This is not medical advice I am posting this for educational and informational purposes.
Always remember homeostasis is the goal.
This is not finished but I need to work on other things and I figure this will give people a good foundation to research and build on.
If your gut becomes inflamed it will become leaky. You will stop absorbing nutrients. This can cause bile to become inhibited. If the gut is inflamed you can develop a burning pain. In more severe cases the pain will travel and a person will feel the burning pain under their right breast , it can even travel to the side below the arm pit. When it gets that severe they start developing a lot of food intolerance. So they are limited on what they can eat, also digestive enzymes can leak into the blood. From the digestive enzymes being in the blood and the body catabolizing the muscles they will also start to burn. This can also cause the calf muscles to hurt and feel heavy. When this occurs a person will need to keep snacking because when the gut is empty it will cause the inflammation to increase. They need to find foods they do not react to, so they can snack on them and always try to keep something in the gut.
Lipopolysaccharide (LPS) is usually used when referring to pathogens. Our commensal microbes produce LPS which our body uses to identify them. Normally they are not harmful to the body and some of the other commensal consume LPS keeping levels down. But a loss of those commensal or leaky gut can cause LPS to enter our blood streams which can lead to sepsis so it is very important to protect and maintain the health of our guts.
If we develop leaky gut and do not correct it toxins like mercury that can be in our food and usually will get excreted can now easily enter the blood stream and a person may develop high levels of mercury, cadmium or other toxins in the body.
If you have leaky gut oxalates that usually get excreted can enter the body. It is very important to heal the gut because oxalates are very damaging to the body. Calcium will bond with oxalates preventing them from being absorb and is why if a person is lactose intolerant they need to work on correcting it because milk with meals would help prevent that. Some calcium supplements are not good for you so if you decide to take that route make sure you do your research. Once oxalates build up in your body it prevents the gut from healing so it is very important to reduce oxalate levels. I have posted on reducing oxalates.
There are 2 components to the intestinal barrier. Intrinsic barrier and extrinsic barrier.
Intrinsic barrier is composed of the epithelial cells lining the digestive tube and tight junctions that tie them together.
Our gut bacteria maintain the health of our gut but damage to our gut can inhibit FUT2 production. Our gut microbiome cannot get established if we are deficient in FUT2. Lactobacillus Casei increases FUT2 production by inducing ERK/JNK. Inducing ERK/JNK stimulates FUT2. Nitric Oxide induces ERK/JNK, arginine rasises NO levels. Hypoxia induces ERK/JNK. Interleukin 10 inhibits FUT2 so a person may want to be cautious when taking probiotics that stimulate IL-10. Lactobacillus species of microbiotia stimulate IL-22 especially L Johnsii. IL-22 stimulates FUT2 secretion.
Extrinsic barrier consist of secretions and other other influences like microbes that influences the epithelial layer but are not physically part of the epithelium cells and maintain their barrier function.
Intrinsic Intestinal Barrier.
The gut is lined by sheets of epithelial cells that define the structure of the mucosa they are tied together by tight junctions, which paracellular spaces and thereby establishing the basic gastrointestinal barrier. Paracellular spaces are were nutrients are transported into the blood stream and toxins can be transported to the intestines for removal. Toxins and microbes that are able to breach this barrier have unimpeded access to the circulatory system. The tight junction layer and the mucus membrane for the most part prevents this from happening when healthy. Some cells in the epithelial are not effected by acid but others do not have the protection so count on the mucus membrane to protect them.
Extrinsic Barrier
Mucus that coats the entire epithelium. Hormones and cytokines that regulate the function of our digestive system and maintain digestive health. Our gut microbiome are a part of the extrinsic barrier. They reside in the mucus membrane.
Tight junctions encircle the epithelial cells and are an important part of the intrinsic layer. Their permeability is regulated by zonulin.
Tight junction controls the equilibrium between tolerance and immunity to non-self antigens. It is involved in macromolecular transport and tolerance and immune balance. If the tight junction layer becomes too porous a person may develop autoimmunity and their bodies immune system will turn on the body and start causing autoimmune disorders. A person will develop food allergies and food intolerances. The longer this goes without being addressed the more a persons health will decline. They will develop many metabolic, genetic and immune dysfunctions. Many things can damage this vaccines have been shown to raise B cell levels which causes the tight junction layer to become more porous. BT Toxins in GMOs have been shown to cause the body to react in a way that the tight junction layer becomes more porous. Many farm chemical cause it to become more porous especially glyphosate and glufonisate cause it to become more porous. Stress and trauma can also cause the tight junction layer to become more porous.
Zonulin is the only intercellular modulator of the tight junctions. If zonulin becomes over expressed the gut becomes more porous leading to leaky gut. It is involved in the transport of macromolecules and in balance between tolerance and immune response balance. If zonulin becomes deregulated it can cause inflammatory bowel, anemia, systematic inflammation, red sore areas on the skin known as Sweet’s syndrome that can eventually develop into blisters that eventually turn ulcerative which is known as Pyoderma Gangrenosum. They can develop swelling and sores in the mouth. The eyes can become red sore and inflamed. This condition is called sceritis it can lead to uveitis which effects the iris and can lead to blindness. Bones may thin and become brittle. Oxalates will develop causing stone formation this can also effect the liver. Not only can it cause endogenous oxalates to be produced but now oxalates consumed in our foods that are normally excreted can readily enter the body. Gall stones may form because bile production and pancreatic enzymes become inhibited and a person can develop chronic diarrhea, constipation or alternate between the two.
When the bile is inhibited it is called Primary Schlerosing Cholangitis. From food particles and toxins entering the blood stream a person could start having excessive blood clotting. A person will start developing nutrient deficiencies from being unable to absorb and break down nutrients properly. A person will eventually develop high histamines if this continues they may develop asthma, they can start developing sarcoidosis throughout the body. Mast Cells can start to degranulate leading to mastocytosis or mast cell activation syndrome. This effects our immune system as you will see below. It can lead to diabetes, heart disease and many other chronic illnesses. It can also lead to obesity or anorexia depending on how the person has been effected.
In order to restore zonulin levels to normal the genetic, metabolic, oxidative stress, changes in ph for example if you have developed acidosis or alkalosis it will have to be addressed along with infections that come along with our immune system being disabled. I have posted on most of those issues and correcting them. There are three isoforms of zonulin. ZO- 1 , ZO-2 and ZO-3.
When we get an infection it is a sign we are lacking a nutrient or gut microbe that protects us. The infection produces lipopolysaccharide (LPS) which stimulates zonulin making our guts more porous. Also antibiotics can kill the butyrate producing gut bacteria which makes our gut more porous. Butyrate keeps many things at homeostasis. We cannot restore normal zonulin levels if we do not replace the butyrate producing bacteria and feed them with fiber, oligosaccharides, galactosaccharides, and fructooligosaccharides. The lower the diversity of our gut microbes the higher our zonulin levels will be showing that our digestive system needs feedback from a variety of microbes to function properly.
The fun part of all of this is they will tell you all this in in your head until you are so ill it will take months or years to heal. In the mean time they will still continue to treat the symptoms instead of the cause. It is a common theme with allopathic medicine. I have seen this with naturopathic also but for the most part naturopaths treat the cause and not the symptoms.
Things that can reduce zonulin is meditating, if you have experienced trauma work very heard to move forward. It is difficult not to look back but constantly looking back causes stress and can increase zonulin. Anger increases zonulin so try to learn to deal with frustration and bad situations in a calm way , the calmer we are the lower our zonulin levels will be.
Replace the butyric acid producing bacteria I listed many microbes that produce it if you search my blog.
Inflammation and immune dis-regulation and can increase zonulin so the microbes that increase T regulatory cells and inflammation will reduce zonulin. If your immune system has been disabled then microbiome that stimulates IL-10 will help restore immune function.
High LPS levels will increase zonulin so we need the gut microbes that reduce LPS. Studies have shown the higher our guts diversity the less ZO-1 is express which prevents leaky gut and inflammation.
Under normal conditions things with gliadin , glutin and lactose will not effect a healthy gut but increase zonulin when the mucus membrane is damaged.
There are many molecules that interact with each other to maintain the Zonulin layer and the tight junction layer.
Occludin plays a role in tight junction maintainence and assembly which is regulated by phosporylation of serine, threonine, and tyrosine risidues. It is important for maintaining TJ stability and function. Loss of occludin can lead to leaky gut, inflammatory bowel, and hyperplasia most likely from the inflammation. Occludin also regulates cell survival or death through the intrinsic system. It is important in receiving and transmitting cell survival signals. Occludin has a strong inhibitory effect on cancer. Loss of Occludin leads to cell death.
If Phosphorylation of tyrosine, threonine and serine residues is inhibited it reduces occludins interaction with zonulin. Dephosphorylation of ser/thr residues and poor phosphorylation of tyr residues causes a reduction in occludins interaction with ZO-1 leading to it’s seperation from the junctional complex and TJ disruption. It also leads to excess ROS production which increases gut permeability. Inflammation reduces occludin levels. Endotoxins also reduce occludin. Another function of occludin is in modulating the TJ response to cytokines to protect and heal the tight junction. Occludin plays an active role in cellular location of caveolin-1. Caveolin-1 is required for cytokine induced TJ barrier changes, where it is required for TJ remodeling. So addressing endotoxins, high B cell or T cell levels and reducing inflammation is very important for preserving occludin. Many of our commensals that increase T regulatory cells balance our immune system which would restore proper T and B cell levels. Many of our commensal microbes reduce inflammation and reduce LPS (endotoxins). I have posted on my blog which of those accomplish these things. TNF-a is involved in caveiolinn-1 mediated internalization of occludin which increases occludin, alleviating cytokine induced gut permeability. This can be induced by TNF-a which is an inflammatory cytokine.
Mucous Membrane
The mucus membrane is thin in most inflammatory bowel diseases but is thick in Chron’s disease which I have not researched much on. Inflammtion usually causes the globin which are the mucin secreting cells to become depleted but for some reason this does not happen in Chron’s disease.
All these genes listed below are negatively effected by leaky gut. It is very important to reduce inflammation and work on getting the gut healed to restore the mucous membrane. Damage to the digestive system and mucus membrane causes many genes to become dis-regulated. MUC2 gene is the major gene responsible for the secretion of gel-forming mucin in the intestinal tract. It coats the endothelial surface protecting it from inflammation,chemicals, damage and infection. There are 20 MUC genes. There are many mucin categories that are enriched with proline, serine, and threonine. They are modified by o-glycosylation that creates oligosaccharides that confer on mucins their individual functions. Mucin is made mostly of fat. Those with inflammatory bowel and ulcerative colitis have low B-oxidation which is needed for the break down and use of fats. Since the mucous membrane is mostly fat this causes it to become dysfunctional. This makes people sensitive to fats and is why it is best if they consume medium chain fatty acids because the body can readily use them. Eggs yolks are a good source of phosphatidylcholine which is what the mucus membrane is mostly made of. Most with inflammatory bowel or colitis are sensitive to lecithin. I used sun flower seed lecithin and I did not react to it and it helped me a lot with my healing. Most other sources of lecithin I had to avoid. There are many studies showing that using sun flower seed as a source of lecithin has been shown to heal the gut. As for Chron’s disease I have a theory I have not had a chance to research but I believe they may be deficient in commensal microbes that digest sialic acid. Many of our commensals need it to thrive. Bacteroides Fragilis, Bacteroides Thetaiotaomicron, Bifidobacterium Bifido, Bifidobacterium Longhum, Bifidobacterium Infantis, Akkermansia Muciniphila all need sialic acid to thrive. Another theory I have about Chron’s that I have not gotten to research is they may have an overgrowth of those and that inflammation or LPS is stimulating the production of excessive sialic acid causing and overgrowth of those microbes.
Phospholipase A2 activity is higher in those with inflammatory bowel and colitis.
If a person is having trouble with methyl donors they will not produce enough phosphatidylcholine because methyl groups are used in the process of producing phosphatidylcholine for the mucous membrane. So combine that with the low B-oxidation and you see why it can be so difficult to heal. Disulfide bridges are also a component of phosphatidylcholine showing the importance of addressing things that can impair sulfation.
Phospholipase A2 is high in those with inflammatory bowel and colitis. Phospholipase is stimulated by inflammation. It is a mixture between inflammation and substance P and is why those with leaky gut have high substance P levels. When substance P levels get high the skin will have a burning sensation especially in the scalp and it may go down the spine. Substance P levels increase at night so the symptoms will worsen at night.
Annexin also known as lipocortin keeps PLA2 in check. Adrenal hormones increase Annexin but in many people with inflammatory bowel the adrenals become depleted from being over activated and they develop Addison’s disease which is a deficiency of adrenal hormones. Adaptogens help alleviate this which would help restore annexin levels. Annexin also helps repair our immune system. If annexin gets low the blood brain barrier becomes porous because it helps maintain the blood brain barrier. Annexin is also involved in protecting the brain from infection. It is very important to support the adrenals with the proper nutrients and to reduce inflammation so the adrenals can recover. Oddly Okadaic Acid a toxin found in shell fish increases annexin. This is something a person would definitely need an experienced medical professional to do. IL-6 increases annexin expression. To restore normal cortisol levels stress management is very important. Increased stress depletes cortisol. Getting rest is important, even if you cannot sleep just laying and resting can help increase cortisol. Avoid, caffeine, alcohol and smoking. Our mucosal layer will take up fats and integrate them to strengthen itself. Omega 3 oils, cod liver oil, nuts, and avocados help increase cortisol. Avoid processed sugar it depletes cortisol levels. Citrus fruits especially grape fruit increases cortisol but grape fruit inhibits certain cytochrome P450 enzymes so should not be eaten too often. Eat foods high in melatonin or take melatonin supplements at night which will increase cortisol. Non processed carbohydrates help increase melatonin. Magnesium is important for maintaining proper cortisol levels. Reducing inflammation can help normalize cortisol levels. Earth grounding and getting sunlight help to normalize cortisol levels. I still laugh when I mention earth grounding because I thought how could something so simple have so many health benefits. So I was determined to find research to show those earth grounders were crazy instead it was I who was crazy and the earth grounders are correct. I could find no research to prove them wrong but plenty of research showing the many health benefits of earth grounding.
We have to keep in mind goblet cells build our mucus membrane and when inhibited by inflammation, toxins or even damage to our digestive system our ability to produce mucin is reduced or inhibited. Bismuth even though it is a metal, is for the most part none toxic it takes very high doses for a very long time to reach toxic levels. It helps the gut heal. It kills many pathogens and can cause commensals that have turned pathogenic to go back to commensal. Mucilage helps protect the gut so it can heal. I have posted on reducing inflammation if you search my blog. Oatmeal is high in mucilage but you must get organic because they use glyphosate and glufonisate on grains and beans to dry them and those destroy our gut and kill our gut microbes. Three very good sources of mucilage is okra, arrow root and oatmeal. Make sure the oatmeal is organic. Most non organic oatmeal has farm chemicals that destroy the gut.
Here is an in depth article on mucus membranes.
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Sialylation has been found to be increased in those with inflammatory bowel dieseases. Excessive sialylation increases inflammation. IL-10 inhibits Sialylation. Their are probiotics that increase IL-10 but IL-10 inhibits FUT2. So an oligosaccharide,galactosaccharride and fructosaccharide would probably have to be supplemented with it. I suspect the body is trying to increase the commensals that rely on the nutrients produced by sialylation and they have been depleted by antibiotics. Some commensals rely on FUT2 but others rely on sialylatin. Some do not produce the enzymes to break down sialic acid and rely on other commensals to produce it. A deficiency in either of them is probably what is causing the high sialylation. The body is trying to feed them. It is not getting the feedback from those commensals.
The bacteria this would help thrive are B Fragilis, B Theaiotaomicron, B Bifidum, B Longhum, B Infantis and A Muciniphila. I believe those with inflammatory bowel especially those with Chron’s will be deficient in those because those with Chron’s have a thicker mucous membrane.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747158/
The increased inflammation and infection caused by the above mentioned things results in an accumulation of ROS which can lead to further damage and it disturbs mitochondria function and autophagy. Once the mucus membrane has been damaged all the things mentioned below lose their protection and become dysfunctional. It may be necessary to take mucilage and bismuth to help protect them and restore their function. Once the mucus membrane breaks down it creates a cycle that has to be broken because the mucus membrane needs the things mentioned below to function properly and they need the mucus membrane to protect them and to function properly. Dysfunction in either of them from infection or toxins can start a cycle that has to be broken to heal. Our gut microbiome cannot become established without the mucus membrane because it also protects them. Our mucus membrane is a mediator between host and microbiota interactions. Decreased mucus membrane thickness causes a change in our gut microbiome and makes us more prone to infections.
This is where addressing sulfation issues, methyl group issues and issues with thiols comes in because the production of mucin requires all of those to be functioning. I have posted previously on how to deal with those issues. For the production of the oligosaccharides the endoplasmic reticulum and stem cell are required.
L-cysteine, L-arganine, L-threonine, L-serine, and L-cysteine increase mucin production in the digestive system and have been shown to promote gut microbiome homeostasis. Citrus fiber increases mucin especially the white part of the fruit. Pectin stimulates Goblet cell formation which secretes mucin. The microbiome that help restore gut health are Bifidobacterium Bifido, Bifidobacterium Breve, Bifidobacterium Lactis, Enterococcus Faecium, Lactobacillus Acidophilus, Lactococcus Lactis
For those who do not have glutamate issues bone broth heals the gut very quickly. Those who have high levels of sulfur digesting bacteria will have problems with the consumption of bone broth also.
The small intestine is the portal for the absorption of most nutrients in the body. The chyme which is the digested food that has exited the stomach enters the small intestine pancreatic enzymes and bile is secreted. This breaks the food down and if functioning properly it will be almost liquid when it enters the lower intestinal tract. Bicarbonate is also added by the body to reduce the acidity before it enters the large intestine. The enteric nervous system and gastrointestinal hormones regulate this process and the intestinal motility. Intestinal dysbiosis can cause incorrect communication or inhibited communication which leads to inflammation, intestinal damage and it could lead to a loss of the ability to produce bile and digestive enzymes. To restore proper function we must reduce the microbe causing the problem. Those who have high sulfur digesting bacteria will develop high hydrogen sulfide levels which interferes with sulfation and can interfere with the proper function of the CBS and BH4 pathways. This can lead to high sulfide levels in the body. BH4 levels will become low causing ammonia to build up when protein is consumed. The high ammonia levels will cause some commensals to go into protection mode and they will become pathogenic. Candida and H Pylori are two examples. To make matters worse they also start producing ammonia to protect themselves from the acidic environment. The digestive tract is supposed to be acidic. Ammonia alkalizes it this also makes us more prone to infections because the commensal microbes that protect us cannot survive in an alkaline environment. When we lose our commensal bacteria we lose proper immune function and our zonulin levels increase and our gut becomes more porous leaving things enter the blood stream that could not normally enter. Inflammation and oxalates can inhibit bile flow causing it to back up, when this happens the gallbladder is effected. Instead of addressing the problem modern medicine gets rid of the symptom by removing the gallbladder thus the illness continues to worsen and taking the gallbadder out can contribute to it’s progression.
If bile becomes inhibited it inhibits the vitamin D receptor further inhibiting bile production and adding to the problem because cholesterol production and conversion becomes inhibited. This will make bile become sludgy leading to low bile flow which will increase estrogen levels and cause high unbound copper levels in the blood. Bitter herbs increase bile flow but the vitamin D receptor has to be addressed along with balancing the microbiome in the gut and healing the intestinal tract.
This is why I often times recommend grape seed extract and bacopa to people. It prevents thrombosis. Inflammation because endotoxins can cause thrombosis. Grape seed extract and bacopa reduce inflammation and prevent thrombosis. If thrombosis occurs in the portal vein it will effect the liver, pancrease, and digestive system. This causes pain in the stomach, bloating, inflammation, pancreatic pain, pain in the gallbladder. This can lead to death. Bile flow will become inhibited speeding up the progression of portal vein thrombosis. Those with hepatitis need to use hawthorne or something else. Resveratrol activates hepatitis.
portal vein thrombosis
gastrointestinal symptoms (ex: abdominal pain, nausea, vomiting, and diarrhea), fever and constitutional symptoms (ex: fatigue, malaise, and anorexia/weight loss) [3]. We can also find hepatomegaly with elevated liver enzymes and jaundice [3], when associated with liver abscess or cholangitis [2]. Laboratory tests usually demonstrate elevated markers of inflammation [2]
https://www.journalmc.org/index.php/JMC/article/view/3050/2378
If not addressed in time it can lead to portal hypertension. This results in brain swelling, abdominal swelling . Confusion, anemia and low white blood cell count.
https://my.clevelandclinic.org/health/diseases/4912-portal-hypertension
Autophagy is very important in maintaining health and we need a proper balance. It can be disrupted if we have intestinal damage. If autophagy is inhibited we become prone to infection and mitochondrial dysfunction. Autophagy is the housekeeper of our cells. One common theme you will see is inflammation and shows the importance of reducing inflammation. Which could involve diet changes, addressing metabolic issues, reducing toxins and infections. Addressing detox issues and detoxing in an appropriate manor for the individual. Addressing gene issues which could be caused by any number of things including a lack of the microbe in the gut that may modulate that genes function.
The mucus membrane in our digestive system protects us from infection, physical and chemical harm. Our commensal bacteria cannot exist without it. It is very important to restore our mucus membrane when damaged in order to restore intestinal homeostasis. Many genes mentioned below are effected when it is damaged because it causes a dysfunction in them. Autophagy is very important for the maintenance or proper gene function.
Paneth cells are located within our mucus membranes and provide immunity, prevent damage to the digestive system and is involved with nutrient absorption. Loss of our mucus membrane from loss of microbiotia, drugs or farm chemicals found in our food can destroy our mucus membrane. This causes damage to the digestive system which can further inhibit the bodies ability to produce mucin. This makes us more susceptible to infection. Paneth cells stimulate the production of AMPs which fight infection and modulate commensal microbiome and innate immunity. A list of AMPs are defensin-like human lyzosome, defensin (HD)-5 and 6, lyzosome, regenerating islet derived gamma(Reg3y), and phospholipase A2 group 2A(sPLA2) as well as inflammatory cytokines such as Transforming Tumor Necrosis Factor A (TNF-a), Growth Factor B1 (TGF-B1), and Postaglandin E2. AMPs are sensitive to ER stress which I discuss below.
Autophagy protects against infection by producing Antimicrobial Peptides and degrading organelles that break down misfolded proteins and AMPs break down pathogens. This can ease the over activated inflammatory response and over active immune response. Some AMPs are defensin and cathelicidens which protect against microbes.
Intestinal Epithelial Cells. (IECs) – form a physical and chemical barrier involved in inflammatory response and immune reaction. IECs work as an interface between the quantitive microbial ecosystem in the intestinal lumen. Lumen is inside space or opening in a tubular structure.
There are 6 types of IECs
Goblet Cells which secrete mucin to build up the mucin barrier.
Enteroendocrine cells which produce gastrointestinal hormones that communicate with the nervous system, the brain and organs throughout the body. They respond to nutrients within the intestines. Helps restore intestinal tissue.
Absorptive Enterocytes – epithelial cells in small intestine. They are involved in nutrient absorption, absorption of conjugated bile acid, lipid uptake, Issues with Absorptive Enerocytes can inhibit glucose absorption and can result in lactose intolerance and many other food intolerances. It can also result in an electrolyte imbalance. Enterocytes secrete a series of chemokines and cytokines which regulate immune responses of subjugant mucosal. (Mucosal control)
Tuft Cells – brush cells which are chemosensory cells in the intestinal epithelial lining. Tuft refers to microvilli projecting from the cells. They increase during parasite infection. They are the sole source of Interleuken 25 which induces NF-kB activation which helps protect from infection. High levels of IL-25 raises eosinophils which causes inflammation and is suspected of causing inflammatory bowel diseases. Eosinophils have been shown to kill many types of cancer cells. Infection also stimulates Tuft Cell to produce IL-25. They are increased through a T cell response through a type of lymphatic tissue. Tuft cell also secret endogenous opioids. Eosinophils cause asthma, cardiovascular disease and can even cause headaches, mood swings and brain fog.
Microfold Villous Cells – are found in the Gut-associated Lymphoid Tissue (GALT) of the Peyers Patches in the small intestine and the Mucus-associated Lymphoid Tissue (MALT). M Cells initiates mucosal immunity. They allow the transport of microbes and across the epithelial cell layer. From the gut lumen to the lamina propria. M cells contain Epidermal growth factor which acts as a sensor to stimulate repair through the intestines including the mucus membrane , tight junction protein layer and it stimulates goblet cell differentiation and many other things in the colon.
Endoplasmic Reticulum are organelles within our cells and plays a major role in the production of proteins and lipids. So this is where our enzymes , hormones and even our detox enzymes are produced.
Endoplasmic Reticulum Stress Unfolded Protein Response (UPR) is activated in response to unfolded or misfolded proteins in the endoplasmic reticulum. It stops the production of unfolded or misfolded proteins it is the quality control mechanism. It will stop production and start cleaning the bad proteins out. If it continues for too long then it will induce apoptosis which is cell death. If overactivated which vaccines and many farm chemicals can cause to happen it can lead to prion disease. It plays a valuable role in intestinal endoplasmic reticulum survival and function. Dysfunction of endoplasmic reticulum can result from genes that have been effected from infection, toxins, or even stress can result in abnormal UPR function. This is referred to as Endoplasmic reticulum stress.
ER stress activates three kinds of proteins which reside in the ER membrane to detect UPR in ER Lumen and resolve them. Autophagy reduces ER stress.
inositol-rquiring membrane kinase endonuclease1 (IRE1) via a really long pathway that I am certain you do not want me to type out. Issues with the genes involved in these mediators in intestinal endothelial cells will change the histological structure of the intestinal epithelium.
XBP1- inhibition will exhibit impaired Paneth Cells, which leads to dysbiosis and spontaneous intestinal inflammation which may induce activation of NF-kB pathway which can lead to inflammation, anxiety, chronic depression, insulin and leptin resistance, it increases risk of cardiovascular disease and high TH17 levels which can lead to psoriasis or lupus, Many who have intersitial cystitis have high TH17 levels. It can cause bone lose and Alzheimers. On the other end of the scale not enough NF-kB can produce many health problems. Like lower cognitive function, inhibited ability to heal, inhibited nerve growth and brain plasticity. This is a good article covering it in more detail. https://www.selfhacked.com/blog/nuclear-factor-kappa-b/
The second gene that can increase risk of inflammatory bowel disease is oromucoid-like3 (ORMDL3). Over expression can lead to immune/inflammatory diseases. It has been linked to childhood asthma. Over expression causes inhibited calcium buffering capacity of the mitochondria. This can disrupt endocytosis, enzyme control , cell growth and proliferation and cell apoptosis. ORMDL3 takes part in protein folding and in regulating UPR. It is believed ERs induced inflammation in paneth cells may disturb ORMDL3 levels leading to inflammation.
TREM1 (Triggering Receptor Expressed On Myeloid Cells-1) inhibits autophagy and increases ERs stress levels. This has been shown to increase the severity of inflammatory bowel diseases. Defective autophagy in the endoplasmic reticulum can predispose someone to inflammatory bowel diseases form a decreased clearance of IRE1 during ERs. High IRE1 levels impairs insulin signaling this can lead to many metabolic diseases. TREM1 can either increase inflammation or decrease it. During infection TREM1 increases inflammation. TREM1 also interacts with other inflammatory pathways which can also result in TREM1 increasing inflammation. TREM1 is high during septic shock. Sustained increased levels of TREM1 can lead to inflammatory bowel disease, cardiovascular disease and atherosclerosis. TREM1 is needed to help clear infection. Unfortunately when an infection that contains OspA protein that are difficult for the body to clear like HIV and Borellia (Lyme Disease) it can cause TREM1 levels to remain high. This is why it is very important to work on reducing inflammation and address infection. Most infectious diseases there are no test for and the test they do have has a high failure rate at detecting the microbe responsible for the illness. But the body and what genes are effected and cytokines present can indicate when there is an infectious agent present. The more difficult infections can be killed but it takes a multilevel approach because most that carry the OspA take multiple forms and have to be addressed differently for each form it has taken.
Inflammatory bowel disease have been shown to have a dis-regulation of T Cell which can be induced by toxins, drugs, vaccine injury, farm chemical or processed foods.
Autophagy is a conserved lysosome-dependent catabolic process involved in degrading and recycling aggregates as well as damaged organelles. Enhancement of autophagy promotes the survival of various cells including intestinal endothelial cells, and nuetrophils by protecting them from microbial toxins. A disturbance in autophagy could disturb the function of intestinal endothelial cells and influence inflammatory response, immune response, ROS levels and endoplasmic reticulum stress. This can lead to inflammatory bowel diseases. Autophagy plays a vital role in alleviating of intestinal inflammtion, degredation of damage associated molecular patterns (DAMPS), which can help prevent inflammatory bowel diseases. PAMPs refer to various kinds of endogenous materials produced by stress, impaired or dying cells covering DNA, RNA, ATP, histones, hyaluronan, uric acid, heparin sulfate, the S100A calgranulins, IL-1, HSP, and chromatin-associated high motility box1(HMGB1).
Basal autopaghy occurs in nearly every cell to maintain homeostasis of the ammino acid pools. There are three types of autophagy.
Macropahy – targets material such as cytoplasmic components or invasive bactria which are surrounded by a double-membrane bound autophagosome.
Autophagosome when combined with lysosomechanges into a single-layer membrane autolysome with a strong degradative and digestive ability.
Microautophagy – during the process of microautophagy lysosomal/vacuolar membranes invaginate (fold in on itself) to engulf intracellular components via a non-selective degradative mechanism.
Chaperone-mediated autophagy transports organelles and proteins into lysosomes only with the assistance of chaperones which are located in lysosomal lumen. Chaperons are proteins that assist in convalent folding or unfolding and the assembly or disassembly of other macromolecular structures. They assist in the assembly of nucleosomes which are basic units of DNA.
Two steps of Autophagy.
The first step of autophagy cup-shaped double membrane phagophores are shaped in the cytoplasma of the cell, and then misfolded proteins, damaged organelles or bacteria are engulfed to become sperical double membraned autophagosomes. Autophagosomes are usually considered to be produced from the nucleation and membrane expansion of phagophores.
During the second step autophgosomes fuse with lysosomes and endosomes to form a single-lipid layer autolysome, which is regard as basal units for degradation and digestion. Autophagy process is induced by the detection of various specific cues such as starvation or invasion by pathogens.
Two proteins are known to participate in autophagy which include Mammaian Target of Rapamycin (mTOR) as an inhibitor and adenosine monophosphate activated protein kinase as an indicator. mTOR is often activated by lower levels of Adenosine Triphosphate (ATP) caused by nutrient sufficiency or several growth factor stimulations. mTORC1 inhibits autophagy in the presence of nutrients. mTORC1 regulates glycolysis, lipid biosynthesis, and the pentose phosphate pathway has been found to be under the control of mTORC1. mTORC1 mediates upregulation of SREBP-1 activity which is necessary for lipid biogenesis. mTORC1 increases mitochondrial DNA copy number and as well as encoding many genes involved in oxidative metablolism. It has been found that mTORC1 promotes transcriptional activity of PPARy coactivator (PCG-1a) which is usually low in those who have inflammatory bowel diseases. This leads to the inability to break down fats and cholesterol causing many health problems because lipids are needed by almost all cells of the body especially the digestive system to maintain proper function and health. Ironically mTORC1 inhibition leads to longer lifespan. mTORC1 inhibits autophagy. mTORC1 increases NRF2 activity the master regulator of the antioxidant system.
Excess mTORC1 activation can cause endoplasmic reticulum stress and excess ROS production.
Low ATP levels inhibits mTORC1. Inhibiting mTORC1 increases glucose uptake. Hypoxia (oxygen deprivation) inhibit mTORC1. Amino Acid deprivation can inhibit the citric acid cycle (TCA cycle) this also inhibits mTORC1. The body inhibits mTORC1 when it senses DNA damage. Autophagy reactivates mTORC1 whose activity then promotes the replacement of lysosomes consumed during autophagy.
Symptoms of excess mTORC1 . Since there is no information on what excess mTORC1 does I will have list the symptoms of inhibited autophagy and high ROS levels since those are issues caused by high mTORC1 levels.
Symptoms of inhibited autophagy. Nuerological problem , inhibited autophagy can lead to inflammation in the brain, mental illness. Mitochondrial dysfunction, decreased antioxidant function which can lead to high levels of ROS. Pancreatic inflammation. Fat accumulation throughout the body and can lead to fatty liver disease. Issues with lysosomal storage, diabetes and sickle cell anemia. Frequent illness from infectious agents.
Symptoms of high ROS. ROS is needed for redox signaling but becomes damaging if levels get too high. High levels of ROS cause inflammation. Leaky gut and can cause a leaky blood brain barrier. This also can lead to nuerological damage and brain inflammation causing mental illness. Can cause liver damage resulting in a hepatic liver. Fatigue from reduced energy levels. Mitochondrial dysfunction which can lead to MS. Here is a link to a good article on oxidative stress.
What is Oxidative Stress? The Health Impact of Free Radicals
Things that stimulate mTORC1. Resistance training, amino acid L-Luecine, Beta Hydroxy Beta-methylbutyric acid which is a precursor of butyric acid. High intake of Iron stimulates mTORC1.
Inhibitors of mTORC1 are green tea, resveratrol, curcumin, caffeine and alcohol. Iron deficiency inhibits mTORC1. Green tea can damage the liver if taken for too long and curcumin chelates iron so can make a person anemic if consumed too long.
VDR
Vitamin D receptor (VDR) mediates the activities of vitamin D3 which is the activated form of vitamin D. A deficiency can effect our digestive system in many ways. The VDR is involved in regulating 33% of the genes in the body so problems with it can effect many things. VDR and Retinoid X receptor interact to with each other and can activate each other so issues with either one can effect vitamin D homeostasis. Inhibited VDR effects calcium homeostasis, electrolyte balance, and blood pressure.
Vitamin D3 acts as a hormone a hormone and helps regulate innate and adaptive immune responses. Those with low vitamin D levels or inhibited VDR receptor are prone to infection with Mycoplasma Tuberculosis. VDR is involved in producing the antimicrobial peptide/IL-37, defensin beta B, CLDN2 encoding claudin 2 and ATG16L1 related autophagy which protects us from inefection.
The VDR receptor is involved in gut microbiome balance and autophagy. Autophagy is the house keeper of our cells it helps clean them out, protect them from infection and helps to prevent misfolded proteins. Inhibited vitamin D receptor can cause inhibited bile flow and a decrease in LDL and increase in HDL. The reduced LDL causes bile to become sludgy which leads to biliary issues and gallbladder problems and can result in gall stones and biliary blockage.
When the VDR receptor is inhibited or there is a vitamin D deficiency we can develop inflammatory bowel diseases. IKBa is an inhibitor of pro-inflammatory NF-kB.
VDR inhibition or vitamin D deficiency alters the composition of intestinal microbiome. Butyrate producing bacteria become less numerous. Butyrate increases expression of VDR so a deficiency in Butyrate would further add to the inhibition of the VDR receptor. Butyrate also suppresses intestinal inflammation and enhances AMPs. AMPs help protect us from infection.
Toxins, mold toxins, infection and a lack of nutrients can inhibit the vitamin D receptor. High levels of vitamin D3 indicates the body has recognized an infection and is trying to fight it.
Farm chemicals especially glyphosate and glufonisate inhibit the vitamin D receptor. Many toxins found in processed food can also inhibit the vitamin D receptor.
Symptoms of inhibited VDR.
If the VDR is inhibited a person may experience problems with methyl donors and low dopamine levels. They may experience frequent infections and be low in GcMAF. Inhibited VDR can cause bone loss, hair loss, brain fog, increased TH17 levels resulting in lupus, psoriasis and/or skin rashes, tooth decay and poor oral health, inflammation throughout the body, can lead to high blood pressure. Low LDL which inhibits bile production resulting in biliary and gall bladder problems and can lead to stone formation. Electrolyte imbalance and iron deficiency. Low dopamine and GABA levels is a result of VDR inhibition. Prolactin level become low when VDR is inhibited. Gut dysbiosis and inflammation in the digestive system. Increased creatine and albumin levels and decreased alkaline phosphatase are symptoms of low vitamin D or inhibited vitamin D receptor. VDR inhibition or vitamin D deficiency can result in mast sell activation syndrome. CYP3a4 an enzyme needed for detoxing xenobiotics and drugs becomes inhibited. Hormonal imbalance is also a result of VDR inhibition. Hashimoto’s syndrome can result from VDR inhibition. Heart disease can be a result of VDR receptor inhibition or vitamin D deficiency. In more severe cases VDR inhibition can lead to liver and kidney disease.
Symptoms of Vitamin D deficiency.
Joint stiffness or pain, back aches, tooth decay, bleeding gums or gum disease, muscle cramps, hair loss, bone loss, weakening of bones, increases risk for cancer, sleep apnea, brain fog, fatigue, depression, leaky gut, excess sweating especially in the head area.
Excess vitamin D can lead to many health problems and can result in loss of bone from a disruption in the mechanisms that control calcium homeostasis. Though it is needed for calcium absorption high doses can have the opposite effects. High levels of vitamin D can lead to oxalate formation. Many studies show anything over 5000 IU a day can lead to oxalate formation and many health problems.The recommended daily allowance of vitamin D is 600 IU. It is best to get vitamin D from food sources. Exposure to sunlight, far infrared, halogen lights can increase the bodies production of vitamin D. Short term raised levels have been found to be beneficial but long term raised vitamin D levels have been found to be harmful to our health. High levels of vitamin D can contribute to the inhibition of the VDR. Excess vitamin D can result in high levels of calcium in the blood resulting in calcium deposits forming in the organs including the lungs.
Sources of vitamin D. Sunlight, halogen lights, far infrared light increases the bodies production of vitamin D. Excess sunlight has been shown to cause high levels of vitamin D and is why life guards have some of the highest rates of kidney stones. Fish oil contains vitamin D. Sardine , salmon and cod liver oil are good sources. I try to make sure the fish is not from contaminated areas. Most sea food is high in vitamin D. Mushrooms and eggs are a good source of vitamin D. Animal liver is another good source of vitamin D. Cestrum Diurnum, Waxy leaf nightshade (solanum glaucophyllum), yellow oat grass (trisetum flavescens) are plant sources of vitamin D. Those plants are so high in vitamin C that they cause calcinosis in grazing animals. Brown and read seaweed are also sources of vitamin D and cholesterol. Mercury found in fish is for the most part only a problem if we have leaky gut. When the gut is intact only about 5% of the toxins like mercury get absorbed that have been consumed and when healthy the body can easily detox that amount unless it is shot directly into the blood stream. I mention this because even though they claim vaccines do not contain mercury some still do.
Things needed for the body to be able to use vitamin D. Vitamin K2, Vitamin A, zinc, sulfur is needed to sulfate vitamin D so sulfation issues need to be addressed. Magnesium increases the bodies response to vitamin D. Boron increases vitamin D in the blood stream. Water is needed, dehydration inhibits many receptors in the body. Silica helps improve the function of many receptors in the body. Sunlight helps to sulfate nutrients. DAO and lysine are also needed to sulfate vitamin D. Boron is touchy, low levels reduce estrogen high levels increases estrogen.
Things that enhance vitamin D receptor activity. Parathyroid hormone, Sirt 1, Dopamine, Omega 3 , Omega 6, Phytoestrogens, Testosterone, Postaglandulins and bile activates VDR. Bitter herbs stimulate bile production. Even if you do not swallow bitter herbs just tasting them stimulates bile production. Resveratrol activates the vitamin D receptor. Querciten enhances vitamin D receptor activity. Curcumin stimulates the vitamin D receptor but if taken for too long it can lead to anemia because it chelates iron from the body. So one may use it at first to help stimulate the VDR receptor but probably should just take maintenance doses to make sure it continues to function. Human Growth Hormone stimulates the vitamin D receptor. Sleep, fasting, and strength training increase HGH.
Things that can inhibit VDR are cortisol/glucocorticoids, high prolactin levels, imbalance in thyroid hormones, TGF-Beta, phosphatonins which regulate phosphate homeostasis, and ubiquitin can inhibit VDR. Many of these things are inhbited by autophagy which would prevent them from inhibiting the VDR receptor. Caffeine can also inhibit the VDR. High TGF-B levels can be an indication of T cell imbalance and/or B cell imblance. Probiotics that reduce inflammatin and increase T regulatory cells should reduce TGF-B. High phosphatonins is a sign of low klotho levels. Exercise increases klotho, Most Acidophilus bacteria and Lactobacillus Lactis increases klotho. Cordyceps mushrooms increase kltoho. PPAR Gamma activators stimulate klothos, Some PPAR gamma activators are berberine, magnolia, and Omega 3s. Those who are obese should not stimulate PPAR gamma because they are usually PPAR gamma dominant. Adaptogenic herbs like suma root and maca root can help normalize adrenal levels. Ubiquitin levels are reduced by autophagy. High prolactin levels can result from toxins in plastic containers used to store food and some farm chemicals found in our food supply. There are also chemicals in processed foods that can cause high prolactin levels. Those who are taking drugs should not use berberine or things that contain it because it inhibits the cytochrome P450 enzymes needed to detox medications.
Fulvic acid and nobiline induce autophagy. We do not want to overstimulate autophagy. Fasting also stimulates autophagy but those who are Type1 diabetics have to be careful fasting can induce ketoacidosis in them. Branch Chain fatty acids can inhibit autophagy. Tumeric, ginger, berberine, gensing, mushrooms and elderberries can stimulate autophagy.
NOD2 – Nucleotidebinding Oligomerization Domaincontaining Protein 2 whew that was a lot. A member of the NLP family which is a group of immune regulating proteins. It is a sensor of muramyl dipeptide which is a constituent of both gram negative and gram positive bacteria. It is found in macropages and paneth cells. When inhibited a-defensin numbers are decreased, lower sensitivity to bacteria infection, and altered immune function from Toll Like Receptors becoming suppressed. This results in the inability to clear bacteria infections from the intestines. Inate and adaptive immunity is impaired. Nod2 induces autophagy through the NOD2 pathway. NOD2 is induced by NLP or bacteria infection, this promotes the delivery of NOD2 which enhances inflammation. Showing that if You have high NOD2 levels you would not want to induce autophagy. NOD2 prevents infection in cells which is mediated by ROS and MAPK pathways. NOD2 altered expression can lead to inflammatory bowel disease. Many cellular proteins interact with NOD2 directly and regulate it’s function positively or negatively. Among these proteins is Erbin. Erbin regulates Erbb2 if Erbin is inhibited Erbb2 levels can go up resulting in cancer growth. Centaurin B1 which I have no idea what it’s function is. Angio-associated migratory protein which is involved in endothelial tube formation and endothelial cell migration. It is involved in angiogenesis. Carbamoyl-phosphate synthase 2 is involved in the production of nucelotides in cells. Mitogen-activated protein 1 which helps down regulate NOD2. Heat shock protein 90 interacts with NOD2. HSP90 is involved in folding , intracellular transport and the degradation and maintenance of proteins. I have post on heat shock proteins like HSP90 and HSP70.
NOD deficiency. NOD2 is involved in maintaining balance between the microbiome and immune response. NOD2 deficiency results in loss of epithelium integrity, and increased susceptibility to intestinal inflammation. NOD2 deficiency can cause dysfunction in intestinal paneth and goblet cells. Deficiency increases IFN-y, and decrease ROS production which protects from infection so we need a balance because excess ROS can damage tissues in the body.
NOD2 upregulation. Vitamin D supplementation has been shown to increase NOD2 which helps to fight infection. Excess NOD2 can lead to rheumatoid arthritis, and systematic inflammation. Excess NOD2 has been linked to cardiovascular disease and pulmonary disease. NOD2 prevents inflammation in the eyes.
NOD2 deficiency causes low TH17 levels, inhibited immunity, and will be more prone to cancer. NOD2 is also involved in the detection and eradication of viruses.
Excess NOD2 causes systematic inflammation and sarcoidosis. Often times it is mistaken for cancer or copd. High NOD2 levels is a sign of infection.
Damage to the mucus membrane and intestinal tissue can cause it’s dis-regulation. This shows the importance of restoring mucus membrane and work on healing the gut.
Atg16L1
Autophagy-Related Protein 16-like Protein 1 – Deficiency in Atg16L1 impairs recruitment of Atg12-Atg-5 complex which impairs the engulfment of pathogens and cellular organelles during the process of autophagic catabolism. Atg16L1 defeciency cause Paneth cell dysfunction and increases inflammation. Atg16L1 causes high leptin and adiponectin levels. A deficiency in Atg16L1 leads to intestinal lesions. Leptin tells the brain we do not need to eat. Leptin increases inflammation in the body. High leptin levels lead to chronic fatigue. Leptin can cause Th1 dominance. Those with high IL-10 levels would want to avoid probiotics that increase IL-10 because leptin increases IL-10. Leptin causes mast cells to become more inflammatory. Leptin causes lower T regulatory cells which keep our immune system at homeostasis. Leptin can cause excess blood clotting (throbosis). Leptin can cause high blood pressure. Leptin increases estrogen levels. Adiponectin is a protein hormone involved in glucose levels and fatty acid breakdown. High adiponectin levels causes a loss of appetite it causes weight loss and works synergistically with leptin. Adiponecton decreases gluconeogenesis. It increases B-oxidation of fats. It protects against endothelial dysfunction. It increases insulin sensitivity. So you can see the importance of Atg16L1 homeostasis.
Mir223 restores autophagy and Atg16L1 homeostasis. Mir233 downregulates inflammation. Mir233 is reduced in sepsis. Mir233 increase HDL cholesterol levels. But Mir233 is upregulated in inflammatory bowel diseases. Increasing Claudin-8 inhibits Mir233 inflammatory effects.
ROS (Reactive Oxygen Species)
ROS or Reactive Oxygen Species modulates cellular function under normal conditions. ROS is produced during the process of oxidative phosphorylation and can be handled by instracellular antioxidants. Injury, toxins , vaccine injury, infection, and stress can cause an over production of ROS which can exceed the generation of antioxidants leading to oxidative stress which can cause a lot of damage throughout the body. It causes inflammation, cell damage and even cell death. When the mitochondria become dysfunctional this can cause a rearrangement of the cytoskeleton which is framework of the plasma membrane and effects the balance between kinases, and phosphatases which promotes the ability of microorganisms to enter the cell and contributes to many inflammatory diseases. Excess ROS increases the permeability of intestinal epithelial. When levels of ROS are normal it will induce autophagy and microphagy which reduces inflammation. Reducing ROS levels too low can have the opposite effect because it would prevent it from inducing autophagy and we would lose the protection it gives us from infection.
Antioxidants can reduce oxidative stress but when homeostasis is achieved a person should only take maintenance doses. Over use of antioxidants can promote cancer by protecting it from apoptosis it also increases our risk of infection by reducing ROS levels too low.
Xenophagy
Xenophagy is the clearance of pathogens regulated by autophagy. Reduces Xenophagy leads to alterations of intestinal microbiota. This leads to a higher rate of infection. The microbiotia induce xenophagy in basal paneth cells which is induced by INF-y to maintain intestinal integrity. This impairs sensing of intracellular micro organisms in the intestinal endothelial cells and contributes to the progression of inflammatory bowel disease. Showing the importance on healing the intestinal tract so that the mucus membrane can be restored. Prebiotic fiber and the tryptophan metabolizing gut microbiota increases IFN-y. The commensal strains of E Coli increases IFN-y. Lactobacillus Gasseri increases IFN-y. Bacteroides Fragilis increases IFN-y and has been found to protect from many types of infections. Butyric Acid must be present to maintain IFN-y homeostasis. So it would also be a good idea to make sure the butyrate producing microbes are established.
IRGM (Immunity Related GTPase Family M protein) – is involved in killing of bacteria, vacuolar trafficking and acidification, it is also involved in autophagy. It is involved in fighting mycoplasmas. Damage to the digestive tract can impair it’s function which wold make you susceptible to mycoplasma infection. Inflammation inhibits IRGM. Our digestive tract needs to be acidic. If it becomes to alkaline then it creates an environment that promotes infection and dysbiosis and we lose our commensal microbiota.
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