Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Chromatin accessibility as assessed by histone modifications at the level of promotors (H3K4me3, H3K27Ac) or enhancers (H3K4me1) is an important mechanism mediating these programs. Through network-level integration of transcriptomics, epigenetics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by beta-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming. Furthermore, fumarate itself induces trained immunity, with induction of an epigenomic program similar to β-glucan-induced trained immunity. In addition, the first steps in the cholesterol synthesis pathway leading to mevalonate accumulation contributes to induction of trained immunity. Monocytes from patients with mevalonate kinase deficiency and hyper IgD syndrome display a trained immunity phenotype. Identification of the metabolic pathways contributing to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.
The impact of gut microbiomes on health has recently become more important. More focus should be placed on their function in neurological diseases since a number of metabolites and other substances generated by the gut have an impact on the brain via the gut-brain axis [1]. With proven effectiveness against metabolic illnesses, diabetes, cancer, cardiovascular diseases, and neurological diseases, beta-glucans are among the most promising dietary supplements. 1,3-1,6 beta-glucans from two strains of the black yeast Aureobasidium pullulans, AFO-202 (Trade name: Nichi Glucan) and N-163 (Trade name: Neu-REFIX), have demonstrated promising results in the treatment of a number of illnesses and ailments. In a study of these beta-glucans on the gut microbiota and faecal metabolome in an animal model of non-alcoholic steatohepatitis (NASH) [2], the gut microbial diversity significantly increased in the AFO-202+N-163 group. Following intervention, the quantity of Bacteroides grew and was greatest in the AFO-202+N-163 group, whereas Firmicutes declined. The AFO-202 and N-163 groups, respectively, showed the largest declines in the abundance of harmful bacteria such as Turicibacter, Bilophila, Enterobacteriaceae and other Firmicutes. There was increase in beneficial bacteria such as Lactobacillus. Beneficial metabolites including butyrates increased. In a randomized pilot clinical study in children with autism [3],. AFO-202 beta 1,3–1,6 glucan, in addition to balancing the gut microbiome, there was effective control of curli-producing Enterobacteriaceae that leads to α-synuclein misfolding and accumulation, thus making these beta-glucans hold potential for prophylactic role in Parkinson’s and Alzheimer’s diseases as well. In a study in patients with multiple sclerosis [4], after consumption of N-163 beta-glucan, Actinobacteria followed by Bacteroides was the major family while beneficial genera such as Bifidobacterium, Collinsela, Prevotella and Lactobacillus’s abundance increased; Prevotella copri, Bifidobacterium longum, Faecalibacterium prausnitzii, Siphoviridae were the species whose abundance was increased. Harmful genera such as Blautia and Dorea decreased in abundance post-intervention. In patients with Duchenne muscular dystrophy (DMD) [5], after N-163 beta-glucan administration, there was an increase in butyrate-producing species such as Roseburia and Faecalibacterium prausnitzii. There was a decrease in harmful bacteria associated with inflammation such as enterobacteria and Alistipes. In all these studies, importantly, there was correlation of improvement in clinical parameters as well [6,7,8,9]. Thus these two beta-glucans (Nichi Glucan and Neu-REFIX) hold potential as disease modifying adjuncts in several diseases especially in neurology, by controlling inflammation, regulation of immunity such as trained immunity at an epigenetic level [10] apart from providing beneficial effects via their effects on the gut microbiome.
References
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