Dysregulation of synaptic pruning as a possible link between intestinal microbiota dysbiosis and neuropsychiatric disorders

Abstract

The prenatal and early postnatal stages represent a critical time window for human brain development. Interestingly, this window partly overlaps with the maturation of the intestinal flora (microbiota) that play a critical role in the bidirectional communication between the central and the enteric nervous systems (microbiota-gut-brain axis). The microbial composition has important influences on general health and the development of several organ systems, such as the gastrointestinal tract, the immune system, and also the brain. Clinical studies have shown that microbiota alterations are associated with a wide range of neuropsychiatric disorders including autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, and bipolar disorder. In this review, we dissect the link between these neuropsychiatric disorders and the intestinal microbiota by focusing on their effect on synaptic pruning, a vital process in the maturation and establishing efficient functioning of the brain. We discuss in detail how synaptic pruning is dysregulated differently in the aforementioned neuropsychiatric disorders and how it can be influenced by dysbiosis and/or changes in the intestinal microbiota composition. We also review that the improvement in the intestinal microbiota composition by a change in diet, probiotics, prebiotics, or fecal microbiota transplantation may play a role in improving neuropsychiatric functioning, which can be at least partly explained via the optimization of synaptic pruning and neuronal connections. Altogether, the demonstration of the microbiota's influence on brain function via microglial-induced synaptic pruning addresses the possibility that the manipulation of microbiota-immune crosstalk represents a promising strategy for treating neuropsychiatric disorders.

Glutamatergic Dysfunction and Synaptic Ultrastructural Alterations in Schizophrenia and Autism Spectrum Disorder: Evidence from Human and Rodent Studies

“…In layer II of the anterior limbic cortex, a 128% increase in the density of total axospinous synapses and a decrease of 40% of synapses on the dendritic shaft were identified in SZ subjects without determining whether the decreased numbers are in excitatory or inhibitory synapses. These results suggest a disruption in the formation of connections in the neuronal assemblages of the anterior limbic cortex or a defective elimination of synapses during early adolescence, when synaptic pruning occurs by discarding weak and redundant synaptic connections, and strengthening the remaining synapses [239,240]. Regarding the structure of synapses, the same study revealed an increase of 14% in the convex synapses in SZ cases with a decrease in flat and concave synapses by 11% and 3%, respectively [124].…”

The Promising Role of Probiotics in Managing the Altered Gut in Autism Spectrum Disorders

“…We described the important potential benefits of using probiotics as a way to upgrade the microbiome, in order to provide with necessary metabolites that were shown to be beneficial for the gut permeability, immunity, and brain function. It was recently shown by El Tokhi et al (2020) [9] that the synaptic pruning in patients with neuropsychiatric disorders was found to be dysregulated and this was associated with a dysbiosis. Dietary changes such as diet and probiotics were proposed to improve brain function via a mechanism of microglial-induced synaptic pruning and the formation of new synapses, thereby improving neural function [9].…”

“…It was recently shown by El Tokhi et al (2020) [9] that the synaptic pruning in patients with neuropsychiatric disorders was found to be dysregulated and this was associated with a dysbiosis. Dietary changes such as diet and probiotics were proposed to improve brain function via a mechanism of microglial-induced synaptic pruning and the formation of new synapses, thereby improving neural function [9].…”

“…The composition of the microbiota begins to stabilize between 6 and 36 months of age; during this time, it is possible to distinguish between the core microbiota and a provisional highly sensitive one [5]. This window of time is also critical for brain development as synaptic formation and myelination expand dramatically during the first few years of age [6][7][8][9]. The gut microbiota is also important for the maturation of the gut-associated lymphoid tissue; it mediates local and systemic immune responses and is therefore essential for both innate and acquired immunity [10].…”

<p>Randomized Clinical Trial Examining the Impact of <em>Lactobacillus rhamnosus</em> GG Probiotic Supplementation on Cognitive Functioning in Middle-aged and Older Adults</p>

“…Along the gut-brain-microbiome axis, the gut microbiota and the brain engage in bidirectional signaling through bile acids, 7,32 metabolites, 34 and immune responses. 31 These means of signaling have been associated with a wide range of neurodegenerative disorders, 7,35 neuronal protein expression, 33 neurotransmission, 29 synaptic pruning, 67,68 and behavioral change. 69,70 As described previously, Lactobacillus strains in particular have been found to reduce inflammatory cytokines 40 and metabolites in humans, 42 and enhance levels of CREB and BDNF in rats.…”