People will forgive you for being wrong, but they will never forgive you for being right – especially if events prove you right while proving them wrong. Thomas Sowell
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.
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.”
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.
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.
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.”
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.
“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
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.
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.”
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:
“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.
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.”
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.
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.”
“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?”
“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.”
“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:
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;
Reduces superoxide generation by enhancing the activity of intracellular antioxidants (mechanism 2);
Prevents calcium overload and prevents reduction in energy production and collapse of mitochondrial membrane potential (mechanism 3);
Directly scavenges HOCl to form N-chlorotaurine in inhibiting a pro-inflammatory response (mechanism 4); and
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.
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.”
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 came from your mother, except in rare cases.
“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.
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:
Non-bioactive dietary fibers (NBDF) were glucomannan, arabinoxylan, carrageenan, xylan, and xanthan gum.
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.”
I eat oat β-glucan three times a day – Avena nuda whole oats for breakfast, and twice daily 3-day-old Avena sativahulled 3-day-old oat sprouts. Not to be confused with training my immune system with daily yeast cell wall β-glucan.
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?
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-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.”
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:
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.
“We aimed to develop and evaluate epigenetic clocks for cats, as such biomarkers are necessary for translating promising anti-aging interventions from humans to cats and vice versa. We also provided the possibility of using epigenetic aging rate of cats to inform on feline health, for which a quantitative measure is presently unavailable. Specifically, we present here DNA methylation-based biomarkers (epigenetic clocks) of age for blood from cats.
Maximum lifespan of cats is 30 years according to the animal age data base (anAge), but most cats succumb to diseases before they are 20 years old. Age is the biggest risk factor for a vast majority of diseases in animals, and cats are no exception.
Interventions to slow aging are being sought. Ideally, testing should occur in species that are evolutionarily close to humans, similar in size, have high genetic diversity, and share the same environment as humans. It has been recognized that domestic dogs fulfill these criteria.
Investigations have yet to be extended to cats although they share similar environments and living conditions with their human owners. Identification of environmental factors and living conditions that affect aging, as well as potential mitigation measures, can be achieved by proxy with cats.
The human-cat clock for relative age exhibited high correlation regardless of whether analysis was applied to samples from both species or only to cat samples. This demonstrated that relative age circumvented skewing that is inherent when chronological age of species with very different lifespans is measured using a single formula.
Evidence is compelling that epigenetic age is an indicator of biological age. These results are consistent with the fact that epigenetic clocks developed for one mammalian species can be employed – to a limited extent – to other species, and reveal association of DNA methylation changes with age.
Human epigenetic age acceleration is associated with a wide array of primary traits, health states, and pathologies. While it is still unclear why age acceleration is connected to these characteristics, it does nevertheless suggest that extension of similar studies to cats may allow for development of epigenetic age acceleration as a surrogate or indicator of feline biological fitness.”
As noted earlier this summer in Smoke and die early, while your twin lives on, Dr. Steve Horvath is on a torrid publishing streak this year. He’s made it questionable for study designs based on published science to omit epigenetic clocks.
I titled this post Your pets because I’m too allergic to have cats, dogs, etc. live with me. Maybe this year’s focus on making my gut microbiota happy will change that?
This 2021 study compared properties of red cabbage and broccoli seeds and sprouts:
“Antioxidant and antidiabetic properties and metabolite profiling of ethanol extracts of red cabbage (RC) and broccoli (BR) seeds and sprouts were investigated:
BR seeds had the highest total phenolic and flavonoid contents;
BR sprouts had the highest saponin content;
RC sprouts demonstrated the highest antioxidant capacity;
BR and RC sprouts showed the most potent inhibition against α-glucosidase and pancreatic lipase; and
BR seeds demonstrated the lowest AGE inhibition.
In vitro assessment of antidiabetic potential of extracts revealed that sprouts demonstrated better potential as antioxidant, α-glucosidase, and pancreatic lipase inhibitors compared to raw seeds. Amino acids and phenolic compounds were the most improved metabolites in the germination process.
Germination not only enhanced levels of metabolites, but also synthesized new compounds in seeds. Germination effectively enhanced functional properties and metabolite profiles of broccoli and red cabbage seeds, making their sprouts more applicable as functional ingredients.”
https://www.mdpi.com/2076-3921/10/6/852/htm “UHPLC-ESI-QTOF-MS/MS Metabolite Profiling of the Antioxidant and Antidiabetic Activities of Red Cabbage and Broccoli Seeds and Sprouts”
I asked coauthors for sprout ages and pertinent growing conditions for the above-pictured sprouts. I’ll guess > 3-days-old, temperature 25° C, and relative humidity 90%. What would you guess?
Update: Two coauthors replied:
“Red Cabbage and Broccoli were germinated for 6 and 7 days respectively. Temperature ranged between 20-23 °C in the dark.”
“In this episode we speak with Neal Peterson, who has devoted over 40 years to breeding pawpaws (Asimina triloba). We talk about how he first fell in love with this delicious fruit, how he tracked down remnants of the early 20th century pawpaw collections just in time, and selected 7 superior pawpaw cultivars out of 1,500 seedlings.”
I first ate a pawpaw while on a Capital Area Hiking Club September 2015 hike on the Susquehanna River. Our hike leader loaded up his backpack and was willing to share when we finished. Didn’t take a photo, but here’s what I picked a year later from a farm:
Ugly looking, but beautiful inside.
In subsequent seasons, I found pawpaws in national and state parks. Can’t find pawpaw fruit sales online that I previously bought from, so may revisit these parks next month.
My son and I engaged in Guerrilla Planting. Maybe it’s time to check on those trees’ progress, too?
This 2021 study investigated Vitamins K1 and K2 associations with hospitalization for atherosclerotic cardiovascular disease (ASCVD):
“In this prospective cohort study, both dietary vitamin K1 intake and vitamin K2 intake were inversely related to ASCVD hospitalization risk, and very low vitamin K1 was associated with a higher risk of ASCVD hospitalizations. Given very different food sources, these data support an independent protective effect for both subtypes of vitamin K.
Relatively higher vitamin K2 intake in our cohort permitted discovery of a nonlinear, more U‐shaped association between vitamin K2 intake and ASCVD risk, which, to the best of our knowledge, has not previously been described. This may reflect a competing increase in ASCVD risk associated with overconsumption of vitamin K2‐rich foods (ie, cheese, eggs, butter).
Our study comes with some limitations common to nutritional epidemiology, and has significant strengths:
A large sample size with up to 23 years of follow‐up, allowing for accumulation of a high number of events;
Availability of important participant characteristics, enabling appropriate methods to be employed to reduce residual confounding; and
Daily broccoli / red cabbage / mustard sprouts for Vitamin K1, and a supplement for Vitamin K2 is what I do. Expect more than staying out of hospitals, but don’t know whether previous damage can be repaired.
This 2021 review highlighted effects of processing oat products:
“Starch contents in oats ranges from 51% to 65%. Resistant starch (RS) accounts for 29.31% of starch content in raw granular form of oat starch.
RS in raw oat starch is RS2 starch, where its slow digestion is mainly due to the compact nature of starch granules making starch less accessible to enzymes. Since amylose–lipid complex is resistant to enzymatic breakdown, high lipid content in oats (3–7%) may be another reason why oat has a relatively high level of RS starch. This type of RS is called RS5.
Although RS2 occurs naturally, most starch needs to be cooked for consumption. RS3 that is formed due to recrystallization of gelatinized starch is more commonly consumed by processing via gelatinization and retrogradation.
β-glucans are found in cell walls of endosperm and aleurone layers of oats, accounting for 1.73-5.70% of oat grains dry basis. Oat β-glucans are not digested in the upper gastric tract, but instead can be consumed by gut microbiota in the colon. This kind of prebiotic can be fermented by colonic microbiota, resulting in production of short chain fatty acids (SCFA) metabolites.
From field to table, oats are processed into various foods for consumption, and these foods exhibit high variability of GI values:
β-glucan dose and molecular weight are crucial determinants affecting viscosity and gastric emptying rate; and
Higher content of protein in oats is an important factor that deserves attention.”
Surface Your Real Self 