Perinatal Interactions between the Microbiome, Immunity, and Neurodevelopment

Abstract

The microbiome modulates host immune function across the gastrointestinal tract, peripheral lymphoid organs, and central nervous system. In this review, we highlight emerging evidence that microbial effects on select immune phenotypes arise developmentally, where the maternal and neonatal microbiome influence immune cell ontogeny in the offspring during gestation and early postnatal life. We further discuss roles for the perinatal microbiome and early-life immunity in regulating normal neurodevelopmental processes. In addition, we examine evidence that abnormalities in microbiota-neuroimmune interactions during early life are associated with altered risk of neurological disorders in humans. Finally, we conclude by evaluating the potential implications of microbiota-immune interventions for neurological conditions. Continued progress toward dissecting mechanistic interactions between the perinatal microbiota, immune system, and nervous system might uncover fundamental insights into how developmental interactions across physiological systems inform later-life health and disease.

Figure 1.. Roles for the microbiome in neuro-, peripheral and enteric immune development.

Microbiota perturbations, including elimination, reduction, or alteration of endogenous microbes, lead to altered immune development in multiple tissue sites. In the brain, absence of the microbiome alters morphological and transcriptional features of brain-resident microglia. Additionally, the cytokine milieu of the brain is altered in the absence of microbes. In the periphery, particular bacteria such as Lactobacillus modulate memory T cells, and microbial metabolites such as the short-chain fatty acid, butryate, regulate Treg cell populations. Depletion of the microbiome results in peripheral immune dysfunction, reducing macrophages (MP) and neutrophils and increasing iNKT cells. Altered diversity of the microbiota also impacts immune development. When microbes are substantially reduced, both Th17 and Treg cell numbers decrease. Conversely, alteration of microbiota composition, as with increased prevalence of Bacteroides fragilis, increases Th17 and Treg cells. In the intestine, transient maternal colonization with non-replicating E. coli, or with altered Schaedler flora, increases ILC3s, while ablation of the microbiota reduces gut ILC3s, mononuclear phagocytes, Paneth cell activity, MHC antigen presentation, and mast cell gene expression.

Figure 2.. Canonical immune molecules play fundamental roles in normal neurodevelopment.

TLRs are expressed in every major cell type of the brain, and exhibit temporally distinct expression patterns that are critical for normal neurodevelopment. Activation of TLRs can have opposing effects on neuroproliferation and neurogenesis. For example, TLR2 activation increased hippocampal (HPC) neuroproliferation, but reduced neuroproliferation in the subventricular zone (SVZ). Activation of TLR3 resulted in reduced neural progenitor cell neurogenesis and neurite outgrowth, highlighting the differential effects of TLR stimulation in the developing brain. Fetal TLR2 activation by the bacterial cell wall component, peptidoglycan, increased hippocampal neuroproliferation. The developing brain is also highly dependent on a balanced cytokine milieu, as different cytokines can have opposing effects on neurogenesis. Maternal treatment with antibiotics resulted in sustained increases in IL-6, IL-10 and Cxcl15 in the cortex of offspring. Further, cytokines induced by maternal immune activation (MIA), were dependent on the maternal microbiota, such as increased prevalence of segmented filamentous bacteria (SFB), which led to exacerbated behavioral deficits in offspring. The complement system is critical for synaptic editing and refinement of neural circuits. Recognition of neuronal C3 by microglial-expressed C3R is important for this process, as are C1q and C4. Mice lacking the fractalkine receptor, CX3CR1, also exhibit disrupted synaptic editing. GF microglia exhibited altered gene expression of complement-associated genes, such as increased C3ar1 and decreased C1qbp and Itgax. Proteins essential for synaptic transmission, such as BDNF, synaptophysin, and PSD95, are also reduced in microbiota-depleted mice. Many other molecules, such as the aryl hydrocarbon receptor (AhR) and MHCI impact neurodevelopment as well (Bryceson et al., 2005; Glynn et al., 2011; Kimura et al., 2016; Latchney et al., 2013; Zohar et al., 2008). Deletion of AhR reduced cell proliferation and neuronal differentiation in the dentate gyrus (DG). Reduction in surface-expressed MHCI resulted in increased synapse density. Several MHCI receptors are expressed in the brain, including PirB, CD3z, Ly49 and KIR.

Figure 3.. The maternal microbiome influences fetal immune and brain development.

The maternal microbiome produces microbe-associated molecular patterns and secondary metabolites that can impact the developing fetus. Several factors influence the initial acquisition of microbes, including the route of delivery and breast-feeding. The initial infant gut microbiota is dominated by Firmicutes and Proteobacteria, and experiences diet-related shifts, such as the increase in Bifidobacterium following breast-feeding, and Bacteroidetes following a transition to solid foods. Bacterial alpha-diversity increases, eventually reaching complexity similar to the adult. Antimicrobial factors in the gut increase concurrent to the changing infant microbiome. Maturation of the immune system also begins in the fetal period and persists into postnatal development. Hematopoiesis first occurs in the yolk sac and continues in the fetal liver. Lymphoid organs, such as the spleen and thymus, follow, and immune circulating immune cells are also found in the developing fetus. Structural maturation of gut immunity is evident just before birth, although immune function is reduced during this phase. The fetus is capable of producing low levels of immunoglobulins, such as IgG, but relies heavily on maternal immunoglobulins. Following birth, acquisition of immunoglobulins is facilitated through breast-milk. Brain development occurs concurrently over defined stages, starting with the proliferation and migration of neuronal progenitor cells. Shortly after, immature macrophages from the yolk sac migrate to the central nervous system where they mature to resident microglial cells. Shortly after, wiring of the brain circuitry begins with the onset of synaptogenesis. During the late gestational period, astrocytes develop to facilitate the increasing metabolic demand for brain growth. During the late fetal period, and into early postnatal development, synaptic remodeling and pruning occurs, with studies demonstrating a clear role for microglial mediated synaptic editing as well as astrocyte-mediated pruning of the synapse.