Targeting Gut Dysbiosis and Microbiome Metabolites for the Development of Therapeutic Modalities for Neurological Disorders.

The gut microbiota, composed of numerous species of microbes, works in synergy with the various organ systems in the body to bolster our overall health and well-being. The most well-known function of the gut microbiome is to facilitate the metabolism and absorption of crucial nutrients, such as complex carbohydrates, while also generating vitamins. In addition, the gut microbiome plays a crucial role in regulating the functioning of the central nervous system (CNS). Host genetics, including specific genes and single nucleotide polymorphisms (SNPs), have been implicated in the pathophysiology of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and autism spectrum disorder (ASD). The gut microbiome dysbiosis also plays a role in the pathogenesis of these neurodegenerative disorders, thus perturbing the gut-brain axis. Overproduction of certain metabolites synthesized by the gut microbiome, such as short-chain fatty acids (SCFAs) and p-cresyl sulfate, are known to interfere with microglial function and trigger misfolding of alpha-synuclein protein, which can build up inside neurons and cause damage. By determining the association of the gut microbiome and its metabolites with various diseases, such as neurological disorders, future research will pave the way for the development of effective preventive and treatment modalities.

Efficacy of coping mechanisms used during COVID-19 as reported by parents of children with autism.

The COVID-19 pandemic's alterations to daily life have been especially challenging for families with Autism Spectrum Disorder (ASD), worsening the core features of ASD and overall mental health. With the increased need for effective coping, the current retrospective study used data from a survey regarding parent reports of how often their child with ASD used certain coping strategies (frequency), as well as the extent to which they felt their child benefitted from their use (efficacy) in mitigating stress during the pandemic. This retrospective study Repeated measures ANOVAs were conducted to evaluate whether there were significant differences in both frequency and efficacy ratings for each coping strategy, for the entire sample as well as for three children's age groups. Using Spearman's rank-order correlations, correlation coefficients between the frequency and efficacy of each coping strategy were explored. Results revealed that maladaptive strategies were used more frequently than adaptive strategies, while parent routine as the most frequently used and efficacious for all age groups. Additionally, for adaptive strategies, humor and focusing on the positive had the strongest correlations between frequency and efficacy ratings amongst all age groups. Of the maladaptive strategies, repetitive behaviors, rumination, and isolation had the strongest correlations for the youngest, middle, and oldest age groups, respectively. Further, for each age group, the adaptive coping strategies had stronger correlations between frequency and efficacy than the maladaptive ones. It is our hope that the results of this study will lay the foundation for developing adaptive coping strategies to alleviate stress in children with ASD. Further investigations using a larger cohort are warranted to determine effective coping strategies for individuals with ASD across a range of situations, including acute stressors (such as future public health emergencies and natural disasters), as well as common daily stressors.

Altered Blood Brain Barrier Permeability and Oxidative Stress in Cntnap2 Knockout Rat Model.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by three core symptoms, specifically impaired social behavior, stereotypic/repetitive behaviors, and sensory/communication deficits. Although the exact pathophysiology of ASD is still unknown, host genetics, oxidative stress, and compromised blood brain barrier (BBB) have been implicated in predisposition to ASD. With regards to genetics, mutations in the genes such as CNTNAP2 have been associated with increased susceptibility of developing ASD. Although some studies observed conflicting results suggesting no association of CNTNAP2 with ASD, other investigations correlated this gene with autism. In addition, CNTNAP2 mediated signaling is generally considered to play a role in neurological disorders due to its critical role in neurodevelopment, neurotransmission, and synaptic plasticity. In this investigation, we studied BBB integrity and oxidative stress in Cntnap2-/- rats. We observed that the BBB permeability was significantly increased in Cntnap2-/- rats compared to littermate wild-type (WT) animals as determined by FITC-dextran and Evans blue assay. High levels of thiobarbituric acid reactive substances and lower amounts of reduced glutathione were observed in brain homogenates of Cntnap2-/- rats, suggesting oxidative stress. Brain sections from Cntnap2-/- rats showed intense inducible nitric oxide synthase immunostaining, which was undetectable in WT animals. Quantification of nitric oxide in brain homogenates revealed significantly high levels in Cntnap2-/- rats compared to the control group. As increased permeability of the BBB and oxidative stress have been observed in ASD individuals, our results suggest that Cntnap2-/- rats have a high construct and face validity and can be explored to develop effective therapeutic modalities.

Altering the gut microbiome to potentially modulate behavioral manifestations in autism spectrum disorders: A systematic review.

There is a potential association between gastrointestinal (GI) symptoms and the severity of autism spectrum disorder (ASD). Given this correlation, the possible impact of probiotics and prebiotics have been explored in research studies to modify the gut microbiome and ameliorate behavioral manifestations of ASD via modulating the gut-brain-microbiome axis. This systematic review focuses on the interplay between these factors in altering the behavioral manifestations of ASD. Probiotic supplementation tended to mitigate some of the behavioral manifestations of ASD, with less of a discernible trend on the microbiome level. Studies supplementing multiple probiotic species, such as microbiota transfer therapy, or including prebiotics performed better than single strain supplementation. Our analysis suggests that gut dysbiosis may increase intestinal permeability, leading to more severe GI symptoms and a systemic inflammatory response, which can alter permeability across the blood-brain barrier and synaptogenesis in the brain. Future studies are warranted to understand the precise contribution of altering gut microbiome on clinical manifestations of ASD that will open up avenues to develop preventive and treatment modalities.

Beneficial Effects of Milk Having A2 ß-Casein Protein: Myth or Reality?

Diet has been shown to play an important role in maintaining normal homeostasis in the human body. Milk and milk products are a major component of the Western diet, but their consumption may predispose sensitive individuals to adverse health outcomes. Current literature about milk products recognizes various bioactive components including lactate, whey protein, and ß-casein protein. Specifically, cow milk has 2 major subvariants of its ß-casein protein, A1 and A2, due to a single nucleotide difference that changes the codon at position 67. Whereas the A2 polymorphism is unlikely to undergo enzymatic cleavage during digestion, the A1 polymorphism is more likely to undergo enzymatic cleavage resulting in the product peptide ß-casomorphin-7, a known µ-opioid receptor agonist. The objective of this article is to review the current understanding of the 2 major ß-casein subvariants and their effects on various organ systems that may have an impact on the health of an individual. Synthesis of the current existing literature on this topic is relevant given the increased association of milk consumption with adverse effects in susceptible individuals resulting in a rising interest in consuming milk alternatives. We discuss the influence of the ß-casein protein on the gastrointestinal system, endocrine system, nervous system, and cardiovascular system as well as its role in antioxidants and methylation. A1 milk consumption has been associated with enhanced inflammatory markers. It has also been reported to have an opioid-like response that can lead to manifestations of clinical symptoms of neurological disorders such as autism spectrum disorder. On the other hand, A2 milk consumption has been associated with beneficial effects and is easier to digest in sensitive individuals. Further research is warranted to investigate the short- and long-term effects of consumption of A1 ß-casein in comparison with milk with A2 ß-casein proteins.

Gut-Induced Inflammation during Development May Compromise the Blood-Brain Barrier and Predispose to Autism Spectrum Disorder.

Recently, the gut microbiome has gained considerable interest as one of the major contributors to the pathogenesis of multi-system inflammatory disorders. Several studies have suggested that the gut microbiota plays a role in modulating complex signaling pathways, predominantly via the bidirectional gut-brain-axis (GBA). Subsequent in vivo studies have demonstrated the direct role of altered gut microbes and metabolites in the progression of neurodevelopmental diseases. This review will discuss the most recent advancements in our understanding of the gut microbiome's clinical significance in regulating blood-brain barrier (BBB) integrity, immunological function, and neurobiological development. In particular, we address the potentially causal role of GBA dysregulation in the pathophysiology of autism spectrum disorder (ASD) through compromising the BBB and immunological abnormalities. A thorough understanding of the complex signaling interactions between gut microbes, metabolites, neural development, immune mediators, and neurobiological functionality will facilitate the development of targeted therapeutic modalities to better understand, prevent, and treat ASD.

Gene therapy for neurological disorders: challenges and recent advancements.

Major advancements in targeted gene therapy have opened up avenues for the treatment of major neurological disorders through a range of versatile modalities varying from expression of exogenous to suppression of endogenous genes. Recent technological innovations for improved gene sequence delivery have focussed on highly specific viral vector designs, plasmid transfection, nanoparticles, polymer-mediated gene delivery, engineered microRNA and in vivo clustered regulatory interspaced short palindromic repeats (CRISPR)-based therapeutics. These advanced techniques have profound applications in treating highly prevalent neurological diseases and neurodevelopmental disorders including Parkinson's disease, Alzheimer's disease and autism spectrum disorder, as well as rarer diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, lysosomal storage diseases, X-linked adrenoleukodystrophy and oncological diseases. In this article, we present an overview of the latest advances in targeted gene delivery and discuss the challenges and future direction of gene therapy in the treatment of neurological disorders.

Nutritional interventions for autism spectrum disorder.

Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental disorder with considerable clinical heterogeneity. With no cure for the disorder, treatments commonly center around speech and behavioral therapies to improve the characteristic social, behavioral, and communicative symptoms of ASD. Gastrointestinal disturbances are commonly encountered comorbidities that are thought to be not only another symptom of ASD but to also play an active role in modulating the expression of social and behavioral symptoms. Therefore, nutritional interventions are used by a majority of those with ASD both with and without clinical supervision to alleviate gastrointestinal and behavioral symptoms. Despite a considerable interest in dietary interventions, no consensus exists regarding optimal nutritional therapy. Thus, patients and physicians are left to choose from a myriad of dietary protocols. This review, summarizes the state of the current clinical and experimental literature on nutritional interventions for ASD, including gluten-free and casein-free, ketogenic, and specific carbohydrate diets, as well as probiotics, polyunsaturated fatty acids, and dietary supplements (vitamins A, C, B6, and B12; magnesium and folate).

Early Disruption of the Microbiome Leading to Decreased Antioxidant Capacity and Epigenetic Changes: Implications for the Rise in Autism.

Currently, 1 out of every 59 children in the United States is diagnosed with autism. While initial research to find the possible causes for autism were mostly focused on the genome, more recent studies indicate a significant role for epigenetic regulation of gene expression and the microbiome. In this review article, we examine the connections between early disruption of the developing microbiome and gastrointestinal tract function, with particular regard to susceptibility to autism. The biological mechanisms that accompany individuals with autism are reviewed in this manuscript including immune system dysregulation, inflammation, oxidative stress, metabolic and methylation abnormalities as well as gastrointestinal distress. We propose that these autism-associated biological mechanisms may be caused and/or sustained by dysbiosis, an alteration to the composition of resident commensal communities relative to the community found in healthy individuals and its redox and epigenetic consequences, changes that in part can be due to early use and over-use of antibiotics across generations. Further studies are warranted to clarify the contribution of oxidative stress and gut microbiome in the pathophysiology of autism. A better understanding of the microbiome and gastrointestinal tract in relation to autism will provide promising new opportunities to develop novel treatment modalities.

Central Auditory Processing Disorders in Individuals with Autism Spectrum Disorders

The etiology and the underlying pathogenetic mechanisms of autism spectrum disorders are still largely unknown. This article provides a comprehensive review of the studies that are relevant to autism spectrum disorders and central auditory processing disorders and also discusses the relationship between autism spectrum disorders and central auditory processing disorders in the light of recent studies on this subject, which may provide new pathways in a therapeutic perspective. Several studies confirm that most of the individuals with an autism spectrum disorder have some degree of sensory dysfunction related to disorders of processing auditory, visual, vestibular, and/or tactile stimuli. Among these studies, some have addressed central auditory processing disorders. There is an increasing amount of effort for studies regarding the link between autism spectrum disorders and central auditory processing disorders. Most of the studies investigating central auditory processing disorders in patients with autism spectrum disorders have used electrophysiological measurements such as mismatch negativity and P300 event-related potentials. In addition to these, several studies have reported deterioration in speech perception and expression in patients with autism spectrum disorders, which may also be related to central auditory processing disorders in this unique group of individuals.