Beneficial reconstitution of gut microbiota and control of alpha-synuclein and curli-amyloids-producing enterobacteria, by beta 1,3-1,6 glucans in a clinical pilot study of autism and potentials in neurodegenerative diseases

Abstract

Background/objectiveGut dysbiosis is one of the major pathologies in children with autism spectrum disorder (ASD). In previous studies, Aureobasidium pullulans (i.e., black yeast AFO-202-produced beta glucan found in Nichi Glucan) yielded beneficial clinical outcomes related to sleep and behaviour. Evaluation of gut microbiota of the subjects in the present randomized pilot clinical study was undertaken and compared with an aim of gaining a mechanistic insight.MethodsThe study involved 18 subjects with ASD who were randomly allocated: six subjects in the control group (Group 1) underwent conventional treatment comprising remedial behavioural therapies and L-carnosine 500 mg per day, and 12 subjects (Group 2) underwent supplementation with Nichi Glucan 0.5 g twice daily along with the conventional treatment for 90 days. The subjects’ stool samples were collected at baseline and after the intervention. Whole genome metagenome (WGM) sequencing was performed.ResultsWGM sequencing followed by bioinformatic analysis in 13 subjects who completed the study showed that among genera of relevance, the abundance of Enterobacteria was decreased almost to zero in Group 2 after intervention, whereas it increased from 0.36% to 0.85% in Group 1. The abundance of Bacteroides increased from 16.84% to 19.09% in Group 1, whereas it decreased from 11.60% to 11.43% in Group 2. The abundance of Prevotella increased in both Group 1 and Group 2. The decrease in abundance of lactobacillus was significant in Group 2 compared to Group 1. Among species, a decrease was seen in Escherichia coli, Akkermansia muciniphila CAG:154, Blautia spp., Coprobacillus sp., and Clostridium bolteae CAG:59, with an increase of Faecalibacterium prausnitzii and Prevotella copri, which are both beneficial.ConclusionAFO-202 beta 1,3-1,6 glucan was able to balance the gut microbiome, which is considered beneficial in children with ASD. Effective control of curli-producing enterobacteria that leads to α-synuclein (αSyn) misfolding and accumulation, which apart from being advantageous in alleviating ASD symptoms, may have a prophylactic role in Parkinson’s and Alzheimer’s diseases where the αSyn misfolding and amyloid deposition are central to their pathogenesis. Additionally, stimulation of natural killer cells to help clear accumulated αSyn amyloids, beneficial microbiome reconstitution, and microglial rejuvenation lead us to recommend larger clinical studies in neurodevelopmental and neurodegenerative diseases of this safety-proven food supplement.Graphical AbstractThe above illustration explains, stepwise, the pathogenesis as well as the way beta glucan tackles each stage of the disease process: (A) & (B) Enterobacteria secretion of curli that causes misfolding of α-synuclein (αSyn); its aggregation in enteric neuronal cells is tackled by (1) control of enterobacteria, (2) scavenging of the accumulated amyloids by activated natural killer cells, and (3) reconstitution of beneficial microbiome. (C) The prion like propagation may not occur because the accumulation of curli proteins and amyloids is controlled at the level of production and aggregation (1) as well as clearing of already accumulated deposits (3). (D) Deposition of Lewy bodies, amyloid fibrils, and misfolded αSyn are tackled by (4) microglial-based scavenging.

Improvement of behavioural pattern and alpha-synuclein levels in autism spectrum disorder after consumption of a beta-glucan food supplement in a randomised, parallel-group pilot clinical study

“…Gram-negative enteric bacteria such as the Enterobacter and Escherichia coli secrete the amyloid curli which causes misfolding 23 and accumulation of the neuronal protein alpha-synuclein in the form of insoluble amyloid aggregations, which has also been shown to propagate in a prion-like fashion from the gut to the brain via the vagus nerve and/or spinal cord, thus culminating in the neurological disorders such as ASD and PD. 24 In a follow-up analysis of this study, we have reported a significant decrease in Enterobacter and E. coli 25 which logically will result in lesser production of alpha-synuclein. In spite of such decreased production, the increase in plasma alpha-synuclein levels can be probably due to the disintegration of the amyloid deposits by natural killer cells leading to these alpha-synuclein entering the blood stream.…”

Beneficial immune-modulatory effects of the N-163 strain of Aureobasidium pullulans-produced 1,3-1,6 Beta glucans in young boys with Duchenne muscular dystrophy: Results of an open-label, prospective, exploratory clinical study

“…Targeting the inflammation component (the criteria for selecting this supplement for this study) having yielded beneficial outcomes, additional studies on this characteristic could be of value to possibly extending their application for other neuroinflammatory diseases, such as multiple sclerosis. At this point, it is essential to mention the gut microbiome for two reasons; one being the association of the microbiome with the severity of neuroinflammatory conditions such as multiple sclerosis [31], and another being the fact that beta glucans have been reported to yield beneficial reconstitution of the gut microbiome in earlier studies [32] in children with autism spectrum disorder, a neurodevelopmental disease. For both multiple sclerosis and DMD, steroids to suppress inflammation are common, but associated implications for gut microbiota in DMD have not been reported often and are worthy of future study.…”

Two unique biological response-modifier glucans beneficially regulating gut microbiota and faecal metabolome in a non-alcoholic steatohepatitis animal model, with potential for applications in human health and disease

“…Beta-glucans derived from two strains of the black yeast Aureobasidium pullulans, AFO-202 and N-163, have beneficial effects against diabetes, [5] dyslipidaemia, [6] ASD, [7,8] Duchenne muscular dystrophy, [9] non-alcoholic steatohepatitis (NASH), [10] and infectious diseases including coronavirus disease (COVID-19). [11,12] A previous study showed that AFO-…”