Sulforaphane vs. too much oxygen

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.” “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.”


Inevitable individual differences

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.


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.” “Behavior Individuality: A Focus on Drosophila melanogaster

Other papers on this subject include:


Offspring brain effects from maternal adversity

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.


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.” “Prenatal Adversity Alters the Epigenetic Profile of the Prefrontal Cortex: Sexually Dimorphic Effects of Prenatal Alcohol Exposure and Food-Related Stress”


The impact of transgenerational epigenetic inheritance and early life experiences

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.” “The epigenetics of early life adversity and trauma inheritance: an interview with Moshe Szyf”

Week 87 of Changing to a youthful phenotype with sprouts

This week I dialed back eating microwaved 3-day-old broccoli / red cabbage / mustard sprouts from twice a day to once a day. For my reasoning, here are two papers on broccoli sprouts and thyroid function, with the first a 2018 human study:

“We analyzed biochemical measures of thyroid function and thyroid autoimmunity in a subset of participants in a broccoli sprout clinical trial. The present work is a retrospective analysis of a subset of serum samples collected during a clinical trial conducted from mid-October 2011 to early January 2012.

130 individuals received placebo beverage, and 137 received broccoli sprout beverage for 84 consecutive days (12 weeks). Blood samples from day 0 and day 84 were analyzed in a subset of 45 female participants (19 placebo, 26 broccoli sprout beverage) for serum thyroid-stimulating hormone (TSH), free thyroxine (fT4), thyroglobulin (TG), anti-TG, and anti-thyroid peroxidase (anti-TPO) antibodies.

The percentage of patients with subclinical hypothyroidism (elevated TSH with normal fT4) was not significantly different between the two groups either before or after treatment.

subclinical hypothyroidism

Daily ingestion of a broccoli sprout extract beverage over 84 days had no deleterious effect on thyroid function tests or measures of thyroid autoimmunity. It may be prudent to evaluate thyroidal safety of plant-based food supplements on a case-by-case basis.” “Broccoli sprout beverage is safe for thyroid hormonal and autoimmune status: Results of a 12-week randomized trial” (not freely available)

A 2020 review by three of these coauthors summarized further details:

“One difference between the thyroid and other tissues is that ROS are not primarily a byproduct of its physiology, but an indispensable part of it. Thyroid follicular cells actively produce H2O2 to facilitate a cascade of redox reactions that sequentially oxidize iodide, iodinate tyrosine residues within Tg, and couple iodinated tyrosine residues of Tg to each other to form T4 and T3 (triiodothyronine).

There exists a fail-safe mechanism in which specific combinations of four Keap1 cysteines can form a disulfide bond to sense H2O2. This sensing mechanism appears to be distinct from that triggered by other Nrf2 inducers, such as electrophiles.

Findings from Keap1KD mice suggest that chronic genetic activation of Nrf2 signaling may have negative consequences for the thyroid gland. However, analysis of data from a clinical trial has shown that consumption of a broccoli sprout beverage (yielding pharmacologically active amounts of the Nrf2-activating compound sulforaphane) is safe for thyroid hormonal and autoimmune status during a 12-week administration period.

Nevertheless, it appears prudent to monitor thyroid function and thyroid volume (at least by palpation) in patients treated with Nrf2-modulating compounds in clinical trials or clinical practice.” “The Keap1/Nrf2 Signaling Pathway in the Thyroid—2020 Update”

My Day 70 lab results for inflammation markers were great:

IL-6 2020

A year later, IL-6 was below the test’s detection limit, and high-sensitivity C-reactive protein could hardly have been better at 0.24 mg/L.

But TSH (reference interval 0.45 – 4.50 μIU/mL) increased from 3.01 to 7.50. Here’s what Labcorp Technical Review L8186 said:

“The panel concluded that despite the fact that serum TSH concentrations higher than 2.5 μIU/mL but less than 4.5 μIU/mL may identify some individuals with the earliest stage of hypothyroidism, there is no evidence for associated adverse consequences. Additionally, consequences of subclinical hypothyroidism with serum TSH levels between 4.5 μIU/mL and 10 μIU/mL are minimal, and the panel recommends against routine treatment of patients with TSH levels in these ranges.”

I went in last weekend to retest. Although the provider verbally agreed to test TSH, free T3, and free T4, a different test was ordered.

TSH was still high at 5.85 μIU/mL. Other measurements (Total T4, T3 Uptake, and Free Thyroxine Index) aren’t suitable substitutes for free T3 and free T4. I’ll specify Labcorp test numbers next time.

My hypothesis is that preconditioning my endogenous ARE system twice daily worked alright elsewhere, but not for my thyroid. We’ll find out in 2022 whether halving the electrophilic activations of my Nrf2 signaling pathway has any effect on thyroid measurements.

I don’t take anything with, or an hour before or after these very reactive isothiocyanates. I continue to eat 3-day-old oat sprouts twice a day with other foods.


Is liver damage reversible?

This 2021 rodent study measured sequential liver changes caused by a high-fat diet:

“Using a longitudinal mouse study of diet-induced obesity in male mice, we investigated kinetics of hepatic DNA methylation and gene expression compared to those of obesity-induction to assess if they could be causal for development of insulin resistance. We aimed to find out if these changes were reversed by massive weight loss induced by vertical sleeve gastrectomy or metformin treatment.

We identified two CpG sites within exon 1 of Fgf21 that became gradually hypomethylated upon HFD feeding. DNA demethylation started between week two and four, to become significant at week five, and significantly correlated with hepatic Fgf21 gene expression.

These DNA methylation changes preceded development of insulin resistance, and were potentially causally involved in increased Fgf21 expression and plasma levels associated with insulin resistance. This points to a key regulatory function of gene body DNA methylation, which was eventually a compensatory response to counteract the developing insulin resistance.

HFD-induced decrease in Fgf21 DNA methylation could not be reversed by vertical sleeve gastrectomy or metformin treatment. As soon as weight loss slowed down or mice started to re-gain weight, differences in DNA methylation were no longer detected compared to sham-operated mice.


As the altered DNA methylation pattern was acquired during adulthood in differentiated cells, our data emphasize that metabolic programming via DNA methylation is dynamic and not restricted to fetal development. This supports the concept that individuals can actively influence their DNA methylation patterns by lifestyle choices.

Our data indicate that DNA methylation alterations in key metabolic tissues can be acquired by an obesogenic diet, and not easily be reversed by interventions common in obese and diabetic subjects.” “Dietary induction and reversal of obesity and insulin resistance is associated with changes in Fgf21 DNA methylation in liver of mice”

This study attempted two interventions that didn’t have desired effects. All about the betaine mentioned others that may reverse liver epigenetic changes.


Reworking evolutionary theory

Dr. Michael Skinner coauthored a 2021 review arguing for inclusion of epigenetic transgenerational inheritance into evolutionary theory:

“Over the past 50 years, molecular technology has been used to investigate evolutionary biology. Many examples of finding no correlated genetic mutations or a low frequency of DNA sequence mutations suggest that additional mechanisms are also involved.

  • Identical twins have essentially the same genetics, but generally develop discordant disease as they age.
  • Only a low frequency (generally 1% or less) of individuals that have a specific disease have a correlated genetic mutation.
  • Dramatic increases in disease frequency in the population cannot be explained with genetics alone.

DNA methylation, histone modifications, changes to chromatin structure, expression of non-coding RNA, and RNA methylation can directly regulate gene expression independent of DNA sequence. These different epigenetic factors do not only act independently, but integrate with each other to provide a level of epigenetic complexity to accommodate the needs of cellular development and differentiation.


Environmental epigenetics is the primary molecular mechanism in any organism that is used to promote physiological and phenotypic alterations. Actions of environmental factors early in development can permanently program the cellular molecular function, which then impacts later life disease or phenotypes.


Integration of epigenetics and genetics contribute to a Unified Theory of Evolution that explains environmental impacts, phenotypic variation, genetic variation, and adaptation that natural selection acts on. The current review expands this proposed concept and provides a significant amount of supporting literature and experimental models to support the role of environmentally induced epigenetic transgenerational inheritance in evolution.” “Role of environmentally induced epigenetic transgenerational inheritance in evolutionary biology: Unified Evolution Theory”

Organisms cited in this review’s references are similar to humans in ancestral influences and developmental influences during the first 1000 days of our lives. Humans are different in that even after all these influences, we can choose to influence our own change and individually evolve. We can also change our internal environments per Switch on your Nrf2 signaling pathway and An environmental signaling paradigm of aging.


Intergenerational epigenetic inheritance of trained immunity

I’ll curate this 2021 rodent study Transmission of trained immunity and heterologous resistance to infections across generations (not freely available) through two instances of its news coverage:

“Here we provide evidence for transmission of trained immunity across generations to murine progeny that survived a sublethal systemic infection with Candida albicans or a zymosan challenge. Progeny of trained mice exhibited cellular, developmental, transcriptional, and epigenetic changes associated with the bone marrow-resident myeloid effector and progenitor cell compartment.

Progeny of trained mice showed enhanced responsiveness to endotoxin challenge, alongside improved protection against systemic heterologous [elicits a reaction in a nonspecific antibody] Escherichia coli and Listeria monocytogenes infections. These results provide evidence for inheritance of trained immunity in mammals, enhancing protection against infections.”

Its most frequent coverages were repetitions of a press release from an institution that funded this research:

“How does this transmission of immunization to subsequent generations work? In contrast to the classical theory of evolution, which assumes slow adaptation through changes in genetic code, this involves very rapid changes via epigenetic regulation of gene activities, irrespective of genetic code.” “Epigenetics: Immunization is passed on to offspring”

Not much objectivity in a sponsor’s press release. May as well ask a coworker if they had a good vacation.

And the second:

“When either parent was subjected to real or simulated infection, offspring showed a stronger immune response to potential pathogens, including E. coli bacteria, than controls whose parents hadn’t been subjected to an immune system challenge. They had lower numbers of the bacteria in their lungs and liver, as well as higher concentrations of immune cells and pro-inflammatory cytokines. The effect persisted further: offspring of these second-generation mice also showed a lower bacterial burden after infection.

One weakness of the study is that results do not clearly show how enhanced immunity is being transferred from parent to offspring. The study found that fungal infection induced changes in sperm DNA methylation. But female mice who recovered from infection also produced offspring with fortified immune systems.” “Mice that Survive Infection Pass on Stronger Immunity”

This reporter gathered good comments from unassociated researchers, but whiffed overall by misinterpreting intergenerational epigenetic inheritance as transgenerational epigenetic inheritance. Per definitions in A review of epigenetic transgenerational inheritance of reproductive disease and Transgenerational effects of early environmental insults on aging and disease, for the term “transgenerational transmission” to apply, researchers need to provide evidence in at least the next 2 male or non-gestating female generations and/or 3 gestating female generations of:

“Altered epigenetic information between generations in the absence of continued environmental exposure.”

I’ll ask about their plans regarding continuing to a F3 generation for further epigenetic inheritance evidence. The interviewed coauthor didn’t indicate that was their current direction, though.

While we wait, train your body’s antioxidant response elements and immune system every day. Exercise your endogenous responses with weak pro-inflammatory isothiocyanates in broccoli sprouts, and your gut with weak antigens in yeast cell wall β-glucan. Daily drills will keep your body’s systems tuned up and ready for both these specific challenges as well as others per this study’s referenced heterologous findings.

Seconds to sunrise


Do genes determine monogamy / polygamy?

This 2021 rodent study developed epigenetic clocks for deer mice:

“We have undertaken a genome-wide analysis of DNA methylation in Peromyscus, spanning different species, stocks, sexes, tissues, and age cohorts. We present CpGs and enriched pathways that relate to different conditions such as chronological age, high altitude, and monogamous behavior.

  • Analysis involved tails, whole brain, and liver samples that are not major target tissues for sex hormones. This implies that sex-specific patterns of methylation are inflicted early during development, and persist at adulthood.
  • Altitude-specific age-related changes are adjacent to genes that play a role in brain development, immune system functioning, and T-cell development.
  • Comparison of brain specimens between older P. leucopus and P. maniculatus indicated that in the latter, coordination of the unfolded protein response is compromised, and evidence of neurodegenerative pathology was obtained.
  • Our study involved three monogamous (P. californicus, P. polionotus, and P. eremicus) and two polygamous (P. maniculatus and P. leucopus) species. The most significant EWAS hits for monogamy included decreased methylation in Zeb2 intron, a key regulator of midbrain dopaminergic neuron development. These results derived from tail tissues, suggesting that inherent differences in bonding behavior instruct specific epigenetic changes in peripheral tissues that may be translated into distinct physiological outcomes. Whether this is due to differential regulation of specific neurohormonal circuits in response to hormones and neurotransmitters related to bonding, and what the exact physiological outputs are, remains to be determined.

Our study provided the first epigenetic clock for Peromyscus, and illustrated the hierarchical association between various biological variables in determining methylation profiles across different scales of biological organization.” “Methylation studies in Peromyscus: aging, altitude adaptation, and monogamy”


All about the betaine, Part 2

Continuing Part 1 by curating a partial outline of a 2021 review:

“This review focuses on the biological and beneficial effects of dietary betaine (trimethylglycine), a naturally occurring and crucial methyl donor.

Betaine has a neuroprotective role, preserves myocardial function, and prevents pancreatic steatosis. Betaine also attenuates oxidant stress, endoplasmic reticulum stress, inflammation, and cancer development.

  • Betaine Protects against Development of Alcohol-Induced Hepatic Steatosis
  • Betaine Protects against Detrimental Effects of HCV and Ethanol on Innate Immunity
  • Betaine Maintains Intestinal Epithelial Barrier Integrity
  • Betaine Maintains Adipose Function


Human intervention studies showed no adverse effects with 4 g/day supplemental administration of betaine in healthy subjects. However, overweight subjects with metabolic syndrome showed a significant increase in total and LDL-cholesterol concentrations. These effects were not observed with 3 g/day of betaine administration.

We suggest betaine as a promising therapeutic for clinical use to treat these aforementioned diseases as well as other liver-/non-liver-related diseases and conditions.” “Beneficial Effects of Betaine: A Comprehensive Review”

This review cited a 2020 study Transgenerational Inheritance of Betaine-Induced Epigenetic Alterations in Estrogen-Responsive IGF-2/IGFBP2 Genes in Rat Hippocampus (not freely available):

“Hippocampal expression of aromatase, estrogen receptor α, and estrogen-related receptor β is downregulated in F1, together with estrogen-responsive insulin-like growth factor 2/insulin-like growth factor binding protein 2 (IGF-2/IGFBP2) genes. However, all these genes are upregulated in F2, which follows the same pattern of F0.

Imprinting control region of IGF-2 gene is hypomethylated in F1 but hypermethylated in F2 and F0. In contrast, the promoter DNA methylation status of all affected genes is hypermethylated in F1 but hypomethylated in F2 and F0.”

  • Intergenerational flip-flops of F0 phenotypes to opposite F1 phenotypes back to F0 phenotypes in the F2 generation can’t conclusively demonstrate transgenerational epigenetic inheritance of alterations due to betaine consumption during pregnancy.
  • Those researchers had to continue on to a F3 female generation for transgenerational results, because F2 generation cells were present in F1 fetuses, and were potentially affected during pregnant F0 treatments.

I came across this paper through a citation chain initiated by Dr. Paul Clayton’s blog post Foie Gras:

“Thanks to our modern diet and lifestyle, nonalcoholic fatty liver disease (NAFLD) is now reckoned to affect an astonishing quarter of the world’s population.”


The Illusion of Knowledge: The paradigm shift in aging research that shows the way to human rejuvenation

Dr. Harold Katcher increased interviews to coincide with release of his book this month. Here’s one in four parts that provides highlights of his rejuvenation research progress:

Previously curated papers of his work include:

Epigenetic clocks so far in 2021

2021’s busiest researcher took time out this month to update progress on epigenetic clocks:

Hallmarks of aging aren’t all associated with epigenetic aging.

epigenetic aging vs. hallmarks of aging

Interventions that increase cellular lifespan aren’t all associated with epigenetic aging.

epigenetic aging vs. cellular lifespan

Many of his authored or coauthored 2021 papers developed human / mammalian species relative-age epigenetic clocks.

epigenetic clock mammalian maximum lifespan

Relative-age epigenetic clocks better predict human results from animal testing.

pan-mammalian epigenetic clock

Previously curated papers that were mentioned or relevant included:

Gut microbiota and critical development periods

This 2021 rodent study focused on global histone acetylation as a model to understand roles of microbially produced short-chain fatty acids in liver function:

“Despite the utility of germ-free mice in probing complex interactions between gut microbiota and host physiology, germ-free mice are developmentally, physiologically, and metabolically unique when compared with their conventionally housed counterparts. We sought to determine whether antibiotic-mediated microbiota depletion would affect global hepatic histone acetylation states through SCFA-dependent mechanisms, as previously observed in germ-free mice.

The inability of antibiotic-mediated microbiota depletion to recapitulate findings observed in germ-free mice suggests that the transition from a germ-free to a colonized mouse leads to resilient alterations in hepatic histone acetylation states that cannot be altered by further modulating the microbial environment. This finding is distinct from other germ-free phenotypes that are considered to be partially reversible, with clear alterations in their function observed after antibiotic treatment.

histone acetylation

Comparing antibiotic-treated and untreated mice that both received CCl4 at 24 and 48 hours after injury, there were almost no histone acetylation differences. This demonstrates that hepatic injury leads to a global shift in histone acetylation that is primarily independent of gut microbiota.

Major chromatin reorganization driven by histone acetylation leads to markers of differentiation, and addition of targeted differentiation signals induces events to stabilize these histone acetylation patterns – a key feature of embryonic development and terminal cellular differentiation. Differences in histone acetylation patterns seen between germ-free and conventionally raised mice may be a developmental-like effect of hepatocytes not yet exposed to microbial by-products.

Results suggest that microbial and dietary modifications to the gut microbiome in conventionally raised mice are not a means to modulate global hepatic histone acetylation. Microbiota-dependent landscaping of the hepatic epigenome appears static in nature, while the hepatic transcriptome is responsive to alterations in the gut microbiota, yet independent of global histone acetylation.

Findings underscore significant differences between these model systems that should be taken into account when considering their relevance to human biology.” “Global Microbiota-Dependent Histone Acetylation Patterns Are Irreversible and Independent of Short Chain Fatty Acids” (not freely available) Thanks to Dr. Elliot S. Friedman for providing a copy.

1. By describing “a key feature of embryonic development,” this study provided a gut microbiota-liver analogy of critical periods. If developmental events don’t happen when they are required, it’s probable that their window is missed, and won’t reopen later for a second chance at normalizing.

2. Many studies used a germ-free animal model, such as:

This study provided evidence for a limitation of this model, especially when extrapolating germ-free animal results to humans without similarly testing humans.


All about vasopressin

This 2021 review subject was vasopressin:

“Vasopressin is a ubiquitous molecule playing an important role in a wide range of physiological processes, thereby implicated in pathomechanisms of many disorders. The most striking is its central effect in stress-axis regulation, as well as regulating many aspects of our behavior.

Arginine-vasopressin (AVP) is a nonapeptide that is synthesized mainly in the supraoptic, paraventricular (PVN), and suprachiasmatic nucleus of the hypothalamus. AVP cell groups of hypothalamus and midbrain were found to be glutamatergic, whereas those in regions derived from cerebral nuclei were mainly GABAergic.

In the PVN, AVP can be found together with corticotropin-releasing hormone (CRH), the main hypothalamic regulator of the HPA axis. The AVPergic system participates in regulation of several physiological processes, from stress hormone release through memory formation, thermo- and pain regulation, to social behavior.

vasopressin stress axis

AVP determines behavioral responses to environmental stimuli, and participates in development of social interactions, aggression, reproduction, parental behavior, and belonging. Alterations in AVPergic tone may be implicated in pathology of stress-related disorders (anxiety and depression), Alzheimer’s, posttraumatic stress disorder, as well as schizophrenia.

An increasing body of evidence confirms epigenetic contribution to changes in AVP or AVP receptor mRNA level, not only during the early perinatal period, but also in adulthood:

  • DNA methylation is more targeted on a single gene; and it is better characterized in relation to AVP;
  • Some hint for bidirectional interaction with histone acetylation was also described; and
  • miRNAs are implicated in the hormonal, peripheral role of AVP, and less is known about their interaction regarding behavioral alteration.” “Epigenetic Modulation of Vasopressin Expression in Health and Disease”

Find your way, regardless of what the herd does.


Choosing your gut immune response

This 2021 paper reviewed evidence for immune system effects associated with specific gut areas:

“The intestinal immune system must not only contend with continuous exposure to food, commensal microbiota, and pathogens, but respond appropriately according to intestinal tissue differences. The entire intestine, inclusive of its lymph nodes, is considered a immunosuppressive organ overall compared to most other tissues, indicating that a state of tolerance to food and commensals – yet vigilance toward pathogens – was an evolutionarily stable strategy.

By operating in compartments, the immune system may generate multiple immune outcomes, even with simultaneous opposite goals e.g., tolerance or inflammation. Generation of unique immunologic niches within the intestine is influenced by a combination of tissue intrinsic properties, extrinsic environmental factors, and regionalized immune populations.

intestinal immune compartmentalization

Complexity of intrinsic and extrinsic driving forces shaping an intestinal niche makes it very challenging to determine causality in disease development and predicting effective therapeutic approaches. We really only stand at the beginning of understanding this interplay.” “Intestinal immune compartmentalization: implications of tissue specific determinants in health and disease”

I patterned this post after Choosing your future with β-glucan:

“So where do you choose to be? In an 80% survival group who were administered β-glucan before they encountered a serious infection? Or in a < 20% survival group who didn’t take β-glucan?”

and Long-lasting benefits of a common vaccine:

“As inferred by “induction of trained immunity by both Bacillus Calmette-Guerin tuberculosis vaccine and β-glucan” many of these findings also apply to yeast cell wall β-glucan treatments.”

This paper’s food allergy references were interesting. It’s an area that personally requires further work, although avoidance has historically been effective.

This paper briefly mentioned broccoli’s effects in the proximal small intestine. It wasn’t informative per gut compartment with this year’s focus on making my gut microbiota happy, such as what our colonic microbiota can do to reciprocate their host giving them what they want.

This review’s human studies referenced what could be done post-disease like surgery etc. in different gut compartments. Very little concerned an individual taking responsibility for their own one precious life to prevent such diseases in the first place. Its Conclusions section claim was a fallacy:

“..very challenging to determine causality in disease development and predicting effective therapeutic approaches.”