Reinforce your immune memory every day

Three papers on trained immunity, with the first a 2021 review:

“Trained immunity is realized by epigenetic reprogramming of cells, primarily monocytes/macrophages and natural killer cells, and is less specific than adaptive immunity. It may cross-protect against other infectious agents.

Various actions of trained innate immunity on precursor cells have a strong potential for therapeutic use, particularly in infected and myelosuppressed individuals. Improvements of effects of some vaccines offer other potential use of β-glucan as an inductor of trained immunity, suggesting novel uses of a traditional therapeutic.”

https://www.mdpi.com/1422-0067/22/19/10684/htm “Trained Immunity as an Adaptive Branch of Innate Immunity”


Became tired of this review’s pedantic repetitions, that cells have a finite existence, as do cell attributes such as one-time trained immunity. Readers get it.

While belaboring the obvious, this paper missed two points:

  • As An environmental signaling paradigm of aging theorized, then demonstrated in A rejuvenation therapy and sulforaphane, and continues in current studies, cells take on phenotypes the body gives them. Focusing on cell attributes missed many signals elsewhere in cells’ environmental milieu, which make a difference in cell, organ, and body functioning.
  • Trained immunity protocol also matters. I’ve trained my immune system with yeast cell wall β-glucan every day for 17 years, recently taking nothing else an hour before or an hour after. That “no effects were found after 20 days” of only one in vitro dose isn’t relevant to my immune responses. I always have cells with one day of training, cells with (pick a number) days / weeks / months / years of training, and millions of primed cells in between.

This first paper cited a 2020 in vitro study:

“(1, 3)/(1, 6)-β-glucan can induce potent trained immunity, however, immunoregulatory activity of oat (1, 3)/(1, 4)-β-glucan has been neglected. Most studies have focused on its metabolic regulatory activity in diseases such as obesity and diabetes.

This study confirmed that β-glucan from oat dietary fiber can modulate responsiveness of innate immune cells through metabolic reprogramming. Proposed mechanism of oat β-glucan for trained immunity induction in monocytes/macrophages:

oat beta glucan trained immunity

This study showed that trained immunity induced by oat (1, 3)/(1, 4)-β-glucan was dependent on glycolysis or SDH/IRG axis in TCA cycle. These findings demonstrated that oat dietary fiber could strengthen and maintain long-term responsiveness of the innate immune system.”

https://doi.org/10.1007/s10753-020-01211-2 “Oat-Derived β-Glucans Induced Trained Immunity Through Metabolic Reprogramming” (not freely available)


A 2021 rodent study cited this second paper:

“Oat beta-glucans can stimulate secretion of anti-inflammatory cytokines, and simultaneously inhibit secretion of pro-inflammatory cytokines. The immunostimulatory effect of beta-glucan intake occurs due to its ability to activate intestinal mucosa immune cells, which results from binding of these polysaccharides to specific membrane TLR and/or Dectin-1 receptors.

We analyzed effects of oat beta-glucans at two time points, 3 and 7 days after TNBS administration:

  • High molecular mass beta-glucan forms a protective coating on the internal intestinal wall, which improves tissue recovery potential and reduces the risk of secondary microbial infection.
  • Low molar mass beta-glucan forms light solutions where short chains are well distributed and dispersed, and due to low viscosity, beta-glucan is accessible for receptors to be reached. Once reaching and complementing the receptor, bonded beta-glucan short polymeric chain induces transmission on metabolic pathways.

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Consumption of oat beta-glucans reduced levels of inflammatory markers, and recovered signaling pathways and histological changes, with stronger effects of low molar mass beta-glucan after 7 days of colitis. Dietary oat beta-glucans can reduce colitis at the molecular and organ level, and accelerate Crohn’s disease remission.”

https://www.mdpi.com/1422-0067/22/9/4485/htm “Anti-Inflammatory Activity of Oat Beta-Glucans in a Crohn’s Disease Model: Time- and Molar Mass-Dependent Effects”


I’d seen this second study’s abstract several times, but glossed over it. I curated another 2021 rodent study from the same institution as this third paper in Oat β-glucan effects on colitis.

None of these studies investigated gut microbiota. Pretty sure our hosted microorganisms had roles in their findings.

All papers called for human studies of their findings. But it would be difficult for drug companies to make money from a research area that’s cheap and readily accessible. Take responsibility for your own one precious life.

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Part 3 of Switch on your Nrf2 signaling pathway

To complement Parts 1 and 2, an informative and detailed video:

sulforaphane defense actions


My daily intake includes most of what’s mentioned in the video. For example, sulforaphane and other beneficial broccoli sprouts compounds, twice a day through 65.5 g of three-day-old broccoli / red cabbage / mustard sprouts microwaved to 60°C. And capers – a high source of quercetin (but see comparisons starting at 31:00, 80% vs. 4% bioavailability) – after soaking and rinsing them several times to reduce sodium content.

I arrived at this video via Dr. Houghton’s paper https://www.researchgate.net/publication/355201137_The_COVID_’Vaccine’_Dilemma_-_a_mechanistic_hypothesis “The COVID ‘Vaccine’ Dilemma – a mechanistic hypothesis” (registration required) posted yesterday.

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Broccoli sprouts and microRNAs

This 2021 in vitro study investigated microRNAs as potential causative factors for broccoli’s beneficial effects:

“A computational analysis was performed to explore processes and pathways associated with genes targeted either by:

  1. Host-expressed miRNAs (endogenous) modulated by bioactive compounds in broccoli; or
  2. miRNAs derived from broccoli (exogenous).

miRNAs are noncoding RNAs containing between 19 and 24 nucleotides, which act as regulators of gene expression both in plants and animals via degradation or inhibition of target mRNAs. miRNAs participate in several biological processes, such as apoptosis, cell growth, differentiation, proliferation, immune response, intercellular communication, RNA stability and processing, stress response, and others.

miRNAs reported in the literature as being upregulated or downregulated in response to broccoli bioactive compounds, with a significant change in expression of at least 2-fold, were selected and used to predict possible mechanisms exerted through miRNA-related actions.

pubmed vs scopus

Sixty-one genes were targeted by both exogenous and endogenous miRNAs, while 6143 and 87 target genes were unique to exogenous and endogenous miRNAs, respectively. Biological processes and molecular functions of genes targeted by both exogenous and endogenous miRNAs were also associated with chromatin, DNA, and RNA regulation.

Cooking, frying, microwaving [2 minutes in a 800W microwave on maximum power], steaming, and blanching were tested along with raw broccoli heads and sprouts and juice. Raw broccoli sprouts showed higher miRNA levels [in half of those tested]. Nearly all treatments did not significantly reduce miRNA levels compared to raw broccoli.

Samples of raw or boiled broccoli, juice, and broccoli sprouts were subjected to in vitro digestion, simulating GI conditions. miRNA survival levels dropped to percentages ranging approximately between 0.1 and 10% at the end of in vitro digestion, although complete elimination was not observed in any case.

Overall, bioinformatic results show that anticarcinogenic and cancer-preventive properties attributed to cruciferous vegetables might be mediated, at least in part, through miRNA-related mechanisms. Moreover, results show that broccoli-derived miRNAs can survive common food-processing conditions and GI digestion.”

https://pubs.acs.org/doi/10.1021/acs.jafc.1c04087 “Connection between miRNA Mediation and the Bioactive Effects of Broccoli (Brassica oleracea var. italica): Exogenous miRNA Resistance to Food Processing and GI Digestion” (not freely available)


I included part of this study’s methods to demonstrate the futility of a PubMed search on any topic. For example, a “caffeic acid and miRNA” search on Scopus returned 499 potential papers. In comparison, that search on PubMed returned 13 papers, or 2.6% of potentially relevant research.

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Eat isoflavones for your nerves

This 2021 rodent study investigated effects of dietary isoflavones and gut microbiota:

“Multiple sclerosis (MS) is a chronic neuroinflammatory disease of the central nervous system (CNS) that results in sensory, motor, and/or cognitive dysfunction. This is due to complex interactions of genetic and environmental factors that trigger activation of autoreactive T cells, leading to subsequent immune cell infiltration into the CNS, neurodegeneration, and axonal damage.

Genetic influences on MS have been well characterized, such as the strong association of certain human leukocyte antigen haplotypes with disease. In contrast, environmental factors – which account for around 70% of disease risk – remain understudied.

In humans, certain gut bacteria digest phytoestrogens, which are plant-based compounds that resemble estrogen. Isoflavones are a major class of phytoestrogens that are highly abundant in legumes such as soy. Humans do not have the necessary enzymes to break down isoflavones, and rely on gut microbiota to harvest these biologically active metabolites.

In the present study, we demonstrate that experimental autoimmune encephalomyelitis (EAE), an animal model for MS, is suppressed in mice fed a diet supplemented with isoflavones.

isoflavones eae

Adlercreutzia equolifaciens and Parabacteroides distasonis, which metabolize isoflavones, were more abundant in mice on an isoflavone diet. Both genera were enriched in healthy individuals but depleted in patients with MS. Conversely, Akkermansia muciniphila was found in greater abundance in mice on an isoflavone-free diet, and this genus is commonly enriched in patients with MS compared to healthy individuals.

isoflavones gut microbiota

We demonstrate that bacterial therapy with P. distasonis and A. equolifaciens results in markedly different clinical disease scores depending on diet of the host. In the absence of isoflavones, isoflavone-metabolizing bacteria may begin to metabolize host products, such as mucins, resulting in a proinflammatory state.

Considering the interplay between diet and gut bacteria is critical when developing dietary and gut microbiome-based therapies for MS and other diseases.”

https://www.science.org/doi/10.1126/sciadv.abd4595 “Isoflavone diet ameliorates experimental autoimmune encephalomyelitis through modulation of gut bacteria depleted in patients with multiple sclerosis”


Parabacteroides distasonis is my second most abundant gut microbiota species at 11.076%. Its main function is to metabolize carbohydrates, which are the bulk of my diet. Haven’t focused on isoflavones.

If you want to increase isoflavones with a soy product like tofu, try to eat it raw, steamed, or simmered in soup. Broiling, grilling, or sautéing tofu causes a dramatic rise in AGEs.

I came across this study by its citation in Dr. Paul Clayton’s rambling blog post Stranger together.

Trained immunity mechanisms

This 2021 cell study investigated how inflammatory memory is established, maintained, and recalled:

“Cells retain a memory of inflammation that equips them to react quickly and broadly to diverse secondary stimuli. Temporal, dynamic changes to chromatin accessibility, histone modifications, and transcription factor (TF) binding occur during inflammation, post-resolution, and in memory recall following injury.

Epigenetic records of inflammation have been found in innate immune cells, including macrophages, monocytes, and natural killer cells, as well as CD8+ and regulatory T cells, granulocyte-monocyte progenitors, and long-term hematopoietic stem cells. Inflammatory memory was recently extended to epithelial barrier tissues, which are the first line of defense against infectious pathogens and noxious agents.

Epigenetic memory of an inflammatory experience is rooted in chromatin of a cell via retention of chromatin accessibility, histone marks, and key TFs that endow it with heightened responsiveness to diverse secondary stimuli. AP-1 (activating protein-1) is a collective term referring to transcription factors composed of JUN, FOS, or ATF (activating transcription factor) subunits that bind to a common DNA site.

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We unearth an essential, unifying role for the general stress-responsive transcription factor FOS, which partners with JUN and cooperates with stimulus-specific STAT3 to establish memory. JUN then remains with other homeostatic factors on memory domains, facilitating rapid FOS re-recruitment and gene re-activation upon diverse secondary challenges.

We offer a comprehensive, potentially universal mechanism behind inflammatory memory and less discriminate recall phenomena with implications for tissue fitness in health and disease:

  1. Stimulus-specific STAT3 and broad stress factor AP1 co-establish memory domains;
  2. Stem cell factors access open memory domains and remain bound after inflammation;
  3. FOS activates open memory domains, enabling secondary responses to diverse stimuli; and
  4. AP1 mediates epigenetic inflammatory memory across cell types, stimuli, and species.”

https://www.sciencedirect.com/science/article/abs/pii/S1934590921002861 “Establishment, maintenance, and recall of inflammatory memory” (not freely available)


Take responsibility for your own one precious life. Train your immune system every day with yeast cell wall β-glucan.

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Gut microbiota responses to inulin

This 2021 rodent study investigated:

“We studied long-term dynamics of gut microbiome and short-chain fatty acids (SCFAs) in isogenic mice with distinct microbiota baselines fed with fermentable fiber inulin compared to non-fermentable fiber cellulose.

  • We found that inulin produced generally rapid response followed by gradual stabilization to new equilibria, and those dynamics were baseline-dependent.
  • Levels of SCFAs such as propionate were associated with abundance of inulin responders, yet inter-individual variation of gut microbiome impedes prediction of SCFAs by machine learning models.
  • Our methods and major findings are generalizable to dietary resistant starch.

We divided the entire gut microbiota into three eco-groups: 5 primary degraders of inulin; 32 generic responders to inulin intervention; and non-responders. Primary degraders and their competitions are key drivers of baseline-dependent ecological dynamics of microbiota response to dietary fibers.

fiber degraders and responders

SCFA concentrations cannot be maintained at its peak, and drop by 35%-40% even under continuous inulin intake until four weeks. 90%-95% SCFAs produced in colonic lumen are absorbed by gut mucosa. The declining phase of SCFAs in our study may be explained by reduced production rate, increased absorption rate, or both.

Our study confirms findings in the literature and advances understanding of effects of dietary fibers on the gut microbiome at the system level:

  1. The small number of fiber degraders (five for inulin and two for resistant starch) suggested that fiber-induced bacterial shifts are very selective and occur to a restricted number of taxa.
  2. Absolute abundance of many fiber-degrading bacteria, such as taxa related to genus Bifidobacterium, failed to expand in both fibers. This indicates that fiber-induced bacterial enrichment cannot be simply predicted from in vitro growth, and suggests that dietary response of a gut bacterial taxa depends on the ecological context.
  3. Personalized fiber-induced response of gut microbiota were largely determined by baseline abundance of fiber degraders and ecological interactions among these degraders.”

https://www.biorxiv.org/content/10.1101/2021.08.20.457175v1.full “Ecological dynamics of the gut microbiome in response to dietary fiber”


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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.”

https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.32043 “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.


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Eat oat avenanthramides for your gut microbiota

This 2021 paper covered a 2016 human clinical trial, and several in vitro and rodent follow-up studies:

“Oat has been widely accepted as a key food for human health. It is becoming increasingly evident that individual differences in metabolism determine how different individuals benefit from diet. Both host genetics and gut microbiota play important roles on metabolism and function of dietary compounds.

Results:

  • Avenanthramides (AVAs), the signature bioactive polyphenols of whole-grain (WG) oat, were not metabolized into their dihydro forms, dihydro-AVAs (DH-AVAs), by both human and mouse S9 fractions.
  • DH-AVAs were detected in colon and distal regions, but not in proximal and middle regions of the perfused mouse intestine, and were in specific pathogen–free (SPF) mice but not in germ-free (GF) mice.
  • A kinetic study of humans fed oat bran showed that DH-AVAs reached their maximal concentrations at much later time points than their corresponding AVAs (10.0–15.0 hours vs. 4.0–4.5 hours, respectively).
  • We observed interindividual variations in metabolism of AVAs to DH-AVAs in humans.
  • Faecalibacterium prausnitzii was identified as the individual bacterium to metabolize AVAs to DH-AVAs by 16S rRNA sequencing analysis.
  • Moreover, as opposed to GF mice, F. prausnitzii–monocolonized mice were able to metabolize AVAs to DH-AVAs.

AVA metabolizers

These findings demonstrate that intestinal F. prausnitzii is indispensable for proper metabolism of AVAs in both humans and mice. We propose that abundance of F. prausnitzii can be used to subcategorize individuals into AVA metabolizers and nonmetabolizers after WG oat intake.

Our findings pave the way to use AVAs and DH-AVAs as exposure biomarkers to reflect WG oat intake, which could more accurately record WG oat intake. Whether production of DH-AVAs is part of the beneficial effect of oats on human health will require further investigation.”

https://academic.oup.com/jn/article/151/6/1426/6165027 “Avenanthramide Metabotype from Whole-Grain Oat Intake is Influenced by Faecalibacterium prausnitzii in Healthy Adults”

Commentary at Faecalibacterium prausnitzii Abundance in Mouse and Human Gut Can Predict Metabolism of Oat Avenanthramides.


This study advanced an understanding of inter-individual variability, rather than usual practices that try to sweep individual differences under a statistical rug. Study designs such as four mentioned in Part 2 of Switch on your Nrf2 signaling pathway could have benefited from a similar approach to their research areas.

Not sure why it took over five years to get this paper published after its clinical trial’s January 21, 2016 completion. Meanwhile, science marched on to study effects of specific F. prausnitzii strains, providing results such as three human studies curated in Gut microbiota strains:

  • The third 2018 study found:

    “Only a small number of bacteria with genetic capacity for producing SCFAs were able to take advantage of this new resource and become dominant positive responders. The response, however, was strain specific: only one of the six strains of Faecalibacterium prausnitzii was promoted.”

  • The second 2021 study investigated 135 known strains of F. prausnitzii; and
  • The first 2021 study found beneficial F. prausnitzii strains not yet covered in genomic databases.

Resistant starch therapy recommended de-emphasizing relative gut microbiota abundance measurements, because:

“Relative abundances of smaller keystone communities (e.g. primary degraders) may increase, but appear to decrease simply because cross-feeders [like F. prausnitzii] increase in relative abundance to a greater extent. These limitations illustrate the necessity of sufficiently powering resistant starch interventions where microbiome composition is the primary endpoint, collecting critical baseline data and employing appropriate statistical techniques.”


Four humpback whales successively diving for lunch

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Natural products vs. neurodegenerative diseases

I was recently asked about taking rapamycin for its effects on mTOR. I replied that diet could do the same thing. Here’s a 2021 review outlining such effects:

“As common, progressive, and chronic causes of disability and death, neurodegenerative diseases (NDDs) significantly threaten human health, while no effective treatment is available. Recent studies have revealed the role of phosphoinositide 3-kinase (PI3K)/Akt (Protein kinase B)/mammalian target of rapamycin (mTOR) in some diseases and natural products with therapeutic potentials.

Growing evidence highlights the dysregulated PI3K/Akt/mTOR pathway and interconnected mediators in pathogenesis of NDDs. Side effects and drug-resistance of conventional neuroprotective agents urge the need for providing alternative therapies.

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Polyphenols, alkaloids, carotenoids, and terpenoids have shown to be capable of a great modulation of PI3K/Akt/mTOR in NDDs. Natural products potentially target various important oxidative/inflammatory/apoptotic/autophagic molecules/mediators, such as Bax, Bcl-2, p53, caspase-3, caspase-9, NF-κB, TNF-α, GSH, SOD, MAPK, GSK-3β, Nrf2/HO-1, JAK/STAT, CREB/BDNF, ERK1/2, and LC3 towards neuroprotection.

This is the first systematic and comprehensive review with a simultaneous focus on the critical role of PI3K/Akt/mTOR in NDDs and associated targeting by natural products.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711321002075 “Natural products attenuate PI3K/Akt/mTOR signaling pathway: A promising strategy in regulating neurodegeneration” (not freely available) Thanks to Dr. Sajad Fakhri for providing a copy.


Natural products mentioned in this review that I eat in everyday foods are listed below. The most effective ones are broccoli and red cabbage sprouts, and oats and oat sprouts:

  • Artichokes – luteolin;
  • Blackberries – anthocyanins;
  • Blueberries – anthocyanins, gallic acid, pterostilbene;
  • Broccoli and red cabbage sprouts – anthocyanins, kaempferol, luteolin, quercetin, sulforaphane;
  • Carrots – carotenoids;
  • Celery – apigenin, luteolin;
  • Green tea – epigallocatechin gallate;
  • Oats and oat sprouts – avenanthramides;
  • Strawberries – anthocyanins, fisetin;
  • Tomatoes – fisetin.

Four humpback whales

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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.”

https://www.nature.com/articles/s41385-021-00420-8 “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.”

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Take taurine for your mitochondria

This 2021 review summarized taurine’s beneficial effects on mitochondrial function:

“Taurine supplementation protects against pathologies associated with mitochondrial defects, such as aging, mitochondrial diseases, metabolic syndrome, cancer, cardiovascular diseases and neurological disorders. Potential mechanisms by which taurine exerts its antioxidant activity in maintaining mitochondria health include:

  1. Conjugates with uridine on mitochondrial tRNA to form a 5-taurinomethyluridine for proper synthesis of mitochondrial proteins (mechanism 1), which regulates the stability and functionality of respiratory chain complexes;
  2. Reduces superoxide generation by enhancing the activity of intracellular antioxidants (mechanism 2);
  3. Prevents calcium overload and prevents reduction in energy production and collapse of mitochondrial membrane potential (mechanism 3);
  4. Directly scavenges HOCl to form N-chlorotaurine in inhibiting a pro-inflammatory response (mechanism 4); and
  5. Inhibits mitochondria-mediated apoptosis by preventing caspase activation or by restoring the Bax/Bcl-2 ratio and preventing Bax translocation to the mitochondria to promote apoptosis.

taurine mechanisms

An analysis on pharmacokinetics of oral supplementation (4 g) in 8 healthy adults showed a baseline taurine content in a range of 30 μmol to 60 μmol. Plasma content increased to approximately 500 μmol 1.5 h after taurine intake. Plasma content subsequently decreased to baseline level 6.5 h after intake.

We discuss antioxidant action of taurine, particularly in relation to maintenance of mitochondria function. We describe human studies on taurine supplementation in several mitochondria-associated pathologies.”

https://www.mdpi.com/1420-3049/26/16/4913/html “The Role of Taurine in Mitochondria Health: More Than Just an Antioxidant”


I take a gram of taurine at breakfast and at dinner along with other supplements and 3-day-old Avena sativa oat sprouts. Don’t think my other foods’ combined taurine contents are more than one gram, because none are found in various top ten taurine-containing food lists.

As a reminder, your mitochondria come from your mother, except in rare cases.

Part 2 of Improving epigenetic clocks’ signal-to-noise ratio

Another excellent blog post by Josh Mitteldorf, A New Approach to Methylation Clocks, that curated the same study:

“The Levine/Horvath PhenoAge epigenetic clock was calibrated using a combination of metabolic factors that correlate with health, including inflammation, DNA transcription, DNA repair, and mitochondrial activity.

Evolution is not an engineer. Living things are not constructed out of parts that are separately optimized for exactly one function.

Every molecule has multiple functions. Every function is regulated by multiple pathways.

For clock technology, using individual CpGs for a starting point may not be optimal. We suspect that CpGs, like other biological entities, work together closely in teams.

CpGs on a team might vary slightly from one individual to the next. But the team has a function and an identity and a signature that is robust. We expect the team to function more consistently than any of its individual members.

The peer-reviewed version of her paper will be published shortly. Full details of algorithms will be available on GitHub, and script in the R programming language will be released for use of other researchers. If principal component analysis clocks correlate well with previously validated clocks but offer tighter uncertainties, we’ll know we’re on the right track.”


Best wishes for Josh to recover from a bike accident.

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Choosing appropriate dietary fibers

This 2021 rodent study investigated effects of dietary fibers on Type 2 diabetes:

“Nine types of dietary fibers were used to investigate and evaluate their effects on type-2 diabetic rats via physiology, genomics, and metabolomics.

In human clinical trials, supplementation with dietary fibers was found inversely associated with risks of diabetes, along with improvement on glycemic control, lipid profiles, and host homeostasis. However, mixed fibers with diverse types from dietary sources are generally used for treatment intervention in clinical trials, and effects of individual dietary fibers on T2D are seldom discussed.

We found that supplementation with β-glucan, arabinogalactan, guar gum, and apple pectin had favorable effects on alleviating T2D:

upset plot

Non-bioactive dietary fibers (NBDF) were glucomannan, arabinoxylan, carrageenan, xylan, and xanthan gum.

dietary fibers effects

Relatively high viscosity was an important driving factor of dietary fibers for hypoglycemic effects. Supplementation with β-glucan, arabinogalactan, guar gum, and apple pectin tended to restore gut microbiota composition.

Our study uncovered effects of different dietary fibers on T2D, along with their potential mechanisms. Different dietary fibers influenced host metabolism via different metabolic pathways.”

https://pubs.acs.org/doi/10.1021/acs.jafc.1c01465 “Bioactive Dietary Fibers Selectively Promote Gut Microbiota to Exert Antidiabetic Effects” (not freely available). Thanks to Dr. Yonggan Sun for providing a copy.


I eat oat β-glucan three times a day – Avena nuda whole oats for breakfast, and twice daily 3-day-old Avena sativa hulled 3-day-old oat sprouts. Not to be confused with training my immune system with daily yeast cell wall β-glucan.

I recommend “Section 6. Biological functions” of the 2021 Plants arabinogalactans: From structures to physico-chemical and biological properties (not freely available), which reviewed:

  • ACE inhibitory;
  • Anti-cancer;
  • Anti-complementary;
  • Anti-diabetic;
  • Anti-ulcer;
  • Antiaging;
  • Antinociceptive;
  • Antioxidant;
  • Antitumor;
  • Antitussive;
  • Antiviral;
  • Complementary system;
  • Complement fixation;
  • Gastrointestinal-protective;
  • Hepatoprotective;
  • Hypoglycemic;
  • Immunomodulating;
  • Immunostimulatant;
  • Immune enhancing;
  • Intestinal immune system;
  • Phagocytosis stimulating; and
  • Prebiotic activities

properties of different arabinogalactans. Thanks to Professor Michaud for providing a copy.

Arabinogalactans were favored in both papers, yet few are commercially available. In January 2021 I used an arabinogalactan supplement, but it was too expensive to continue. Maybe multiple processing steps were a cost factor?

arabinogalactan processing

Changing your immune system / gut microbiota interactions with diet

This 2021 human clinical trial investigated associations between gut microbiota and host adaptive immune system components:

“Diet modulates gut microbiome, and gut microbes impact the immune system. We used two gut microbiota-targeted dietary interventions – plant-based fiber or fermented foods – to determine how each influences microbiome and immune system in healthy adults. Using a 17-week randomized, prospective study design combined with -omics measurements of microbiome and host and extensive immune profiling, we found distinct effects of each diet:

  • Those in the high-fiber diet arm increased their fiber consumption from an average of 21.5±8.0 g per day at baseline to 45.1±10.7 g per day at the end of the maintenance phase.
  • Participants in the high-fermented food diet arm consumed an average of 0.4±0.6 servings per day of fermented food at baseline, which increased to an average of 6.3±2.9 servings per day at the end of the maintenance phase.
  • Participants in the high-fiber diet arm did not increase their consumption of fermented foods (Figure 1.C dashed line), nor did participants consuming the high-fermented food diet increase their fiber intake.

fiber vs fermented

Fiber-induced microbiota diversity increases may be a slower process requiring longer than the six weeks of sustained high consumption achieved in this study. High-fiber consumption increased stool microbial protein density, carbohydrate-degrading capacity, and altered SCFA production, indicating that microbiome remodeling was occurring within the study time frame, just not through an increase in total species.

Comparison of immune features from baseline to the end of the maintenance phase in high-fiber diet participants revealed three clusters of participants representing distinct immune response profiles. No differences in total fiber intake were observed between inflammation clusters. A previous study demonstrated that a dietary intervention, which included increasing soluble fiber, was less effective in improving inflammation markers in individuals with lower microbiome richness.

In both diets, an individual’s microbiota composition became more similar to that of other participants within the same arm over the intervention, despite retaining the strong signal of individuality.

Coupling dietary interventions to longitudinal immune and microbiome profiling can provide individualized and population-wide insight. Our results indicate that fermented foods may be valuable in countering decreased microbiome diversity and increased inflammation.”

https://www.cell.com/cell/fulltext/S0092-8674(21)00754-6 “Gut-microbiota-targeted diets modulate human immune status” (not freely available). See https://www.biorxiv.org/content/10.1101/2020.09.30.321448v2.full for the freely available preprint version.


Didn’t care for this study’s design that ignored our innate immune system components yet claimed “extensive immune profiling.” Not.

There was sufficient relevant evidence on innate immunity cells – neutrophils, monocytes, macrophages, natural killer cells, and dendrites – when the trial started five years ago. But maybe this didn’t satisfy study sponsors?

This study found significant individual differences in the high-fiber group. These individual differences failed to stratify into subgroup p-value significance.

I won’t start eating fermented dairy or fermented vegetable brines to “counter decreased microbiome diversity and increased inflammation.” I’m rolling the die with high-fiber intake (2+ times more grams than this clinical trial, over a 3+ times longer period so far).

Changing to a high-fiber diet this year to increase varieties and numbers of gut microbiota is working out alright. No worries about “increased inflammation” because twice-daily 3-day-old microwaved broccoli sprouts since Day 70 results from Changing to a youthful phenotype with broccoli sprouts have taken care of inflammation for 15 months now.

What effects have this year’s diet changes had on my adaptive and innate immune systems? 2021’s spring allergy season wasn’t pleasant. But late summer’s ragweed onslaught hasn’t kept me indoors – unlike other years – despite day after day of readings like today’s:

ragweed

Regarding an individual’s starting point and experiences, those weren’t the same as family, friends, significant other, identified group members, or strangers. Each of us has to find our own way to getting well.

Agenda-free evidence may provide good guidelines. So does how you feel.