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 MIA1-4. Studies with this model found that pregnant mice subjected to MIA bear offspring that display behavioral symptoms of ASD1-4, in conjunction with dysbiosis of commensal microbiota2-4, alterations in serum metabolites1-4, and defective gastrointestinal integrity3. Specifically, MIA offspring exhibit increased levels of IL-61,3,4 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 behavior2-4.

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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 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 HA107 strain show prevention of the translocation of that bacterial strain to the mesenteric lymph node2. Molecular products of both the offspring and maternal microbiota affect the immune responses of the offspring, correlating with ASD-like behaviors.

MIA induction leads to delayed expression of markers important for cortical development1, as well as dysregulation of genes that regulate fetal brain development processes such as axon guidance, growth and differentiation5 in the offspring. Another cytokine, IL-17a, is elevated in the serum of some autistic children, and the same increase is seen in the serum of MIA offspring, seen only after a few days of MIA induction by poly (I:C)1. Injection of recombinant IL-17a into the fetal brain leads to the appearance of disorganized cortical patches and ASD-like behavioral abnormalities, and treating pregnant mice with an antibody that blocks IL-17a protects against MIA-induced behavioral deficits, as well as abnormal cortical phenotype1. This result suggests IL-17a may directly affect neural tissue through an IL-17a receptor expressed in the brain. Similar to the IL-17a-blocking antibody treatment,

knocking out T-cell specific ROR? in mothers prevents MIA-induced cortical malformation in the offspring, demonstrating ROR? is important for the development of ASD-like behaviors1. The transcription factor, ROR?, is commonly associated with Th17 differentiation. Not surprisingly, specific types of maternal intestinal bacteria promote Th17 cell differentiation4. Commensal maternal bacteria sensitive to vancomycin is required for MIA-induced behavioral abnormalities in the offspring, since it has been observed that pretreating poly (I:C)-injected pregnant mice with vancomycin results in smaller numbers of Th17 cells in the small intestine and lower levels of IL-17a in maternal plasma, in addition to bearing offspring who do not develop brain and behavioral abnormalities4. Segmented filamentous bacteria (SFB) are present in mice and are sensitive to vancomycin4. “Jax” mice from Jackson Laboratory lack SFB and have few intestinal Th17 cells compared with “Tac” mice from Taconic Biosciences, which have an abundant amount of SFB and a high number of Th17 cells4. Even after poly (I:C) injection, “Jax” mice do not have offspring with cortical abnormalities nor an increase in maternal IL-17a levels4 , highlighting again, the significance of the composition of maternal commensal microbiota in the development of ASD in their offspring. Toll-like-receptor 3 (TLR3) signaling on CD11c+ dendritic cells in poly (I:C) injected mice are required for MIA-induced behavioral abnormalities in the offspring4, most likely to detect dsRNA and initiate innate immune signaling that will produce IL-6. Taken together, increased levels of maternal intestinal IL-6 may lead to Th17 cell polarization, resulting in higher levels of IL-17a, the predominant cytokine secreted by Th17 cells. Maternal IL-17a is able to cross the placenta to affect the offspring.

In summary, the offspring and maternal commensal microbiota composition can shape the populations and diversity of immune cells present in the intestine, and if combined with a proinflammatory 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 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 system6 or do they directly traverse across the blood brain barrier to take its effect on neural cells? The integrity of the blood brain barrier needs to be investigated in MIA 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 and in a MIA model? There have been many studies reporting findings on intestinal immune cells or peripheral immune cells involved in the MIA model of autism, but research into the types of cells in the brain that are essential for the development of ASD-like behavior in MIA 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 profile5.

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 dysregulation of 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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