Autism Spectrum Disorders (ASD) encompass a range of developmental disabilities where poor sleep and alterations in gut microbiota are common, leading to detrimental effects on daily cognitive and social functioning. A study by a consortium of clinicians and scientists from India and Japan, including Dr Samuel JK Abraham, Dr K Raghavan, and Mr Takashi Onaka, provides insight into the beneficial effects of the biological response modifier glucan, Nichi GLOW, on the gut microbiota, sleep, and behavioural patterns in children with ASD.
Disorders of the central nervous system can be divided into early onset neurodevelopmental disorders diagnosed in childhood and late onset neurodegenerative disorders diagnosed in adulthood. Neurodevelopmental disorders affect nervous system development and are marked by impairments in cognitive, social, and motor functioning and include ASD, Attention Deficit Hyperactivity Disorder (ADHD) and schizophrenia, among others. Continuous loss of structure and function of the nervous system are features of neurodegenerative disorders and include diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease.
Autism spectrum disorders are a spectrum of developmental disabilities characterised by impaired social and communication abilities and repetitive behaviour. The prevalence of ASD is 1 in 44 of the population, with more boys affected than girls. Although the aetiology is not fully elucidated, both environmental and genetic factors are implicated. Sleep difficulties associated with low melatonin levels are common in ASD. In a pilot study, Dr Samuel JK Abraham of University of Yamanashi, Japan, and Dr K Raghavan of Jaicare Hospital, Madurai, India, investigate the effects of a biological response modifier glucan, Nichi GLOW, on sleep and behavioural patterns, gut microbiota, blood melatonin and alpha synuclein (αSyn) levels, in children with ASD. They assess the potential utility of this food supplement as an adjunct treatment, along with conventional treatments, in this population.
Sleep and the gut–brain axis in ASD
Sleep difficulties are common in ASD due to low melatonin (the hormone regulating circadian rhythm) levels with issues ranging from difficulty getting to sleep, frequent waking up, and poor sleep quality. Sleep difficulties can worsen other ASD symptoms and cause negative effects for the patient and their family, therefore good quality sleep is vital in the management of ASD. Current ASD treatments include melatonin supplements to improve sleep quality, but its effectiveness is varied among individuals.
The gut microbiome refers to the microorganisms colonising the gut. Gut dysbiosis arises due to changes in the type or quantity of microorganisms in the gut and can lead to intestinal inflammation. Gut dysbiosis is a known feature of ASD, and it can cause symptoms such as constipation or diarrhoea. The gut–brain axis, a connection and communication between the gut and brain is evidenced by links between gut dysbiosis and the presence of neurodevelopmental and neurodegenerative disorders. For example, αSyn, a neurotransmitter found in presynaptic terminals, is important for normal synaptic function. Abnormal changes in the nature and levels of αSyn are reported in ASD. Enterobacteria produce curli (amyloid proteins on the surface of cells) which cause misfolding and accumulation of insoluble αSyn. This accumulated protein in the enteric nervous system of the gut can migrate to the brain via the gut–brain axis and accumulate, causing the development of diseases such as ASD, AD, and PD.
Biological response modifier glucans
Biological response modifier glucans are biologically active compounds and components of yeast and fungi cell walls. The Nichi Glucan range of products are produced as an exo-polysaccharide by different strains of black yeast, Aureobasidium pullulans. They are nutritional supplements containing beta-1,3/1,6-glucan, among which the Nichi GLOW used in the study is a product of AFO-202 strain, whose initial isolation was achieved by Professor Noboru Fujii of Miyazaki University in the 1980s. This was scaled up to a GMP production by Mr Takashi Onaka.
Nichi glucans have been an approved food supplement in Japan since 1996 and have been shown to help inflammation, glucotoxicity, lipotoxicity and other ailments. In animal studies, Nichi Glucan has been reported to upregulate melatonin levels, while human studies reveal benefits of Nichi Glucan in metabolic diseases. Reported neuroinflammation in the brains of children with ASD leads to abnormal neuron connections and subsequent behavioural changes. An increase in the expression of several inflammatory markers such as Interleukin-6 (IL-6), Interleukin-10 (IL-10), and tumour necrosis factor alpha (TNF-α) have been described. Previous studies in mice show Beta-Glucan can decrease expression of such inflammatory cytokines, specifically, IL-6, TNF-α and IL-1β. Considering these findings, Nichi GLOW has now been studied in children with ASD to explore its potential value.
Nichi GLOW oral consumption by children with ASD: A pilot study
Abraham and Raghavan conducted a pilot study investigating the effects of Nichi GLOW on gut microbiota, plasma αSyn, behaviour (assessed using the Childhood Autism Rating Scale (CARS)), sleep pattern (assessed using a Children’s Sleep Habits Questionnaire (CSHQ)) and serum melatonin in children with ASD.
A control group received conventional therapy whereas the treatment group received Nichi GLOW in addition to conventional therapy for 90 days. Analysis of gut microbiota found a shift towards more favourable gut microbiota and decreased abundance of bacteria which secrete curli (Enterobacteria and E.Coli) in the treatment group.
The study also examined CARS scores and α-Syn plasma levels in both groups with these results published in BMJ Neurology Open. Significantly decreased CARS scores were noted in the treatment group (on average, a three-point improvement in CARS scores) compared to controls, which indicates an improvement in behavioural patterns of these subjects. The team suggest such an improvement in behavioural patterns may be due to improved sleep following consumption of Nichi GLOW.
Regarding plasma αSyn levels, these increased in the treatment group compared to the control group. The researchers postulate possible mechanisms for the increased plasma αSyn. Firstly, higher plasma αSyn levels could be due to Nichi GLOW preventing neural synapse αSyn build up and natural killer cells scavenging amyloid deposits, raising plasma levels. The other proposed mechanism is that Nichi GLOW actively reduces the gut bacteria responsible for αSyn misfolding and aggregation.
More research is needed to fully elucidate these proposed mechanisms and ascertain whether clinically meaningful changes in CARS and αSyn levels can be achieved with Nichi GLOW treatment in children with ASD. In addition, further research in neurodegenerative diseases is required to ascertain the potential of Nichi GLOW as a prophylaxis for neurodegenerative disorders such as AD and PD (diseases marked by αSyn abnormalities and amyloid build up).
With findings of improved melatonin levels in animal studies following treatment with Beta Glucans, serum melatonin levels and sleep patterns were investigated in this pilot study. Analysis revealed significantly reduced CSHQ scores, indicating improved sleep patterns in the treatment group following supplementation with Nichi GLOW, whereas no significant improvements were noted in the control group.
Furthermore, serum melatonin levels increased more in the treatment group compared to the controls. With sleep difficulties affecting the functioning and daily life of these children and their family, effective sleep treatments are essential in the management of ASD. This is one of the first studies showing that a non-pharmacological intervention can improve sleep patterns and sleep quality in children with ASD.
The researchers suggest future studies should also explore the effects of Nichi GLOW on other symptoms of ASD. Before Nichi GLOW can be recommended as a food supplement in children with ASD, larger multicentre studies with follow-ups are required to confirm these findings. This study does, however, provide early novel insights into the potential utility of Nichi GLOW in ASD.
- Raghavan, K, Dedeepiya, VD, Ikewaki, N, et al, (2022) 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. BMJ Neurol Open, 4 (1), e000203. doi.org/10.1136/bmjno-2021-000203
- Raghavan, K, Dedeepiya, VD, Yamamoto, N, et al, (2021) 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. medRxiv preprint, doi.org/10.1101/2021.10.26.21265505.
- Raghavan, K, Dedeepiya, VD, Kandaswamy, RS, et al, (2021) Improvement of sleep patterns and serum melatonin levels in children with autism spectrum disorders after consumption of beta-1,3/1,6-glucan in a pilot clinical study. Research Square preprint, doi.org/10.21203/rs.3.rs-701988/v1.
- Ouellette, J, Lacoste, B, (2021) From Neurodevelopmental to Neurodegenerative Disorders: The Vascular Continuum. Front. Aging Neurosci, 13, Article 749026. doi.org/10.3389/fnagi.2021.749026
- Ikewaki, N, Iwasaki, M, Abraham, S, (2020) Biological response modifier glucan through balancing of blood glucose may have a prophylactic potential in COVID-19 patients. Journal of Diabetes & Metabolic Disorders, 19, 2041-2044.
- Carding, S, Verbeke, K, Vipond, DT, Corfe, BM, Owen, LJ, (2015) Dysbiosis of the gut microbiota in disease. Microbial Ecology in Health and Disease, 26, 26191.
Indian and Japanese joint study on the effects of Nichi GLOW on children with ASD, with emphasis on the gut microbiome.
The Government of Japan & the Prefectural Government of Yamanashi sanctioned a special loan for this study and M/s Yamanashi Chuo Bank processed the transactions.
- Dr K Raghavan, co-founder & consultant paediatric neurologist, JAICARE Hospital, Madurai, India
- Mr Takashi Onaka, founder & chairman, Sophy Inc, Kochi, Japan
Samuel JK Abraham , a clinician and scientist, is involved in an array of interdisciplinary research on biomaterial-based tissue engineering to develop cell-based therapies in regenerative medicine, immune modulation through gut microbiome & NK cells based anti-cancer solutions, and in vitro cellular senescence, micro-gravity-based enhancement of cellular function.
Dr K Raghavan
Mr Takashi Onaka
3-8 Wakamatsu, Kofu 400-0866, Yamanashi, Japan