Between Dysbiosis, Maternal Immune Activation and Autism: Is There a Common Pathway?

Abstract

Autism spectrum disorder (ASD) is a neuropsychiatric condition characterized by impaired social interactions and repetitive stereotyped behaviors. Growing evidence highlights an important role of the gut-brain-microbiome axis in the pathogenesis of ASD. Research indicates an abnormal composition of the gut microbiome and the potential involvement of bacterial molecules in neuroinflammation and brain development disruptions. Concurrently, attention is directed towards the role of short-chain fatty acids (SCFAs) and impaired intestinal tightness. This comprehensive review emphasizes the potential impact of maternal gut microbiota changes on the development of autism in children, especially considering maternal immune activation (MIA). The following paper evaluates the impact of the birth route on the colonization of the child with bacteria in the first weeks of life. Furthermore, it explores the role of pro-inflammatory cytokines, such as IL-6 and IL-17a and mother's obesity as potentially environmental factors of ASD. The purpose of this review is to advance our understanding of ASD pathogenesis, while also searching for the positive implications of the latest therapies, such as probiotics, prebiotics or fecal microbiota transplantation, targeting the gut microbiota and reducing inflammation. This review aims to provide valuable insights that could instruct future studies and treatments for individuals affected by ASD.

Keywords: autism spectrum disorders; brain–gut axis; delivery; dysbiosis; gastrointestinal; gut microbiota; maternal immune activation (MIA); microglia; neurodevelopment; short-chain fatty acids (SCFA).

Figure 1

Diagram of the effect of overproduction of short-chain fatty acids (SCFAs). I—Increased production of one of the SCFAs, propionate (PPA), inhibits oxidative phosphorylation in the mitochondrion, increases propionyl-coenzyme A levels and causes carnitine sequestration. All of this can result in impaired SCFA oxidation, increasing sensitivity to oxidative stress and disrupting enterocyte function. The result can be gut dysmobility, manifested as constipation. II—Larger amounts of PPA can cross the intestinal–blood barrier and then the blood–brain barrier (BBB). Once across the barrier, they can be captured by microglia and alter its function, and bind to Toll like receptors TLR4 and activate the inflammatory response.

Figure 2

Diagram showing the role of microglia in brain formation. Microglia is regulated by cytokines, neurotropic factors, complement factors, neurotransmitters and short-chain fatty acids (SCFAs). Microglia: eliminate synaptic connections (synaptic pruning), influence morphological, electrophysiological and molecular characteristics of neurons (neuronal maturation) and they are responsible for neural circuit formation by synapse formation between neurons.

Figure 3

Diagram showing the link between gut bacteria and neuroinflammation. (A). Dysbiosis causes the release of lipopolysaccharide (LPS) and peptidoglycans (PGNs) (1). The molecules bind to Toll like receptors (TLRs) (2). Gut-associated lymphoid tissue (GALT) activation occurs (3). This leads to increased production of pro-inflammatory cytokines (4) and inflammation (5). Information is transmitted to the enteric nervous system (ENS) (6) and to the central nervous system (CNS). (B). Probiotics also secrete molecules that bind to TLRs (1), which affects the activation of regulatory T cells (Tregs) (2), secreting IL-10 (3), reducing inflammation (4) and transmitting the information to the ENS (5) and then the CNS.

Figure 4

Stress, autoimmune diseases, infections and dysbiosis promote the release of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPS), binding to TLR receptors on maternal leukocytes and placental cells, resulting in maternal immune activation (MIA). Increased IL-6 concentration affects neural cells via pro-inflammatory sIL-6R signaling, simultaneously promoting an inflammatory response with a predominance of Th17 lymphocytes over immunosuppressive regulatory T cells.