About the only independent variable appearing to cause permanent change in the gut is dietary change, but did you know that your microbiome and microflora are drug manufacturers?
It’s a little known fact that one of our body’s innate pharmacies resides in our gut.
Where, exactly, in our gut, you ask?
Well, in neurochemicals isolated in various microbial species whose diversity depends on our microbiome’s health. This speaks to another emerging area of interest: probiotics as pharmacy.
This article will briefly discuss five neurochemical isolated from various genera of normal gut bacteria:
1. GABA: Lactobacillus and Bifidobacterium. GABA is the main inhibitory neurotransmitter in the central nervous system, helping to induce a parasympathetic response, and significantly impacting and regulating various processes both physiologically and psychologically. Several animal studies indicate that various species of Lactobacillus and Bifidobacterium are capable of producing GABA in the gut. (1, 2, 3, 4)
2. Norepinephrine: Escherichia, Bacillus, and Saccharomyces. Norepinephrine is a naturally occurring neurotransmitter active during a sympathetic response which is upregulated during fight or flight and acts as a stress hormone. Several animal studies have shown that various species of Escherichia, Bacillus, and Saccharomyces play a role in upregulatting and producing norepinephrine. (5, 6, 7, 8)
3. Serotonin: Candida, Streptococcus, Escherichia, and Enterococcus. Serotonin is a key hormone, an estimated 90% of which is thought to be produced in the gut, that is key in mood stabilization and happiness, as well as impacting learning, attention, and memory processes. Several animal studies have indicate that various species of Candida, Streptococcus, Escherichia and Enterococcus play a role in serotonin production. (9, 10, 11, 12)
4. Dopamine: Bacillus and Serratia. Dopamine is a key neurotransmitter in our ability to experience pleasure, as well as cognitive control in our prefrontal cortext. Several animal studies have shown that certain species of Bacillus and Serratia play a key role in the production of dopamine. (13, 14)
5. Acetylcholine: Lactobacillus. Acetylcholine is the main neurotransmitter of the parasympathetic nervous system and its receptors are present all throughout our smooth muscle, blood vessels, and even heart muscle, as it helps to downregulate the function of certain organs during rest and digest. Several animal studies show that various species of Bacillus and Serratia are capable of producing acetylecholine in the gut. (15, 16)
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. Probiotics Antimicrob Proteins. 2020 Sep;12(3):973-979. doi: 10.1007/s12602-019-09601-1. PMID: 31677091
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]. Prikl Biokhim Mikrobiol. 2010 Nov-Dec;46(6):672-7. Russian. PMID: 21261078
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. 2005;26(4):335-337. doi:10.1016/j.ijantimicag.2005.07.006
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Banskota S, Regmi SC, Gautam J, Gurung P, Lee YJ, Ku SK, Lee JH, Lee J, Chang HW, Park SJ, Kim JA. Serotonin disturbs colon epithelial tolerance of commensal E. coli by increasing NOX2-derived superoxide
. Free Radic Biol Med. 2017 May;106:196-207. doi: 10.1016/j.freeradbiomed.2017.02.034. Epub 2017 Feb 17. PMID: 28216386
Evrensel A, Ceylan ME. The Gut-Brain Axis: The Missing Link in Depression
. Clin Psychopharmacol Neurosci
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- Liu J, Xu F, Nie Z, Shao L. Gut Microbiota Approach-A New Strategy to Treat Parkinson’s Disease. Front Cell Infect Microbiol. 2020;10:570658. Published 2020 Oct 22. doi:10.3389/fcimb.2020.570658
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. 2020;13:1361. Published 2020 Jan 14. doi:10.3389/fnins.2019.01361
Cholecystectomy is a common surgical procedure in which the gallbladder is removed, usually because of bile duct stones or gallstones. (1)
Bile acids are made by the liver and stored in the gallbladder, but when the gallbladder has been removed, there is no place for them to be stored. (2)
Bile acids are required particularly for the promotion of lipid absorption, but they also play a significant role in activating enzymes responsible for phase I, phase II, and phase III metabolism in the liver. (3)
Hence, if someone has had a cholecystectomy, then their primary detoxification pathways will be compromised by the fact that they are bile acid deficient.
It goes without saying that a person who has had cholecystectomy is thereby more likely to have toxins build up in their system, tissues, and blood, which means that supporting the detoxification pathways in patients who are missing their gallbladder is essential. (4)
Also, supplementing with bile salts may be necessary, but it is essential to consult your naturopathic doctor instead of self-diagnosing and self-treating.
- Njeze GE. Gallstones. Niger J Surg. 2013;19(2):49-55. doi:10.4103/1117-6806.119236
- Secretion of Bile and the Role of Bile Acids In Digestion. (n.d.). http://www.vivo.colostate.edu/hbooks/pathphys/digestion/liver/bile.html.
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. Drug Metab Dispos. 2013 Mar;41(3):562-7. doi: 10.1124/dmd.112.049098. Epub 2012 Dec 13. PMID: 23238784.
Grant DM. Detoxification pathways in the liver
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Iron deficiency anemia is a common condition, prevalent in around 10% of non-Hispanic white women and nearly 20 percent of black and Mexican-American women. (1)
Iron is stored by a protein called ferritin, which is made by the liver, and so if ferritin is low, then there is not sufficient storage capacity in the body. (2)
Checking ferritin is the best way to check for iron deficiency, for this reason.
A little known fact is that the cytochrome P450 enzymes also made in the liver require heme-iron structurally in order to function. (3)
These enzymes play a critical role in the metabolism and clearance of drugs, in something called Phase 1 detoxification.
Hence, having low iron can mean that our detoxification pathways will not function at their highest level, as the p450 enzymes may not have the iron they require to be built in sufficient quantity.
Also, because ferritin and the cytochrome p450 enzymes are both made by the liver, supporting a healthy liver will aid in their production.
Killip S, Bennett JM, Chambers MD. Iron deficiency anemia
. Am Fam Physician. 2007 Mar 1;75(5):671-8. Erratum in: Am Fam Physician. 2008 Oct 15;78(8):914. PMID: 17375513
Anderson ER, Shah YM. Iron homeostasis in the liver
. Compr Physiol
. 2013;3(1):315-330. doi:10.1002/cphy.c120016
- Correia MA, Sinclair PR, De Matteis F. Cytochrome P450 regulation: the interplay between its heme and apoprotein moieties in synthesis, assembly, repair, and disposal. Drug Metab Rev. 2011;43(1):1-26. doi:10.3109/03602532.2010.515222
In my book, “The Serpent and The Butterfly: The Seven Laws of Healing,” I present a paradigm of health with a practical, evidence-based approach to naturopathic medicine.
Globally, hundreds of millions—over 157 million in the United States alone—struggle with a chronic disease such as type 2 diabetes, hypertension, and heart disease.
But through the seven laws of healing, my book offers a definitive starting point for anyone looking to understand how to prevent and resolve chronic disease.
You, too, can embrace a new paradigm of health with this practical, evidence-based approach to alternative medicine.
Here are three reasons to read my book, “The Serpent and The Butterfly: The Seven Laws of Healing“:
1. Taking a Balanced Approach to Alternative Medicine
Alternative medicine is more divided than ever before between the bright, shiny objects of the latest anti-aging tech trends and reverence for the traditional roots of ancient medical wisdom.
While trend is not destiny, tradition can also fall out of vogue and become scientifically outdated.
Both sides argue for evidence-based medicine but the question, “Whose evidence?”
Some health and wellness fads fall on a spectrum from one extreme to another, yet one truth remains constant: people are seeking vitality.
I discuss what it means to take a practical, balanced approach that integrates science and technology with traditional wisdom.
2. How to Use the Seven Laws of Healing to Optimize your Health
Our body is our messenger, even if we don’t always like what it has to say.
In order to find true health, it’s essential to support this messenger and become fluent and conversant in its language.
We must learn how to rely on and trust the laws of healing operating within the human body, which have been not only been steadfast through time, but now have a strong evidential basis in the sciences.
I articulate the seven laws of healing and what it means to trust these laws operating within the human body along with practical means in which to apply them to optimize health and prevent chronic disease.
3. How to Live a Disease-Free Life
The Law of Disease states that disease is an imbalance caused by three things: toxicity, deficiency, and lack of energy.
A life free of chronic disease starts with the knowledge of how disease is engendered in the human organism.
Turning the concept of The Law of Disease inside-out, we have what I call The Triangle of Optimal Health, which says that optimal health is maintained by three things: a non-toxic lifestyle, adequate nutrition, and a robust vitality.
I discuss how to use this knowledge to lead a non-toxic lifestyle, maintain an adequate nutrient status, have plenty of energy, live a life free of chronic disease.
Calcium D-glucarate is a popular supplement with some buzz these days, used for cancer prevention, liver detoxification, and hormone regulation, but few know why exactly it’s recommended. This article will discuss why it’s used and discuss whether it’s a band-aid or a root cause approach to chronic disease.
First, let’s take a closer look at the compound itself.
Calcium D-glucarate is a calcium salt of D-glucaric acid, a non-toxic compound found in many fruits and vegetables, especially grapefruits, apples, oranges and even cruciferous vegetables, such as broccolini and Collard greens, but in trace amounts. (1)
Calcium D-Glurate and Liver Detoxification
The liver works 24/7 to help carry waste products out of your body.
The liver has three phases of detoxification, and the middle or second phase, or Phase II, uses a process called glucuronidation, which involves processing end-metabolite hormones such as estrogen so that as end-metabolites they can safely move out of the body. (2, 3)
All steroid hormones, for example, are detoxified in the liver via glucuronidation.
Oral supplementation of Calcium D-glucarate has been shown to inhibit beta-glucuronidase, an enzyme produced by colonic microbiota heavily involved in liver detoxification. (4) This inhibitory enzyme can be produced in excessive amounts when our microbiome is compromised by a pathogenic bacterial foothold.
Beta-Glucuronidase Run Amuck
When our gut microbiota are thrown off, a state otherwise called dysbiosis, a host of byproducts are generated which can lead to dysbiosis-associated changes. (5) Some common agents which can wreak havoc on our microbiome include antibiotics, such as clindamycin, and NSAIDS, such as ibuprofen. (6, 7) And one of these dysbiosis-associated changes include the overproduction of the enzyme beta-glucuronidase. (8)
But the danger here is that if there is excessive beta-glucuronidase in the body due to pathogenic bacteria having taken ahold in the gut, then these end-metabolites of estrogen can be cleaved at the junction of (soon-to-be-excreted) toxin and glucuronic acid, and the toxin can then stay in the body and lead to the formation of carcinogens in the bowel, increasing the risk of cancer.
This whole process can lead to the promotion of enterohepatic recirculation wherein a toxic soup of toxins, hormones and even drugs circulates freely throughout the body. (9)
A deeper discussion of enterohepatic recirculation can be saved for a future article, but it has been shown to lead, for example, to higher estrogen levels, which in turn increases the risk for breast cancer.
In other words, elevated beta-glucuronidase activity is associated with hormone-dependent cancers.
Calcium D-Glucarate to the Rescue
Supposedly, enter the supplement, calcium D-glucarate, to the rescue. Studies indicate that calcium D-Glucarate will actually prevent the excess beta-glucuronidase from cleaving the end-products of estrogen, allowing them to remain glucuronidated and to be excreted properly.
Beta-glucuronidase actively conjugates estrogens into their active forms, a process which is impaired by dysbiosis and results in less circulating estrogen, which may contribute to conditions such as obesity, metabolic syndrome, PCOS,
cardiovascular disease, and cancer. (10)
Calcium D-glucarate is thought to confer protective properties against breast cancer via estrogen clearance.
In mice models, D-glucarates themselves appear to suppress cell proliferation and inflammation, and can also induce cell apoptosis, that is, they can potentially support proper cell death so as to keep malignancy in check. (11)
Other compounds thought to inhibit breast cancer include diindolylmethane (DIM) and isothiocyanates (sulphoraphane) found in cruciferous vegetables. (12) Hence, make sure to eat adequate amounts of these sulfur-rich foods.
In other words, it is thought that oral supplementation of calcium D-glucarate is a way of favoring the body’s natural defense mechanism by upregulating the clearance of carcinogens.
Is Excessive Beta-Glucuronidase A Calcium D-Glucarate Deficiency?
Is the above a leading question? Somewhat. Is it a rhetorical question: Well, kind of. But the short answer is no.
And taking calcium D-glucarate, though it may be highly indicated, especially as part of a naturopathic or functional treatment plan, is more a band-aid treatment than a root cause approach.
In other words, the right question to be asking is, “What exactly is mediating or causing the excessive beta-glucuronidase producing dysbiosis?”
In other words, the root cause isn’t even the dysbiosis. The dysbiosis is a symptom of an imbalance that likely has a multifactorial etiology that requires the assistance of a naturopathic physician or other integrative medicine practitioner.
Basically, it can be said that the imbalance is occurring in the gut and that by correcting whatever is causing the dysbiosis, that will lead to an improvement in symptomatology and potentially a resolution.
Hence, taking calcium D-glucarate is a potential first step, that should be part of a root cause oriented approach, to mitigate the effects of high estrogen but it is only a band-aid.
However, it’s best to start with restoring your gut microbiome by way of eliminating the instigators and mediators of dysbiosis, such as multiple rounds of antibiotics or a daily non-steroidal anti-inflammmatory (NSAID) such as ibuprofen, regularly eating your food intolerances, eating a Standard American Diet (S.A.D.), being in constant fight-or-flight, or any other number potential culprits known to compromise gut function.
In other words, because the microbiome is one of the main regulators of estrogen circulation, by taking care of our microbiome, our hormones are more likely to remain in balance.
However, remember to consult your naturopathic doctor, or your integrative medicine practitioner, before considering introducing calcium D-glucarate into your supplement regimen.
- Hanausek M, Walaszek Z, Slaga TJ. Detoxifying cancer causing agents to prevent cancer. Integr Cancer Ther. 2003 Jun;2(2):139-44. doi: 10.1177/1534735403002002005. PMID: 15035900.
Dwivedi C, Heck WJ, Downie AA, Larroya S, Webb TE. Effect of calcium glucarate on beta-glucuronidase activity and glucarate content of certain vegetables and fruits
. Biochem Med Metab Biol. 1990 Apr;43(2):83-92. doi: 10.1016/0885-4505(90)90012-p. PMID: 2346674.
- Calcium-D-glucarate. Altern Med Rev. 2002 Aug;7(4):336-9. PMID: 12197785.
- Gillis CC, Hughes ER, Spiga L, Winter MG, Zhu W, Furtado de Carvalho T, Chanin RB, Behrendt CL, Hooper LV, Santos RL, Winter SE. Dysbiosis-Associated Change in Host Metabolism Generates Lactate to Support Salmonella Growth. Cell Host Microbe. 2018 Jan 10;23(1):54-64.e6. doi: 10.1016/j.chom.2017.11.006. Epub 2017 Dec 21. Erratum in: Cell Host Microbe. 2018 Apr 11;23 (4):570. PMID: 29276172; PMCID: PMC5764812.
- Langdon A, Crook N, Dantas G. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Med. 2016 Apr 13;8(1):39. doi: 10.1186/s13073-016-0294-z. PMID: 27074706; PMCID: PMC4831151.
- Rogers MAM, Aronoff DM. The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. Clin Microbiol Infect. 2016 Feb;22(2):178.e1-178.e9. doi: 10.1016/j.cmi.2015.10.003. Epub 2015 Oct 16. PMID: 26482265; PMCID: PMC4754147.
- Baker JM, Al-Nakkash L, Herbst-Kralovetz MM. Estrogen-gut microbiome axis: Physiological and clinical implications. Maturitas. 2017 Sep;103:45-53. doi: 10.1016/j.maturitas.2017.06.025. Epub 2017 Jun 23. PMID: 28778332.
- Court MH. Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system. Drug Metab Rev. 2010 Feb;42(1):209-24. doi: 10.3109/03602530903209288. PMID: 19821798; PMCID: PMC6174030.
- Roberts MS, Magnusson BM, Burczynski FJ, Weiss M. Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet. 2002;41(10):751-90. doi: 10.2165/00003088-200241100-00005. PMID: 12162761.
- Zółtaszek R, Hanausek M, Kiliańska ZM, Walaszek Z. Biologiczna rola kwasu D-glukarowego i jego pochodnych; potencjalne zastosowanie w medycynie [The biological role of D-glucaric acid and its derivatives: potential use in medicine]. Postepy Hig Med Dosw (Online). 2008 Sep 5;62:451-62. Polish. PMID: 18772850.
- Zoltaszek R, Kowalczyk P, Kowalczyk MC, et al. Dietary D-glucarate effects on the biomarkers of inflammation during early post-initiation stages of benzo[a]pyrene-induced lung tumorigenesis in A/J mice. Oncol Lett. 2011;2(1):145-154. doi:10.3892/ol.2010.221
- Thomson CA, Ho E, Strom MB. Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies. Nutr Rev. 2016;74(7):432-443. doi:10.1093/nutrit/nuw010
Methionine and The Goldilocks Principle of Protein Intake
I’m sometimes asked how much protein consumption is optimal and what types of protein are most easily metabolized by the body. I have some clients who consume very little protein and others who consume large amounts, in some cases bordering on a carnivore diet (i.e., a diet of principally meat).
Just to be transparent, I am a meat eater, and this article is not about meat being a bad thing from a nutrition standpoint.
The truth is that too little or too much protein will potentially cause a host of issues and side effects. In other words, the Goldilocks principle applies to protein consumption—not too much and not too little protein is best.
There are a couple of reasons as to why this is the case, which I will break down here.
How to Calculate Required Grams of Protein
There is a trick I sometimes use to quickly calculate how many grams of protein your body needs daily, minimally. Multiply your body weight by 0.40 (or 40%) and that is the number, approximately, that your body requires in grams per day to function.
So, if a person weighs 150 lbs, they would require a minimum of 60 grams (150 x 0.40 = 60) of protein daily, as a baseline. Of course, this does not account for those who need higher amounts of protein, such as bodybuilders, personal trainers, and professional athletes, to name a few.
But before I get ahead of myself, let’s circle back to the essentials.
What is Methionine?
Methionine is an essential amino acid. We obtain methionine from protein, which is converted to homocysteine in the body.
Recent research demonstrates that methionine serves to regulate metabolism, the innate immune system, and digestive function. (1)
Methionine, Homocysteine and Methylation
If we have too much homocysteine, we downregulate our ability to use SAM (S-Adenosyl Methionine), which is a critical cofactor that helps many of our genes function properly. (2)
Without SAM, methylation does not occur, histamine cannot be properly broken down, and we are in danger of developing chronic disease.
For example, histamine, which is released by mast cells when they degranulate, is responsible for causing the symptoms of an allergic reaction, such as itching and redness.
This compound cannot be broken down properly, by way of the HNMT gene (pathway), without the presence of cofactor, SAM. (3, 4)
SAM, of course, requires methylfolate or vitamin B9 (L-5-MTHF), as a cofactor, in order to be made. (5, 6)
In kind, we may be low in B9 because we don’t have enough vitamin B2 (riboflavin). (7)
Hence, someone who is eating a carnivore diet may experience the effects of higher histamine; their faces may become more ruddy in complexion, they may report episodes of pruritus on various areas of their bodies, or they may even report that their breathing becomes restricted or asthmatic, as histamine causes smooth muscle contraction in the lungs. (8)
The Role of Methionine in Glutathione Biosynthesis
It is a lesser known fact that methionine intervenes in the biosynthesis of glutathione to prevent oxidative stress. (9)
Hence, a person who does not consume enough methionine will likely become depleted in glutathione, the body’s main antioxidant. And if the body doesn’t have sufficient antioxidant status, then it won’t be able to stave off the free radicals which cause cellular damage.
In summary, eating too much protein can block methylation and interfere with the breakdown of histamine.
On the other hand, eating too little protein can deplete your body of its main antioxidant, glutathione.
In conclusion, the Goldilocks Principle applies to protein consumption—not eating too much and not eating too little is generally best; and about 40% of your body weight in grams per day is likely the safest amount.
But, as always, I recommend that you work with a naturopathic doctor or other integrative medicine practitioner to dial in what is optimal for you.
- Martínez Y, Li X, Liu G, Bin P, Yan W, Más D, Valdivié M, Hu CA, Ren W, Yin Y. The role of methionine on metabolism, oxidative stress, and diseases. Amino Acids. 2017 Dec;49(12):2091-2098. doi: 10.1007/s00726-017-2494-2. Epub 2017 Sep 19. PMID: 28929442. https://pubmed.ncbi.nlm.nih.gov/28929442/
- Guo T, Chang L, Xiao Y, Liu Q. S-adenosyl-L-methionine for the treatment of chronic liver disease: a systematic review and meta-analysis. PLoS One. 2015 Mar 16;10(3):e0122124. doi: 10.1371/journal.pone.0122124. PMID: 25774783; PMCID: PMC4361566.
- Comas-Basté O, Sánchez-Pérez S, Veciana-Nogués MT, Latorre-Moratalla M, Vidal-Carou MDC. Histamine Intolerance: The Current State of the Art. Biomolecules. 2020 Aug 14;10(8):1181. doi: 10.3390/biom10081181. PMID: 32824107; PMCID: PMC7463562.
- Yoshikawa T, Nakamura T, Yanai K. Histamine N-Methyltransferase in the Brain. Int J Mol Sci. 2019 Feb 10;20(3):737. doi: 10.3390/ijms20030737. PMID: 30744146; PMCID: PMC6386932.
- Papakostas GI, Cassiello CF, Iovieno N. Folates and S-adenosylmethionine for major depressive disorder. Can J Psychiatry. 2012 Jul;57(7):406-13. doi: 10.1177/070674371205700703. PMID: 22762295.
- Vidmar M, Grželj J, Mlinarič-Raščan I, Geršak K, Dolenc MS. Medicines associated with folate-homocysteine-methionine pathway disruption. Arch Toxicol. 2019 Feb;93(2):227-251. doi: 10.1007/s00204-018-2364-z. Epub 2018 Nov 29. PMID: 30499019.
- Kennedy DO. B Vitamins and the Brain: Mechanisms, Dose and Efficacy–A Review. Nutrients. 2016 Jan 27;8(2):68. doi: 10.3390/nu8020068. PMID: 26828517; PMCID: PMC4772032.
- Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007 May;85(5):1185-96. doi: 10.1093/ajcn/85.5.1185. PMID: 17490952.
- Wang ST, Chen HW, Sheen LY, Lii CK. Methionine and cysteine affect glutathione level, glutathione-related enzyme activities and the expression of glutathione S-transferase isozymes in rat hepatocytes. J Nutr. 1997 Nov;127(11):2135-41. doi: 10.1093/jn/127.11.2135. PMID: 9372907.