patrick.net

Epigenetic reprogramming of innate immunity involves regulating the genes that induce or suppress inflammatory signalling, such as pro-inflammatory chemokines and cytokines; dysregulation of which is responsible for the cytokine storm (37). Different epigenetic modifications control the gene expression of many of these regulators. The remarkable impact of epigenetic changes in inducing or suppressing inflammatory signalling is increasingly being recognised. Several studies have highlighted the interplay of histone modification, DNA methylation, and post-transcriptional proinflammatory microRNAs (miRNAs)-mediated modifications in inflammatory diseases (38).

Histone modification

Numerous phytochemicals have been shown to regulate epigenetic mechanisms and inhibit aberrant inflammation. One study found that 99% of 200 government approved traditional Chinese medicine (TCM) formulas are histone-modifying agents (including through histone acetylation, a critical epigenetic modification etc.) and that 36% of the 3,294 TCM medicinals interact with human histone-modifying enzymes (39).

DNA methylation

Several studies show that numerous phytochemicals [resveratrol, curcumin, genistein and epigallocatechin-3-gallate (EGCG) can inhibit DNA methyltransferases (DNMT) activity or downregulate DNMT expression, and modulate DNA methylation (40).

MicroRNAs-mediated modification

It has recently been shown that phytochemicals, including resveratrol, EGCG, curcumin, quercetin, 3,3′-diindolylmethane (DIM), sulforaphane, genistein, boswellic acid, silymarin, β-Sitosterol-d-glucoside etc., may regulate the expression of miRNAs to exert their anticancer effects by altering miRNA expression (41).

PRR antagonism/agonism

Natural PRR antagonists are a potential therapeutic agent in chronic inflammatory diseases. Phytochemicals have been studied as possible immunomodulating agents due to their multiple and pleiotropic (produce more than one) effects. Phytochemicals have been shown to inhibit PRRs, including TLRs, by recognising PAMPs and activating innate immune responses for host defence (42). On the contrary, TLR agonists are a class of agents which have been shown to trigger the phenomenon of trained immunity through metabolic reprogramming and epigenetic modifications (43). Many phytochemicals including curcumin, naringenin, piperine, baicalin, paeoniflorin, oxyberberine, eriodictyol etc. have been demonstrated to target TLR4 (44). An article published in Frontiers in Immunology in March 2021 describes how phytochemicals modulate the TLR4/NF-κB pathway by regulating the expression of proinflammatory miRNAs, especially those upregulated after NF-κB activation (38). Again, NF-κB is the master regulator of innate immune responses and TLR4 regulates trained immunity (21, 27). These phytochemicals will be discussed further in ‘Herbal Medicine to Train Innate Immunity: Part I’.

Metabolo-epigenomics

As described, the interplay between metabolism and epigenetics to support trained immunity is termed metabolo-epigenomics or immunometabolism. Metabolic reprogramming of monocytes (differentiate into macrophages and DCs) and trained immunity, in particular, has been studied (15). Two sides to innate immunity and macrophages have been found; training (functional, metabolic and epigenetic adaptation of innate immunity) and tolerance (prevention of an immune response against a particular antigen) (45). Whilst both metabolic and epigenetic reprogramming are key regulatory mechanisms of trained immunity, many of these mechanisms are still poorly understood at the biochemical level. To understand the epigenetic regulatory mechanisms of trained immunity, one also needs to understand the role of specific metabolites and metabolic networks involved (14).

During infection innate effector cells require large amounts of energy in the form of adenosine triphosphate (ATP). Glycolysis and fatty acid oxidation (FAO) are the main sources of ATP, although carbohydrates, fats and proteins drive ATP synthesis (37). Flavonoid-mediated immunomodulation of human macrophages involves key metabolites and metabolic pathways including glycolysis, amino acid metabolism, tricarboxylic acids (TCA) cycle and oxidative phosphorylation (OxPhos). Studies on macrophages exposed to phytochemicals have explored these metabolites and metabolic pathways. Flavonoids influence different metabolic pathways to have a broad range of metabolic effects on pro-inflammatory macrophages. Three flavonoids (quercetin, naringenin and naringin) were tested and the metabolic effects common to all flavonoids were restricted to decreased lactate and ATP levels. Quercetin and naringenin promoted a decrease in succinate, alanine, creatine and phosphocreatine (fuel sources for mitochondria to produce ATP) whereas naringenin and naringin-treated macrophages displayed increased glutamate and adenosine diphosphate (ADP) levels. Whilst an increased intracellular ADP: ATP ratio is recognised as an indicator of cell death, this study showed that, despite the relative decrease in ATP and the concomitant increase in ADP, the viability of macrophages incubated for 24 h with flavonoids was not compromised (46).

Beneficial gut microbiota

Gut microbiota (GM) can influence the generation of innate memory. Some intestinal genes related to innate immunity are influenced by microbiota through DNA methylation (47). As mentioned, innate immunity relies on self-(like) PRRs. The intestine maintains control over the intestinal microflora utilising the innate immune response with TLR involvement (48). Beneficial gut microbiota (BGM) as a source of PAMPs, is recognised by PRRs on innate immune cells, thus a potential role exists for GM to induce and regulate innate immune memory. Training of PRRs expressing innate cells with gut microbial/non-microbial ligands is a required protective mechanism (49). PRR and PAMP interaction is pivotal as it triggers the sequence of signalling events and epigenetic rewiring that not only play a fundamental role in modulating the activation and function of the innate cells, but also to convey memory response (49). Many herbal medicines (HMs) increase BGM.

The first pathway

The first pathway is that the GM ‘digests’ HMs into absorbable active small molecules, which enter the body and induce physiological changes. The TCM formula Shi Quan Da Bu Tang (Ten Significant Tonic Decoction) can alter the expression of heat shock protein (HSP) genes in the intestine and liver. This formula is known as Juzentaihoto in traditional Japanese Kampo medicine. HSPs are known as the ‘intestinal gatekeeper’ and protect intestinal epithelial cell function (50, 51). HSPs also stimulate innate and acquired immunity (52).

The second pathway

The second pathway is that HMs regulate the composition of the GM and its secretions to induce physiological changes. For example, Indian mulberry (Morinda officinalis/ Ba Ji Tian) can reduce the abundance of the pathogenic GM, and increase the abundance of BGMs such as Lactobacillus and Bifidobacterium. Liquorice (Glycyrrhiza glabra/ Gan Cao) also promotes increases in Lactobacillus and Bifidobacterium. Southern ginseng (Gynostemma pentaphyllum/ Jiao Gu Lan) may effectively increase BGM levels, reduce sulphate-reducing bacteria levels, and inhibit several pro-inflammatory cytokines. Garlic (Allium sativum L./ Da Suan), southern ginseng and astragalus (Astragalus membranaceus/ Huang Qi) have been used to increase the levels of Lactobacillus in the small intestine of chickens(53). The traditional Japanese Kampo HM formula Bofutsushosan increases the abundance of BGM. Bofutsushosan is also known as Fang Feng Tong Sheng San in TCM. The formula consists of schizonepeta, (Shizonepetae spica/ Jing Jie Sui), liquorice root (Glycyrrhiza uralensis / Gan Ciao), ephedra (Ephedra sinica/ Ma Huang), and forsythia fruits (Forsythiae fructus/ Lian Qiao). Other TCM formulas including, Bawei Xileisan, Wuji Wan, and Gegen Qinlian, also increase the abundance of BGM. The phytochemical rhein, derived from rhubarb (Rheum palmatum/ Da Huang) increases BGM (53).

Polysaccharides (complex carbohydrates), comprise starches and dietary fibres. Plant polysaccharides benefit the growth, promotion and proliferation of intestinal epithelial cells. Many HMs contain polysaccharides which cannot be ‘digested’ by ordinary digestive enzymes, thus Bifidobacterium and Bacteroides secrete hydrolases and reductases, such as d-glucosidase, β-glucuronidase, and β-glucosidase, which assist carbohydrate and protein breakdown. These digestive enzymes convert molecules in HMs into smaller units through oxidation, reduction, and acetylation (53). Polysaccharides assist in stimulating the fermentation rate and increasing the production of short-chain fatty acids (SCFAs), which benefit the differentiation and proliferation of intestinal epithelial cells (54). HMs are an important source for SCFA production, and HMs have been demonstrated to modulate GM composition and regulate SCFA production (55). Butyrate is a SCFA produced by the GM. Recently, butyrate has gained attention as a powerful immune modulatory metabolite in vitro and in vivo. This has been linked to its potent activity as a histone deacetylase (HDAC) inhibitor. Via (histone deacetylase 3) (HDAC3) inhibition, butyrate preconditioning of macrophages enhances their anti-bacterial properties, which enhances glycolysis and mammalian target of rapamycin (mTOR) functions, facilitating an inflammatory response (56). HMs can also play a role by regulating other GM secretions including hippurate, trimethylamine oxide (TMAO) and lipopolysaccharide (LPS) (38).

Conclusion

Coronaviruses have evolved multiple means to evade host antiviral immune responses (14). A distinguishment must be made between immune-modulating mechanisms that can mitigate infection and disease and immune effector mechanisms that neutralise (kill) the virus or kill virus-infected cells. All antiviral mechanisms are prone to immune escape, especially when operating during a pandemic, unless they are non-selective (e.g., NAbs and NK cells). Whilst ‘training’ of innate immunity is only achieved by exposure of innate IgM-producing B cells to these self-like glycan patterns at the surface of the virus, the full benefit of training can only be exploited by a fully functional innate immune system. This can be achieved by optimising health and properly educating (i.e., functional reprogramming) innate immune cells to ensure their improved adaptation to the pathogen. Whilst a greater understanding at a biochemical level needs to be had, HMs have been shown to both epigenetically and metabolically reprogramme innate immunity, not only due to their phytochemical content, but also because they feed BGM which acts as a source of PAMPs to train innate immunity. As GVB warns, the danger humanity faces is that innate immunity may be wiped out by C-19 vaccines. The positive news is that dietary and lifestyle changes can contribute to a fully functioning immune system, so that when our innate cells are exposed to the virus again, they can get the full benefit of training. Look out soon for a follow-on articles in VSS entitled, ‘Herbal Medicine to Stimulate Innate Immunity: Part I and II’. In good health be.

https://voiceforscienceandsolidarity.substack.com/p/how-herbal-medicines-reprogramme