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

Raghavan, Kadalraja; Dedeepiya, Vidyasagar Devaprasad; Srinivasan, Subramani; Pushkala, Subramanian; Bharatidasan, Sudhakar S; Ikewaki, Nobunao; Iwasaki, Masaru; Senthilkumar, Rajappa; Preethy, Senthilkumar; Abraham, Samuel JK

doi:10.1016/j.ibneur.2023.06.007

Cited by 6 publications

(12 citation statements)

References 41 publications

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“…Followed by that, in a human clinical study, the N-163 strain produced BRMG has shown in 27 patients with DMD, significant anti-inflammatory effects evident from decrease of IL-6 and anti-fibrotic effects evident from decrease in TGF-β levels. Plasma dystrophin levels increased by up to 32% in that study and medical research council (MRC) grading showed muscle strength improvement in 12 out of 18 patients (67%) in the treatment group 8 . However, studying some of the intricate effects on inflammation and fibrosis by extensive muscle biopsies that are required is not feasible in human clinical studies.…”

Section: Introductionmentioning

confidence: 68%

Resolution of fibrosis in mdx dystrophic mouse after oral consumption of N-163 strain of Aureobasidium pullulans produced β-glucan

Preethy,

Aoki,

Minegishi

et al. 2023

Sci Rep

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Recent advances in the management of Duchenne muscular dystrophy (DMD), such as exon skipping and gene therapy, though have reached a clinical stage, the outcome at its best is still considered suboptimal. In this study, we evaluated a novel N-163 strain of Aureobasidium pullulans produced β-glucan (Neu-REFIX) for its potential as an adjuvant to slow down the progression of the disease by anti-inflammatory and anti-fibrotic effects. In this study, 45 mice in the three groups, 15 each in a group; Gr. 1 normal mice, Gr.2 mdx mice as vehicle, and Gr.3 mdx mice administered the N-163 β-glucan for 45 days. The N-163 β-glucan group showed a significant decrease in the plasma ALT, AST, and LDH levels (126 ± 69 U/l, 634 ± 371 U/l, 3335 ± 1258 U/l) compared with the vehicle group (177 ± 27 U/l, 912 ± 126 U/l, 4186 ± 398 U/l). Plasma TGF-β levels increased, and plasma IL-13 levels decreased in the N-163 group. The inflammation score of HE-stained muscle sections in the N-163 group (1.5 ± 0.8) was lower than that in the vehicle group (2.0 ± 0.8). The N-163 strain β-glucan group (24.22 ± 4.80) showed a significant decrease in the fibrosis area (Masson’s Trichrome-positive area) compared with the vehicle group (36.78 ± 5.74). The percentage of centrally nucleated fibres evaluated by Masson’s trichrome staining was 0 in the normal group, while it increased to 80% in the vehicle group but remained at 76.8% in the N-163 group. The N-163 β-glucan group showed a significant decrease in the fibrosis area. Considering their safety and easy oral consumption, Neu-REFIX β-glucan could be worth large multicentre clinical studies as adjuvant in slowing down the progress of DMD.

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Section: Introductionmentioning

confidence: 68%

Resolution of fibrosis in mdx dystrophic mouse after oral consumption of N-163 strain of Aureobasidium pullulans produced β-glucan

Preethy,

Aoki,

Minegishi

et al. 2023

Sci Rep

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“…These effects included the regulation of gut dysbiosis, enhancement of butyrate producers, and metabolites, including endogenous butyrate production and amino acids. Importantly, these results correlated with the improvement in the clinical parameters of relevance [6,7].…”

Section: Introductionmentioning

confidence: 73%

Beneficial changes in the gut microbiome of patients with multiple sclerosis after consumption of Neu-REFIX B-glucan in a clinical trial

Dedeepiya,

Vetrievel,

Ikewaki

et al. 2023

Preprint

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Background: Multiple sclerosis (MS) is a debilitating demyelinating disease and recent evidences are giving cues towards correlation of disease severity to gut microbiome dysbiosis. However, there have not been any reported interventions that beneficially modifies the gut microbiome to yield a clinically discernible improvement. Having earlier reported the clinical effects of a biological response modifier beta-glucan (BRMG) produced by the N-163 strain of Aureobasidum pullulans, commercially available as Neu-REFIX, which decreased the biomarkers of inflammation and produced beneficial immune-modulation in twelve MS patients in 60 days, we evaluated their gut microbiome in the present study. Methods: Twelve patients diagnosed with MS participated in the study. Each consumed 16 g gel of the NEU-REFIX beta-Glucan for 60 days. Whole genome metagenomic sequencing was performed on the fecal samples before and after Neu-REFIX intervention. Results: Post-intervention analysis showed that Actinobacteria followed by Bacteroides was the major family. Abundance of beneficial genera such as Bifidobacterium, Collinsela, Prevotella, Lactobacillus and species such as Prevotella copri (p-value=0.4), Bifidobacterium longum (p-value=0.2), Faecalibacterium prausnitzii (p-value=0.06), Siphoviridae (p-value=0.06) increased while inflammation associated genera such as Blautia (p-value=0.06), Ruminococcus (p-value=0.007) and Dorea (p-value = 0.03) decreased in abundance. Conclusion: Restoration of gut eubiosis in terms of both increase in abundance of the good microbiome and suppression of the harmful ones which also correlate with earlier reported clinical improvement in MS patients makes this Neu-REFIX beta-glucan, a potential disease modifying therapy (DMT) requiring larger studies for validation in MS and other auto-immune-inflammatory conditions where a safe intervention for immune modulation is vital.

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“…Additionally, if the therapeutic strategy can also address inflammation and enhance muscle regeneration, it will be ideal. The N-163 beta-glucan (Neu-REFIX) strategy has demonstrated its potential in reducing DMD fibrosis and inflammation in earlier clinical and pre-clinical studies by decreasing the inflammation score, plasma TGF-β levels and plasma IL-13 apart from enhancing muscle regeneration and clinically relevant improvement in ambulation [5][6][7][8]. In the current study, its effects on significant decrease in collagen Type-I in the myocardium of mdx mice proves its potential as a anti-fibrotic agent in both DMD as well as myocardial fibrosis at a tissue level.…”

Section: Resultsmentioning

confidence: 99%

“…Medications that target fibrosis including cardiac fibrosis are in the early stages of development. We have previously reported the anti-inflammatory, anti-fibrotic and immune-modulating effects of a biological response modifier beta-glucan (BRMG) produced by the N-7 163 strain of Aureobasidium pullulans (A.pullulans) (Trade name: Neu-REFIX) in pre-clinical mdx mice model [5,6] and human clinical studies of DMD [7,8]. In the current study we wanted to evaluate the effects of this Neu-REFIX beta-glucan food supplement on myocardial fibrosis in mdx mice model of DMD.…”

Section: Introductionmentioning

confidence: 99%

“…CC-BY-NC-ND 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted September 28, 2023. ; https://doi.org/10.1101/2023.09.25.559276 doi: bioRxiv preprint 7 163 strain of Aureobasidium pullulans (A.pullulans) (Trade name: Neu-REFIX) in pre-clinical mdx mice model [5,6] and human clinical studies of DMD [7,8]. In the current study we wanted to evaluate the effects of this Neu-REFIX beta-glucan food supplement on myocardial fibrosis in mdx mice model of DMD.…”

Section: Introductionmentioning

confidence: 99%

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Reduction in myocardial fibrosis in MDX mice on oral consumption ofAureobasidium Pullulansproduced Neu REFIX Beta-glucans; holds potential as an adjuvant in managing post-transplantation organ fibrosis

Preethy,

Yamamoto,

Cherian

et al. 2023

Preprint

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Organ fibrosis is one of the major causes of morbidity and mortality globally. Though fibrosis in genetic diseases such as Duchenne muscular dystrophy (DMD) may be attributed to the genetic defect, chronic microinflammation remains a key mechanism underlying such fibrosis, which also precedes both other organ fibrosis and post-organ transplant fibrosis. Having proven the anti-inflammatory, anti-fibrotic effects of Beta-1,3-1,6-glucan (Neu-REFIX) produced by N-163 strain ofAureobasidium Pullulansin earlier clinical and pre-clinical studies, we performed the current study to evaluate its effects on myocardial fibrosis. N-163 beta-glucan was administered to 45 mice in three groups, each fifteen animals, Gr. 1, normal mice, Gr.2, mdx mice as vehicle, Gr.3, mdx mice which were administered Neu REFIX beta-glucan orally. Evaluation of Collagen Type I (Col-I) in myocardium was performed by immunohistochemistry. Percentage of myocardium Col-I positive area of 6.42 ± 2.67 significantly decreased in the Neu-REFIX group (4.32 ± 1.78) (p-value < 0.01). As myocardial fibrosis has been shown to be reduced following treatment with N-163 beta glucan in a genetic, muscle structure anomaly disease such as DMD, in addition to adding value to DMD patients, in whom myocardial failure occurs in the advanced stages leading to pre-mature death, Neu-REFIX beta-glucan adjuvant treatment in the setting of solid organ transplantation may be of value to reduce the incidence of fibrosis which is a known feature of chronic allograft rejection leading to graft loss.

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

Cited by 6 publications

References 41 publications

Resolution of fibrosis in mdx dystrophic mouse after oral consumption of N-163 strain of Aureobasidium pullulans produced β-glucan

Resolution of fibrosis in mdx dystrophic mouse after oral consumption of N-163 strain of Aureobasidium pullulans produced β-glucan

Beneficial changes in the gut microbiome of patients with multiple sclerosis after consumption of Neu-REFIX B-glucan in a clinical trial

Reduction in myocardial fibrosis in MDX mice on oral consumption ofAureobasidium Pullulansproduced Neu REFIX Beta-glucans; holds potential as an adjuvant in managing post-transplantation organ fibrosis

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