Vitamin A and the Epigenome

https://www.researchgate.net/publication/283790487_Vitamin_A_and_the_Epigenome
A download of the full pdf is available through the link.

The epigenetic phenomena refer to heritable changes in gene expression other than those in the DNA sequence, such as DNA methylation and histone modifications. Major research progress in the last few years has provided further proof that environmental factors, including diet and nutrition, can influence physiologic and pathologic processes through epigenetic alterations, which in turn influence gene expression. This influence is termed nutritional epigenetics, and one prominent example is the regulation of gene transcription by vitamin A through interaction to its nuclear receptor. Vitamin A is critical throughout life. Together with its derivatives, it regulates diverse processes including reproduction, embryogenesis, vision, growth, cellular differentiation and proliferation, maintenance of epithelial cellular integrity and immune function. Here we review the epigenetic role of vitamin A in cancer, stem cells differentiation, proliferation, and immunity. The data presented here show that retinoic acid is a potent agent capable of inducing alterations in epigenetic modifications that produce various effects on the phenotype. Medical benefits of vitamin A as an epigenetic modulator, especially with respect to its chronic use as nutritional supplement, should rely on our further understanding of its epigenetic effects during health and disease, as well as through different generations.

The vicious cycle of vitamin a deficiency: A review

Vitamin A deficiency (VAD) is a serious and widespread public health problem and the leading cause of preventable blindness in young children. It is also associated with increased rates of death from severe infections, especially in developing countries. Over the past 35 years, researchers have examined the numerous activities of vitamin A in different tissues of the human body. VAD can lead to a series of ocular symptoms, anemia, and weak resistance to infection, which can increase the severity of infectious diseases and the risk of death. Cell development, vision, growth, and normal metabolism are among the vital processes that are insufficiently supported in the presence of VAD. VAD leads to impaired tissue function especially during the developmental periods of infancy, childhood, pregnancy, and lactation. We describe a multidirectional model of VAD that demonstrates how VAD can have progressive, negative effects on vital processes of the human body throughout the life cycle. This model starts with impaired intake and its link to decreased absorption and digestion and includes outcomes such as malnutrition, inflammation, and improper growth processes, including possible mechanisms. Together, these clinical and biochemical manifestations contribute to the vicious cycle of VAD.

Im actually looking at a possible problem here before Accutane, and bacterial metabolism in the small intestine could play a role.

With all of this, in my mind you really have just two things to look at,
Our own genes, and our microbiome that includes all the genes that come along with it, that far outnumber our own.

2 Likes

Wow. The long-term vit-A toxicity proponents are going to love reading or not reading this one.
Never thought I would see the day when people would argue against a balanced diet, including fish and green-leafy vegetables.

Thanks!

1 Like

Too much Vit-A makes it toxic, not enough makes Vit-A deficiency. Same goes for all lipo-soluble vitamins, most minerals and many of the water solubles vitamins.

I still report increased genital sensitivity from adequate Vit-A intake, both as a supplement and in my diet.

My diet is almost exclusively ghee, beef, pork fat, spinach, lentils and occasional avocados and mackerel for omega 3 and mono-unsaturated (listed from the largest to the least amounts). I get 2/3 of my calories from fat, 30% from protein, mostly beef and almost no carbs. I often do 1 meal a day (intermittent fasting) and caloric deficit along with a few other pro-sirtuin, epigenetic fixing tricks. This has been going on for 2 years and a half.

Some more symptoms have disappeared in the last 6 months: burning eyes almost never happens anymore, same with burning dry lips, and for the first few times since I crashed, I feel tired and yawn in the hours before bedtime. It sometime looks like I could sleep without meds and I once forgot to take 2mg out of 3.5mg of Clonopin (a benzo) and I still slept alright that night. (Benzo withdrawal is bad so I can’t just stop it. I’ll have to slowly decrease over 7 months)

There’s almost no fiber in my diet. In the last few months, I have been making efforts to increase fiber by increasing lentils and taking crushed spylllium husks. The results have been bad. I get a pasty mouth and a white tongue in the morning, a sore throat and nausea. All indications of upper track bacterial infection and maybe the large intestine also. I recently decreased fibers and symptoms have decreased.

I’m now interested in the guts biome. It makes no doubt to me the disease is epigenetic and I’m treating it as such but I’m suspecting unbalanced gut biome along with parasitic bacteria exacerbate and sustain the disease. This would have been triggered by the initial crash but the prolongation of this imbalance may hinder progress we may otherwise make on the epigenetic level. This remains to be seen.
I know most of us have no bifidus or e-colie strain in their guts, which is very unusual for mammals, while having pathogenic levels of other strains. Guts biome imbalances can be responsible for a plethora of symptoms (including autism), many of those symptoms similar to some of the symptoms experienced by some of us.

I will soon check my Immunoglobulin E levels to see if I’m fighting an infection and have my guts biome tested to see if I can rectify any imbalance. I’m also taking zinc, Vit-D and an ionophore to combat intra cellular infections. So far the results are good.

Check this post:

And this link from a 10 year pfs sufferer who claims to be symptom free for the last 18 months:

Im actually looking at retinoic acid mainly, not the intake of vitamin a through diet or supplements.
There would be no reason to be concerned about lack of dietary intake of vitamin a, and precursor supplements to retinoic acid are easily available. im looking at a possible conversion issue from diet or supplements to retinoic acid.

Bacterial community collapse or instability, you see where this could take place and this is the area that is more rapidly modifiable through diet or drugs.

Downregulation of Th17 Cells in the Small Intestine by Disruption of Gut Flora in the Absence of Retinoic Acid

Th17 cells are pivotal in autoimmune diseases, inflammatory
bowel diseases, and infections (4, 33, 46). Moreover, malnutrition,
from which many children in developing countries suffer, may
lead to impairment of many aspects of host defense (47). Our
results in this study clearly demonstrate that nutrients, such as
vitamin A, regulate development and maintenance of Th17 cells
in the intestines. Thus, future studies that seek cures for inflammatory and infectious diseases should consider the roles of nutrients and disease.

Its why I also find myself going back to this specific probiotic.
Another patent
A formulation comprising Bifidobacteria infantis 35624 in an amount to induce the expression of retinaldehyde dehydrogenase (RALDH) and a substrate that provides a source of retinal which is metabolised to all-trans retinoic acid by RALDH. The substrate may be retinal, retinol, retinyl acetate, retinyl palmitate, retinol acetate or retinol palmitate.

This strain was isolated directly from the epithelium of the terminal ileum of a healthy human subject, and is one of the most researched probiotic strains.
This could possibly be considered what they call a keystone bacteria.
You’d also maybe need to be high enough on this dosage to combat any type of already established bacterial resistance, so unfortunately in most of the world outside of the states the 1 billion dosage per capsule might not be the best option.
Not sure though.

To add to this and ive posted this before, it might be possible to have both simultaneous vitamin a toxicity and deficiency. Accutane could further complicate things.

All- trans -retinoic acid generation is an antidotal clearance pathway for all- trans -retinal in the retina*
2019 Dec

Excess accumulation of atRal provoked intracellular reactive oxygen species (ROS) overproduction, heme oxygenase-1 ( HO-1 ) expression, and increased cleaved poly(ADP-ribose) polymerase 1 (PARP1) expression in RPE cells. In contrast, comparable dosage of atRA-induced oxidative stress was much weaker, and it could not activate apoptosis in RPE cells. These results suggest that atRA generation is an antidotal metabolism pathway for atRal in the retina.

antidotal - counteracting the effects of a poison

Like you said though, there are advocates of a vit-A deficient diet to ameliorate Accutane side effects, even those side effects that linger for years to decades after the last dose.

They refuse to accept vit-A as an essential nutrient in the moderate doses obtained through diet and only view it as a toxin/poison.

1 Like

Just looking at a few things here, first with the skin, Ive always had pale skin post Accutane.
Also looking at skin thickness,

Retinoids reduce fine lines and wrinkles by increasing the production of collagen. They also stimulate the production of new blood vessels in the skin , which improves skin color. Additional benefits include fading age spots and softening rough patches of skin .

Retinoids minimize the appearance of wrinkles, bolster skin’s thickness and elasticity, slow the breakdown of collagen (which helps keep skin firm), and lighten brown spots caused by sun exposure.

Retinoids work by prompting surface skin cells to turn over and die rapidly, making way for new cell growth underneath. They hamper the breakdown of collagen and thicken the deeper layer of skin where wrinkles get their start, Jacob says.

It’s not true, Farris says, that retinoids thin the skin. They typically cause peeling and redness in the first few weeks of use – but they actually thicken the skin.

Also looking at this patent again

  1. A formulation as claimed in any one of claims 1 to 1 1 for use in maintaining a normal structure and function of the skin and mucous membranes.

  2. A formulation as claimed in any one of claims 1 to 1 1 for use in the prophylaxis and/or treatment of a mucosal inflammatory condition. 14. A formulation as claimed in claim 13 wherein the mucosal inflammatory condition is associated with gastrointestinal health such as diarrhoea, inflammatory bowel disease or irritable bowel syndrome; respiratory inflammatory disorders such as asthma and broncho-pulmonary dysplasia; disorders of the eyes such as uveitis; disorders of the nose such as rhinitis or allergy; or cancer associated with mucosal surfaces such as lung or the gastrointestinal tract.

  3. A formulation as claimed in any one of claims 1 to 1 1 for use in the prophylaxis and/or treatment of one or more inflammatory disorder selected from the group comprising: asthma, gastrointestinal inflammatory activity such as inflammatory bowel disease e.g. Crohns disease or ulcerative colitis, irritable bowel syndrome, pouchitis, or post infection colitis, gastrointestinal cancer(s), systemic disease such as rheumatoid arthritis, autoimmune disorders, cancer due to undesirable inflammatory activity, diarrhoeal disease due to undesirable inflammatory activity, such as Clostridium difficile associated diarrhoea, Rotavirus associated diarrhoea or post infective diarrhoea, diarrhoeal disease due to an infectious agent, such as E.coli.

  4. A formulation as claimed in any one of claims 1 to 8 wherein Bifidobacteria infantis 35624 induces expression of RALDH2.

  5. A formulation as claimed in any one of claims 1 to 1 1 for use in the prophylaxis and/or treatment of vitamin A deficiency.

^The last line strikes me the most, I think theres a chance Accutane could run interference on the body’s own natural production of Retinoic acid, some of which might come from bacteria.
This could be strain dependant but also very common in the normal population, hence possible rare type disease.

RALDH2 This is the main enzyme involved in RA signaling.

“This research could be critical in determining therapies in the case of autoimmune diseases, such as Crohn’s disease or other inflammatory bowel diseases, as well as vitamin A deficiency.”

This is just one example,
“The role of vitamin A in inflammation is context-dependent and is very hard to tease apart,” the researcher adds. In the future, the scientists plan to examine why Rdh7 suppression is vital for the immune response, and how bacteria control Rdh7 gene expression.

Our data demonstrates for the first time that gut bacteria-dependent RA synthesis is critical for regulating local immune responses.

Recent studies show that both commensal and pathogenic bacteria drastically alter vitamin A metabolism in the host.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553882/

The effect of vitamin A is not limited to the host. Acute vitamin A deficiency triggers a significant change in the community structure in human gut microbiota–associated mice [6]. RA regulates the levels of antimicrobials as well as secretory immunoglobulin A (IgA), which also influences the microbial composition in the gut [7, 8]. A recent study has discovered synthetic retinoids that have direct antibacterial properties, adding a new dimension to vitamin A–microbiome interactions [9].

^idk I think this could be it, its just a matter of figuring it out further.

A more comprehensive understanding of vitamin A metabolism and distribution in the body is required to better inform how we define vitamin A deficiency and help us design effective dosing and delivery strategies to reduce the morbidity associated with enteric diseases. Furthermore, probiotics can be mined for their ability to modulate vitamin A metabolism. A combination of probiotics and vitamin A supplements can be a holistic way to restore vitamin A sufficiency while maintaining host–commensal homeostasis.

I have found hand rashes have eliminated taking retinyl palmitate, if I stop hand rashes come back. But my dosage is not recommended.

Looking into this patent a little more, a couple things jump out at me.
First, other bifido strains tested did not induce raldh2
Second, they had a dosage in mind, but I think this could vary espcially initially when looking at possible bacterial resistance or whats already there, basically fighting numbers with numbers.
Also a vitamin a supplement might not be necessary because there could already be an excess of preformed vitamin a.
Theory of course.

“A PROBIOTIC FORMULATION”

The invention relates to retinoic acid and immune regulation.

In another aspect the invention provides a screening method for identifying immunoregulatory Bifidobacteria comprising the co-incubation of a test bacterium with mammalian cells and assaying retinoic acid production.

Bifidobacterium strain capable of inducing RALDH and retinoic acid production.

The invention provides a formulation comprising Bifidobacteria infantis 35624 in an amount to induce the expression of retinaldehyde dehydrogenase (RALDH) and a substrate that provides a source of retinal which is metabolised to all-trans retinoic acid by RALDH.

The invention also provides a method of maintaining normal structure and function of the skin and mucous membranes comprising the step of administering an effective amount of formulation described herein to a subject.

We have made the surprising discovery that B. infantis 35624 induces the immune-regulatory enzyme RALDH2 in dendritic cells and the product of this enzyme, retinoic acid, was essential for the induction of regulatory T cells. Thus, a formulation which combines the substrate, i.e vitamin A or its derivatives, with a bacterial strain that induces expression of the enzyme responsible for substrate conversion will ensure the optimal conversion of the substrate to its immunologically active product. This formulation will provide a profound therapeutic benefit in patients suffering from inflammatory disorders.

a graph showing gene expression of the enzymes required for retinoic acid metabolism, RALDH1 , 2 & 3, quantified every 4 hours, until 24 hours, following B. infantis stimulation. RALDH2 rapidly increased in expression, peaking at 12 hours following stimulation. Retinoic acid production by dendritic cells is an important feature of mucosal immune health.

the induction of vitamin A metabolizing enzymes by B. infantis 35624 is an essential molecular step in its ability to suppress proinflammatory disorders.

An example of base dosage,
B. infantis 5-10mg (> I x 109 cfu) in cryoprotectant (inc. sucrose, trehalose, sodium citrate) Vitamin A* (retinol) 2500-5000 IU

If there were to be a case for this, this could be a problem from birth, early antibiotic exposure, food poisoning, or drug exposure like Accutane.

Even if I was right about some of this, I needed to figure this out at least 20 years ago.