The interplay between gut microbiota and autism spectrum disorders: A focus on immunological pathways
Introduction
It is now well established that there is bidirectional communication between gut microbiota and brain, known as the microbiome-gut-brain axis. Dysregulation in any part of this axis might contribute to the pathogenesis of not only gut-related disorders such as inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS) and celiac disease but also neuropsychological conditions such as depression, Alzheimer’s disease, schizophrenia and autism spectrum disorders (ASD) (Hsiao et al., 2013; Nemani et al., 2015; Petra et al., 2015; Shen et al., 2020). In support, it has been shown that ASD is accompanied by gastrointestinal (GI) problems such as abdominal pain, diarrhea and constipation (Li et al., 2019). The precise mechanisms linking the gut and the brain are not fully understood yet. However, there is increasing evidence regarding the fundamental role of the immune system in mediating this interaction.
It has been demonstrated that even slight activation of the immune system early in life exerts a significant impact on the central nervous system (CNS) development. For instance, sustained action and proliferation of glial cells, i.e., microglia and astrocytes (Kierdorf and Prinz, 2013) due to various exogenous and endogenous stimuli could lead to pathological changes in the CNS since the activated forms of these cells release pro-inflammatory factors and cause neuroinflammation. In this regard, post-mortem brains of ASD patients represent higher levels of microglia, astrocytes, as well as pro-inflammatory biomarkers, suggesting the possible role of the immune system in ASD pathogenesis (Vuong and Hsiao, 2017).
Recent evidence proposes the necessity of normal gut composition for expression, maturation and proliferation of microglia. In this regard, studies on germ-free rodents with altered commensal population displayed atypical microglia and disturbed activity of the immune system as a result, which were both corrected after recolonizing gut microbial populations (Erny et al., 2015). Importance of gut microbes, their metabolites and mucosal barrier integrity in neurodevelopmental conditions such as ASD has been reflected by the presence of altered composition of gut microbiota and intestinal permeability in autistic children compared to healthy controls (de Magistris et al., 2010; Matta et al., 2019). In addition, Matta and colleagues showed that both microglia characteristics and ASD phenotypes improve following recolonization of the gut with normal microbiota (Matta et al., 2019). This issue has led to the introduction of microbiota-related treatment approaches like probiotics in the management of ASD behavioral symptoms.
Although there is mounting evidence linking ASD with gut microbiota and immune system independently, data of the interaction between these three systems together remains limited. Therefore, in this paper, we review recent evidence regarding immune modulation of the microbiome-gut-brain axis as a possible critical pathway in mediating ASD. First, we review the literature focusing on the ASD-related GI problems, including microbiota alterations, altered intestinal permeability and altered microbial metabolites profile and we propose a number of factors that could result these conditions. Then, we explain the presence of immune dysregulation in ASD and discuss the immunologic signaling pathways that interconnect the gut problems with CNS dysfunction. Finally, all the discussions end with potential clinical advances that could be achieved in the near future as well as a hypothetical model of the system’s biology in ASD.
Section snippets
Gastrointestinal system and ASD
The prevalence of GI symptoms in ASD patients is widely variable, ranging from 9% to as far as 90% (Vuong and Hsiao, 2017). However, it is now considered a fact that ASD patients suffer from significantly higher rates of GI symptoms (e.g., chronic diarrhea and or constipation, abdominal pain, gastroesophageal reflux disease) compared to the healthy persons. Endoscopy examination of the GI tract has revealed several findings in this respect, including but not limited to, patchy inflammation,
Immune dysregulation and ASD
There is growing evidence on the association between ASD and altered activity of the immune system. First, coexistence of ASD and various immune-based disorders (i.e., inflammatory bowel diseases, allergy, diabetes type 1) has been repeatedly addressed in recent years (Onore et al., 2012; Wang et al., 2014). Second, positive family history for autoimmune disorders has been linked with a higher risk of autism (Atladottir et al., 2009; Molloy et al., 2006; Vinet et al., 2015). Third, specific
Microglia
Microglia colonize the brain in the first days of embryo development and contribute to the regulation of synaptic formation (Reemst et al., 2016). These cells are much involved in fine pruning of dendritic spines and trees as well as the gross apoptosis of neurons (Kettenmann et al., 2013). Besides, they also release chemical transmitters such as glutamate and ATP that help in modulating the synaptic activity (Araque and Navarrete, 2010). Hence, the intercommunication between microglia and
The NF-κB signaling pathway
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a transcription factor acting on multiple aspects of innate and adaptive immune responses. NF-κB increases the expression of pro-inflammatory genes, regulates the proliferation and differentiation of a wide range of immune cells and is considered as a mediator linking immunological etiologies to immune cells (Liu et al., 2017). It has been indicated that NF-κB signaling mediates the association between alterations in the
Clinical implications of the gut-brain axis in ASD
A significant proportion of the literature addresses the gut microbiota as an appropriate target to alleviate behavioral disturbances related to the ASD. For instance, psychobiotics were shown to alleviate not only GI problems but also behavioral abnormalities in individuals with ASD. Psychobiotics are in fact a group of probiotics that have the capacity to influence the CNS related functions and behaviors. The effects of these reagents in the ASD course have been investigated by a vast number
Concluding Remarks and Future Perspectives
ASD patients usually show limited response to contemporary treatments since the underlying etiology remains unclear. There are ongoing efforts to resolve the existing uncertainties in the implicated mechanisms. In the current report, we reviewed the recent evidence for the link between gut microbiota, immune system and CNS in ASD. Autism symptoms are not limited to behavioral abnormalities and multiple organs are affected by the disease. There is a complex interaction between these
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Competing Interest
The authors of this manuscript declare that they have no conflicts of interest.
Acknowledgments
None.
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