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Glutathione: It’s Your Gut

glutathione levelsSome things are so grossly unconventional that we think they’ll never get off the ground. To the contrary is the ultimate use of waste water, but not the kind you’re thinking of. This is olive water, the leftovers from the olive grinding mill. It seems that this material is able to influence some measures of oxidative stress in humans by affecting levels of glutathione, the body’s premier endogenous (self-made) antioxidant, able to be synthesized by all cells of the body.

It has already been accepted that plant phenols are beneficial compounds. Because of increasingly sophisticated testing techniques, those in olives are receiving more and more attention as amplifiers of the body’s antioxidant capacity. A French study performed in 2009 discovered that olive mill waste water has a positive effect on plasma antioxidant potency. Ingesting a mere 2 milliliters of this benevolent elixir contributed to,”…a significant increase in total plasma glutathione concentration…,” involving, “…both the reduced and oxidized forms…”  (Visioli. 2009)  It is widely recognized that specific groups of individuals benefit substantially from increased glutathione levels, most notably the geriatric population. Research has robustly demonstrated that the natural compounds in olives and now, apparently, their waste, play important roles within the living organism.

Glutathione is made from three amino acids—cysteine, glycine, and glutamine—none of which is absolutely essential.  In times of great physical stress, such as major surgery, however, glutamine may be conditionally essential, meaning it has to come from a food or a supplement. Glutathione is your personal antioxidant powerhouse, and it pays super dividends to keep stores as healthy as possible. It’s the presence of a sulfur group on the cysteine portion of the molecule that’s at the foundation of its powerful antioxidant capacity.

Widely found in all forms of life, glutathione plays an essential role in the health of an organism. Cysteine, the businessman of the molecule, but itself a relatively insoluble entity at normal pH, needs to be part of the glutathione tripeptide to do its work. Glutathione synthesizes and repairs DNA, transports amino acids, metabolizes toxins and carcinogens, strengthens the immune system, prevents oxidative damage, and activates enzymes.  It’s pretty busy, don’t you think? Levels of glutathione increase during exercise, but fall with old age, and are found to be deficient in age-related macular degeneration, diabetes, lung and gastrointestinal disease, pre-eclampsia, Parkinson’s disease, and other neurological maladies.

Glutathione exists within cells in its reduced form (GSH), meaning it has an extra electron. In the process of neutralizing reactive oxygen species it becomes oxidized (GSSG), but reacts with another oxidized glutathione to become glutathione disulfide.  Because of enzymatic activity, glutathione is self-healing, particularly in the presence of available cysteine.  (Miller. 2002)  In healthy cells, more than ninety percent is the reduced form…and it should stay that way.  (Owen. 2010) This has strong implications for dietary habits.

Raising GSH through direct supplementation is difficult.  Research suggests that oral glutathione is not well-absorbed across the gastrointestinal tract, since it may be inactivated by peptidase enzymes in the gut.  (Witschi. 1992)  At least in the brain, GSH may be elevated by vitamin D. (Garcion. 2001)   However, the supplements, N-acetyl cysteine (NAC) and lipoic acid can increase GSH levels.  (Gross.1993)   (Busse. 1992)   (Shay. 2009) Ongoing research will determine the true bioavailability of oral supplementation.  In cases of Acetaminophen (Tylenol) poisoning, the number one cause of emergency room poisoning visits, the hospital will likely use NAC as an antidote.  Among health care providers, at least a little speculation has focused on the inclusion of NAC in acetaminophen tablets and capsules.

Although no specific foods contain glutathione, there are some that can elevate levels, most by virtue of their sulfur content, including animal products, red peppers, cabbage, broccoli, Brussels sprouts, onions, oats, lentils, beets, eggs, and parsley.  Because it is fundamental to a raft of physiological process, especially as an antioxidant, it’s wise to eat the foods that will ramp it up, including olives.

References

Visioli F, Wolfram R, Richard D, Abdullah MI, Crea R.
Olive phenolics increase glutathione levels in healthy volunteers.

J Agric Food Chem. 2009 Mar 11; 57(5):1793-6.

Lauren T. Miller, Walter H. Watso, Ward G. Kirlin, Thomas R. Ziegler and Dean P. Jones
Oxidation of the Glutathione/Glutathione Disulfide Redox State Is Induced by Cysteine Deficiency in Human Colon Carcinoma HT29 Cells
J. Nutr. 132:2303-2306, 2002

Owen JB, Butterfield DA.
Measurement of oxidized/reduced glutathione ratio.
Methods Mol Biol. 2010;648:269-77.

Witschi A, Reddy S, Stofer B, Lauterburg BH.
The systemic availability of oral glutathione.
Eur J Clin Pharmacol. 1992;43(6):667-9.

Garcion E, Wion-Barbot N, Montero-Menei CN, Berger F, Wion D.
New clues about vitamin D functions in the nervous system.
Trends Endocrinol Metab. 2002 Apr;13(3):100-5.

Gross CL, Innace JK, Hovatter RC, Meier HL, Smith WJ.
Biochemical manipulation of intracellular glutathione levels influences cytotoxicity to isolated human lymphocytes by sulfur mustard.
Cell Biol Toxicol. 1993 Jul-Sep;9(3):259-67.

Busse E, Zimmer G, Schopohl B, Kornhuber B.
Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo.
Arzneimittelforschung. 1992 Jun;42(6):829-31.

Kate Petersen Shay, Régis F. Moreau, Eric J. Smith, Anthony R. Smith, and Tory M. Hagen
Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential
Biochim Biophys Acta. 2009 October; 1790(10): 1149–1160.

Wu G, Fang YZ, Yang S, Lupton JR, Turner ND.
Glutathione metabolism and its implications for health.
J Nutr. 2004 Mar;134(3):489-92.

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

Gut Health, Body Health

stomachThe large intestine is seldom the topic of conversation, with the possible exception of surgeons and gastroenterologists. Most “civilians” don’t pay attention to it until it isn’t working right. The inability to move material out of it is one reason. Unusual egesta might be another. Regardless of its laid back persona, the colon is actually an interesting character. It runs from the cecum (the beginning of the large intestine, where the appendix hangs) to the rectum (the dumpster), and extends about five or six feet. If you want to be technical, the colon runs between these two points. The large intestine has no digestive function, but lubricates wastes and absorbs water and remaining salts, and stores useless stuff for eventual removal. It takes about sixteen hours to evacuate the hold. You need to know that the large intestine absorbs vitamins made by colonic bacteria, such as vitamin K and the vitamin A converted from beta-carotene.

Despite that the colon is known for removal of material, there exists inside a raft of bacteria that keep a permanent residence. In fact, there are more bacteria in the colon than cells in the body. If you have ten trillion cells in your body, you have ten times that many microbes, weighing from two to five pounds. This microflora is sometimes called the microbiome or microbiota. Whichever term is used, the activities performed by these bacteria parallel that of an organ, rivaling the metabolic capacity of the liver (MacFarlane, 2010). For example, carbohydrates are fermented to form short-chain fatty acids that support epithelial cell growth, which helps to reduce the absorption of toxic products. The flora recycle carbon and nitrogen, manufacture methane, metabolize steroids, convert lignans and phytoestrogens to other compounds and fight invasion by unwelcome species. Although people can survive without them, these bacteria are among the best of friends. Damaged or abnormal gut flora is the cause of much human agony as a prime factor in disease. Treating the microbiome with dignity and respect may prevent, or even reverse, disorders that include heart disease, autoimmune conditions, allergies and cancer (deVrese, 2008) (Garcovich, 2012).

There are hundreds of different species of micro-organisms living in the gut, more than 95% of which are anaerobic and genetically diverse. A lactobacillus is more different from a bifidobacterium than a human is from a rabbit. Identification of all species is difficult because not all can be cultured, but you can rest assured that your bacteria belong to you, remaining fairly constant throughout your life time. Talk about close friends!  The healthy bacteria provide a natural barrier against pathogenic bacteria, parasites, fungi, viruses, toxins and whatever else would wreak havoc with our health. Basically, there are half a dozen main groups:  Bacteroides, Firmicutes (Clostridia, Lactobacilli, Streptococci), Actinobacteria (Bifido-), Proteobacteria (Entero-), Fusobacteria and Verrucomicrobia. Not all of these offer salubrity. Some are so complex they almost defy taxonomy, but to our benefit, the good control the evil (Vedantam, 2003) (Beaugerie, 2004).

Analyses have determined that specific gut microbes are associated with what we eat. Some are associated with carbohydrates and some with animal proteins, fats and amino acids. It appears they come to the front of the class when it’s their turn to perform. Changing diet from one type of macro-nutrient to another can alter which bacterial strain is on stage at the time. A baby’s gut is clean and sterile until it entertains bacteria from its mother. Vaginal birth may afford bacterial strains directly from mom’s gastrointestinal tract, while caesarean might present strains from the ambient environs, including the air and the attending medical folks. The infant doesn’t establish his own microbiota for up to six months after caesarean delivery, only one month for normal birth. In any case, the microbiota shapes the development of the immune system, and the immune system in turn shapes the composition of the microbiota (Nicholson, 2012).

The influence of gut microbes on immunity is profound and, therefore, associated with long-term health, particularly since microflora is relatively stable throughout adulthood. The dynamics of the gut environment are subject to perturbations, though, such as from stresses or dietary changes. It’s comforting to know that there is considerable interest in developing modalities that can manipulate biome composition to benefit the host through a kind of metabolic communication, such as would affect obesity and type 2 diabetes (Kootte, 2012). In these matters, therapeutic pathways may be designed by enlisting short-chain fatty acids, prebiotics, bile acids and probiotics. Realizing that antibiotics are non-selective in destroying bacteria—they kill the good as well as the bad—this give us the means for resolution of myriad complaints. In general, the host immune system can prevent the overgrowth of pathogens, which, upon ingestion, fall to this complex integrated structure.

Probiotics are helpful in many cases, but are not silver bullets. When used as part of a broad nutritional protocol, they are likely effective in establishing or re-establishing a healthy microbiome. Stress management, elimination of detrimental medications and dietary interventions need to be included in such a protocol. Because they are many and varied in their composition, probiotics are often viewed tentatively until they are administered and monitored for efficacy. Eating fermented foods, like sauerkraut, yogurt and kefir, fosters a nurturing environment for your own microbiome. The florae best known are the Lactobacilli (there are more than 50 strains) and Bifidobacteria (there are more than thirty). Lacto-, in one strain or another, have been used to treat and to prevent a variety of conditions, from bacterial vaginosis to childhood abdominal distress and diarrhea, to childhood respiratory infections. Bifidobacteria comprise about 90% of the intestinal community, and appear in an infant’s gut within days of parturition, especially if breastfed. The Bifido- species has been used to address irritable bowel syndrome, dental caries, blood lipids and glucose tolerance.  A knowledgeable nutrition professional can guide you in the choice of probiotics to meet a specific need if you have one. Oh, yeah, there is a yeast probiotic, called Saccharomyces boulardii, which is quite effective in treating diarrhea associated with antibiotic use, and may even be helpful with Clostridium difficile and acne.

Hey, what about short-chain fatty acids (SCFA), especially butyrate?  We’re glad you asked. Butyrate is derived from the bacterial fermentation of resistant starches and fibers. Its multiple beneficial effects have been demonstrated beyond the colon, mostly because SCFA can be absorbed across the colonic epithelium. Now that gut health has its own fan club, what with renewed interest in the GI barrier defense system, SCFAs are the darlings of moneyed research. These 2-carbons to 5-carbons fatty acids include acetate, propionate, butyrate and valerate, but the 4-carbon butyrate is the featured performer due to its multiplicity of virtues. Among butyrate’s mechanisms of action are the regulation of gene expression, inhibition of histone deacetylase (an action which helps to make copies of DNA), sequestration of ammonia (ammonia causes cloudy thinking), mobilization of renegade fats, and clearance of biotoxins (Soret, 2010) (Fusunyan, 1999) (Yin, 2001). Because butyrate availability in the colon is lower than the other SCFAs, supplementation is highly recommended. You can’t eat enough resistant starches to make enough butyrate to be physiologically significant. However, even at low concentrations, butyrate can inhibit cell proliferation of several colon cancer lines. At high concentrations, it works like gangbusters against cancer cells while leaving healthy cells alone (Omaida, 1996) (Gamet, 1992).

The extraordinary complexity of the human microbiome is only recently revealed, despite having been known for decades. The interdependence between beneficial bacteria and the immune system demands recognition. If the florae can fight the inflammation that threatens them, they can fight whatever threatens their host.

References

Arora T, Sharma R, Frost G.
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Appetite. 2011 Apr;56(2):511-5. doi: 10.1016/j.appet.2011.01.016. Epub 2011 Jan 19.

Bäckhed F, Fraser CM, Ringel Y, Sanders ME, Sartor RB, Sherman PM, Versalovic J, Young V, Finlay BB.
Defining a healthy human gut microbiome: current concepts, future directions, and clinical applications.
Cell Host Microbe. 2012 Nov 15;12(5):611-22.

Beaugerie L, Petit JC.
Microbial-gut interactions in health and disease. Antibiotic-associated diarrhoea.
Best Pract Res Clin Gastroenterol. 2004 Apr;18(2):337-52.

Bischoff SC.
‘Gut health’: a new objective in medicine?
BMC Med. 2011 Mar 14;9:24.

Calder PC, Krauss-Etschmann S, de Jong EC, Dupont C, Frick JS, Frokiaer H, Heinrich J, Garn H, et al
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Roberto Berni Canani, Margherita Di Costanzo, and Ludovica Leone
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Cummings JH, Antoine JM, Azpiroz F, Bourdet-Sicard R, Brandtzaeg P, Calder PC, Gibson GR, et al
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de Vrese M, Schrezenmeir J.
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Fanaro S, Chierici R, Guerrini P, Vigi V.
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Flint HJ, Scott KP, Louis P, Duncan SH.
The role of the gut microbiota in nutrition and health.
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Fusunyan RD, Quinn JJ, Fujimoto M, MacDermott RP, Sanderson IR.
Butyrate switches the pattern of chemokine secretion by intestinal epithelial cells through histone acetylation.
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Gamet L, Daviaud D, Denis-Pouxviel C, Remesy C, Murat JC.
Effects of short-chain fatty acids on growth and differentiation of the human colon-cancer cell line HT29.
Int J Cancer. 1992 Sep 9;52(2):286-9.

Garcovich M, Zocco MA, Roccarina D, Ponziani FR, Gasbarrini A.
Prevention and treatment of hepatic encephalopathy: Focusing on gut microbiota.
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Guarner F, Malagelada JR.
Gut flora in health and disease.
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Kootte RS, Vrieze A, Holleman F, Dallinga-Thie GM, Zoetendal EG, de Vos WM, Groen AK, et al
The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus.
Diabetes Obes Metab. 2012 Feb;14(2):112-20.

Lin HV, Frassetto A, Kowalik EJ Jr, Nawrocki AR, Lu MM, Kosinski JR, Hubert JA, Szeto D, Yao X, Forrest G, Marsh DJ
Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms.
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Macfarlane S, Macfarlane GT.
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MacFarlane, George T. and McBain, Andrew J. (2010). The Human Colonic Microbiota. In Colonic Microbiota, Nutrition and Health. Glenn Gibson, Ed. Dordrecht, the Netherlands: Kluwer Academic Publishers; pp 1-25

Martin FP, Dumas ME, Wang Y, Legido-Quigley C, Yap IK, Tang H, Zirah S, Murphy GM, et al
A top-down systems biology view of microbiome-mammalian metabolic interactions in a mouse model.
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Martin FP, Wang Y, Sprenger N, Yap IK, Lundstedt T, Lek P, Rezzi S, Ramadan Z, van Bladeren P, et al
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Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, Pettersson S.
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O’Hara AM, Shanahan F.
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Omaida C. Velázquez MD, Howard M. Lederer MD, Dr. John L. Rombeau MD
Butyrate and the colonocyte
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Roberfroid M, Gibson GR, Hoyles L, McCartney AL, Rastall R, Rowland I, Wolvers D, Watzl B, et al
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Schwiertz A, Gruhl B, Löbnitz M, Michel P, Radke M, Blaut M.
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Scott KP, Duncan SH, Louis P, Flint HJ.
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Scott KP, Gratz SW, Sheridan PO, Flint HJ, Duncan SH.
The influence of diet on the gut microbiota.
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Soret R, Chevalier J, De Coppet P, Poupeau G, Derkinderen P, Segain JP, Neunlist M.
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Tsai F, Coyle WJ.
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Vedantam G, Hecht DW.
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Yin L, Laevsky G, Giardina C.
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Yonezawa H, Osaki T, Hanawa T, Kurata S, Zaman C, Woo TD, Takahashi M, Matsubara S, Kawakami H, Ochiai K, Kamiya S.
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J Med Microbiol. 2012 Apr;61(Pt 4):582-9.

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

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.
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Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X, Deng Y, Blennerhassett PA, et al
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Xiao Chen, Roshan D’Souza, Seong-Tshool Hong
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Collins SM, Surette M, Bercik P.
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Cryan JF, Kaupmann K.
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Cryan JF, Slattery DA.
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Cullinan WE, Ziegler DR, Herman JP.
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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
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Foster JA, McVey Neufeld KA.
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*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

Gut Bacteria And The Brain

brain-gears

They’re called flora. Their name comes from the Roman goddess of plants, flowers and fertility, and refers to the plant life occurring in a particular region. The region in this case is the intestine, and the florae that occupy it are micro-organisms that total almost a hundred trillion, a number considerably larger than the number of cells in the human body. So phenomenal are the metabolic activities of these bacteria that they are considered an organ (O’Hara, 2006). Gut bacteria are so influential that they affect more than just a few bodily functions, from immunity to weight control to behavior and concentration (Bravo, 2011). And without them we couldn’t make biotin, vitamin K, or the short-chain fatty acids that energize intestinal cells. An absence of intestinal bacteria is associated with reduction in mucus cell turnover, muscle wall thickness, cytokine production (regulatory proteins), and of course, digestion. The micro-organism population begins in the mouth, where about two hundred different kinds live. They bypass the almost-sterile stomach and then increase on their way to the colon, where several hundred species thrive (Canny, 2008). For all that we know about the body, this area is not completely understood.

Gut diversity is more pronounced in adults than in children and, once developed, tends to remain stable unless dietary changes are dramatic. Generally, those who consume lots of vegetables and fiber have a different composition from those whose diets typify the Western regimens that are high in unwholesome fats and carbohydrates. Studies have demonstrated that what happens in the gut affects what happens in other areas of the body as well, including those that manage mood, anxiety, and possibly the onset of chronic and degenerative diseases (Tillisch, 2013). Suppose we could manipulate intestinal conditions to address health issues, either one at a time or as a group, by using probiotics.

Lactic acid bacteria and Bifidus bacteria are the most common ones used as probiotics, but others may also be employed. The WHO recognizes probiotics as living micro-organisms that confer a health benefit when taken in adequate amounts. The “health benefit,” however, is undefined. What is defined is that specific strains of a beneficent bacteria offer specific effects that cannot be ascribed to other strains, even in the same variety. Therefore, the probiotic used to treat irritable bowel syndrome will be different from the one used for pediatric diarrhea (Verna, 2010). What’s more, the optimal remedial number of colony forming units (CFU’s) for each bacterial strain is still uncertain; and the doses used in animal studies do not necessarily translate to humans. Then there’s the delivery system. Do we use yogurt, milk or a capsule? The gut environs make a difference, too. If too acidic or alkaline, some bacteria cannot survive.

One micro-organism has shown significant promise as a therapeutic agent in the matter of hypertension. It’s called Lactobacillus helveticus, a bacterium used to add a nutty flavor to American Swiss cheese and to prevent bitterness, although it lends character to other cheeses, including cheddar and various Italian varieties. The name helveticus derives from a Gallic tribe that occupied Switzerland in the first century B.C.

L. helvicus produces a compound called a tripeptide. A peptide consists of two or more amino acids linked end to end, sort of like joining batteries in series (That would be positive to negative in order to increase voltage.)  They always hook up between the oxygen-bearing carbon end of one amino and the nitrogen-bearing end of the other. When you get ten or more amino acids in this parade, it’s called a polypeptide; fifty or more give you a protein. That’s the stuff we’re made from. Some peptides, though, are hormones. The biological synthesis of protein depends on messenger RNA that lives on ribosomes; that of peptides doesn’t. A tripeptide has three amino acids. A familiar one is glutathione, an antioxidant made by the body to shield itself from reactive oxygen species. When L. helveticus is used to make a fermented milk product, it forms a tripeptide called IPP, or isoleucine-proline-proline, which acts like an ACE inhibitor.

Without getting too complicated, an ACE inhibitor deals with angiotensin-converting enzyme, a substance that makes angiotensin, which narrows blood vessels after the lub-dub and consequently raises blood pressure. Most of these drugs end in “-pril,” but have different brand names, such as Univasc, Altace or Vasotec. As with all pharmaceuticals, there are side effects, the most common being a bothersome cough. With L. helveticus there are none.  The Finns realized this after conducting a gold-standard clinical trial—randomized, double-blind, placebo-controlled—in which one hypertensive group received no intervention and the other received 150 milliliters (5 oz.) of L. helveticus fermented milk twice a day for ten weeks. There was a four-point difference in systolic pressure and a two-point difference in diastolic pressure between groups, indicating efficacy of the IPP tripeptide (Jauhiainen, 2005). Though these numbers don’t seem like much, they are, indeed, significant. If you prefer higher numbers, another, earlier, Finnish study reported six point and four point differences (Seppo, 2003). Contributing to this positive outcome is a reduction in the arterial stiffness that contributes to hypertension, particularly as we age. Additional study along these lines found that L. helveticus dairy wrought moderate changes in gene expression in the aorta, which you know to be the main artery leading away from the heart (Ehlers, 2011).

Finland is not the only venue enjoying the anti-hypertensive nature of fermented dairy. The Sant’Orsola-Malpighi University Hospital, in Bologna, Italy, noticed that subjects with high-normal blood pressure experienced a drop in numbers, while those with normal readings were unaffected, which is not a surprise (Cicero, 2010). To make this enterprise even more affable, the Japanese used powdered fermented milk to draw similar results, adding a kind of portability to the protocol (Aihara, 2005).

It’s almost hard to bridle one’s encouragement at the prospect of a hypertension management system based on functional food. A few probiotics already contain the strain: Dr. Stephen Langer’s, Garden of Life, and New Chapter are three. Spectra Probiotic by Integrative Therapeutics is another. Kefir, a probiotic drink available in the supermarket, contains L. helveticus, as well as other beneficent micro-organisms. Be advised not to stop any medications. Just know that any decrease in BP is welcome.

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Javier A. Bravo, Paul Forsythe, Marianne V. Chew, Emily Escaravage, Hélène M. Savignac, Timothy G. Dinan, John Bienenstock, John F. Cryan
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*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

Probiotics and Blood Pressure

bloodpressure

Maybe what happens in Las Vegas stays in Las Vegas, but what happens in your gut doesn’t stay in your gut, the place we think of as the processing plant that makes nutrients available for use by the body and wastes available for disposal. That part’s correct, but recent interest in the machinations of the system has researchers looking at its relationship to the brain. That means that some of what happens in the gut goes to your head and bypasses the enteric nervous system (ENS), that part of the body called the second brain. Working autonomously, the enteric nervous system is able to coordinate reflexes while controlling the gastrointestinal activity upon which humans rely. Although it communicates with the brain by way of the vagus nerve, the ENS can work independently through a series of neurons that control peristalsis (churning of intestinal contents) and monitor mechanical, chemical and electrical conditions within the system, such as those involved in enzyme secretion and neurotransmitter manufacture. The neurotransmitters of the gut are the same as those in the central nervous system (CNS): acetylcholine, dopamine and serotonin. In fact, more than ninety percent of the body’s serotonin lies in the gut, where it modulates cells of the immune system (Sepiashvili, 2013) (Mawe, 2013). That’s uncommon knowledge, for sure.

What’s this got to do with the brain? Using functional magnetic resonance imaging (fMRI), scientists at UCLA Medical School found that women who regularly consumed probiotic-rich yogurt showed altered activity of brain regions that control the processing of emotion and sensation. The lead author, Dr. Kirsten Tillisch, M.D., commented that the study is of singular merit because it’s the first to show an interaction between a probiotic and the brain. In this work, healthy women with no GI or psychiatric symptoms ate fermented yogurt containing Bifido-, Lacto-, and Strepto- bacterial strains twice a day for a month, and were compared/contrasted to groups that either abstained from such a dairy product or ate one lacking fermented cultures. Before-and-after fMRI’s measured resting brain activity and brain responses to emotion-recognition tasks. Those are the kind in which you look at an image and determine a person’s mood by his facial expressions. This avenue was taken because a previous relationship between gut flora and affective behavior was realized (Umu, 2013) (Dinan, 2013) (Gomborone, 1993) (Robertson, 1989).

Dr. Tillisch observed brain effects in several areas, including those involved in sensory processing and emotional response. An additional conclusion, practically foregone, is that gut flora composition is directed by what we eat (Tillisch, 2013). It is widely accepted that relatively high fiber diets create a gut environment different from typical Western diets. If the brain can send signals to the gut that make you nauseous in times of mental stress, why can’t the gut send messages to the brain?  Inspection has found that Lactobacillus rhamnosus bacteria, common to many yogurt products, affect GABA levels in the brain (Bravo, 2011). GABA is an inhibitory neurotransmitter that reduces anxiety and depression-related behavior. Whether or not Dr. Tillisch’s work is preliminary to something more definitive makes little difference because interest in this field had been piqued years ago (Robertson, 1989).

Some areas of medical and functional study are rife for contrivance, either of outcomes or numbers or some other elements of scientific reporting. The study of autism and its related spectrum of anomalies are not excused from academic chicanery. However, the gut-brain nexus in the study of cerebral challenges offers a fertile arena for probiotic-central nervous system exploration. That there exist perturbations in the gut flora of autistic individuals is properly recognized (Parracho, 2005) (Finegold, 2002). Moving on this link, researchers have identified the higher levels of “bad bacteria” in the guts of children with autism as a variety of Clostridia, though not necessarily defining a cause-effect relationship, but only an association (Pilcher, 2004). Admittedly, genetic and environmental factors play a role in the etiology of this condition. Nonetheless, it is speculated, with at least a small certainty, that probiotics might allay some symptoms of autism by attenuating the toxic by-products of these ignoble bacteria strains.

Anxiety and depression are comorbidities of functional bowel disorders. In subjects so affected, discordant alterations in GABA receptors were remediated by the administration of Lactobacillus rhamnosus, highlighting the valuable role of bacteria in the bi-directional communication of the gut-brain axis (Bravo, 2011) and hinting that certain micro-organisms can be used to treat stress-related disorders, such as anxiety and depression (Cryan, 2012 and 2011).

A venture into neurogastroenterology is as labyrinthine an exercise as can be imagined, right up there with the Biblical epiphany of being fearfully and wonderfully made, and has prompted a convention of “experts” called the International Scientific Association for Probiotics and Prebiotics (ISAPP). Available data on the role of gut bacteria in brain function ascertain the interaction of this microbiota with the ENS, the CNS, and the neuroendocrine and neuroimmune systems. Mammalian brain development and subsequent adult behavior are likewise affected. This could account for the behavioral abnormalities that occasionally accompany gastrointestinal ailments such as IBS and Crohn’s disease, aside from their discomfort.

Short-chain fatty acids are made in the colon when dietary fiber is fermented. These acids contribute to the integrity of the immune and digestive systems, and to the regulation of intestinal (and other) inflammation (Smith, 2013), but their overexpression can be hazardous to cerebral health because they deplete inhibitory GABA (El-Ansary, 2011). Propionic acid (PA) is the main player in this cranial drama, inciting autistic features (El-Ansary, 2012) by increasing markers of oxidative stress, including lipid peroxidation and concomitant decreases in glutathione. Lactic acid bacteria ameliorate the state by increasing GABA stores, (Bravo, 2011) even in the presence of PA, by virtue of their psychoactive character (Perez-Burgos, 2013). And they control PA production by sequestering the Clostridia responsible for its appearance in the first place.

The potential of gut microflora to fine tune human physiology goes beyond the digestive, cardiovascular and immune systems, now to include the nervous system. The thought of regulating cognitions, behaviors, sensations and emotions with bacteria is more than just enlightening.

References

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Effect of powdered fermented milk with Lactobacillus helveticus on subjects with high-normal blood pressure or mild hypertension.
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Aleixandre A, Miguel M, Muguerza B.
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Boelsma E, Kloek J.
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Javier A. Bravo, Paul Forsythe, Marianne V. Chew, Emily Escaravage, Hélène M. Savignac, Timothy G. Dinan, John Bienenstock, John F. Cryan
Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve
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Geraldine O. Canny and Beth A. McCormick
Bacteria in the Intestine, Helpful Residents or Enemies from Within?
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Cicero AF, Rosticci M, Veronesi M, Bacchelli S, Strocchi E, Melegari C, Grandi E, Borghi C.
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Cremonesi P, Chessa S, Castiglioni B.
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Ehlers PI, Kivimäki AS, Turpeinen AM, Korpela R, Vapaatalo H.
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Gonzalez-Gonzalez C, Gibson T, Jauregi P.
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Jauhiainen T, Vapaatalo H, Poussa T, Kyrönpalo S, Rasmussen M, Korpela R
Lactobacillus helveticus fermented milk lowers blood pressure in hypertensive subjects in 24-h ambulatory blood pressure measurement.
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*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

Colon and Butyrate: The Colon Beyond Punctuation

crammed-jarQuite a lot of people do not like to share their space. It’s understandable that some are uncomfortable when a conversation, as with a stranger, is carried on nose to nose. In Arab countries, it is offensive to step or lean away during such an encounter. There is, however, an instance where closeness cannot be avoided with the microbiome that occupies not only our space, but also us. The human body holds ten times more microbes than human cells, some on the outside, and others on the inside. The skin, the largest organ of the body, houses a range of microbes that live in distinct communities yet work together to protect us from attack by sickness and disease (Grice, 2009). But our attention here is to those on the inside, the microbiota that weigh up to three pounds and contain tens of trillions of members. There might even be more than a thousand different species, about a third of which are common to most of us. The other two-thirds belong only to you.

Though we have a tailor-made personal microbiome, all perform the same physiological functions and have a direct impact on our health. Besides completing digestion by absorbing water and storing wastes, the gut microbes help to make biotin and vitamin K while fighting aggression from the pathogenic gang of bugs and bolstering the immune system. Each of our gut communities remains stable throughout our lives, unless dietary changes are dramatic. Those who consume lots of vegetables and fiber have a different composition from those who live on fatty meats and simple carbohydrates. What happens in the gut telegraphs to what happens in other areas of the body, including areas that manage mood and possibly the onset of chronic and degenerative diseases (Tillisch, 2013).

The neonatal biome starts to form right after birth, when the digestive tract becomes colonized by micro-organisms that come from the mother and from the environment into which it is born. In about three years the biome becomes stable. To keep it that way, we need to take measures that transcend dietary behavior and the mere swallowing of probiotics as adults. Probiotics are micro-organisms. To analogize, they’re like police whose local precinct needs a workplace conducive to efficiency.  If a probiotic, or any array of gut bacteria for that matter, is to augment or to enhance the native population, it needs a favorable place to work. The problem with the typical Western diet is that we feed the upper GI tract without feeding the gut. One way to do that is with resistant starch, the fermentation of which manufactures short-chain fatty acids, notably butyrate. Butyrate nourishes the gut barrier and helps to prevent inflammation.  Very often, however, dietary intake of resistant starch is insufficient to make enough butyrate to be physiologically significant.

What does butyrate do?  It has powerful effects on several colonic functions, not the least of which is the inhibition of inflammation and carcinogenesis, and the reinforcement of the defenses that fight infection and oxidative stress (Hamer, 2008). Butyrate has partners and precursors in the form of acetates and propionates, likewise made by the bacterial fermentation of resistant starch and fiber.  In the company of acetate, butyrate is reported to protect against diet-induced obesity without causing hypophagia, while propionate may reduce food intake. Unfortunately, there is little understanding why this works (Hua, 2012). What distinguishes one from another?  The number of carbons it holds. Acetic acid has two, propionic acid has three and butyric acid has four. The first of these has the scent of vinegar. Propionic acid is found in sweat; butyric acid in rancid butter and vomit.

Butyrate, joined with calcium, magnesium, potassium, sodium or a combination of these minerals inhibits histone deacetylase enzymes, helping butyric acid to enhance the transcription activity of DNA. Sodium butyrate, for example, has been found to increase lifespan in animal experiments (Zhang, 2009). Of the three short-chain fatty acids mentioned, butyrate is more potent than the others at inhibiting invasive colon cancers (Emenaker, 1998). If this activity of the butyrate molecule has been known since the late 1990’s, why has it not received the publicity that newly-concocted drugs, with their hosts of nasty side effects, have?

The reasons for paying attention to your gut go beyond what you read while seated. Some problems can be attenuated with an occasional laxative, although increasing dietary fiber is a better technique. Even the orange-flavored stuff in the plastic canister, used every day, is an improvement. But a butyrate supplement, despite its pungency, is the best thing going, especially as we get older.

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