Michael E. Ash, BSc.(Hons) DO. ND. F.Dip ION has written an overview from a clinical perspective of the emerging science related to the mucosal immune system and the health of the brain in relation to affect. Published by the in house journal from Allergy Research Group it provides a strategic approach to managing individuals using a novel probiotic strategy.
From our early days in utero until we die, the ability of the GI tract to renew and replenish itself and maintain a stable relationship with trillions of bacteria is astounding. On a typical day the innate immune system of our gastrointestinal tract will process more immunological information than the rest of our body in its entire lifetime. It’s an absolute immunological miracle we can consume antigenic particles of food and not drop down dead every time we do so.
In fact, the joy of modifying the gut mucosal immune system is that we can at the same time treat urinary, respiratory, inner ear and oral tissue. Gut originating immune molecules migrate out through the lymphatic tissue, circulatory system and influence the vagal nerve to deliver information systemically. Mucosal immunity is the key to gut health, overall immune balance, and even brain function and mood. It’s this last I am reporting on in this article, for gut immunity and neuro-immunity are intimately bound, sharing the same receptors and the same signals. Information that initiates in the gut ends up in the brain and vice versa, providing a comprehensive cross talk between the two sets of tissues.
I have discovered that tweaking the immune system through very careful use of targeted, strain specific probiotics is a novel and effective treatment for atypical depression—the most common subtype of depression and the form most commonly seen in women today. I have arrived at this unusual approach after 26 years of practice as an osteopath, naturopath and clinical nutritionist treating over 10,000 patients. I believe many clinicians today consider probiotics in the same manner that medicine looked at antibiotics back in the 1950’s: with little regard for strain specificity, timing and dose. Here I report on the very specific reasons why probiotics can treat depression, how to stage their successive application, and why timing, dosing, and delivery mechanisms of probiotics are key to their effective use.
The Gut-Brain Dialogue
So how in the world might probiotics—friendly gut organisms—treat depression? In a few words: cytokines, inflammation and immune response. Cytokines are messenger molecules that regulate our inflammatory and immune response. They operate continuously throughout our entire body and profoundly influence neuro-endocrine functioning. Depression has been linked with altered levels of cytokines like IL-1, IL-6 and TNFα, the inflammatory cytokine. Interleukin-1B is linked to dysthymia (low grade, chronic depression).
A good reliable set of bowels is worth more to a man than any quantity of brains.
– Henry Wheeler Shaw, American humorist
The gut-brain link was first seriously suggested by Dr. Julius Wagner-Jauregg, the only psychiatrist to have won a Nobel Prize back in 1927 (for medicine). He wrote; “Biological mediators primarily designed to combat pathogens may affect the course of psychiatric disorders.” Way before cytokines were discovered this clinician described how innate immune cytokines influence virtually every pathophysiological domain relevant to depression including monoamine neurotransmission, tryptophan metabolism, neuroendocrine function, synaptic plasticity and regional brain metabolism.
There is a well defined correlation between the severity of depression and the levels of TNFα. Patients suffering from chronic fatigue syndrome and sleep apnea will show excessive blood levels of TNFα (see NO/ONOO-: A Brief Summary of the Work of Martin Pall, Ph.D.). And when patients with cancer, multiple sclerosis, or hepatitis C are given interferons or interleukins as part of their treatment as many as 40% develop depression.
Animal studies have supported clinical observations in humans. When animals are injected with molecules that stimulate cytokines, they become lethargic, fatigued, and anorexic. This is called “sickness behavior” and is associated with acute and some types of chronic infections.
The gut is a locus of many of these cytokines as the majority of our innate immune system is in the GI tract. The literature on the profound dialogue between the gut and the brain is surprisingly robust and at the same time, woefully under the mainstream radar.
In a fascinating 2007 study in Brain, Behavior and Immunology, researchers found that when the gut releases molecules signaling local infection, anxiety is enhanced—most likely through the vagus nerve. The vagus nerve provides a neural highway from the neurons of the gut right into the brain. Researchers inoculated mice with the intestinal bug Campylobacter jejuni, and found that vagal sensory neurons as well as the hypothalamus, amygdala and other important brain areas associated with anxiety and stress were activated. Infected animals also showed more cautious behavior. The authors conclude that treating infection and inflammation in the gut may help symptoms like anxiety and depression.
In another 2009, randomized, double-blind study in the European Journal of Clinical Nutrition, 39 patients suffering from chronic fatigue syndrome were given either placebo or probiotics. Two months of supplementation with probiotics was associated with a significant decrease in anxiety symptoms (p = 0.01, highly significant). In a 2007 study, consumption of yogurt-containing probiotics improved mood. This double blind placebo controlled trial explored 124 patients and found that mood improved in those who were initially depressed.
How Pathogens Sing the Blues
When our immune system encounters a gut pathogen, proteins on the pathogen’s surface bind to specialized receptors. Inflammatory cytokine chemicals such as IL-1, IL-6 TNFα and the chemokine IL-8 are triggered. These in turn stimulate the inflammatory regulator, NF Kappa B. This is necessary for an aggressive immune response that will help eradicate that pathogen. The immune system when healthy has a series of checks and balances to contain the damage and return to a neutral state after eradication. But in chronic low-grade gut infection, or dysbiosis, there may be persistently variably elevated cytokines. These impact mood in a waxing and waning manner.
The gut lining first needs to be matured through the selective use of probiotics that specifically stimulate SIgA, and must then be exposed to key strain specific probiotics.
How important to our immune health are friendly gut bacteria? Immeasurably so. When rat pups were separated from their mother—causing extreme stress—and then reintroduced to their moms days later, their immune system was forever altered. They were permanently more sensitized to stress displaying high levels of anxiety. However, when rat pups were separated and provided probiotics, and then returned to their mothers, their immune system was equal to that of their never-separated peers and were no more anxious than their non-separated siblings. This shows how profoundly important our gut biota is—to both immunity and mood. Our microbiota not only live with us, they carry an enormous skill set that helps us navigate life, from release of key nutrients to modulation of our immune system. We are a giant two-legged petri dish, more efficient at keeping our bacterial companions alive than any other medium on earth. To celebrate this unique ecological niche they provide a range of immune specific effects and help us to safely navigate a threatening world of pathogens and antigens.
In addition, serotonin levels can be impaired by chronic gut pathogens. Certain pathogens including bacteria, and viruses favor tryptophan as a primary fuel source. The body may recognize that tryptophan starvation (through the release of a specialized enzyme) is an effective strategy to help suppress and eliminate that pathogen. However, reduced tryptophan means reduced levels of the feel-good neurotransmitter, serotonin. And prescribing an SSRI in this situation can mean that increased circulating levels of serotonin will go right into the gut. The majority of serotonin receptors in the GI tract promote peristalsis—so, like many on SSRI’s, you may get diarrhea. In turn, the induction of inflammatory cytokines in response to increased levels of the pathogen will cause further mind-body disturbance by preventing the uptake of serotonin at the synapses because of inflammatory enzymatic binding.
You can see the exquisitely complex dance of pathogens and the neuroendocrine and immune system. The common thread of chronic illness is persistent, low-grade inflammation and disturbed cytokine patterns. Not surprisingly, a response to conventional antidepressant medications is associated with a decrease in inflammatory biomarkers.
A Little Help from My Friends
And so we come to probiotics—which by regulating cytokine levels in the gut, can influence infection and inflammation throughout the body, and even help balance brain function and mood. In recent years the interface between neuropsychiatry and gastroenterology has converged into a new discipline referred to as enteric neuroscience. Emerging studies have shown that intestinal bacteria can directly communicate with the central nervous system by way of the vagal sensory nerve fibers and the peripheral immune system. If we understand how potent a neuro-immune effect probiotics can have, we can use them in a stepwise fashion to tickle and coax our immune system into a state of tolerance and ideal, balanced responsiveness. And because the immune and nervous systems are intimately entwined, our brains will respond as well.
Think of probiotics as old friends—gentle protectors and supporters with whom you began your life’s journey. Your own personal microbiota is your own symphony, one that begins the moment you’re born (actually, it may even begin before you’re born, since the cord blood of caesarean born infants carries at least sixteen different species of bacteria). It is influenced by your diet, medications, your geography, and your genetics.
In ideal circumstances, you inherit healthy lactobacilli from your mother’s vaginal canal, and breastfeeding provides you with immunoglobulins, Bifido species and antibodies that help your gut lining mature properly, learning tolerance and balance. Those first months of your life may establish a ‘setpoint’ for immune susceptibility that is key to health. If you were born caesarean but breastfed, you will slowly catch up to your natural-born peers but it may take as long as two years. But if you were fed formula, your gut biota may not be ideal. You may be more likely to suffer from allergies or immune-related issues. Add in early and frequent antibiotic treatment and a diet of pre-biotic deficient, processed foods and you may now have a gut lining that was never given the opportunity to mature properly. Your core microbiota, which you will carry through your life, is essentially established by age two but has remarkable plasticity as well, responding both positively and negatively to medications and probiotics.
In treating patients, the first thing to do is take a complete history—back to birth. It’s very important to know that early history during those formative months and years, as it will help guide your treatment protocol.
However, you can’t just take a handful of probiotic capsules containing variable strains and expect to regain your health. The principle function of a probiotic is as an immune modulator but some strains increase pro inflammatory cytokines and others increase IL-10, the main immune inflammation controller.
When used correctly, probiotics ameliorate mucosal inflammation in the gut, liver, synovium and brain.
I have discovered that in order for probiotics to work most effectively, the gut lining first needs to be matured through the selective use of probiotics that specifically stimulate SIgA (secretory Immunoglubulin A), and must then be exposed to key strain specific probiotics. SIgA is the great, forgotten immunoglobulin, but I’ve championed it for twenty years because it is so beneficial to the GI tract. SIgA determines our ability to communicate to our immune system exactly what bacteria we are harboring and what to do about it.
If you don’t have enough SIgA, you can consume probiotics forever and never transfer enough of their relevant information to the appropriate immune tissues in enough volume to impact health. SIgA and the T-regulatory family of cells work in a cooperative manner to maintain tolerance, yet SIgA requires bacteria in the mucosal lumen to be stimulated. The use of an anti-inflammatory, SIgA-promoting yeast species can be a valuable adjuvant to optimizing gastrointestinal immune tolerance.
The Treatment Plan
The first step is to determine if your patient is an atypical depressive. Typical features include: a tendency towards excessive sleep without feeling refreshed, cravings for carbohydrates, low energy, a feeling their limbs are heavy, poor response to SSRI’s, more often female, and highly sensitized to stress and relationship breakdowns. I also do an organic acid urinary profile to look for tryptophan catabolite ratios: Quinolinate/Kynurenate. These are metabolites of tryptophan that can lead to excitotoxicity and excess stimulation of NMDA receptors (see NO/ONOO- A Brief Summary of the Work of Martin Pall, Ph.D.). If a patient has a reasonably good clinical workup to support a diagnosis of atypical depression, and has raised ammonia, quinolinic acid or kynurerine in the urine (all indications of dysbiosis) I consider it likely their depression is a GI-mediated immune event. You can also check their stool for pathogens, or their blood for raised levels of cytokines such as Il-6, Il-1, IL-4, and TNFα as well as the anti-inflammatory IL-10. Also consider increased gut permeability as a compounding barrier defect allowing cell particulates (LPS) to trigger inflammatory cytokines.
If so, the next step is to do testing to establish levels of SIgA, the predominant immunoglobulin in the body, and the key anti-inflammatory, immunomodulating molecule protecting our mucosa in the mouth, nose, lungs, gut, and vaginal tissue. If you give probiotics in a cavalier manner to someone who does not have enough SIgA, you won’t get a good clinical response because of diminished immune interpretation. In other words, the immune system does not process information from bacteria and pathogens as effectively as it needs to when levels of SIgA are low. I discovered nearly twenty years ago that if we can improve an individual’s SIgA status, we will then see a change in how they respond to subsequent probiotics. I measure SIgA from a salivary sample, since it’s systemic across mucosal tissues.
If SIgA is low, I give Saccharomyces boulardii, which is superb at promoting SIgA and has hundreds of peer-reviewed studies demonstrating its safety and effectiveness. I begin with as little as ¼ capsule in children and ½ capsule in adults, because this probiotic is very potent. Saccharomyces boulardii helps the body break down carbohydrates more effectively, reduces gut candida and neutralizes clostridium difficile toxins A and B, thus improving mucosal barrier effectiveness. It also lowers inflammatory IL-8.
I may also give a month or two of a nutritional product called Garum Amoricum®, as this has quite quick effects in the improvement of mood and sleep and really helps the patient to feel that a change is occurring. It can take a couple of months with probiotics getting the dose and timing correct to see any change in the pattern of mood and behavior.
The Three Steps to Successful Use of Probiotics in Depression
- Establish that your patient is suffering from atypical depression (inflammation driven)
- Examine their levels of SIgA by salivary analysis and correcting if required.
- Use the most effective human derived strains of ‘old friends’ to suppress excess inflammatory cytokines by induction of IL-10 and regulate immune response systemically.
Remember, you don’t have to be aggressive to be pervasive. You can take a small dose of probiotics that stay in the gut yet influence the entire body systemically. You do need to be consistent and persistent as it may take some months to change long term dysbiosis.
Once SIgA levels are up, I add in Lactobacillus GG, another probiotic with hundreds of studies demonstrating its benefit. This probiotic is a standout because it is so well studied. No other probiotic except Saccharomyces boulardii comes close. LGG is a known inducer of anti-inflammatory cytokines in humans like IL-10. It also increases the production of regulatory T-cells, which help to maintain control over inflammation. LGG is a human-derived strain and I believe using human strains (ones that have been isolated from the gut of a healthy human) is important because they are well recognized by the innate immune system receptors and are efficient at priming immunoregulation. They will, when used correctly, ameliorate mucosal inflammation in the gut, liver, synovium and brain. Both LGG and Saccharomyces boulardii are the best studied and probably most effective probiotics we have today.
I then also add in other human strains of lactobacillus and bifido species, as well as Vitamin D, proteolytic enzymes, and herbs, including, as required; artemisinin, black walnut, olive leaf, TOA-free uña de gato, and oregano to modify bacterial communities and help kill gut pathogens.
This approach can work phenomenally well. A recent female patient of mine suffered from classic atypical depression after her divorce. She has reduced her antidepressant medications to 1/5th of her initial dose, has started her own business and has lost twenty-one pounds on this simple protocol. I expect that in another half year she will be able to discontinue all of her medications and yet remain depression-free.
Go with the Gut
The gut influences the brain, and the brain influences the gut. This bi-directional perspective provides a fertile area for surprising insights into CNS pathologies that have until now proven highly elusive to effective treatment. Ask yourself—what’s better? A gut reaction or a reasoned response? Instinct or intellect? Or is the answer literally: what’s the difference?
1. Mayer L. Mucosal immunity. Pediatrics. 2003 Jun;111(6 Pt 3):1595-600 View Abstract
2. Kiyono et al. in Ogra et al., eds., Handbook of Mucosal Immunology, 263-274
3. Bienenstock, J et al. Mood and gut feelings. Brain, Behavior, and Immunity. In press
4. Collins, S.M., Bercik, P., The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology. May 2009; 136(6): 2003-14. View Abstract
5. Parker G, Roy K, Mitchell P, Wilhelm K, Malhi G, Hadzi-Pavlovic D. Atypical depression: a reappraisal.Am J Psychiatry. 2002 Sep;159(9):1470-9. View Abstract
6. Anisman H, Ravindran AV, Griffiths J, Merali Z. Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features. Mol Psychiatry. 1999 Mar;4(2):182-8 View Abstract
7. Maes M (2008). The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuro endocrinology letters, 29 (3), 287-91 PMID: 18580840
8. Capuron, L., Raison, C.L., Musselman, D.L., Lawson, D.H., Nemeroff, C.B., Miller, A.H., 589 2003. Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am. J. Psychiatry 160, 1342–1345. View Abstract
9. Hart, B.L., 1988. Biological basis of the behavior of sick animals. Neurosci. Biobehav.Rev. 12, 123–137. View Abstract
10. Goehler LE, Lyte M, & Gaykema RP (2007). Infection-induced viscerosensory signals from the gut enhance anxiety: implications for psychoneuroimmunology. Brain, behavior, and immunity, 21 (6), 721-6 PMID: 17428636
11. Rao, AV, Bested AC, Beaulne TM, Katzman MA, Iorio C, Berardi JM, Logan AC A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog. 2009 Mar 19;1(1):6. View Abstract
12. Benton D, Williams C, & Brown A (2007). Impact of consuming a milk drink containing a probiotic on mood and cognition. European journal of clinical nutrition, 61 (3), 355-61 PMID: 17151594
13. Gareau, M., Jury, J., MacQueen, G., Sherman, P., & Perdue, M. (2007). Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation Gut, 56 (11), 1522-1528 DOI: 10.1136/gut.2006.117176
14. Kohl C, Sperner-Unterweger B. IDO and clinical conditions associated with depressive symptoms. Curr Drug Metab. 2007 Apr;8(3):283-7. View Abstract
15. Gram L. Fluoxetine.N Engl J Med. 1994 Nov 17;331(20):1354-61. View Abstract
16. Zhu, C.B. et al. (2005) p38 MAPK activation elevates serotonin transport activity via a trafficking-independent, protein phosphatase 2A-dependent process. J. Biol. Chem. 280, 15649–15658 View Abstract
17. Maes, M., 2001. The immunoregulatory effects of antidepressants. Hum. 728 Psychopharmacol. 16, 95–103. View Abstract
18. Desbonnet L, Garrett L, Clarke G, Bienenstock J, Dinan T: The probiotic Bifidobacteria Infantis: an assessment of potential antidepressant properties in the rat. J Psychiatr Res, December 1, 2008; 43(2): 164-74. View Abstract
19. Jiménez Esther; Fernández Leonides; Marín María L; Martín Rocío; Odriozola Juan M; Nueno-Palop Carmen; Narbad Arjan; Olivares Mónica; Xaus Jordi; Rodríguez Juan M. Isolation of commensal bacteria from umbilical cord blood of healthy neonates born by cesarean section.Current microbiology 2005;51(4):270-4. View Abstract
20. Murano,A; Dreborg,S. et al. Dietary prevention of allergic diseases in infants and small children. Part 3 :Critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatr. Allergy. Immunol. 15, 291-307 (2004). View Abstract
21. Schultz M, Linde HJ, Lehn N, Zimmermann K, Grossmann J, Falk W, Schölmerich J. Immunomodulatory consequences of oral administration of Lactobacillus rhamnosus strain GG in healthy volunteers. J Dairy Res. 2003 May;70(2):165-73. View Abstract
22. Smits HH, Gloudemans AK, van Nimwegen M, Willart MA, Soullié T, Muskens F, de Jong EC, Boon L, Pilette C, Johansen FE, Hoogsteden HC, Hammad H, Lambrecht BN Cholera toxin B suppresses allergic inflammation through induction of secretory. IgA.Mucosal Immunol. 2009 Jul;2(4):331-9. Epub 2009 Apr 29. View Abstract
23. Buts,JP.Twenty-five years of research on Saccharomyces boulardii trophic effects: updates and perspectives.Dig Dis Sci, Jan 2009; 54(1): 15-8. View Abstract
24. Dingledine, R., Borges, K., Bowie, D. & Traynelis, S. F. The glutamate receptor ion channels. Pharmacol. Rev. 51, 7–61 (1999). View Abstract
Keywords:antibiotics, autism, bacteria, brain, CAM, cytokines, diet, dysbiosis, evidence, gut, immune, immunity, inflammation, microbiome, mucosal, nutrition, probiotics, regulatory T cells, research, treatment
39 Responses to “A Novel Approach to Treating Depression – How Probiotics Can Shift Mood by Modulating Cytokines”
See what others are saying about this post...
You can ask technical questions, be as supportive, critical or controversial as you like, but please don't get personal or offensive, and do keep it brief. Your comments will be published only after verification.