Maternal Immune Activation and Gut Microbiota in Autism Spectrum Disorder

Maternal immune activation (MIA) is correlated with the development of Autism Spectrum Disorder (ASD). It is also suspected that autism may be a disease involving the gut’s impact on the immune and nervous systems³.

Viral infection in women during pregnancy is correlated with a higher frequency of ASD in their offspring¹. To investigate this correlation, poly (I:C), a synthetic double-stranded RNA (dsRNA), is injected intraperitoneally in rodents to model human MIA^1-4. Studies with this model found that pregnant mice subjected to MIA bear offspring that display behavioral symptoms of ASD^1-4, in conjunction with dysbiosis of commensal microbiota^2-4, alterations in serum metabolites^1-4, and defective gastrointestinal integrity³. Specifically, MIA offspring exhibit increased levels of IL-6^1,3,4 and 4EPS, a commensal microbially modulated metabolite, which is associated with anxiety-like behavior³. In addition, these offspring display abnormal intestinal cytokine profiles such as decreased CLDN8 and increased CLDN15³, which are responsible for gut permeability regulation. Furthermore, MIA offspring have alterations in the diversity of Bacteroides species in their commensal microbiota³. Since cytokines such as IL-6 and certain intestinal microbes can regulate intestinal tight junction expression and intestinal barrier integrity³, an altered level of cytokines and an altered composition of microbes may increase intestinal permeability. This results in leakage of gut-derived metabolites, such as 4EPS, into the bloodstream to affect other cells and organ systems. Treatment of MIA offspring with human commensal B.fragilis corrects intestinal permeability defects, lowers IL-6 levels, alters commensal microbiota, and ameliorates ASD-related behavioral abnormalities³, further supporting the relationship between commensal microbiota composition and behavior^2-4.

Traditionally, offspring’s immune alterations were thought to be driven by only the offspring’s microbiota, but more evidence points to maternal commensal microbiota shaping the immune system of the offspring². When germ-free pregnant female mice are subjected to transient gestational colonization with a genetically engineered Escherichia coli HA107 strain, an increase in the amount of small intestinal innate lymphoid cell 3 (ILC3) in their offspring is observed². Furthermore, maternal colonization alters intestinal transcriptional profiles in their offspring². This includes an increased expression in genes associated with the metabolism of microbial molecules, upregulation of C-lectin Reg family and antibacterial defensins transcripts². These changes are dependent on the transmission of maternal microbial metabolites during pregnancy and during breastfeeding². Antibodies, ILC3 populations, and antibacterial defensins in the offspring shape their innate immunity to take on the massive amount of microbes that will colonize their intestine, and prevent further unnecessary adaptive immune responses², which may harm the offspring. Pups of transiently colonized mothers challenged with Escherichia coli

In summary, the offspring and maternal commensal microbiota composition can shape the populations and diversity of immune cells present in the intestine. If combined with a pro-inflammatory stimulus in the form of maternal immune activation, specific immune cells activate and secrete cytokines in effect. In addition, certain types of intestinal microbes secrete metabolites that may affect behavior. What remains unknown is how cytokines secreted by immune cells in the intestine and metabolites secreted by gut microbiota are able to affect the brain and behavior of an individual. Do cytokines and metabolites act on peripheral immune cells to modulate their responses in the central nervous system or do they directly traverse across the blood-brain barrier to take their effect on neural cells? The integrity of the blood-brain barrier needs to be investigated in maternal immune activation offspring displaying brain and behavioral abnormalities to determine if it is “leaky,” permitting microbial metabolites and cytokines to cross. Another important question is: what types of cells in the brain are affected by the gut in a maternal immune activation model? There have been many studies reporting findings on intestinal immune cells or peripheral immune cells involved in the maternal immune activation model of autism, but research into the types of cells in the brain that are essential for the development of Autism Spectrum Disorder-like behavior in maternal immune activation models is lacking. One could begin to look into the neural cells that may have an IL-17a receptor expression or altered fetal brain development genetic expression profile.

References

1. Choi, G.B. et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science, 351, 933-939 (2016).
2. Gomez de Agüero, M. et al. The maternal microbiota drives early postnatal innate immune development. Science, 351, 1296-1302 (2016).
3. Hsiao, E.Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell, 155, 1451-1463 (2013).
4. Kim, S. et al. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature, 549, 528-532 (2017).
5. Lombardo, M.V. et al. Maternal immune activation dysregulates the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder. Molecular Psychiatry, 23, 1001-1013 (2018).
6. Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature, 523, 337-341 (2015).

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