Several diseases, one treatment?

This 2021 review summarized three dietary supplements’ effects on psychiatric symptoms:

“Upregulation of Nrf2 has been suggested as a common therapeutic target for major neuropsychiatric disorders. In this paper, evidence is presented showing how NAC [N-acetyl-cysteine], coenzyme Q10 (CoQ), and melatonin can ameliorate many important effects of oxidative stress by upregulating Nrf2.

Given its key role in governing cellular antioxidant response, upregulation of Nrf2 has been suggested as a common therapeutic target in neuropsychiatric illnesses such as major depressive disorder, bipolar disorder, and schizophrenia. These are associated with chronic oxidative and nitrosative stress, characterised by elevated levels of reactive oxygen species, nitric oxide, and peroxynitrite.

CoQ:

  • Acts as a superoxide scavenger in neuroglial mitochondria;
  • Instigates mitohormesis;
  • Ameliorates lipid peroxidation in the inner mitochondrial membrane;
  • Activates uncoupling proteins;
  • Promotes mitochondrial biogenesis; and
  • Has positive effects on the plasma membrane redox system.

Melatonin:

  • Scavenges mitochondrial free radicals;
  • Inhibits mitochondrial nitric oxidesynthase;
  • Restores mitochondrial calcium homeostasis;
  • Deacetylates and activates mitochondrial SIRT3;
  • Ameliorates increased permeability of the blood-brain barrier and intestine; and
  • Counters neuroinflammation and glutamate excitotoxicity.”

https://www.researchgate.net/publication/348309816_Increasing_Nrf2_Activity_as_a_Treatment_Approach_in_Neuropsychiatry “Increasing Nrf2 Activity as a Treatment Approach in Neuropsychiatry” (registration required)


These reviewers explored three selected supplements, citing 380 references. They overlooked something, though. There was only one mention of sulforaphane in their paper, yet four references’ titles included sulforaphane?

I take two of the three exogenous supplements discussed. The one I stopped taking over a year ago – NAC – was thoroughly discussed, but not in contexts directly related to the Nrf2 transcription factor. Why?

Switch on your Nrf2 signaling pathway pointed out:

“We use NAC in the lab all the time because it stops an Nrf2 activation. So that weak pro-oxidant signal that activates Nrf2, you switch it off by giving a dose of NAC. It’s a potent antioxidant in that right, but it’s blocking signalling. And that’s what I don’t like about its broad use.”

The current review noted that Nrf2 is activated by oxidative stress. NAC is a precursor to glutathione – our main endogenous antioxidant – and neither one activates Nrf2 pathways.

What does? Sulforaphane.

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Repositioning DNA methylation

This 2021 human study found:

“We report on a randomized controlled clinical trial conducted among 43 healthy adult males between the ages of 50-72. The 8-week treatment program included diet, sleep, exercise and relaxation guidance, and supplemental probiotics and phytonutrients.

This is the first randomized controlled study to suggest that specific diet and lifestyle interventions may reverse Horvath DNAmAge (2013) epigenetic aging in healthy adult males. Larger-scale and longer duration clinical trials are needed to confirm these findings, as well as investigation in other human populations.

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In both treatment and control groups, there was no net increase or decrease in methylation of 353 sites that compose the Horvath clock. This finding suggests that intervention did not lead to an overall increase in methylation of Horvath clock sites, but rather it prompted a repositioning of clock CpG methylation patterns consistent with a younger biological age.

One significant limitation of this pilot trial is limited statistical power due to relatively small sample size. It is not yet fully established whether interventions that slow any methylation clocks necessarily curtail risks of age-related disease.”

https://www.aging-us.com/article/202913/text “Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial”


Baffled as to why these researchers relied on 2013 research rather than at least Dr. Horvath’s improved 2018 skin and blood clock, a review of which noted:

“Although the skin-blood clock was derived from significantly less samples (~900) than Horvath’s clock (~8000 samples), it was found to more accurately predict chronological age, not only across fibroblasts and skin, but also across blood, buccal and saliva tissue. A potential factor driving this improved accuracy in blood could be related to the approximate 18-fold increase in genomic coverage afforded by using Illumina 450k/850k beadarrays.”

Which would you prefer? A 2013 flip phone, or a 2018 smartphone?

A bat epigenetic clock

This 2021 study subject was bats:

“Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity.

Hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that:

  • Age-related methylation change is influenced by developmental processes, while
  • Longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that
  • Bat longevity results from augmented immune response and cancer suppression.

Molossus molossus [a short-lived species] age genes are not enriched for immunity genes or genes that frequently mutated in cancer. However, M. molossus longevity genes exhibit significant overlap with genes involved in immunity and genes frequently mutated in human tumors.

Similar overlap patterns among immunity, longevity, and tumor-mutated genes also exist for long-lived bats.

Two species’ genetic adaptations for tumor suppression have been described to help explain their extreme longevity. Bats also have genetic mechanisms that enable strong antiviral immune responses without inducing damaging inflammatory reactions that may enable them to tolerate high levels of viral exposure.

Our results are consistent with an epigenetic clock theory of aging that connects beneficial developmental and cell maintenance processes to detrimental processes causing tissue dysfunction.”

https://www.nature.com/articles/s41467-021-21900-2 “DNA methylation predicts age and provides insight into exceptional longevity of bats”


The founder of the epigenetic clock has been busy, coauthoring more published studies than there have been weeks in this year! I’ve read five other 2021 studies he’s coauthored on dogs, horses, mammals (2), and humans in DNA methylation biomarker for cumulative lead exposure is associated with Parkinson’s disease. This one stood out for its “longevity results from augmented immune response and cancer suppression” findings.

If we’re interested in longevity, this clarity can direct efforts to both improve our immune systems and avoid problems like cancer. Symptoms may be subclinical, but that doesn’t provide adequate rationale to not address causes.

Peer review comments and responses were informative:

Reviewer #1 – “Developing an aging clock that works for a diverse set of bat species is a spectacular achievement.”

Reviewer #2 – “This is a tour de force study.”

Replies to Reviewer #3:

“Difference in recorded lifespans between three long-lived species and two short-lived species that we used to identify longevity DMPs [differentially methylated positions] is 20 years or more, even though they have similar body sizes (20-40 g). The three long-lived species [maximum ages 29.9, 30.5, and 37.1 years] also represent three different phylogenetic lineages.

CpG sites that undergo hypomethylation with age do so largely at random. In contrast, sites that undergo hypermethylation with age are highly nonrandom, and as has been noted before, are near genes associated with development. So yes, we believe there are predictable methylation changes with age.”

Train your gut microbiota with taurine

This 2021 rodent study found:

“We show that gut microbiota from previously infected hosts display enhanced resistance to infection. This long-term functional remodeling is associated with altered bile acid metabolism leading to expansion of taxa that utilize taurine.

Supplying exogenous taurine alone is sufficient to induce this alteration in microbiota function and enhance resistance. Taurine potentiates microbiota production of sulfide, an inhibitor of cellular respiration, which is key to host invasion by numerous pathogens.

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This work reveals a process by which the host, triggered by infection, can deploy taurine as a nutrient to nourish and train microbiota, promoting its resistance to subsequent infection.”

https://www.cell.com/cell/fulltext/S0092-8674(20)31681-0 “Infection trains the host for microbiota-enhanced resistance to pathogens” (not freely available)


News coverage added:

“The studied infections induced host taurine production and expansion of taurine utilizers. Taurine was the trigger for activity of a class of bacteria that fight these infections.

The group’s data suggest that low levels of taurine allow pathogens to colonize the gut, but high levels produce enough hydrogen sulfide to prevent colonization. Taurine given to mice in drinking water prepared microbiota to prevent infection. However, when mice drank water containing bismuth subsalicylate, a common over-the-counter drug used to treat diarrhea and upset stomach, infection protection waned because bismuth inhibits hydrogen sulfide production.”

Can’t calculate a human equivalent dose without access to this study. I take 1 gram of taurine twice a day.

Per Treating psychopathological symptoms will somehow resolve causes? I resumed taurine supplementation last year after taking a year’s break. From that paper’s taurine section:

“Most studies that reported enhanced GSH [glutathione] in the brain following taurine treatment were performed under a chronic regimen and used in age-related disease models.

Such positive effects of taurine on GSH levels may be explained by the fact that cysteine is the essential precursor to both metabolites, whereby taurine supplementation may drive metabolism of cysteine towards GSH synthesis.”

If that paper’s hypothesis is correct, and the current study’s evidence is replicable, taurine supplementation is a win-win for both our brain and gut microbiota.


Sunrise minus 5 minutes

Let β-glucan train your brain

This 2021 rodent study investigated yeast cell wall β-glucan’s effects on the brain’s immune system:

“Innate immune memory can manifest in two different ways, [1] immune training and [2] immune tolerance, which means [1] an enhanced or [2] suppressed immune response towards a secondary challenge. Lipopolysaccharide (LPS) and β-glucan (BG) are two commonly used ligands to induce immune training and tolerance.

Microglia, the innate immune cells of the central nervous system, can adopt diverse phenotypes and functions in health and disease. In our previous study, we have shown that LPS preconditioning induces immune tolerance in microglia.

Compared to LPS, relatively little is known about effects of BG on microglia. In this study, we report for the first time that systemic administration of BG activates microglia in vivo, and that BG preconditioning induces immune training in microglia.

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Our results show that BG activated microglia without inducing significant cytokine expression.

BG- and LPS-preconditioning both induced immune training in microglia two days after the first challenge. However, with an interval of 7 days between the first and second challenge, LPS-preconditioning induced immune tolerance in microglia where BG-induced immune training was no longer detected.”

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02103-4 “Systemic administration of β-glucan induces immune training in microglia”


One solution to “BG-induced immune training was no longer detected” after 7 days is to take β-glucan every day. I haven’t seen studies that found β-glucan induced immune tolerance, i.e. “suppressed immune response towards a secondary challenge.”

I take allergy medicine twice a day. Switched over to a different β-glucan vendor and dose per Year One of Changing to a youthful phenotype with broccoli sprouts.

I take 1 gram of Glucan 300 capsules without eating anything an hour before or an hour afterwards. I’ve only been doing it for a week, though, and haven’t been able to separate out β-glucan effects on seasonal allergies. I’ll try stopping allergy medicine when pollen stops coating my car.

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Swarming a spring sea trout run. Ospreys outcompeted gulls for breakfast.

Eat broccoli sprouts for your heart

This 2021 rodent study investigated mechanisms of sulforaphane’s persistent cardiac protection:

“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.

jcmm16504-fig-0006-m

SFN reduces CpG methylation and promotes enrichment of Ac‐H3 in Nrf2 promoter by inhibiting DNMTs and HDACs. This partially contributes to long‐acting activation of cardiac Nrf2, thereby preventing Ang II‐induced cardiomyopathy.”

https://onlinelibrary.wiley.com/doi/10.1111/jcmm.16504 “Sulforaphane prevents angiotensin II‐induced cardiomyopathy by activation of Nrf2 through epigenetic modification”


This study used the same dose of sulforaphane as Broccoli sprouts activate the AMPK pathway, but stopped at six months (equivalent to a 34-year-old human) rather than continuing to eight months (a 42-year-old human):

“0.5 mg/kg SFN in mice is converted to a human dose of 0.0405 mg/kg. In some clinical studies, the dose of SFN used to treat chronic diseases is usually higher.”

Findings highlighted:

  1. A disease condition existed in young adults that wasn’t severe enough for them to experience overt symptoms; and
  2. A disease condition could be reversed or prevented when its causes were addressed before it became a problem.

Studies such as one mentioned in Part 2 of Eat broccoli sprouts for your eyes showed that if one waited until a disease condition became a problem, capabilities to adequately address causes and prevent it may be lost. Do you want to be limited to addressing a disease’s symptoms once it gets bad enough to be noticeable?

Both studies found positive effects of sulforaphane in preventing cardiomyopathy. The 2020 study demonstrated in myocardial cells that sulforaphane’s activation of the AMPK pathway – which is upstream of the Nrf2 pathway – activated Nrf2:

“NRF2-mediated antioxidative effects can be activated via AMPK/AKT/GSK3β pathway, developing another pathway to confront cardiac oxidative damage.”

The current study similarly stated:

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


Both studies’ “human dose of 0.0405 mg/kg” were a minuscule 2.8 mg (.0405 mg/kg x 70 kg) human dose compared with my estimated daily 52 mg of sulforaphane from eating 65.5 grams of microwaved 3-day-old broccoli sprouts twice daily. Yet that small amount of sulforaphane was able to prevent a daily dose of angiotensin II from causing conditions that would lead to heart disease.

I linked this study yesterday in Reversing osteoporosis with Nrf2 as an example of similarities with exercise and eating broccoli sprouts. While activating my Nrf2 pathways this morning by walking four miles at sunrise, I came across a heron who tolerated me getting close to them:

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It ate breakfast off a branch, and pecked morsels from the water if they hopped off.

Reversing osteoporosis with Nrf2

This 2021 rodent study made old females out of young females by removing their ovaries, which induced osteoporosis. They then demethylated the Nrf2 gene promoter with exercise, increasing its expression, which reversed osteoporosis:

“Nrf2 repression due to aberrant Dnmt elevation and subsequent Nrf2 promoter hypermethylation is an important epigenetic feature of osteoporosis (OP) pathogenesis.

Nrf2 promoter demethylation

Ovariectomized mice display increased femoral Dnmt1/3a/3b (Dnmts), Nrf2 promoter hypermethylation, and Nrf2 suppression, which promote oxidative stress (OS), osteoclastogenesis (OCG) and OP (dashed line).

Running exercise (RE, solid line) normalizes Dnmt aberrations, resulting in Nrf2 promoter demethylation, Nrf2 recovery and reduced femoral osteoporotic pathologies.

Nrf2 repression due to aberrant Dnmt elevations and associated promoter hypermethylation contributes significantly to epigenetic development of OP. RE effectively corrects epigenetic abnormalities and pathogenesis of OP.”

https://www.nature.com/articles/s41413-020-00128-8 “Nrf2 epigenetic derepression induced by running exercise protects against osteoporosis”


Running an hour every day has effects on Nrf2 gene promoter expression similar to eating broccoli sprouts. A 2021 study Sulforaphane prevents angiotensin II‐induced cardiomyopathy by activation of Nrf2 through epigenetic modification found:

“SFN reduced Ang II‐induced CpG hypermethylation and promoted Ac‐H3 accumulation in the Nrf2 promoter region, accompanied by inhibition of global DNMT and HDAC activity, and a decreased protein expression of key DNMT and HDAC enzymes.”

A 2019 study Sulforaphane‑induced epigenetic regulation of Nrf2 expression by DNA methyltransferase in human Caco‑2 cells found:

“DNMT1 protein expression was inhibited by sulforaphane. Nrf2 promoter methylation decreased significantly in the sulforaphane group.

Sulforaphane may promote demethylation of the Nrf2 promoter region to increase activation of Nrf2.”


Per Week 6, my running days are over, though not walking, climbing, etc. Nrf2 activation with broccoli sprouts began after two weeks of self-quarantine more than a year ago.

Improving one’s own health provides sufficient rationale to act.

Oat β-glucan effects on colitis

This 2021 rodent study investigated oat β-glucan effects on colitis:

“In this study, we determined effects of consumption of low- and high-molar-mass oat beta-glucans on expression of selected markers of apoptosis and autophagy in colonocytes in TNBS colitis-induced rats. We analyzed expression of colon wall receptors, including TLRs and Dectin-1, which are involved in recognition of molecular patterns of pathogens in colon epithelial cells.

Rats were divided into two main groups: healthy control (H) and a TNBS (2,4,6-trinitrobenzosulfonic acid)-induced colitis (C) group, both including subgroups fed feed without beta-glucans (βG−) or feed supplemented with low- (βGl) or high-molar-mass oat beta-glucans (βGh) for 3, 7, or 21 days. Expression of autophagy (LC3B) and apoptosis (Caspase-3) markers, as well as Toll-like (TLRs) and Dectin-1 receptors in colon epithelial cells, was determined.

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1. [Autophagy] Autophagy contributes to adaptation of cells and maintenance of intracellular homeostasis enabling cells to survive under stressful conditions. The autophagy marker in colon wall and intestinal epithelial cells (IECs) investigated was expression of LC3B protein, which participates in formation and maturation of autophagosomes.

A decrease in this protein was found in colon wall after TNBS administration, which indicates intense repair processes of intestinal epithelium accompanying / preceding the period of Crohn’s disease (CD) remission. The above data indicate a significant effect of oat beta-glucans in restoring autophagy in inflamed IECs, and a stronger effect of oat beta-glucans with a high molar mass, which also increased activity of autophagy in colon tissue of control animals without colitis.

2. [Apoptosis] In early development of acute colitis, expression of Caspase-3, the executive enzyme of apoptosis, was very low. The highest expression of Caspase-3 protein was observed in control (HβGh+), feed supplemented with high-molar-mass oat beta-glucans.

  • After 7 days of TNBS administration, Caspase-3 expression in colitis-induced animals was approximately eight times higher than in control group, which indicates an increase in apoptosis in response to intestinal inflammation.
  • Consumption of feed supplemented with high-molar-mass oat beta-glucans by colitis animals resulted in approximately two times lower Caspase-3 expression after 7 days. Physical properties of high-molar-mass beta-glucans favor formation of a protective layer on inner wall of intestine, effectively supporting development of beneficial microbiota producing short-chain fatty acids.
  • Consumption of feed with low-molar-mass oat beta-glucans resulted in expression of this enzyme in colitis animals at a similar level as in control group.

This confirms significant effect of oat beta-glucans in reducing expression of Caspase-3 during ongoing inflammation, with low-molar-mass beta-glucans having a stronger effect.

3. [Dectin-1] Expression of Dectin-1 across all experimental time points was found to be reduced due to induced inflammation. We analyzed Dectin-1 expression in intestinal epithelial cells, not in colon wall or immune cells. Decrease in Dectin-1 expression in colonocytes noticed in our study may be related to disrupted intestinal barrier integrity by the ethanolic TNBS solution, that as a consequence, causes infiltration of pathogens / antigens into deeper layers of colon wall and allows their direct contact with cells of the immune system.

Results showed an increase in expression of Dectin-1 in inflamed IECs under influence of oat beta-glucans. A similar effect on expression of LC3B protein was noted, with oat beta-glucans of a high molar mass having a stronger effect.

4. [TNF-α] Concentration of TNF-α and other proinflammatory cytokines in colon wall of animals with TNBS-induced inflammation was significantly increased at all time points. Consumption of oat beta-glucans reduced concentration of these inflammatory factors.

The extrinsic pathway of apoptosis is induced by binding of this factor to the TNFR1a receptor. Increased autophagy in inflamed intestinal epithelium protected cells against TNF-α-induced apoptosis, which in turn helped to maintain integrity of the intestinal barrier and reduce inflammation.

5. [TLRs] After 3 days of TNBS administration, expression of TLR 4 and TLR 6 receptors in colonocytes was significantly lower in the colitis group receiving feed without beta-glucans as compared to control group. In the same group of rats (CβG−), TLR 5 expression was lower.

Decrease in expression of these receptors is mostly influenced by acute intestinal inflammation. Oat beta-glucans caused a significant increase in expression, especially TLR 5 and TLR 6, in inflamed IECs.

In summary, oat beta-glucans were found to alleviate the course of induced inflammation.”

https://www.mdpi.com/2072-6643/13/2/321/htm “Effects of Dietary Oat Beta-Glucans on Colon Apoptosis and Autophagy through TLRs and Dectin-1 Signaling Pathways – Crohn’s Disease Model Study”


Eat oats to prevent inflammatory diseases:

“Oat beta-glucans with a high molar mass increased activity of autophagy in colon tissue of control animals without colitis.”

If we don’t do that, eat oats to treat inflammation:

“Confirms significant effect of oat beta-glucans in reducing expression of Caspase-3 during ongoing inflammation, with low-molar-mass beta-glucans having a stronger effect.”

I eat primarily low- and medium-molecular-weight oat β-glucan twice a day with 3-day-old hulled Avena sativa oat sprouts. For breakfast I eat primarily high-molecular-weight oat β-glucan in hulless Avena nuda oats soaked 12+ hours and microwaved 20 minutes at 80% power in a 1000W microwave.

An oats β-glucan clinical trial tested low-, medium-, and high-molecular-weight oat β-glucan in 14 people. It found:

Bioprocessing of oat bran with enzyme treatment, causing depolymerization of β-glucan, affects nutritional properties of bran and functional properties of β-glucan in human gastrointestinal tract.”

Neither study investigated gut microbiota. Pretty sure our hosted microorganisms had roles in both studies’ findings.

Gut microbiota topics

Here are thirty 2019 and 2020 papers related to Switch on your Nrf2 signaling pathway topics. Started gathering research on this particular theme three months ago.

There are more researchers alive today than in the sum of all history, and they’re publishing. I can’t keep up with the torrent of interesting papers.

on

2020 A prebiotic fructo-oligosaccharide promotes tight junction assembly in intestinal epithelial cells via an AMPK-dependent pathway

2019 Polyphenols and Intestinal Permeability: Rationale and Future Perspectives

2020 Prebiotic effect of dietary polyphenols: A systematic review

2019 Protease‐activated receptor signaling in intestinal permeability regulation

2020 Intestinal vitamin D receptor signaling ameliorates dextran sulfate sodium‐induced colitis by suppressing necroptosis of intestinal epithelial cells

2019 Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

2020 The Immature Gut Barrier and Its Importance in Establishing Immunity in Newborn Mammals

2019 Prebiotics and the Modulation on the Microbiota-GALT-Brain Axis

2019 Prebiotics, Probiotics, and Bacterial Infections

2020 Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases

2020 Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor

2019 Involvement of Astrocytes in the Process of Metabolic Syndrome

2020 Intestinal Bacteria Maintain Adult Enteric Nervous System and Nitrergic Neurons via Toll-like Receptor 2-induced Neurogenesis in Mice (not freely available)

2019 Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1−/Δ7 mice

2020 Plasticity of Paneth cells and their ability to regulate intestinal stem cells

2020 Coagulopathy associated with COVID-19 – Perspectives & Preventive strategies using a biological response modifier Glucan

2020 Synergy between Cell Surface Glycosidases and Glycan-Binding Proteins Dictates the Utilization of Specific Beta(1,3)-Glucans by Human Gut Bacteroides

2020 Shaping the Innate Immune Response by Dietary Glucans: Any Role in the Control of Cancer?

2020 Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer’s disease mice

2019 Prebiotic supplementation in frail older people affects specific gut microbiota taxa but not global diversity

2020 Effectiveness of probiotics, prebiotics, and prebiotic‐like components in common functional foods

2020 Postbiotics-A Step Beyond Pre- and Probiotics

2019 Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential

2020 Postbiotics: Metabolites and mechanisms involved in microbiota-host interactions

2020 Postbiotics against Pathogens Commonly Involved in Pediatric Infectious Diseases

2019 Glutamatergic Signaling Along The Microbiota-Gut-Brain Axis

2019 Lipoteichoic acid from the cell wall of a heat killed Lactobacillus paracasei D3-5 ameliorates aging-related leaky gut, inflammation and improves physical and cognitive functions: from C. elegans to mice

2020 Live and heat-killed cells of Lactobacillus plantarum Zhang-LL ease symptoms of chronic ulcerative colitis induced by dextran sulfate sodium in rats

2019 Health Benefits of Heat-Killed (Tyndallized) Probiotics: An Overview

2020 New Horizons in Microbiota and Metabolic Health Research (not freely available)

Microwave broccoli sprouts to increase sulforaphane

This 2020 review explored sulforaphane stability and formation:

“Sulforaphane (SF) is beneficial to our health since it can reduce incidence of a number of tumors, induce cell cycle arrest and apoptosis in multiple experimental models. However, since neither SF nor myrosinase is thermostable, it is essential to increase stability of SF and/or enhance conversion of glucoraphanin (GRP) to SF by myrosinase to maximize SF therapeutic benefits.

  • Since little or no water is needed for microwaving and stir-frying, and broccoli is not immersed in water during steaming, SF content in broccoli florets is higher in these processes compared to that in boiled florets.
  • Thermostability of Brassicaceae myrosinase varies across different species and cultivars, as well as the plant organ. For example, myrosinase in broccoli florets are more thermosensitive compared to that in sprouts, likely due to the presence of a seed-specific myrosinase.
  • GRP in cooked broccoli can be hydrolyzed by intestinal microbiota to SF, sulforaphane nitrile, and/or other isothiocyanates and nitriles, although the decomposition rate is very low. However, continuous feeding of rats or mice with broccoli increased myrosinase-like activities in colon and cecum contents.

Mild heating (40-60 °C) by microwave increased SF content in broccoli. High-power microwave heating with temperature control at 60 °C could retain higher bioavailability.

Continuous broccoli ingestion enhances myrosinase-like activity of gut microbiota. Regardless of differences in endogenous amounts of glucosinolates and myrosinase across multiple broccoli varieties, moderate microwaving ensures optimum SF availability.”

https://www.sciencedirect.com/science/article/abs/pii/S0308814620326339 “Approaches for enhancing the stability and formation of sulforaphane” (not freely available)


Several studies previously curated were referenced, including:

  1. Microwave broccoli seeds to create sulforaphane;
  2. Microwave broccoli to increase sulforaphane levels;
  3. Enhancing sulforaphane content.

Why wait around for approval or citation or social validation of research? When Study 2 showed microwaving increased sulforaphane and glucoraphanin content this time last year, I followed the evidence and acted accordingly.

Researchers who deny microwaving’s beneficial effects on broccoli compounds up to 60° C can publish contrary findings, or keep their biased opinions to themselves. See Increase broccoli compound amounts with thermosonication for further evidence.

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Year One of Changing to a youthful phenotype with broccoli sprouts

1. My subjective experiences these past 52 weeks are that noticeable changes keep happening due to combinations of:

  • Eating clinically-relevant, twice-daily doses of microwaved 3-day-old broccoli sprouts, and taking nothing else an hour before or an hour after;
  • Eating 3-day-old oat sprouts twice a day;
  • Exercising every day;
  • Taking yeast cell wall β-glucan and other supplements twice a day;
  • Eating AGE-less chicken vegetable soup twice a day;
  • Eating 81+ grams (dry weight before soaking 12+ hours) of Avena nuda oats for breakfast;
  • Working from home 40 hours a week.

I look forward to more evidence on youthening during Year Two.

2. The three previous blog posts concerned yeast cell wall β-glucan. I haven’t received expected results from my New Year’s resolution to be prepared for Spring’s allergy onslaught. Actions included:

  • Changing diet to be more gut-friendly;
  • Taking WellImmune β-glucan in a morning dose of 500 mg for over two months;
  • Continuing with another company’s β-glucan in an evening 400 mg dose.

Consider this graphic from a third competitor regarding their Glucan 300 β-glucan:

dosage

My weight is probably 150-ish. I’d take three or four 500 mg capsules daily if I used Glucan 300. β-glucan comparisons evaluated it as the most active of five dozen commercially available products.

My lack of expected 2021 allergy results may be due to both insufficient dose and less-active products. Glucan 300 discloses its active content in specific percentages of 1,3/1,6 terminal-linked glucose molecules:

  1. Yeast cell wall β-glucan’s effects depend on biologically active content.
  2. Companies with evidence-based competitive products will disclose these contents.
  3. Neither β-glucan product I currently take does that.

I’ll use Glucan 300 exclusively when I receive it later this week. Can’t grow a fire by piling on more wet green wood if I’m serious about improving my innate and adaptive immune systems. Allergy season continues another few weeks, so it shouldn’t take long to find out if this change makes a difference.

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Evaluating a company-sponsored β-glucan paper

This 2020 review subject was yeast cell wall β-glucan effects in humans:

“The first aim of this review is to collate and interpret the existing pre‐clinical research on β‐1,3/1,6‐glucan with regard to immunity in order to clarify its molecular mechanism of immunomodulatory action.

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The second aim of this review is to collate and evaluate the literature in order to provide a comprehensive overview of human studies assessing the effect of supplementation with high quality, well‐characterized β‐1,3/1,6‐glucan from commercially available sources on immunity across multiple populations. Inclusion criteria consist of randomized, double‐blind, placebo‐controlled human studies that investigated efficacy of orally administered β‐glucan with a purity of over 75%.”

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.201901071 “β‐1,3/1,6‐Glucans and Immunity: State of the Art and Future Directions”


I don’t usually curate company-sponsored research, aka puff pieces. I wondered why, after taking WellImmune β-glucan 500 mg daily for over two months, I didn’t have expected results.

There are always several possible explanations for experimental failures. I didn’t see applicable items in this paper.

There was much information regarding things their sponsor’s customers don’t need to know. Just like their sponsor’s product label, there was little about what customers need to know, such as:

What was each product’s content, in specific percentages, of 1,3/1,6 terminal-linked glucose molecules? That makes a difference.

The sponsor knows, but doesn’t disclose it on their product’s label. These researchers could have found out and presented that information on their sponsor’s and other companies’ products for each study reviewed.

Not doing so deprived readers of an important evaluation criteria that could possibly explain variable results and provide a better measure for comparability. Stopping at “a purity of over 75%” instead of investigating and disclosing exact information was evasive.

Choosing your future with β-glucan

This 2020 rodent study investigated yeast cell wall β-glucan effects on bacterial infections:

“β-glucan is a potent inducer of epigenetic and functional reprogramming of innate immune cells, a process called trained immunity, resulting in an enhanced host response against secondary infections. We investigate whether β-glucan exposure confers protection against pulmonary Mycobacterium tuberculosis (Mtb) infection.

  • β-glucan induces trained immunity via histone modifications. β-glucan-induced trained immunity confers protection against virulent Mtb via the IL-1 signaling pathway.
  • β-glucan-induced trained immunity enhances production of proinflammatory cytokines in human monocytes challenged with heat-killed Mtb. Increase in cytokine production capacity was the result of epigenetic reprogramming and mediated via the PI3K/Akt/mTOR pathway.

Most important, β-glucan-treated mice infected with Mtb demonstrated remarkably enhanced survival, which was dependent on IL-1 signaling.

survival Mtb

β-glucan epigenetically reprograms human monocytes, leading to a phenotype characterized by a unique IL-1 signature and anti-mycobacterial properties. β-glucan-treated mice were protected against pulmonary Mtb infection.

While both β-glucan and BCG [Bacillus Calmette-Guerin tuberculosis vaccine] reprogram HSCs to induce trained immunity, BCG reprogramming of HSCs was dependent on IFNγ signaling. β-glucan reprogramming of HSCs was mediated via IL-1 signaling, which was also required for protection against Mtb infection.

Considering safety of β-glucan in a human clinical trial, our results strongly suggest potential clinical implications of β-glucan for both prophylactic and therapeutic use in TB.”

https://www.cell.com/cell-reports/fulltext/S2211-1247(20)30587-8 “β-Glucan Induces Protective Trained Immunity against Mycobacterium tuberculosis Infection: A Key Role for IL-1″


My comment “many of these findings also apply to yeast cell wall β-glucan treatments” in Long-lasting benefits of a common vaccine lacked clarity. This post provides part of that evidence.

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?

Which is better for resolving a health situation before it becomes a problem?

  • Roll the dice, and hope for luck / providence?
  • Do nothing constructive, and depend on interventions after a problem occurs?
  • Take responsibility for your own one precious life?

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β-glucan comparisons

This 2018 rodent study compared and contrasted commercially available β-glucans:

“β-glucans are natural biologically-active compounds called ‘biological response modifiers.’ This study is a follow-up of our three previous studies that tested 43 different glucans.

We used 16 different glucans isolated from yeasts, mushrooms, algae, and oats. We compared their effects on phagocytosis, IL-2 production, antibody secretion, and inhibition of three experimental cancer models.

16 beta glucans

Our results showed significant differences among tested glucans, despite the fact that glucans in general have strong stimulating effects on most aspects of the immune system. Differences between activities of commercially available glucans might be an explanation for the sometimes confusing results found in the literature. In all tests employed, Glucan #300 was the most active.

Highly purified and active glucans have significant pleiotropic effects.”

https://www.researchgate.net/publication/323523231_Glucans_and_Cancer_Comparison_of_Commercially_Available_b-glucans_-_Part_IV “Glucans and Cancer: Comparison of Commercially Available β-glucans – Part IV” (registration required)


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Oat digestibility

A reader questioned one part of Oat species comparisons of the good stuff regarding Avena nuda hull digestibility. This 2019 study partially investigated that aspect:

“We investigated effects of proteins, lipids, and β-glucan in naked oat flour on in vitro digestibility of starch. Content of rapidly digested starch increased, and content of resistant starch decreased after removing non-starch constituents.

There are three categories of starch in accordance with the rate and degree of starch digestion, namely, rapidly digested starch, slowly digested starch, and resistant starch. Resistant starch cannot be digested. Instead, it promotes growth of beneficial colonic flora.

Digestibility of starch is influenced by size and shape of starch granules, food processing method, physical and chemical modifications, viscosity, and food matrix components. Physicochemical properties of naked oat starch and naked oat flour after removing non-starch constituents were compared to study relationships between starch digestibility and intrinsic factors:


Oats contain more proteins and lipids than other common grains. Proteins can effectively reduce starch digestibility by several mechanisms:

  • Proteins can form a protection around starch granules, restricting entry of enzymes into substrates.
  • Surface proteins can block catalytic binding of enzymes on starch granule exterior.
  • α-amylase can partially bind to proteins, reducing enzyme utilization.

By contrast, effects of lipids on starch digestibility is primarily due to forming complexes with amylose, which is better able to resist amylase.

β-glucan, particularly the extracted water-soluble fraction, can lower digestion rate of starch by increasing viscosity. β-glucan can create a complex of adjacent proteins to form a robust structure that resists amylase, resulting in a decrease in starch digestibility.”

https://www.sciencedirect.com/science/article/abs/pii/S0308814619310556 “Non-starch constituents influence the in vitro digestibility of naked oat (Avena nuda L.) starch” (not freely available)


When viewing the above graphic, keep in mind that its order wasn’t sequential. So “degreased” oat flour (lipids removed, DG-NOF) wasn’t included in “deproteinized” oat flour (DP-NOF).

This in vitro study missed an opportunity to investigate human-practical aspects. Nobody eats oats without preparing them with water. But effects on digestibility from minutes and hours of soaking, boiling, microwaving, etc. weren’t analyzed.

Gut microbiota outnumber human cells. Treat them well with both Avena nuda resistant oat starch and indigestible hulls, and expect reciprocity.