Impact of maternal microbiota imbalance during pregnancy on fetal cerebral neurodevelopment: Is there a link to certain autistic disorders?

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with a heterogeneous group of psychiatric disorders primarily characterized by impairments in communication and social interactions. ASD typically emerges around 18 months of age. While no single etiology has been identified, theories suggest a combination of genetic predisposition and environmental factors, such as exposure to toxics, viral infections, and neuroinflammatory processes. However, the mechanisms linking environmental risk factors to ASD remain poorly understood, particularly during the prenatal period. Among the various hypotheses, the gut microbiota has been proposed as a potential modulator of nervous system development and function. During pregnancy, the maternal microbiota could trigger gestational inflammatory responses, leading to maternal immune activation (MIA). These deleterious processes could play a causal role in the etiopathogenesis of neurodevelopmental disorders in offspring. The gut microbiota could be the missing link between genetic susceptibility and environmental exposures in certain forms of ASD. The gut microbiome induces the production of microbiota-derived signaling metabolites, immune mediators, gut hormones, and neural signaling via the spinal cord and vagus nerve. This review synthesizes the current knowledge from preclinical rodent models and human studies that investigate the impact of the maternal gut microbiota during pregnancy on ASD risk in offspring. Additionally, the potential roles of the maternal oral and vaginal microbiota are also discussed in the context of this maternal-offspring pairing. Finally, we examine how restoring maternal microbiome balance, through interventions such as pre/probiotics, may help reduce the perinatal risk of certain ASD by positively influencing prenatal environmental factors.

Keywords: Fetal neurodevelopment; MIA; Maternal microbiome.

Graphical abstract

Fig. 1

Different communication pathways of the gut-brain axis, in ASD pathology. Part of the figure was designed using resources from Biorender.com.

Fig. 2

A) Schematic illustration of leaky gut following dysbiosis, showing increased barrier permeability (bacteria, microbial metabolites, release of lipopolysaccharides (LPS) and peptidoglycans (PGNs), etc.) which induce inflammation (increased pro-inflammatory macrophage phenotype and elevated levels of pro-inflammatory cytokines). Visualization of Zonulin, a protein that regulates the tight junctions (TJs) between cells in the intestinal wall. B) Schematic representation of the blood-brain barrier (BBB) in (a) physiological and (b) pathological states created by Parker et al. (Parker et al., 2019).

Fig. 3

Potential pathways of fetal microbiota colonization and possible links between maternal impact and the occurrence of ASD in children, adapted from Kuperman et al. (Kuperman and Koren, 2016).

Fig. 4

Suggested mechanisms of maternal transfer of bacteria to the fetus in utero, from Walker et al. (Walker et al., 2017).

Fig. 5

Interventions to modulate the gut microbiome.