The Gut-Brain-Immune Axis in Autism Spectrum Disorders: A State-of-Art Report

Abstract

The interest elicited by the large microbial population colonizing the human gut has ancient origins and has gone through a long evolution during history. However, it is only in the last decades that the introduction of high-throughput technologies has allowed to broaden this research field and to disentangle the numerous implications that gut microbiota has in health and disease. This comprehensive ecosystem, constituted mainly by bacteria but also by fungi, parasites, and viruses, is proven to be involved in several physiological and pathological processes that transcend the intestinal homeostasis and are deeply intertwined with apparently unrelated body systems, such as the immune and the nervous ones. In this regard, a novel speculation is the relationship between the intestinal microbial flora and the pathogenesis of some neurological and neurodevelopmental disorders, including the clinical entities defined under the umbrella term of autism spectrum disorders. The bidirectional interplay has led researchers to coin the term gut-brain-immune system axis, subverting the theory of the brain as an immune-privileged site and underscoring the importance of this reciprocal influence already from fetal life and especially during the pre- and post-natal neurodevelopmental process. This revolutionary theory has also unveiled the possibility to modify the gut microbiota as a way to treat and even to prevent different kinds of pathologies. In this sense, some attempts have been made, ranging from probiotic administration to fecal microbiota transplantation, with promising results that need further elaboration. This state-of-art report will describe the main aspects regarding the human gut microbiome and its specific role in the pathogenesis of autism and its related disorders, with a final discussion on the therapeutic and preventive strategies aiming at creating a healthy intestinal microbial environment, as well as their safety and ethical implications.

Keywords: autism spectrum disorder; dysbiosis; fecal microbiota transplantation (FMT); gut-brain axis; microbiota; neuroinflammation; probiotics.

Figure 1

Cells and molecules involved in the gut-brain-immune axis. The lower box represents the intestinal microenvironment, where microbial niches interact with the gut mucosa by directly secreting active metabolites or by indirectly stimulating the release of neurotransmitters by enteroendocrine cells (EC cells). Furthermore, the microbe-associated molecular patters (MAMPs) stimulate Toll-like receptors (TLR) on enterocytes and dendritic cells, resulting in innate and adaptive immune triggers. The upper box shows a magnification of the cerebral parenchima—blood-brain barrier interface, where neurons, astrocytes, microglial cells, and immune cells carried by brain lymphatics all take part in a well-coordinated interplay. In addition to the signals provided by circulating molecules acting in a paracrine and endocrine fashion, the bidirectional gut-brain interaction includes afferent and efferent neural pathways also involving the autonomous and the enteric nervous systems, resulting in modulation of perception, gut motility, secretion, mucosal permeability, and even changes in the microbial ecosystem.

Figure 2

Progressive colonization of the gut mucosa by bacterial species. The figure displays the major microbial species colonizing the intestine from prenatal life to early childhood, highlighting the differences according to external factors able to influence the microbial composition (C-section vs. vaginal delivery, breastfeeding vs. formula feeding). Stability of the microbial ecosystem is reached around 1 year of age, when the child microbiota has become similar to the maternal one. An additional influencing role is played by the diet in the first months of life. Not surprisingly, the introduction of solid food causes a significant change in the intestinal microbial composition.

Figure 3

History of the gut microbiota. This timeline shows the most significant facts about the attitude, the first trials, and the scientific goals in the field of intestinal microbiota during human history, starting from ancient times until nowadays.