Why pudding makes us happy - the melatonin/opioid tangent.

News to Use! Butyrate promotes happy endogenous mu-opioid receptors. Lack of butyrate leads to distress/dysphoria k-opioid receptors.

An upset digestive system and microbiome dysbiosis may add to a bad mood beyond the achy gut it can cause. When we have resistant starches in our diet and adequate zinc then butyrate producing bacterial species can flourish. The butyrate they produce from undigested resistant starches can feed our colon cells or activate the niacin GP109 receptor. The niacin/butyrate receptor can help reduce inflammation and promote mitochondrial function. See: Protocol Collation & Therapy Goals.

This melatonergic pathway was a tangent I didn’t expand on in the post Houston we have a problem, but it was interesting. Why is ME/CFS depressing? Because of lack of melatonin production, due to the lack of CoA production, basically.

Butyrate levels also can affect which types of endogenous opioid receptors will be produced. More butyrate is associated with more m-opioid receptors which respond to endorphin and partially to met-enkephalin and promote a positive mood. Less butyrate is associated with more k-opioid receptors which respond to dynorphin and promote a distressed mood and dysphoria. Dysphoria - “A state of feeling unhappy, dissatisfaction or frustration.”

Not any pudding will do. Corn starch thickened commercial pudding or foods generally is promoting an unhealthy gut and leaky gut membranes more than helping the gut or microbiome species.

Early adopters - turn back time and start making your own pudding from scratch again. Eventually better restaurants may catch up with you. Make pudding with healthier starches like tapioca or arrowroot starch and pre-soaked tapioca pearls for more resistant starch for our microbiome. I increase protein content in my dairy free version with the addition of garbanzo bean flour as part of the thickening and coconut milk, full fat, for the richness. Tapioca and arrowroot make a clearer gelatin like dessert with more spring back power than cornstarch or the bean flour. The garbanzo bean thickening is creamy without the stretchiness factor of tapioca with interlinking fibers that need to be cut with the edge of the spoon.

Adding fresh aloe vera gel after a thick pudding cools a little is a technique for adding fresh juice or aloe to a cooked pudding.

My basic tapioca pudding recipe is on this page: How much butyrate? (jenniferdepew.com) and more information about Resistant Starches and microbiome health is on page Resistant Starch/Butyrate.

Taking butyrate supplements might help, and melatonin, and niacin, but if over-conversion of Retinoic acid is involved, then the change in butyrate levels is also linked to the reduction in the melatonergic pathway . . . caused by the inhibition of CoA production by PPAR promoting PDK . . . which leads to inhibition of PDC and blocking use of the Citric acid cycle by mitochondria.

Related poem: For want of a nail - the kingdom was lost. - Benjamin Franklin (goodreads)

Mitigating damage with targeted supplements can help but re-shoeing a horse can help it keep going for many more miles and years. Identifying and resolving the very root problem makes all the rest of its ripple effects stop too. Stopping the first domino from falling prevents a cascading chain of dominoes all consecutively falling.

Don’t knock over the first domino and then you won’t have a cascading domino problem.

Flowchart of my interpretation of what might be happening in ME/CFS if it is related to an earlier change in the liver due to a viral or other immune challenge:

1. EBV or other viral (CoV - Bonilla et al, 2022, preprint) or other immune challenge causes a gene change in the liver that leaves it over-activating carotenoids and retinol (vit A) to Retinoic Acid and transports it out of the liver. This may leave the liver and eyes and body with low levels of retinol and excess of the active form which can affect gene transcription of many thousands of proteins. *See my document: Retinoids and Schizophrenia (*and other conditions).

2. The excess Retinoic acid may be activating the PPAR receptor to promote PDK, (normally triggered by a high-saturated fat diet); which would inhibit the Pyruvate Dehydrogenase Complex (PDC) which would inhibit CoA production and Citric Acid cycle use in mitochondria. (5)

   1. (*Normally insulin resistance and elevated insulin would decrease PDK and promote the Citric Acid Cycle for burning sugar - glycolysis. Promoting PDK normally occurs when the body needs to switch to burning fats temporarily.)

3. Not using the Citric Acid Cycle is inefficient and would lead to fatigue. If it were due to Retinoic acid activating PPAR beta/delta, then there might be fluctuating symptoms as intake of vitamin A and carotenoids might vary from day to day. The conversion to Retinoic acid seems to happen overnight and through the next day or two after eating the food (personal experience). The same day as eating a retinol/beta-carotene food might provide a temporary improvement as the retinol is a beneficial need of its own.

   1. Over-conversion to Retinoic acid is depleting use of retinol for other things - like promoting mitochondrial use of the Citric Acid Cycle and biogenesis of more mitochondria.

   2. Lack of Retinol (vitamin A or half a beta-carotene) might also lead to a decrease in butyrate producing species in the gut microbiome. (5)

   3. Butyrate also helps promote the Citric Acid Cycle (5) and can help reduce inflammation by decoupling mitochondria from ATP production and producing warmth instead similar to brown adipose tissue, via activation of the GP109 niacin receptor. (various references)

4. The lack of CoA would inhibit the melatonergic pathway and elevated ceramide is also common in ME/CFS and Major Depressive Disorder (MDD) and would add to inhibition of the pathway. Elevated ceramide was seen more often in ME/CFS patients with IBS as a comorbidity (Nagy-Szakal et al., 2018). (5) Serotonin is converted into melatonin. Lack of tryptophan or niacin/nicotinic acid (not nicotinamide) could also reduce serotonin and melatonin. *More about ceramide is included later - Tangent.

   1. LPS, bacterial endotoxin, is seen with ME/CFS (5) and LPS effects can be worsened by chimeric spike protein effects. Bacteriophages are also seen with ME/CFS and those can be a reservoir for SARS-CoV-2.

5. Pyruvate would accumulate as it was not being converted to CoA and it would instead be converted to lactate which is more acidic and inflammatory. Elevation of lactate levels is seen in ME/CFS. (5)

6. Inhibition of melatonin production could lower beta-endorphin levels, which activate the positive mood m-opioid receptors. Auto-immune antibodies against m-opioid receptors has been observed in 15% of patients with ME/CFS. (Tanaka et al., 2003) (5) Melatonin also suppresses the k-opioid receptors that have more of a distress/dysphoria effect instead of a positive mood effect, (Ni et al., 2015) (5), so lack of melatonin would be adding to a depressive effect in two ways with the opioid system. See the Additional Tangent at the end for a little more on depression, breast milk and the gut microbiome.

Lack of melatonin and lack of butyrate are bad for a good mood. Just taking supplements wouldn’t stop the rest of the dominoes that also fell down.

The dominoes got knocked over, very little standing room now, lots to clean up.

Clean up would be easier if we stop knocking over more dominoes every day.

Prevention is about preventing a big problem before it is a big problem. A recent interaction reminded me again that focusing on the severity of the damage at an embalmer’s office and how it couldn’t possibly be fixed . . . well true, the problem was found by an embalmer in a corpse - deceased. We cannot fix that, no.

We need to see it as a warning that prevention is VERY IMPORTANT for everyone that got a certain experimental product. Not everyone has been harmed equally. There may have been different batches, there may be genetic susceptibility for some people and there is increased risk for people with Metabolic Syndrome, which is already a hyperinflammation condition. Chimeric spike adds to that exponentially when not stopped promptly with a good detoxification system and/or supplements. Some of the increased genetic risk is in poorer detox or lack of methylation ability.

I have shared info patiently since I got sick in early 2020 because while the false PCR tests meant a lot of people weren’t really sick - others, including me, were really sick. I had LongCovid symptoms too, and am higher risk with autoimmune history. It was that history that left me more prepared to cope with the hyperinflammation of the chimeric spike protein. Bioengineered, patented, not natural - let’s not get caught up in “virus aren’t real” type of discussions when Gain of Function gene manipulation is very real.

The sooner prevention starts the more likely it will be able to help and you won’t really know how much it helped if you don’t get a stroke, or kidney, liver, or brain damage - and that would be a good thing.

Ceramide, sphingomyelin and endocannabinoids - tangent.

Ceramide sidenote - considered a ‘toxic’ fat which is seen with excess calorie diets (weight gaining) and may increase risk or be associated with insulin resistance, Type 2 diabetes, and heart disease. It can be a signal for apoptosis - cell death. Ceramides can be formed from smaller molecules or be a breakdown product of sphingolipids. (Ceramide/sciencedirect) Sphingolipids are signaling chemicals that can be in cell membranes similar to endocannabinoids. During inflammation membrane breakdown in part occurs because the signaling chemicals are released from where they had been building blocks for the membrane.

“Endocannabinoids and sphingolipids are lipid signaling molecules that regulate human energy metabolism (4, 10, 16, 30, 42). In in vitro studies of rodent and human skeletal muscle, sphingolipids were shown to interfere with mitochondrial oxidative activity and integrity (17, 18).” (Heinitz, et al, 2018)

Anandamide, the THC equivalent of endocannabinoids, is involved in sphingomyelin promoting less energy use while we sleep. Our bodies cool down and have reduced activity while we sleep, by a significant ~25% maybe but I would want to check that.

“In skeletal muscle, AEA [anandamide/THC equivalent] is responsible for the sphingomyelin effect on [sleeping energy expenditure] SLEEP, indicating that endocannabinoids and sphingomyelins may jointly reduce human whole-body energy metabolism.” (Heinitz, et al, 2018)

During inflammation more endocannabinoids and sphingomyelin would be released. Part of the ME/CFS symptom set is likely due to a combination of many inflammatory lifestyle or dietary issues including a high saturated fat or trans-fat diet that all add to more release of endocannabinoids and sphingomyelin and the breakdown of membranes leading to more allergens or autoimmune molecular mimicry food risks entering the body. The blood brain barrier is also affected by inflammation.

Additional Tangent - the melatonergic pathway may be critical in breast milk production and help establish the breast fed infant’s microbiome (in addition to the oligofructosaccharides in breast milk which feed good species of our microbiome.) ****And that may help the baby have a more happy and healthy life due to the butyrate producing species’ effects on our opioid system.

“The melatonergic pathways are intimately associated with highly researched processes in the gut, gut microbiome and gut-brain axis. As the melatonergic pathways are dependent on the levels of serotonin availability as a necessary precursor, decreased melatonin is linked to depression and depression-associated disorders.” (Anderson, et al, 2017)

Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference list

• (5) G. Anderson, M. Maes, Mitochondria and immunity in chronic fatigue syndrome, Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 103, 2020, 109976, ISSN 0278-5846, https://doi.org/10.1016/j.pnpbp.2020.109976.

  https://www.sciencedirect.com/science/article/pii/S027858462030292X Full text pdf: https://www.dropbox.com/s/vofaipxk1tknxu0/1-s2.0-S027858462030292X-main.pdf?dl=0 *carried over from the post: Houston we have a problem.

• H Bonilla, TC Quach, A Tiwari, et al., Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is common in post-acute sequelae of SARS-CoV-2 infection (PASC): Results from a post-COVID-19 multidisciplinary clinic, medRxiv 2022.08.03.22278363; doi: https://doi.org/10.1101/2022.08.03.22278363 *Preprint, https://www.medrxiv.org/content/10.1101/2022.08.03.22278363v1 - via Frank Herrmann, Thanks!

• *I can be reached directly (but possibly not quickly) via Contact Jen/jenniferdepew.com or Contact/peace-is-happy.org.

• Heinitz S, Basolo A, Piomelli D, Krakoff J, Piaggi P. Endocannabinoid Anandamide Mediates the Effect of Skeletal Muscle Sphingomyelins on Human Energy Expenditure. J Clin Endocrinol Metab. 2018 Oct 1;103(10):3757-3766. doi: 10.1210/jc.2018-00780. PMID: 30113648; PMCID: PMC6179180. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179180

Tangent - the melatonergic pathway may be critical in breast milk production and help establish the breast fed infant’s microbiome (in addition to the oligofructosaccharides in breast milk which feed good species of our microbiome.)

“The melatonergic pathways are intimately associated with highly researched processes in the gut, gut microbiome and gut-brain axis. As the melatonergic pathways are dependent on the levels of serotonin availability as a necessary precursor, decreased melatonin is linked to depression and depression-associated disorders.” (Anderson, et al, 2017)

Anderson G, Vaillancourt C, Maes M, Reiter RJ. Breastfeeding and the gut-brain axis: is there a role for melatonin? Biomol Concepts. 2017 Sep 26;8(3-4):185-195. doi: 10.1515/bmc-2017-0009. PMID: 28723608. https://pubmed.ncbi.nlm.nih.gov/28723608/