Epigenetics

Intergenerational epigenetic inheritance of trained immunity, Part 2

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Memory, Stress , ,

A 2022 McGill University rodent study couldn’t replicate Part 1 findings:

“We find that using similar mouse models of trained immunity induced by:

  1. Live vaccination (BCG);
  2. PAMPs (β-glucan); or
  3. Infection (C. albicans),

protection against:

  1. Viral (influenza virus);
  2. Bacterial (Mycobacterium tuberculosis (Mtb)); or
  3. Fungal (C. albicans)

infections was the same between offspring of trained and non-trained parents.

BCG-vaccination-in-the-offspring-of-vaccinated-parents-does-not-enhance-trained-immunity_W640

BCG vaccination in the offspring of vaccinated parents does not enhance trained immunity in macrophages.

a) Mice were vaccinated with BCG-iv (1 × 10⁶ CFU) for one month and mated with vaccinated or naive counterparts. 6–8 week-old F1.1 and F1.3 offspring were then vaccinated or not with BCG-iv (1 × 10⁶ CFU).

b), c) At 1 month post BCG vaccination, protective capacities of BMDM from BCG-iv vaccinated and nonvaccinated F1.1 (b), or F1.3 (c) offspring from naïve or BCG-iv vaccinated parents were assessed against M. tuberculosis (H37Rv, MOI 1) infection. * p < 0.05.”

https://www.nature.com/articles/s41590-021-01102-0 “Lack of evidence for intergenerational inheritance of immune resistance to infections” (not freely available)

Part 1 coauthors replied:

“We are very encouraged that this topic is gaining increased interest. The reason for the discrepancy between findings in the two studies is unclear. It likely involves local differences in mouse substrains, housing, diet, microbiome, infection models, or other factors.

These findings underscore the effect of environment on intergenerational inheritance of infection resistance. What these environmental factors are and how these factors are integrated with regards to intergenerational inheritance remains largely elusive at this time.

One intriguing possibility that needs to be tested in future studies is whether such effects may be more robust in outbred wild mice, in which subtle environmental changes may have less strong impact.”

https://www.nature.com/articles/s41590-021-01103-z “Reply to: ‘Lack of evidence for intergenerational inheritance of immune resistance to infections'”

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Lifespan Uber Correlation

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebellum, Cerebrum, Epigenetics, Immune system, Lower brain , , , , ,

This 2022 study developed new epigenetic clocks:

“Maximum lifespan is deemed to be a stable trait in species. The rate of biological function decline (i.e., aging) would be expected to correlate inversely with maximum species lifespan. Although aging and maximum lifespan are intimately intertwined, they nevertheless appear in some investigations to be distinct processes.

Some cytosines conserved across mammals exhibit age-related methylation changes so consistent that they were used to successfully develop cross-species age predictors. In a similar vein, methylation levels of some conserved cytosines correlate highly with species lifespan, leading to the development of highly accurate lifespan predictors. Surprisingly, little to no commonality is found between these two sets of cytosines.

We correlated the intra-species age correlation with maximum lifespan across mammalian species. We refer to this correlation of correlations as Lifespan Uber Correlation (LUC).

We overlapped genes from the LUC signature with genes found in human genome-wide association studies (GWAS) of various pathologies and conditions. With all due caution, we report that some genes from the LUC signature were those highlighted by GWAS to be associated with type II diabetes, stroke, chronic kidney disease, and breast cancer.

Human aging genes vs mammalian LUC

We used the subset of CpGs found to be significant in our LUC to build age estimators (epigenetic clocks). We demonstrated that these clocks are able to capture effects of interventions that are known to alter age as well as lifespan, such as caloric restriction, growth hormone receptor knockout, and high-fat diet.

We found that Bcl11b heterozygous knockout mice exhibited an increased epigenetic age in the striatum. BCL11B is a zinc finger protein with a wide range of functions, including development of the brain, immune system, and cardiac system.

This gene is also implicated in several human diseases including, but not limited to, Huntington disease, Alzheimer’s diseases, HIV, and T-cell malignancies. BCL11B plays an important role in adult neurogenesis, but is less studied in the context of lifespan disparities in mammals.

Bcl11b knockout affected both DNA methylation and mRNA expression of LUC genes. Our current study does not inform us about the potential role of Bcl11b in aging processes during adulthood since observed patterns could be attributed to developmental defects.

We are characterizing other genetic and non-genetic interventions that perturb the LUC clocks. These we will feature in a separate report that will uncover biological processes regulated by LUC cytosines and their associated genes.”

https://www.biorxiv.org/content/10.1101/2022.01.16.476530v1 “Divergent age-related methylation patterns in long and short-lived mammals”

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Gut microbiota’s positive epigenetic effects

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Three papers with the first a 2021 review:

“Gut microbiota along with their metabolites are involved in health and disease through multiple epigenetic mechanisms including:

  • Affecting transporter activities, e.g. DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs);
  • Providing methyl donors to participate in DNA methylation and histone modifications; and
  • miRNAs that can lead to gene transcriptional modifications.

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These mechanisms can participate in a variety of biological processes such as:

  • Maturation of intestinal epithelial cells (IECs);
  • Maintenance of intestinal homeostasis;
  • Inflammatory response;
  • Development of metabolic disorders; and
  • Prevention of colon cancer.”

https://www.mdpi.com/1422-0067/22/13/6933/htm “Dissecting the Interplay Mechanism between Epigenetics and Gut Microbiota: Health Maintenance and Disease Prevention”

A second 2022 review added subjects such as crotonate (aka unsaturated butyrate):

“Studies are carving out potential roles for additional histone modifications, such as crotonylation and ethylation, in facilitating crosstalk between microbiota and host. Lysine crotonylation is a relatively less studied histone modification that is often enriched at active promoters and enhancers in mammalian cells.

While addition or removal of crotonyl motifs can be catalyzed by specialized histone crotonyltransferases and decrotonylases, HATs and HDACs have also been reported to exhibit histone crotonyl-modifying activity. Microbiota stimulate multiple types of histone modifications and regulate activity of histone-modifying enzymes to calibrate local and extra-intestinal chromatin landscapes.”

https://www.tandfonline.com/doi/full/10.1080/19490976.2021.2022407 “Epigenetic regulation by gut microbiota”

A third 2021 review added subjects such as broccoli sprout compounds’ epigenetic effects:

“Glucosinolates are converted into isothiocyanates (ITCs) by bacteria that regulate host epigenetics. Levels of ITCs produced following broccoli consumption are highly dependent on the functional capacity of individual microbiomes, as much interindividual variability exists in gut microbiota composition and function in humans.

Sulforaphane inhibits HDAC activity both in vitro and in vivo, and protects against tumor development. Microbial-mediated production of ITCs represents a strong diet-microbe interaction that has a direct impact on host epigenome and health.”

https://www.sciencedirect.com/science/article/pii/S0955286321000516 “The interplay between diet, gut microbes, and host epigenetics in health and disease”

Clearing the channel

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The aryl hydrocarbon signaling pathway

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Neurochemicals, Serotonin, Stress , ,

I’ll emphasize this densely packed 2021 review’s broccoli sprout compounds / gut microbiota / health interactions:

“The aryl hydrocarbon receptor (AhR) senses cues from environmental toxicants and physiologically relevant dietary/microbiota-derived ligands. AhR signaling mediates bidirectional host-microbiome interactions in a wide range of cellular functions in a ligand-, cell type-, species-, and context-specific manner.

Brassicaceae family plants are rich sources of glucobrassicin, the glucosinolate precursor of indole-3-carbinol (I3C). Glucobrassicin can be enzymatically hydrolyzed and converted into I3C by myrosinase, which is present in intact plant cells and gut microbiota.

I3C activates AhR but exhibits low binding affinity. However, in acidic conditions found in the stomach, I3C undergoes acid condensation reaction to generate a variety of more potent AhR ligands, such as 3,3′-diindolylmethane (DIM).

AhR activation by natural AhR ligands (e.g., I3C) has been shown to prevent pathogenic gut microbial dysbiosis by altering gut microbiome composition in mice with colitis. Depletion of AhR ligands in the diet decreased α diversity of gut microbiota, while I3C supplementation restored microbiota composition.

I3C treatment is effective for treating IBD patients, partly by upregulating IL-22. Targeting AhR could modulate the amplitude and duration of IL-22 signaling to treat IBD patients.

Administration of I3C or DIM significantly reduced the number of tumors in the cecum and small intestine. Supplementation of I3C reduces the number of colorectal tumors in WT, but not in AhR null mice.

nihms-1759454-f0003

Gut microbiota and diet are major sources of AhR ligands that influence the whole body, including gut, liver, brain, and the immune system. Many human diseases are associated with decreased circulating levels of AhR ligands, partly due to dysbiosis.

The ability of AhR signaling to regulate self-renewal and differentiation of intestinal stem cells intrinsically or extrinsically has recently been brought into the spotlight.”

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8667662/ “Diet–Host–Microbiota Interactions Shape Aryl Hydrocarbon Receptor Ligand Production to Modulate Intestinal Homeostasis”

Young hawk

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Every baby needs a sugar mama

gettingwell4 2-3 stars Required further work, Epigenetics, Immune system , ,

This 2021 in vitro study examined butyrate producers:

“Butyrate produced by gut microbiota has multiple beneficial effects on host health. Oligosaccharides derived from host diets, and glycans originating from host mucus, are major sources of its production.

Butyrate is the major energy source for epithelial cells in the distal colon, induces differentiation of colonic regulatory T cells, and functions as an inhibitor of host histone deacetylase. These activities are essential for documented beneficial properties of butyrate, including anti-inflammation, gut immune homeostasis, inhibition of proliferation, and induction of apoptosis of colorectal cancer cells.

FOS-type oligosaccharides (kestose, nystose, fructooligosaccharide) were metabolized by only 6 of 14 butyrate-producing strains tested:

Growth of butyrate producers

Faecalibacterium prausnitzii, which is the most abundant butyrate producer in the healthy human gut, metabolized only FOS-type oligosaccharides among tested oligosaccharides. Anaerostipes spp. exhibited a similar pattern, except that A. caccae metabolized kestose but not nystose.

Glycoside hydrolase (GH)32 enzymes exhibiting FOS degradation activities were conserved in all six strains metabolizing FOS, and in three of the eight strains that did not metabolize FOS. This suggests that GH32 enzymes in those three strains are not actively used in metabolism.

The present study highlighted that even if functional genes are present in microbes, they are sometimes unable to metabolize substrates. This should be carefully considered in metagenomic studies to understand metabolic potential of gut microbiota.”

https://www.tandfonline.com/doi/full/10.1080/19490976.2020.1869503 “Characterization of fructooligosaccharide metabolism and fructooligosaccharide-degrading enzymes in human commensal butyrate producers”

These researchers had some work to do to show that selected strains’ characteristics were representative of their species. This post’s title was excerpted from Citation 37.

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Sulforaphane vs. too much oxygen

gettingwell4 5+ stars Premium, Epigenetics, Immune system, Memory, Stress , , ,

This 2021 rodent study investigated perinatal effects of hyperoxia and sulforaphane:

“We demonstrated that early-life oxidant-induced acute lung injury had significant consequences later in life on NRF2-dependent respiratory syncytial virus (RSV) susceptibility in mice. We also determined that increased antioxidant conditions in utero potentially contribute to a decreased risk of postnatal airway disease as we found that prenatal antioxidant sulforaphane (SFN) protected developing lungs from bronchopulmonary dysplasia (BPD)-like oxidative pathogenesis in mice.

Unexpectedly, our results indicated that prenatal SFN-mediated postnatal protection against BPD-like phenotypes are not NRF2-dependent. Prenatal SFN markedly improved hyperoxia-caused severe BPD-like lung injury parameters in Nrf2−/− pups while we observed relatively marginal protection by in utero SFN in hyperoxia-resistant Nrf2+/+ pups.

SFN is a strong NRF2 and ARE gene inducer for cytoprotection by NRF2 stabilization. However, SFN also acts through other mechanisms, including NF-κB inhibition, MAPK activation, and histone deacetylase inhibition for anti-inflammation, chemoprevention, apoptosis, and autophagy.

Our study provided new insights into infant oxidant lung injury severity influence on persistence of pulmonary morbidity and therapeutic intervention for NRF2 agonists. Our results also provided justification for further studies on feto–placental barrier crossing of SFN metabolites and SFN-triggered molecular and epigenetic aspects of maternal cues for barrier and fetal lung signaling.”

https://www.mdpi.com/2076-3921/10/12/1874/htm “Murine Neonatal Oxidant Lung Injury: NRF2-Dependent Predisposition to Adulthood Respiratory Viral Infection and Protection by Maternal Antioxidant”

This study’s oral human-equivalent dose for treatment dams was 9 mg sulforaphane (1.67 mg x .081 x 70 kg) every other day during the last half of pregnancy. A small dose per How much sulforaphane is suitable for healthy people?

“The daily SFN dose found to achieve beneficial outcomes in most of the available clinical trials is around 20-40 mg.”

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Eat broccoli sprouts for your workouts

gettingwell4 2-3 stars Required further work, Epigenetics, Stress

This 2021 human study investigated effects of pre- and post-workout glucoraphanin intake:

“The tablets used in this study contained 30 mg/3 tablets of sulforaphane glucosinolate [properly termed glucoraphanin], a precursor of sulforaphane (SFN), which is converted to SFN in the intestinal lumen by intestinal microflora. Subjects took one tablet of SFN supplement per meal, three times a day. Healthy men without exercise habits, smoking, or medication were included in the experiment:

eccentric exercise subjects

Pain on palpation reached its peak 1–2 days after exercise and recovered to baseline 5 days after exercise. Muscle soreness on palpation and range of motion were significantly lower 2 days after exercise in the sulforaphane group:

range of motion

Serum malondialdehyde, an indicator of exercise-induced oxidative stress, showed significantly lower levels 2 days after exercise in the sulforaphane group. SFN intake may protect the balance of antioxidant capacity and suppress excessive oxidative stress caused by exercise.

Continuation of SFN intake – from 2 weeks before and up to 4 days after eccentric exercise – suppressed exercise-induced oxidative stress and inhibited muscle soreness and muscle damage. To our knowledge, this study is the first to analyze these effects of SFN in humans.”

https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.15130 “Effect of a sulforaphane supplement on muscle soreness and damage induced by eccentric exercise in young adults: A pilot study”

This study found that four days wasn’t enough time for 19-to-23-year-old men to fully recover from bicep eccentric exercise, regardless of glucoraphanin treatment or control group status. What’s an appropriate exercise recovery time? found a similar result using taurine as treatment with 20-to-33-year-old recreationally fit men who didn’t fully recover from bicep eccentric exercise after three days.

These researchers referenced Autism biomarkers and sulforaphane to acknowledge that this study’s daily 30 mg of glucoraphanin wasn’t sufficient to fully activate Nrf2 signaling pathways:

“When SFN was added to PBMCs of healthy subjects in ex vivo experiments, NQO1 expression was increased, while HO-1 was not increased at a low SFN concentration (0.5 µM). However, when 2 or 5 µM of SFN was added to PBMCs, both NQO1 and HO-1 gene expression were increased. Concentration of the SFN supplement may be a reason why the amount of supplementation used in our protocol did not increase HO-1 expression.”

I create isothiocyanates by microwaving 3-day-old broccoli / red cabbage / mustard sprouts at 1000 W to 60°C (140°F) shortly before eating them. Unlike this study, I don’t depend on metabolism after the stomach to produce isothiocyanates from glucosinolates:

  • Less dependence on these subjects’ gut microbiota for sulforaphane production would have reduced a source of dose variability. Broccoli sprout compounds and gut microbiota first paper reviewed that subject.
  • Glucoraphanin intake with nothing else an hour before and after would have also reduced chances of sulforaphane loss by reacting with food. See Week 19 item 2 for two studies that found eating protein, fats, and fiber along with broccoli sprouts lowered isothiocyanates’ bioavailability.

Still, this was a step forward in research. Have fun with New Year’s resolutions.

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Defend yourself with taurine

gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Brain development, Cerebellum, Cerebrum, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Locus coeruleus, Lower brain, Neurochemicals, Stress , ,

This densely packed 2021 review subject was taurine:

“Taurine (Tau), a sulphur-containing non-proteinogenic β-amino acid, has a special place as an important natural modulator of antioxidant defence networks:

  • Direct antioxidant effect of Tau due to scavenging free radicals is limited, and could be expected only in a few tissues (heart and eye) with comparatively high concentrations.
  • Maintaining optimal Tau status of mitochondria controls free radical production.
  • Indirect antioxidant activities of Tau due to modulating transcription factors leading to upregulation of the antioxidant defence network are likely to be major molecular mechanisms of Tau’s antioxidant and anti-inflammatory activities.
  • A range of toxicological models clearly show protective antioxidant-related effects of Tau.”

antioxidants-10-01876-g001-550

https://www.mdpi.com/2076-3921/10/12/1876/htm “Taurine as a Natural Antioxidant: From Direct Antioxidant Effects to Protective Action in Various Toxicological Models”

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Your lungs and Nrf2 activity

gettingwell4 4-5 stars Advanced knowledge, Cortisol, Epigenetics, Immune system, Neurochemicals, Stress, Telomeres , ,

Two 2021 papers of Nrf2 activation effects on lung diseases, with the first a McGill University review:

“Oxidative stress and subsequent activation of Nrf2 have been demonstrated in many human respiratory diseases. The purpose of this review is to summarize involvement of Nrf2 and its inducers in acute respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), asthma, and lung fibrosis in both human and experimental models.

fphys-12-727806-g004

These inducers have proven particularly effective at reducing severity of oxidative stress-driven lung injury in various animal models. In humans, these compounds offer promise as potential therapeutic strategies for management of respiratory pathologies associated with oxidative stress, but there is thus far little evidence of efficacy through human trials.

Perhaps, by analogy with biologics, patients with demonstrated deficient antioxidant responses to their disease should be selected for study in future clinical trials.”

https://www.frontiersin.org/articles/10.3389/fphys.2021.727806/full “Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches – Pulmonary Disease/Asthma”

A second paper was a human/rodent study of COPD:

“We investigated Nrf2 expression and epigenetic regulation, and mechanisms by which the Nrf2 signaling pathway in ferroptosis is related to COPD. These findings elucidated pathways of ferroptosis in bronchial epithelial cells in COPD, and revealed Nrf2 as a potential target for COPD treatment.

COPD_A_340113_t0001

DNA hypermethylation at specific CpG sites of the Nrf2 promoter in primary epithelial cells and in clinical lung tissues is correlated with decreased Nrf2 expression, which is related to COPD occurrence and development.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684379/ “Hypermethylation of the Nrf2 Promoter Induces Ferroptosis by Inhibiting the Nrf2-GPX4 Axis in COPD”

Similar to this second paper’s CpG findings, Eat broccoli sprouts for your heart found:

“Sulforaphane (SFN) reduced Ang II‐induced CpG hypermethylation and promoted Ac‐H3 [histone H3 acetylation] accumulation in the Nrf2 promoter region, accompanied by inhibition of global DNMT [DNA methyltransferase] and HDAC [histone deacetylase] activity, and a decreased protein expression of key DNMT and HDAC enzymes. Overall, DNA methylation and histone deacetylation are considered to inhibit gene transcription with a synergistic effect.

Nrf2 can also be regulated independently of Keap1. Evidence indicates that SFN may indirectly activate Nrf2 by affecting activity of several upstream kinases.”

However, this second paper didn’t measure DNMT and HDAC inhibition, although their therapeutic effects in reducing oxidative injury and inflammation may have been present.

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Gut microbiota vs. disease risks

gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Neurochemicals, Serotonin, Stress , , ,

This 2021 review subject was risk relationships between diseases from the perspective of gut microbiota:

“There is a significant inverse relationship between the onset of Alzheimer’s disease/Parkinson’s disease (AD/PD) and cancer, but the mechanism is still unclear. Considering that intestinal flora can connect them, we briefly introduced the relationship among AD/PD, cancer, and intestinal flora, studied metabolites or components of the intestinal flora, and the role of intestinal barriers and intestinal hormones in AD/PD and cancer.

According to existing evidence:

  • Bifidobacterium and Lactobacillus positively affect AD/PD and cancer;
  • Ruminococcaceae, Prevotellaceae, and Prevotella significantly improve on AD/PD but harm cancer; and
  • Blautia has universal anticancer ability, but it may aggravate AD pathology.

1-s2.0-S0753332221011276-gr1_lrg

This may partially explain the antagonistic relationship between neurodegenerative diseases and cancer. When some individuals suffer from one disease, their intestinal flora change to obtain a stronger resistance to the other disease than healthy individuals, which is consistent with statistical data.”

https://www.sciencedirect.com/science/article/pii/S0753332221011276 “Composition of intestinal flora affects the risk relationship between Alzheimer’s disease/Parkinson’s disease and cancer”

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Inevitable individual differences

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics, Immune system, Memory, Neurochemicals, Serotonin, Stress , , , , ,

This 2021 review subject was individual differences:

“We will focus on recent findings that try to shed light on the emergence of individuality, with a particular interest in Drosophila melanogaster.

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Another possible source of potential behavioral variability might come from the interaction of individuals with environmental microbes, from Wolbachia infections to changes in the gut microbiome. In this particular case, no genetic variation or neural circuit alteration would be responsible for the change in behavior.

Finally, from an evolutionary point of view, individuality might play an essential role in providing an adaptive advantage. For example, we have described that animals might use diversified bet-hedging as a mechanism to produce high levels of variation within a population to ensure that at least some individuals will be well-adapted when facing unpredictable environments.”

https://www.frontiersin.org/articles/10.3389/fphys.2021.719038/full “Behavior Individuality: A Focus on Drosophila melanogaster”

Other papers on this subject include:

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Immune system aging

gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Dopamine, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Serotonin, Stress, Telomeres , , , , , , ,

This 2021 review by three coauthors of Take responsibility for your one precious life – Trained innate immunity cast a wide net:

“Non-specific innate and antigen-specific adaptive immunological memories are vital evolutionary adaptations that confer long-lasting protection against a wide range of pathogens. However, these mechanisms of memory generation and maintenance are compromised as organisms age.

This review discusses how immune function regulates and is regulated by epigenetics, metabolic processes, gut microbiota, and the central nervous system throughout life. We aimed to present a comprehensive view of the aging immune system and its consequences, especially in terms of immunological memory.

aging immune system

A comprehensive strategy is essential for human beings striving to lead long lives with healthy guts, functional brains, and free of severe infections.”

https://link.springer.com/article/10.1007/s12016-021-08905-x “Immune Memory in Aging: a Wide Perspective Covering Microbiota, Brain, Metabolism, and Epigenetics”

Attempts to cover a wide range of topics well are usually uneven. For example, older information in the DNA Methylation In Adaptive Immunity section was followed by a more recent Histone Modifications in Adaptive Immunity section.

This group specializes in tuberculosis vaccine trained immunity studies, and much of what they presented also applied to β-glucan trained immunity. A dozen previously curated papers were cited.

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Glutathione primes β-glucan-trained immunity

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Immune system, Memory, Stress , ,

Two 2021 papers on glutathione interactions with β-glucan, with the first studying human cells from healthy donors:

“(1→3)-β-D-Glucan stimulation induces epigenetic and transcriptomic changes in monocytes associated with increased glutathione (GSH) synthesis and metabolism. Intracellular glutathione levels were crucial in regulating several monocyte antifungal functions including resilience to oxidative stress, immunometabolism, nitric oxide production, phagocytosis, and cytokine production.

Our findings demonstrate an important role for GSH in immunity, and outline a better understanding of the acute response of monocytes to infections.”

https://www.frontiersin.org/articles/10.3389/fimmu.2021.694152/full “Glutathione Metabolism Is a Regulator of the Acute Inflammatory Response of Monocytes to (1→3)-β-D-Glucan”

A second study investigated the subject with a dozen rodent experiments:

“We demonstrated that antioxidation by GSH supported an environment essential for β-glucan-induced metabolic and epigenetic changes in monocytes. We found that GSH induced glycolysis and glutaminolysis in β-glucan-trained immunity in a mTOR-dependent manner.

These results uncovered the GSH/mTOR/c-Myc signaling axis as the central effector of metabolic reprogramming in trained immunity. We revealed that the delicate GSH/ROS redox balance determines discrete, long lasting metabolic modifications that are causal to β-glucan-trained immunity.

Our results suggest that H3K27me3 demethylation is a necessary event. We identified H3K27me3 demethylation as a novel histone modification mark that was impaired by GSH deficiency in β-glucan-trained bone marrow derived macrophages.

We identified EZH2 as a potential tool to boost trained immunity under GSH deficiency conditions, or to enhance trained immunity in clinical settings where excessive inflammatory responses could be beneficial.

ezh2 survival

Overall, these insights contribute to unraveling metabolic and epigenetic changes during trained immunity.”

https://www.sciencedirect.com/science/article/pii/S2213231721003669 “Glutathione synthesis primes monocytes metabolic and epigenetic pathway for β-glucan-trained immunity”

The second paper of Remembering encounters provides future benefits also explored this subject.

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Offspring brain effects from maternal adversity

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Cortisol, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Memory, Stress , , , , , ,

This 2021 rodent study investigated conception through weaning effects on offspring from stressing their mothers:

“We investigated consequences of two prenatal insults, prenatal alcohol exposure (PAE) and food-related stress, on DNA methylation profiles of the rat brain during early development. We analyzed patterns in prefrontal cortex, a key brain region involved in cognition, executive function, and behavior, of both males and females, and found sex-dependent and sex-concordant influences of these insults.

The pair-fed (PF) group in the PAE model is a standard control for effects of alcohol in reducing food intake. However, compared to the PAE group that, albeit eating less, eats ad libitum, pair-feeding is a treatment in itself, with PF dams receiving a restricted ration, which results in both hunger and a disrupted feeding schedule. These stress-related effects could potentially parallel or model food scarcity or food insecurity in human populations.

We observed more DMRs (Differentially Methylated Regions) that showed decreased DNAm rather than increased DNAm in PF animals, suggesting that food-related stress may interfere with one-carbon metabolism and the pathways that deposit methylation on DNA. We also identified a sex-concordant DMR that showed decreased DNAm in PF animals in the glucocorticoid receptor Nr3c1, which plays a key role in stress responsivity and may reflect a reprogramming of the stress response.

This result is in line with previous studies that have shown that pair-feeding is a considerable stressor on dams, with lasting consequences on development, behavior, and physiology of their offspring. Altered DNAm of this key HPA axis gene may reflect broader alterations to stress response systems, which may in turn, influence programming of numerous physiological systems linked to the stress response, including immune function, metabolic processes, and circadian rhythms.

In PAE and PF animals compared to controls, we identified 26 biological pathways that were enriched in females, including those involved in cellular stress and metabolism, and 10 biological pathways enriched in males, which were mainly involved in metabolic processes. These findings suggest that PAE and restricted feeding, both of which act in many respects as prenatal stressors, may influence some common biological pathways, which may explain some of the occasional overlap between their resulting phenotypes.

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This study highlights the complex network of neurobiological pathways that respond to prenatal adversity/stressors and that modulate differential effects of early life insults on functional and health outcomes. Study of these exposures provides a unique opportunity to investigate sex-specific effects of prenatal adversity on epigenetic patterns, as possible biological mechanisms underlying sex-specific responses to prenatal insults are understudied and remain largely unknown.”

https://www.mdpi.com/2073-4425/12/11/1773/htm “Prenatal Adversity Alters the Epigenetic Profile of the Prefrontal Cortex: Sexually Dimorphic Effects of Prenatal Alcohol Exposure and Food-Related Stress”

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The impact of transgenerational epigenetic inheritance and early life experiences

gettingwell4 4-5 stars Advanced knowledge, Cortisol, Epigenetics, Immune system, Memory, Neurochemicals, Primal Therapy, Stress , , , , , , , ,

A 2021 interview with McGill University’s Moshe Szyf:

“There is a rejection of transgenerational inheritance as it goes against progressive thinking because it ties us to previous generations. The theory faces rejection because it sounds deterministic.

But if you understand what epigenetics is, it’s not deterministic. There is stability, and there’s also room for dynamic change.

The only way things change in the body for the long term is via epigenetics. We don’t know everything yet, new discoveries are yet to happen, and then we will just say, ‘Wow, it’s so obvious!’

The immune system is tightly connected to the brain and is directly affected by early adversity. Even though we will not be able to learn what’s going on in the brain, as far as epigenetics in living people, we will gain a lot of information from how the immune system responds to early adversity, and how this is correlated with behavioral phenotype and with mental health.

This brings into question the whole field of neuroimmunology, of which there is a lot of data. But it seems that a lot of psychiatrists are totally oblivious to these data, which is astounding, because the glucocorticoid hormone – the major player in this mechanism due to its involvement in early life stress as well as control of behavior – also controls immune function.

Nobody can live long enough to oversee a human transgenerational study. In humans, correlations are usually in peripheral tissue, where changes are small. The jury’s not out yet, but if evolution used it for so many different organisms, some of which are very close to us in the evolutionary ladder, it’s impossible that humans don’t use it.

How are current findings in animal models relevant to humans? How do we develop human paradigms that will allow us to achieve a higher level of evidence than what we have now?

  • One way is the immune-inflammatory connection to other diseases. I think this is where the secret of epigenetic aging lies, as well as epigenetics of other diseases.
  • Every disease is connected to the immune system. The brain translates the behavioral environment to the immune system, and then the immune system sends chemical signals across the body to respond to these challenges.

We need to understand that epigenetic programs are a network. Move beyond candidate genes, understand the concept of a network, and really understand the challenge: Reset the epigenetic network.

Epigenetics is going to be rapidly translated to better predictors, better therapeutics, and more interesting therapeutics. Not necessarily the traditional drug modeled against a crystal structure of an enzyme, but a more networked approach. Ideas about early life stress are critical and have impacted the field of childcare by highlighting the importance of early childhood relationships.”

https://www.futuremedicine.com/doi/10.2217/epi-2021-0483 “The epigenetics of early life adversity and trauma inheritance: an interview with Moshe Szyf”