, are visibly the cause of the syndrome. Their extent indicates that there is a deficiency of cellular proliferation during the intrauterine period and that these patches of aberrant cells play an important role in the manifestations of autism. Nevertheless, the link between these displaced neurons and the functioning of neural networks and behavior has remained a correlative rather than a compeling type. Two recent studies on mice, from a same group and published by Nature, provide direct and compeling data on the following points.

i) during pregnancy (and not after), an inflammation produced by the early activation of the immune system – which mimics an important infection during pregnancy (second trimester) – will create deleterious effects on new-borns by mimicking an autistic behaviour. This inflammation is mediated by the activation of inflammatory molecules, identified here as 17a Interleukin.

ii) this inflammation and the formation of displaced cells aggregates also requires the infection of macrobiotic system cells – this is the convergence of actions at the intestinal and central level that will cause the autistic syndromes. Antibiotics or other manipulations that prevent the inflammatory bacterial process in utero also reduce the autistic syndrome. It should be emphasized that this only concerns the pregnancy period and a specific period during labor, it cannot be inferred that antibiotics have a beneficial effect later on.

iii) cell clusters in some regions of the cortex, identified here for the first time in a direct and compeling manner, play a role in the deleterious manifestations because the activation of these regions produces the syndrome and inhibition of these regions activity inhibits it. In other words, these aberrant networks formed in utero due to the inflammation persist in adults and are the cause of the syndrome.

To summerize, this is the demonstration of a quadruple connexion between microbiota, cortex, pregnancy and pathogenesis of autism. We will not understand and therefore we will not treat autism without understanding how the malformations are induced in utero. This work is strongly in line with works that suggest, in accordance with the concept of Neuroarchaeology that I proposed, that many diseases and notably autism are born in utero. The initial causes of the pathology, whether genetic or environmental, produce their deleterious sequelae by modifying the brain building process by forming aberrant networks that prevent the functioning of the neuronal sets which are essential for integration and communication. It is these malformations that must be treated and not the initial cause (the mutation) because the diagnostic takes place a long time after the pregnancy and the discovery of new genetic mutations will not change this situation. It is essential to be more invested in the understanding of the maturative phenomenon and the reason of its deviation because of pathogenic events. Although these articles have no immediate clinical implications, because of the impossibility of early diagnosis of autism (a fortiori in utero), they are part of the development of treatments that selectively block these aberrant activities. This is what we are doing with the phase 3 of a large clinical approved by the European authorities based on the selective blockage of activities produced by aberrant neuronal networks. We hope that these articles, as well as many others, will contribute to a greater involvement in the physiology and pathophysiology of brain development.

Kim et al. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring ; Nature, september 2017, in press

Yim et al. Reversing behavioural abnormalities in mice exposed to maternal inflammation, Nature, september 2017, in press

 

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