I got it from my Mama: Maternal factors regulating a child’s neurodevelopmental disorders

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Just like humans, the life of most other animals is highly influenced by what the embryo experiences while in the mother’s womb, during birth, or by conditions following their birth. Neurodevelopmental, inflammatory, and metabolic defects in the offspring may stem from adverse conditions endured by the pregnant mother. These conditions might fare from feeding on high-fat food to falling sick during the period of pregnancy.

More precisely, scientists establish a potential connection between viral infections in pregnant females and the fact that the offspring born end up suffering from autism and behavioral defects. Not only are those offsprings afflicted with neurodevelopmental issues, but also an unruly bunch of immune dysfunctions such as excessive amounts of inflammation including an exacerbated version of colitis. Despite years of research, the association between neurological and inflammatory ailments and how they manifest are still a mystery.
To demonstrate the occurrence of these “immune dysfunctions” and other co-morbidities in offsprings from an infected mother, scientists used mice as test subjects. They induced bacterial colitis in a pregnant mouse after injecting them with poly I:C (polyinosinic: polycytidylic acid) – a chemical capable of mimicking a viral infection. How can a chemical mimic a virus you ask? The reason is that poly I:C is a “synthetic” analog of double-stranded RNA which occurs in many viruses as genetic material or as a replication intermediate. Once inside the system, it acts as a potential red flag, activating immune receptors called TLR 3 (Toll-like receptor 3) which then kicks off an inflammatory immune response. This process is called MIA (Maternal Immune Activation) as the immune system of the mother is being deliberately activated. In fact, they noticed something interesting after this. They saw a trend where, predominantly, the male pups of these MIA mothers suffered from behavioral defects. When challenged with a bacterial infection, these MIA-pups rapidly released inflammatory signals, whereas the non-MIA-pups had normal immunity. Hence, one can deduce that these heightened immune responses in the mother are somehow affecting the neurodevelopment of the offspring and making them more susceptible to inflammation.
While the threads of the behavioral abnormalities were manifested during the prenatal state of the offspring, scientists were able to show that the immune dysfunctions on the flip side were being determined postnatally. They proved this by performing a special type of experiment called cross-fostering where the offsprings were switched between MIA and non-MIA mothers. When MIA-pups were being raised by non-MIA mothers, they did suffer from behavioral defects, but surprisingly there were no traces of a dysfunctional immune system in them. On the other hand, non-MIA-pups, who shouldn’t have suffered from defects in behavior, showed symptoms of a dysregulated immune system when they were being fostered by MIA mothers. Hence, establishing a foothold for the fact that behavior in the offsprings was being molded before birth while the postnatal factors shaped the messed up immune system.

Scientists were also able to show that the key player in this game was a certain subset of helper T cells called Th17. These cells were being primed by the mother’s immune system on a chromosomal level via epigenetic changes (thanks to the viral infection during pregnancy). These changes make those Th17 cells push the accelerator on releasing the notorious inflammatory IL17a (interleukin 17a). IL17a then traveled into the developing body of the fetus on a fine but unmonitored passage via the placenta and wreaked havoc in its nervous system. Meanwhile, the regulatory T cells that downregulate the immune system and prevent it from overdoing things were muffled in this passage. Interestingly, the authors also found out that IL17a induces susceptibility to inflammation in MIA-pups via dysregulating the pregnant mother’s gut microbiome and causing subsequent changes in chromatin accessibility in the pup’s T helper cells. These days the secret of every disorder is hidden within our microbiome! It’s the consequences of the interplay of these factors that can be seen in the offspring as intestinal inflammation in ASDs (autism spectrum disorders) and other related defects after birth.

The biggest takeaway from the whole story is that both Th17 cell and IL17a (so far) are the major players running the behavioral-immune-priming show here. A clear-cut solution here seems like hunting for a possibility to regulate both and bringing them back to homeostasis. But it might not be that simple. The Gut Microbiome-Immune circuitry is a very complex machinery and over several years of research scientists have slowly mapped out this intricate chess board, some of the pieces on it, and how exactly they move. But the more we learn, the more questions arise and the more arduous it becomes to devise a treatment without creating a domino effect of other problems. But regardless of that, the deeper we get into this rabbit hole, the closer we get to understanding the origin of autism and its comorbidities, and possibly even a cure for these ailments.

Source:

Kim E, Paik D, Ramirez RN, Biggs DG, Park Y, Kwon HK, Choi GB, Huh JR. Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4+ T cells. Immunity. 2022 Jan 11;55(1):145-158.e7. doi: 10.1016/j.immuni.2021.11.005.

Article author: Lalit Anand. Lalit is a Biotechnology major at the Vellore Institute of Technology. He loves reading about the immune system and its peculiar interactions with other bodily systems.

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