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
Authors: Raghavan Kadalraja , Dedeepiya Vidyasagar Devaprasad , Yamamoto Naoki , Ikewaki Nobunao , Sonoda Tohru , Iwasaki Masaru , Kandaswamy Ramesh Shankar , Senthilkumar Rajappa , Preethy Senthilkumar , Abraham Samuel JK 
Published: October 2021

Background/objective

Gut 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.

Methods

The 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.

Results

WGM 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.

Conclusion

AFO-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 Abstract

The 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.