Feeling Anxious? Maybe Not

anxious-womanGood for you. You’re going to Disney World. But don’t say you’re anxious about it. It’s okay to be anxious about going to the dentist. It’s understandable that you’d be anxious about your debut at an IRS audit. Unless you‘re terrified by the characters, you’re eager, not anxious, about visiting Walt’s place. To be anxious is to be afraid, apprehensive, uneasy, or distressed, but not enthusiastic. Anxiety is a disorder with more than one characterization. It can display as panic disorder, obsessive-compulsive disorder, post-traumatic-stress disorder, social anxiety, and a few others, including various phobias. It’s even possible to be anxious about being anxious, to the point that the subsequent distress precludes a normal life.

A common emotion, anxiety is felt by most humans once in a while. Taking a test, facing a novel problem at the office, or making a difficult decision is enough to get you anxious. Being lost in a strange town makes you feel like a rat in a laboratory maze. These little upsets are supposed to go away. If they cause a lingering burn, it’s time to talk about it. Frustration with a task can cause anxiety, and anxiety about doing it in the first place can cause frustration, which then perpetuates the cycle. Replacing uncomfortable cognitions with calming thoughts—something you can learn to do yourself—is one path to serenity.  The Roman Emperor Marcus Aurelius wrote about dealing with frustration and anxiety two thousand years ago. So, this isn’t a new challenge. However, what is new is the discovery that the ninety percent of the cells that compose the body have the potential to respond to anxiety. These would be the intestinal bacteria that have the uncanny ability to communicate with the brain, a conclusion attributed to evolution but more than likely decided at the ontogeny. That a bidirectional communication system between the gut and the cerebrum exists has been established, and that it influences brain development and behavior through complex signaling mechanisms is amply defined (Diaz-Heijtz, 2011) (Collins, 2012) (Chen, 2013).

The connection between gut and brain is controlled by the vagus nerve, which is the longest cranial nerve, passing through the neck and thorax into the abdomen, where it directs motor and secretory impulses of the viscera—your innards. Stimulation of this nerve can instigate activity in a body process known as the HPA axis (Hosoi, 2000) (O’Keane, 2005), the hypothalamic-pituitary-adrenal axis, the control center for most of the body’s hormones, one of which is the steroid hormone cortisol. Cortisol is used as a biomarker for psychological stress (Djuric, 2008).  In response to physical or mental stress, the hypothalamus produces corticotropin-releasing factor, which binds to specific receptors in the pituitary gland, where adrenocorticotropic hormone (ACTH) is made. ACTH then moves to the adrenals to direct the secretion of cortisol. The idea behind cortisol is to break down body tissue to be used as energy. When rampant, it breaks down lean tissue to liberate amino acids that can be used to raise blood sugar. In adipose tissue, cortisol breaks fats into fatty acids and glycerol, which also elevate blood sugar.

To calm this activity in a kind of physiological riot control, the body enlists the major inhibitory neurotransmitter, called gamma-aminobutyric acid—GABA—to slow down the firing of nerve cells in the brain. Emily Dean, M.D., a psychiatrist practicing in Massachusetts, likens GABA to a glass of wine in front of a fire, to restful sleep, or to tranquility and yoga (http://www.psychologytoday.com/blog/evolutionary-psychiatry/201206/do-probiotics-help-anxiety). Paints a nice picture, eh? Negative alterations in GABA receptor expression are implicated in the development of anxiety and depression, which are comorbid with functional bowel disorders.

It’s been hypothesized that probiotics are able to make compounds that enhance the brain-gut link by acting as delivery vehicles for neuroactive substances, with each neurochemical being related to a specific strain of intestinal flora (Lyte, 2011). The strain Lactobacillus rhamnosus is known to modulate the immune system by manipulating tumor necrosis factor alpha (TNFa) and Interleukin 8 (Ma, 2004), two cytokine signaling molecules related to immunity and inflammation. In mouse studies performed in Ireland a couple years back, those animals preloaded with L. rhamnosus were spared a frantic response to physiological insult and stress, contrasted to their cage mates denied the probiotic, whose cortisol levels were extreme (Bravo, 2011). As expected, mice whose vagus nerves were severed had no similar neurochemical and behavioral effects, indicating the vagus nerve as the major thoroughfare between gut bacteria and the brain (Ibid). Even in the absence of insult, mice treated with lactobacillus presented with higher levels of anxiety-reducing receptors, the observation of which could not be made until their sacrifice. A lactobacillus, then, reduces stress-induced levels of corticosterone (the rodent equivalent of cortisol) by normalizing the HPA axis (Gareau, 2007).

The HPA axis helps to regulate physiological processes that include temperature, digestion, immunity, mood, sexuality and energy usage, besides controlling your response to stress, trauma and injury. If, as believed, the hypothalamus is involved with fibromyalgia and the adrenals with chronic fatigue syndrome, the use of a probiotic to tend to the HPA axis should ameliorate these assaults. If GABA plays a major role in the HPA stress response (Herman, 2004) (Cullinan, 2008), and if GABA production is enhanced by lactic acid bacteria (Dhakal, 2012), then a five-dollar treatment for anxiety is at hand.  Not only L. rhamnosus, but also L. brevis (Li, 2010), L. reuteri (Ma, 2004), and strains of Bifidobacteria (Barrett, 2012) work to produce GABA. This should settle once and for all that not all bacteria are bad.

References

Barrett E, Ross RP, O’Toole PW, Fitzgerald GF, Stanton C.
γ-Aminobutyric acid production by culturable bacteria from the human intestine.
J Appl Microbiol. 2012 Aug;113(2):411-7.

Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X, Deng Y, Blennerhassett PA, et al
The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication.
Neurogastroenterol Motil. 2011 Dec;23(12):1132-9.

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.

Xiao Chen, Roshan D’Souza, Seong-Tshool Hong
The role of gut microbiota in the gut-brain axis: current challenges and perspectives
Protein & Cell. June 2013, Volume 4, Issue 6, pp 403-414

Collins SM, Surette M, Bercik P.
The interplay between the intestinal microbiota and the brain.
Nat Rev Microbiol. 2012 Nov;10(11):735-42.

Cryan JF, Kaupmann K.
Don’t worry ‘B’ happy!: a role for GABA(B) receptors in anxiety and depression.
Trends Pharmacol Sci. 2005 Jan;26(1):36-43.

Cryan JF, Slattery DA.
GABAB receptors and depression. Current status.
Adv Pharmacol. 2010;58:427-51.

Cullinan WE, Ziegler DR, Herman JP.
Functional role of local GABAergic influences on the HPA axis.
Brain Struct Funct. 2008 Sep;213(1-2):63-72.

Dhakal R, Bajpai VK, Baek KH.
Production of gaba (γ – Aminobutyric acid) by microorganisms: a review.
Braz J Microbiol. 2012 Oct;43(4):1230-1241.

Rochellys Diaz Heijtz, Shugui Wang, Farhana Anuar, Yu Qian, Britta Björkholm, Annika Samuelsson, Martin L. Hibberd, Hans Forssberg, Sven Pettersson
Normal gut microbiota modulates brain development and behavior
PNAS. February 15, 2011 vol. 108 no. 7 3047-3052

Zora Djuric, Chloe E. Bird, Alice Furumoto-Dawson, Garth H. Rauscher, Mack T. Ruffin IV, Raymond P. Stowe, Katherine L. Tucker and Christopher M. Masi
Biomarkers of Psychological Stress in Health Disparities Research
The Open Biomarkers Journal. 2008; 1: Pp 7-19

Foster JA, McVey Neufeld KA.
Gut-brain axis: how the microbiome influences anxiety and depression
Trends Neurosci. 2013 May;36(5):305-12

Gareau MG, Jury J, MacQueen G, Sherman PM, Perdue MH.
Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation.
Gut. 2007 Nov;56(11):1522-8.

Glover V.
Maternal depression, anxiety and stress during pregnancy and child outcome; what needs to be done.
Best Pract Res Clin Obstet Gynaecol. 2013 Sep 18. pii: S1521-6934(13)00132-6.

D A Gorard, J E Gomborone, G W Libby, and M J Farthing
Intestinal transit in anxiety and depression.
Gut. 1996 October; 39(4): 551–555.

Herman JP, Mueller NK, Figueiredo H.
Role of GABA and glutamate circuitry in hypothalamo-pituitary-adrenocortical stress integration.
Ann N Y Acad Sci. 2004 Jun;1018:35-45.

Hosoi T, Okuma Y, Nomura Y.
Electrical stimulation of afferent vagus nerve induces IL-1beta expression in the brain and activates HPA axis.
Am J Physiol Regul Integr Comp Physiol. 2000 Jul;279(1):R141-7.

Jaremka LM, Glaser R, Loving TJ, Malarkey WB, Stowell JR, Kiecolt-Glaser JK.
Attachment anxiety is linked to alterations in cortisol production and cellular immunity.
Psychol Sci. 2013 Mar 1;24(3):272-9.

Li H, Qiu T, Huang G, Cao Y.
Production of gamma-aminobutyric acid by Lactobacillus brevis NCL912 using fed-batch fermentation.
Microb Cell Fact. 2010 Nov 12;9:85.

Mark Lyte
Probiotics function mechanistically as delivery vehicles for neuroactive compounds: Microbial endocrinology in the design and use of probiotics
BioEssays. Volume 33, Issue 8, pages 574–581, August 2011

Ma D, Forsythe P, Bienenstock J.
Live Lactobacillus rhamnosus [corrected] is essential for the inhibitory effect on tumor necrosis factor alpha-induced interleukin-8 expression.
Infect Immun. 2004 Sep;72(9):5308-14.

Messaoudi M, Lalonde R, Violle N, Javelot H, Desor D, Nejdi A, Bisson JF, Rougeot C, Pichelin M, Cazaubiel M, Cazaubiel JM.
Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.
Br J Nutr. 2011 Mar;105(5):755-64.

Mombereau C, Kaupmann K, Froestl W, Sansig G, van der Putten H, Cryan JF.
Genetic and pharmacological evidence of a role for GABA(B) receptors in the modulation of anxiety- and antidepressant-like behavior.
Neuropsychopharmacology. 2004 Jun;29(6):1050-62.

Ohland CL, Kish L, Bell H, Thiesen A, Hotte N, Pankiv E, Madsen KL.
Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome.
Psychoneuroendocrinology. 2013 Sep;38(9):1738-47.

O’Keane V, Dinan TG, Scott L, Corcoran C.
Changes in hypothalamic-pituitary-adrenal axis measures after vagus nerve stimulation therapy in chronic depression.
Biol Psychiatry. 2005 Dec 15;58(12):963-8.

Pilc A, Nowak G.
GABAergic hypotheses of anxiety and depression: focus on GABA-B receptors.
Drugs Today (Barc). 2005 Nov;41(11):755-66.

Surdea-Blaga T, Băban A, Dumitrascu DL.
Psychosocial determinants of irritable bowel syndrome.
World J Gastroenterol. 2012 Feb 21;18(7):616-26.

Kirsten Tillisch, Jennifer Labus, Lisa Kilpatrick, Zhiguo Jiang, Jean Stains, et al
Consumption of Fermented Milk Product With Probiotic Modulates Brain Activity
Gastroenterology. Volume 144, Issue 7 , Pages 1394-1401.e4, June 2013

Uspenskiĭ IuP, Balukova EV.
Pathomorphosis of anxiety disorder in patients with intestinal dysbiosis.
Eksp Klin Gastroenterol. 2009;(7):91-6.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

Print Friendly, PDF & Email