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Psychobiotics, the Pharmacology of Probiotics, and Our Body’s Naturally Innate Pharmacy

Psychobiotics, the Pharmacology of Probiotics, and Our Body’s Naturally Innate Pharmacy

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)

Resources:

  1. Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):16050-5. doi: 10.1073/pnas.1102999108. Epub 2011 Aug 29. PMID: 21876150; PMCID: PMC3179073
  2. Patterson E, Ryan PM, Wiley N, Carafa I, Sherwin E, Moloney G, Franciosi E, Mandal R, Wishart DS, Tuohy K, Ross RP, Cryan JF, Dinan TG, Stanton C. Gamma-aminobutyric acid-producing lactobacilli positively affect metabolism and depressive-like behaviour in a mouse model of metabolic syndrome. Sci Rep. 2019 Nov 8;9(1):16323. doi: 10.1038/s41598-019-51781-x. PMID: 31704943; PMCID: PMC6841999
  3. Duranti, S., Ruiz, L., Lugli, G.A. et al. Bifidobacterium adolescentis as a key member of the human gut microbiota in the production of GABASci Rep 10, 14112 (2020). https://doi.org/10.1038/s41598-020-70986-z
  4. Yunes RA, Poluektova EU, Vasileva EV, Odorskaya MV, Marsova MV, Kovalev GI, Danilenko VN. A Multi-strain Potential Probiotic Formulation of GABA-Producing Lactobacillus plantarum 90sk and Bifidobacterium adolescentis 150 with Antidepressant Effects. Probiotics Antimicrob Proteins. 2020 Sep;12(3):973-979. doi: 10.1007/s12602-019-09601-1. PMID: 31677091
  5. Lopes, J.G., Sourjik, V. Chemotaxis of Escherichia coli to major hormones and polyamines present in human gutISME J 12, 2736–2747 (2018). https://doi.org/10.1038/s41396-018-0227-5
  6. Strandwitz P. Neurotransmitter modulation by the gut microbiotaBrain Res. 2018;1693(Pt B):128-133. doi:10.1016/j.brainres.2018.03.015
  7. Galland L. The gut microbiome and the brainJ Med Food. 2014;17(12):1261-1272. doi:10.1089/jmf.2014.7000
  8. Malikina KD, Shishov VA, Chuvelev DI, Kudrin VS, Oleskin AV. [Regulatory role of monoamine neurotransmitters in Saccharomyces cerevisiae cells]. Prikl Biokhim Mikrobiol. 2010 Nov-Dec;46(6):672-7. Russian. PMID: 21261078
  9. Mayr A, Hinterberger G, Dierich MP, Lass-Flörl C. Interaction of serotonin with Candida albicans selectively attenuates fungal virulence in vitro. Int J Antimicrob Agents. 2005;26(4):335-337. doi:10.1016/j.ijantimicag.2005.07.006
  10. Yano JM, Yu K, Donaldson GP, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis [published correction appears in Cell. 2015 Sep 24;163:258]. Cell. 2015;161(2):264-276. doi:10.1016/j.cell.2015.02.047
  11. 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
  12. Evrensel A, Ceylan ME. The Gut-Brain Axis: The Missing Link in Depression. Clin Psychopharmacol Neurosci. 2015;13(3):239-244. doi:10.9758/cpn.2015.13.3.239
  13. Liu J, Xu F, Nie Z, Shao L. Gut Microbiota Approach-A New Strategy to Treat Parkinson’s DiseaseFront Cell Infect Microbiol. 2020;10:570658. Published 2020 Oct 22. doi:10.3389/fcimb.2020.570658
  14. Zhu F, Li C, Chu F, Tian X, Zhu J. Target Dysbiosis of Gut Microbes as a Future Therapeutic Manipulation in Alzheimer’s DiseaseFront Aging Neurosci. 2020;12:544235. Published 2020 Oct 6. doi:10.3389/fnagi.2020.544235
  15. STEPHENSON M, ROWATT E. The production of acetylcholine by a strain of Lactobacillus plantarum. J Gen Microbiol. 1947 Sep;1(3):279-98. doi: 10.1099/00221287-1-3-279. PMID: 20270627
  16. Yong SJ, Tong T, Chew J, Lim WL. Antidepressive Mechanisms of Probiotics and Their Therapeutic Potential. Front Neurosci. 2020;13:1361. Published 2020 Jan 14. doi:10.3389/fnins.2019.01361
The Potential Impact of Cholecystectomy on Drug and Xenobiotic Metabolism, and Liver Detoxification

The Potential Impact of Cholecystectomy on Drug and Xenobiotic Metabolism, and Liver Detoxification

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.

Resources:

  1. Njeze GE. GallstonesNiger J Surg. 2013;19(2):49-55. doi:10.4103/1117-6806.119236
  2. Secretion of Bile and the Role of Bile Acids In Digestion. (n.d.). http://www.vivo.colostate.edu/hbooks/pathphys/digestion/liver/bile.html.
  3. Hoekstra R, Nibourg GA, van der Hoeven TV, Plomer G, Seppen J, Ackermans MT, Camus S, Kulik W, van Gulik TM, Elferink RP, Chamuleau RA. Phase 1 and phase 2 drug metabolism and bile acid production of HepaRG cells in a bioartificial liver in absence of dimethyl sulfoxide. Drug Metab Dispos. 2013 Mar;41(3):562-7. doi: 10.1124/dmd.112.049098. Epub 2012 Dec 13. PMID: 23238784.
  4. Grant DM. Detoxification pathways in the liver. J Inherit Metab Dis. 1991;14(4):421-30. doi: 10.1007/BF01797915. PMID: 1749210.
The Antioxidant Function of Cholesterol

The Antioxidant Function of Cholesterol

A little known fact is that cholesterol actually possesses antioxidant function.

In particular, HDL, the so-called ‘good’ cholesterol, can protect LDL, the so-called ‘bad’ cholesterol, from oxidative damage. (1)

LDL particles are also rich in antioxidants, such as α-tocopherol, β-carotene and ubiquinol-10, which protects LDL from free radical attack and oxidation. (2)

This is yet another reason why the quality of the cholesterol consumed in our diet is critical, and why ample fat soluble vitamins and nutrients are a key component.

Also, given that antioxidants are protective, and there is an antioxidant component in cholesterol, could it be that at times, in certain individuals, the presence of high cholesterol may be an intelligent mechanism on the part of the body to protect us in some way?

Resources:

  1. Soran H, Schofield JD, Durrington PN. Antioxidant properties of HDL. Front Pharmacol. 2015;6:222. Published 2015 Oct 16. doi:10.3389/fphar.2015.00222
  2. Singh N, Singh N, Kumar Singh S, Kumar Singh A, Kafle D, Agrawal N. Reduced Antioxidant Potential of LDL Is Associated With Increased Susceptibility to LDL Peroxidation in Type II Diabetic Patients. Int J Endocrinol Metab. 2012;10(4):582-586. doi:10.5812/ijem.5029
Three Reasons to Read My Book, “The Serpent & The Butterfly: The Seven Laws of Healing”

Three Reasons to Read My Book, “The Serpent & The Butterfly: The Seven Laws of Healing”

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, Your Microbiome, and You: A Closer Look at Hormone Regulation

Calcium D-Glucarate, Your Microbiome, and You: A Closer Look at Hormone Regulation

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.

Resources

  1. 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.
  2. 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.
  3. Calcium-D-glucarate. Altern Med Rev. 2002 Aug;7(4):336-9. PMID: 12197785.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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
  12. 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
What Exactly Does Food Intolerance Mean?

What Exactly Does Food Intolerance Mean?

Food intolerance is different than food allergy. Food intolerance is a non-specific, non-immune mediated reaction to specific foods.

According to one’s individual biochemistry and digestion, the digestive tract’s intestinal lining doesn’t recognize certain foods as nutritive, but rather as toxic or indigestible, responding with symptoms such as gas, bloating, abdominal pain, diarrhea, constipation, and many others. This also may be due to an enzyme deficiency.

Food intolerance is easily confused by the lay public with food allergies, which are immunologic in nature.

Food allergy can be potentially life threatening, inducing such reactions as anaphylactic shock, whereas food intolerances usually produce more chronic, in the background, low lying states

of inflammation. Food intolerance has to do with the body’s ability to sufficiently metabolize, digest, and absorb the nutrients from certain foods.

Though food intolerance is not immune mediated, the resulting inflammation is an immune response, characterized clinically by redness (rubor), heat (calor), swelling (tumor), and pain (dolor).

According to naturopathic doctors, inflammation is actually a compensatory, protective response on the part of the organism to reestablish normal balance in structure and function, to ward off “the bad guys,” or to resolve the underlying mechanisms or causes of the disease/state/condition.

The inflammatory response, in other words, is part of the body’s attempt to heal itself, and so should not be suppressed but rather worked with and supported. Unless, of course, a much more serious condition is at hand, such as the anaphylactic shock or severe IgE- mediated food allergy.

The dietary food intolerance evaluation is not a food allergy test or a lab, which classically measure IgG and IgE antibody titers that serve as biomarkers of the level of one’s individual response to certain foods as antigenic compounds.

In fact, this food intolerance assessment is a naturopathic, diagnostic tool, or rather, a functional evaluation that is evaluating the body’s ability to break down and absorb certain foods.

The foods listed above, in your results report, will likely irritate your intestinal lining and lead to symptoms of inflammation downstream, due to higher levels of toxicity in the blood (“toxemia”). These symptoms will be unique to each individual.

The only way to truly know how the foods listed below affect your digestive system is to remove them from your diet for a time. Knowledge empowers, and health is a journey, not a destination.

This information empowers you with more knowledge about what makes your body move in the direction of health and what makes it go against the trajectory- it’s up to you to determine what you want to do with it.