Connecting the Dots between GI Health, Brain Function and Genetic Expression
A few weekends ago, I spent a day learning from Dr. Andrew Rostenberg, author of the website www.BeyondMTHFR.com. Dr. Rostenberg has been using genetics to help his patients for several years, and his blog is a great resource for anyone wanting to more deeply understand and apply their genetic test results.
After a conference, I like to take some time to summarize what I’ve learned, which helps me retain more of the material, and allows me to archive it for later access, but the best part is that I get to share the information with all of you!
Why is an MTHFR mutation so impactful across so many body systems?
Because it’s responsible for folate metabolism, which can influence the final form of ANY growing tissue due to its participation in nucleic acid synthesis and regulation of DNA and protein methylation.
Cleft palate, scoliosis and neural tube defects are all signs of improper methylation.
B vitamins are required all throughout the methylation pathways, as well as in the mitochondria of the cell, fueling energy metabolism. The flip side of this is that bacteria and yeast also have a methylation cycle, so they also benefit from B-vitamins. Poor tolerance of added B vitamins can indicate a bacterial or yeast overgrowth in the gut.
Bacteria in our gut manufactures many of our B vitamins, in part because they are also dependent on B vitamins. This is good to keep in mind when we see an elevation in folic acid on serum testing—it’s possible that bacterial production is the cause for elevation. (I would also suspect it could come from processed foods, which are often enriched with folic acid—which BTW, doesn’t occur anywhere in nature—folic acid is a synthetic version of folate….folate occurs in foliage, aka dark, leafy greens/plants, which is what it’s named after.)
In humans, folate and other B vitamins are important for recycling of BH4 (tetrahydrobiopterin), an essential precursor to brain neurotransmitters. Sufficient amino acids and balanced blood sugar are also critical in neurotransmitter production. Some patients experience increased anxiety with B vitamins because increasing intake can result in too many excitatory neurotransmitters being produced—this class of neurotransmitters are easier to make than serotonin (which is calming) and are harder to degrade and remove from our systems, thus the anxiety.
Why are Depression and Anxiety so Common?
- Depression and anxiety risk increases with every antibiotic exposure because the 3 most important amino acids involved in neurotransmitter production are made by our gut flora (tyrosine, tryptophan and phenylalanine used to make catecholamines (aka “cats”) and serotonin). A healthy supply of these is needed for brain and mood balance. (To learn more about the balance between the “cats” and serotonin, check out my neurotransmitter notes from this lecture (scroll down a bit).
- Pesticide and herbicide exposure shows a positive association with depression because our gut flora are metabolically similar to weeds and pests, so chemicals that target them will also have a negative impact on our gut flora. These chemicals are effective because they deprive their targets of manganese. Manganese is important for the production of energy (in our metabolism as well as the metabolism of gut flora), the production of SOD (the most important antioxidant inside cells), and to maintain healthy ligaments (just for us, not our flora).
- MTHFR genetic errors increase the risk for depression by 400-500% because methylation is responsible for production and recycling of BH4, an enzyme that makes serotonin, dopamine and thyroid hormones (a deficiency in any of these can cause or contribute to depression and/or anxiety).
Stress Hormones and their Link to GI Issues
Stress produces catecholamines (adrenalin, noradrenalin and cortisol), which in turn uncouples iron from its binding proteins (lactoferrin and transferrin), allowing bacteria to hijack the body’s iron and use it for its own energy purposes, often resulting in chronic anemia.
The mammalian gut is extensively innervated with noradrenaline- and dopamine-containing sympathetic nerve terminals, which are distributed throughout the enteric (intestinal) nervous system. Half of all norepinephrine (aka noradrenaline, one of several catecholamines) releases into the GI tract, and catecholamines can cause RAPID pathogen growth…10,000% or more! This is why stress can cause digestive upset and even diarrhea.
Yet another reason stress has a negative impact on the gut is that adrenalin increases biofilm formation. Biofilms are defensive slime layers microbes build around themselves to evade the immune system, one reason GI infections can often be difficult to resolve (dental plaque is a biofilm created by the bacteria in our mouths).
Episodes of low blood sugar are also very detrimental to digestion and health in general. The body responds with an outpouring of adrenalin when blood sugar is low, which helps mobilize glucose out of storage (this is the same physiological response seen in a fight-flight stress response w all the same implications for digestion). The storage form of sugar that is used in this reaction is glucagon, and when glucagon is elevated, stomach acid secretion is inhibited, which also inhibits digestion and opens the door for microbes to survive digestion, since stomach acid should sterilize the food coming in.
The stress of running a marathon (or similar exhaustive exercise) raises glucagon to 4- or 5-fold normal concentrations. Not only does this decrease stomach acid secretion with all the same implications as low blood sugar or fight-flight response, it also deprives the gut of circulation (think oxygenation and nutrition), sometimes resulting in “runner’s gut” which can also be seen in distance biking and other extended forms of exercise. The result can be extreme, such as severe diarrhea, or milder, producing ongoing GI issues.
Another function of stress impacting the GI tract is its inhibiting effect on secretory IgA, a type of antibody that protects against infection in the mucosal surfaces of the mouth, airways and digestive tract. SIgA antibodies make up a majority of your immune system, and are important in protecting against, yeast, bacterial, viral and parasitic infections as well as cancer, and can help to lower inflammation. As the immune response gets over-run, leaky gut results, which allows entry of undigested food and pathogens from the intestines into the bloodstream. This can cause and contribute to autoimmunity and seasonal/environmental/food allergies and sensitivities.
Because stress causes vessel constriction, it reduces blood flow to the skin and organs, including the digestive tract.
Connecting the Dots in Digestive Health
A healthy stomach has a pH of about 3.0. To put that in perspective, vinegar has a pH of 5.0, which is 100 times less acidic than a pH of 3.0. Acid in the stomach acts to increase the pressure on the lower esophageal sphincter, which keeps the stomach acid in place, rather than allowing it to reflux up the throat. Some people need to first address a hiatal hernia before restoring acidity to their GI tract.
A-fib is 21 times more common in patients with a hiatal hernia, because the hiatal hernia can have a direct mechanical effect of pressing against the heart. Rarely does hiatal hernia truly require surgery. Many bodyworkers and chiropractors do manual manipulations that pull down the hiatal hernia and help restore function.
Data now shows the gut microbiota communicates with the central nervous system (CNS) through neural, endocrine and immune pathways, influencing brain function and behavior. Supporting the right balance of flora with probiotics, fermented foods and restriction of refined carbohydrates and sugars are a critical part of addressing mood disorders, pain and impaired cognition.
A healthy microbiome has also been found to be critical for proper myelination of neurons (nerve cells) in the prefrontal cortex (think depression, MS, schizophrenia and autism).
Remember that stress lowers digestive secretion of acid, which is crucial for the next steps in digestion: pancreatic enzyme and bile secretion. Chronic deficiency of these digestive factors can lead to small intestine bacteria overgrowth (SIBO). Other contributing factors are motility disorders, painkillers and ongoing alcohol consumption.
Bile acids emulsify cholesterol, dietary fat and fat-soluble vitamins, enabling their absorption. They also facilitate intestinal calcium absorption and modulate pancreatic enzyme secretion and cholecystokinin release, in addition to being potent antimicrobial agents that prevent bacterial overgrowth in the small bowel.
SNP (“snip”) Specifics
SNPs, or single nucleotide polymorphisms, are an amino acid substitution at a specific location on a gene. Genes are like recipes that tell the body what shape to make a protein. Just like substituting an ingredient in a recipe will result in a different outcome, an amino acid substitution on a gene results in a protein that is shaped a little differently than it otherwise would be. Everyone has SNPs, or genetic variants, and understanding your specific SNPs can help you be preventative, and even help you find your way back to health. Dr. Rostenberg discussed some specific SNPs:
FUT2 gene errors can impair gut amino acid synthesis, and have been found to be strongly linked to difficulty absorbing B12 and other nutrients, as well as a decrease in the production of prebiotics (food for probiotics). Lysine and carnitine deficiency are commonly seen with those who have these SNPs. Lysine is needed for production of B6, so this is an additional commonality, and lysine deficiency can make one more prone to viral infections, since lysine inhibits viral replication.
Candida albicans release aldehydes and ethanol (ethanol is also found in drinking alcohols) as normal cellular byproducts. These two compounds deplete B3, cofactors for ALDH, ADH and ALR genes and shut off methionine synthase (MTR), all of which are involved in the methylation pathways.
Oxalates are a plant self-defense mechanism that act as anti-nutrients when consumed by herbivores (plant-eaters). They do this by forming an insoluble calcium oxalate salt that can lead to kidney stones and calcium deficiency. Oxalates also inhibit SULT, UGT, MTHFR and NAT genes, and impair sulfation in phase II liver detox pathways. Increasing calcium intake while eating oxalate-rich foods can prevent hyperoxaluria (high oxalates). Those with fatty acid malabsorption (gallbladder removal or impaired digestion) may have an increased issue with oxalates, since fatty acids bind to calcium, leaving the oxalates to be absorbed in the colon. High dose B6 (250-500 mg daily) has been shown to decrease the frequency of oxalate stone formation. Dr. Rostenberg typically uses 5mg/kg/day of pyridoxine B6 for patients with high oxalates upon testing.
Further, pathogenic bacteria in the gut induce or aggravate metabolic stone disease, particularly the calcium oxalate type. Therefore, it shouldn’t be surprising that antibiotics are seen to increase oxalate levels, while probiotics decrease oxalates, particularly B. Infantis, L. Plantarum and L. Brevis.
Be aware that stopping dietary oxalates too quickly can cause oxalate dumping symptoms: urination, night sweats, nausea, kidney pain. If this occurs, increase fluids, calcium citrate and increase oxalates in the diet, then more slowly lower them once symptoms subside.
Catecholamine neurotransmitters are considered “excitatory” brain messengers and are responsible for helping us feel focused, alert and energetic. These are also the neurotransmitters involved in fight-flight responses.
Symptoms of low catecholamines: food cravings, addictions, substance abuse, anger, impulsivity, high risk behaviors and excessive sleepiness.
Symptoms of high catecholamines: schizophrenia, aggression/violence, delirium, anxiety/panic/worry, tachycardia, high blood pressure, insomnia, paranoia, chronic pain.
Serotonin is an “inhibitory” or calming and uplifting brain messenger.
Symptoms of low serotonin: violence, aggression, depression, apathy, lack of pleasure, suicide, high risk behaviors, chronic fatigue, anorexia/cravings, low libido and interrupted sleep.
Symptoms of high serotonin: mania, agitation, hyperreflexia, excess sweating, fever, shaking, diarrhea.
Dopamine deficiency symptoms can occur with normal dopamine and high serotonin. Serotonin deficiency symptoms can occur w/low serotonin or high dopamine.
High serotonin is only seen in 1% of individuals tested.
Histamine and serotonin are both released in type 1 basophil and mast cell responses.
Dopamine has no built-in braking system like serotonin does and it’s harder to clear from the system once it’s made. Those with COMT errors will clear dopamine even more slowly, and SNPs on this gene are associated with poor memory and learning. Every antipsychotic drug works on dopamine.
Glyphosates (found in Roundup) not only kill off our friendly flora, they bind minerals needed to make the 3 aromatic amino acids (tyrosine, tryptophan and phylalanine) needed to make catecholamines and serotonin.
Insulin’s Impact on Neurotransmission:
High levels of insulin push higher amounts of tryptophan and tyrosine into the brain, competing with access by branched chain amino acids’. (High insulin is common in type 2 diabetes, and also results from eating too many quickly releasing carbohydrates.)
Low levels of insulin and insulin-resistance increase glucagon, which inhibits tyrosine and tryptophan from entering the brain.
Taking branched chain amino acids lowers brain tryptophan uptake and serotonin synthesis, as well as tyrosine uptake and dopamine synthesis, so athletes with mood disorders should beware.
Supplementation of tyrosine lowers serotonin, and supplementation of tryptophan lowers dopamine.
Tryptophan has functions in the body other than the production of serotonin, and it’s becoming increasingly scarce in our food supply. Additionally, B3 is needed to make tryptophan, so yeast overgrowth, which depletes B3 to clear the aldehyde byproducts they produce, can result in low serotonin.
MAO-A enzymes have a much higher affinity for breaking down serotonin when the body is inflamed.
The following compounds compete for clearance from the body: adrenaline, dopamine, histamine, estrogens, acetaldehyde and aldehyde.
To stabilize mast cells: SPM Active given 2 TID for 1 bottle, then 2 BID for 1 bottle then 2 QD thereafter
Key products for oxalates: bone builder vegetarian 1 tab 5 min before meals/snacks containing oxalates
Trancor 2 TID or Lipo-gen 2 TID
Sulfuroclear 2 tabs BID
UF Intensive care 2 tabs QD
Metagest 1-7 tabs after meals
vessel care 2 tabs BID for cranky and high homocysteine
Blisphora 1 tab BID for low or normal homocysteine
Glycogenics 2 tabs BID for sarcopenia
Serosyn 1 tab TID
SJW w/folate and B12 1-4 tabs QD
Ultra Meal advanced protein, 2 scoops BID
Trancor, 2 tabs TID if anxious
Glutaclear, 2 tabs BID
Serosyn 1 tab TID
Benesom, 1-4 tabs QD, 10 min before bed
After gut is improved, look at mitochondrial support, detox and vitamins (don’t use before or you feed bad gut bacteria too)
Mitovive 1 scoop QD
Nutragems COQ10 300 1 cap QD
MetaLipoate 300 1 cap BID
Ceralin forte 3 tabs QD
Glutaclear 2 tabs BID
Sulfuroclear 2 tabs BID
Silymarin 1 tab TID
Advacearl 1 tab TID
Patty Shipley, Naturopath, RN, Herbalist