[Lotus]

Serotonin, tryptophan metabolism and the brain-gut-microbiome axis.
Review article
O'Mahony SM, et al. Behav Brain Res. 2015.
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Abstract
The brain-gut axis is a bidirectional communication system between the central nervous system and the gastrointestinal tract. Serotonin functions as a key neurotransmitter at both terminals of this network. Accumulating evidence points to a critical role for the gut microbiome in regulating normal functioning of this axis. In particular, it is becoming clear that the microbial influence on tryptophan metabolism and the serotonergic system may be an important node in such regulation. There is also substantial overlap between behaviours influenced by the gut microbiota and those which rely on intact serotonergic neurotransmission. The developing serotonergic system may be vulnerable to differential microbial colonisation patterns prior to the emergence of a stable adult-like gut microbiota. At the other extreme of life, the decreased diversity and stability of the gut microbiota may dictate serotonin-related health problems in the elderly. The mechanisms underpinning this crosstalk require further elaboration but may be related to the ability of the gut microbiota to control host tryptophan metabolism along the kynurenine pathway, thereby simultaneously reducing the fraction available for serotonin synthesis and increasing the production of neuroactive metabolites. The enzymes of this pathway are immune and stress-responsive, both systems which buttress the brain-gut axis. In addition, there are neural processes in the gastrointestinal tract which can be influenced by local alterations in serotonin concentrations with subsequent relay of signals along the scaffolding of the brain-gut axis to influence CNS neurotransmission. Therapeutic targeting of the gut microbiota might be a viable treatment strategy for serotonin-related brain-gut axis disorders.

[Lotus]

The brain-gut axis is worth further investigation on our part, not only for overall health, additionally (ideally) for NBE.

Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options.
Review article
Konturek PC, et al. J Physiol Pharmacol. 2011.
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Abstract
Stress, which is defined as an acute threat to homeostasis, shows both short- and long-term effects on the functions of the gastrointestinal tract. Exposure to stress results in alterations of the brain-gut interactions ("brain-gut axis") ultimately leading to the development of a broad array of gastrointestinal disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and other functional gastrointestinal diseases, food antigen-related adverse responses, peptic ulcer and gastroesophageal reflux disease (GERD). The major effects of stress on gut physiology include: 1) alterations in gastrointestinal motility; 2) increase in visceral perception; 3) changes in gastrointestinal secretion; 4) increase in intestinal permeability; 5) negative effects on regenerative capacity of gastrointestinal mucosa and mucosal blood flow; and 6) negative effects on intestinal microbiota. Mast cells (MC) are important effectors of brain-gut axis that translate the stress signals into the release of a wide range of neurotransmitters and proinflammatory cytokines, which may profoundly affect the gastrointestinal physiology. IBS represents the most important gastrointestinal disorder in humans, and is characterized by chronic or recurrent pain associated with altered bowel motility. The diagnostic testing for IBS patients include routine blood tests, stool tests, celiac disease serology, abdominal sonography, breath testing to rule out carbohydrate (lactose, fructose, etc.) intolerance and small intestinal bacterial overgrowth. Colonoscopy is recommended if alarming symptoms are present or to obtain colonic biopsies especially in patients with diarrhoea predominant IBS. The management of IBS is based on a multifactorial approach and includes pharmacotherapy targeted against the predominant symptom, behavioural and psychological treatment, dietary alterations, education, reassurance and effective patient-physician relationship. When evaluating for the stress-induced condition in the upper GI tract, the diagnostic testing includes mainly blood tests and gastroscopy to rule out GERD and peptic ulcer disease. The therapy for these conditions is mainly based on the inhibition of gastric acid by proton pump inhibitors and eradication of Helicobacter pylori-infection. Additionally, melatonin an important mediator of brain gut axis has been shown to exhibit important protective effects against stress-induced lesions in the gastrointestinal tract. Finally, probiotics may profoundly affect the brain-gut interactions ("microbiome-gut-brain axis") and attenuate the development of stress-induced disorders in both the upper and lower gastrointestinal tract. Further studies on the brain-gut axis are needed to open new therapeutic avenues in the future.

http://www.ncbi.nlm.nih.gov/m/pubmed/21303428/

[Huggy]

Hi Lotus

Some of the things I have been reading lately definitely agrees with this idea of a link between stress and the Brain-Gut relationship you are talking about here.

But what I also found interesting is that there are actual brain cells in a thin layer along the full length of the gut, from the mouth to the rectum. Enough cells to equal the brain of a cat (if I remember correctly).

Also, I had re-introduced anti-histamines a little while ago and seemed to be getting on well with them. But I ran out last week and have noticed a distinct drop in my ability to manage stress. It's not something I would directly have linked together but it kinda makes sense? An over active immune system and inflammation is certainly going to cause physical stress (which is problem enough) but perhaps there is should no surprise there is a mental aspect too? I will be stocking up tomorrow and I am intrigued to see what happens.

Huggy.

[Lotus]

Hiya Huggs, great info, i hope it works out for you.

Hi Lotus


Some of the things I have been reading lately definitely agrees with this idea of a link between stress and the Brain-Gut relationship you are talking about here.

But what I also found interesting is that there are actual brain cells in a thin layer along the full length of the gut, from the mouth to the rectum. Enough cells to equal the brain of a cat (if I remember correctly).

Ok thanks, I didn't know that (does explain why some folks are cat people, j/k ).


Interesting what olives do to inhibit histamine.

I forgot to mention olives,


In addition to their function as antioxidants, many of the phytonutrients found in olives have well-documented anti-inflammatory properties. Extracts from whole olives have been shown to function as anti-histamines at a cellular level. By blocking special histamine receptors (called H1 receptors), unique components in whole olive extracts help to provide us with anti-inflammatory benefits. In addition to their antihistamine properties, whole olive extracts have also been shown to lower risk of unwanted inflammation by lowering levels of leukotriene B4 (LTB4), a very common pro-inflammatory messaging molecule. Oleuropein—one of the unique phytonutrients found in olives—has been shown to decrease the activity of inducible nitric oxide synthase (iNOS). iNOS is an enzyme whose overactivity has been associated with unwanted inflammation. Taken as a group, these research findings point to olives as a uniquely anti-inflammatory food.

Olives
http://www.whfoods.com/genpage.php?tname=foodspice&dbid=46

Some good info (background) on histamine.


Are Allergies Causing your Anxiety and Depression? | NutriBlog By Wholesale Nutrition
http://nutri.com/blog/2012/03/are-allerg...epression/


Histamines Antagonists and Local Anesthetics
http://faculty.weber.edu/ewalker/Medicin...ihista.htm

[Lotus]

Huggs,

I think we should give cimetidine/Tagamet a serious look at reducing CFS (chronic fatigue syndrome).


DRUG CLASS AND MECHANISM: Cimetidine is a drug that blocks the production of acid by acid-producing cells in the stomach and can be administered orally, IM or IV. It belongs to a class of drugs called H2 (histamine-2) blockers that also includes ranitidine (Zantac), nizatidine (Axid), and famotidine (Pepcid). Histamine is a naturally-occurring chemical that stimulates cells in the stomach (parietal cells) to produce acid. H2-blockers inhibit the action of histamine on the cells, thus reducing the production of acid by the stomach. Since excessive stomach acid can damage the esophagus, stomach, and duodenum by reflux and lead to inflammation and ulceration, reducing stomach acid prevents and allows acid-induced inflammation and ulcers to heal. Cimetidine was approved by the FDA in 1977.
http://www.medicinenet.com/script/main/m...clekey=839

Now, if we follow this trail I believe it addresses brain/gut acid and a reduction of pain receptors associated with CFS, fibromyalgia too, or tied to many of the " immune and stress-responsive systems-----aka-brain-gut axis ".

One other bonus is how cimetidine can inhibit the CYP17 androgen pathway. I didn't think cimetidine had what it took for denying androgen production, but.........inhibiting CYP17 is at the top of the food chain (albeit the steroidgenous chain of enzymes).

Careful on the interactions though, cimetidine combined with birth control can send E2 into the stratosphere.

[Lotus]

Well my friends, there's a " NEW " estrogen receptor in town named ER-X (estrogen receptor X). Now here's the thing, this ER-X is slightly imperious to anti-estrogens, is that good?? let's find out. A quick note about some alternative research I've meant to follow up on:

1) estrogen and androgens occupy the same receptor (that's a big deal)
2) prediction- a super estrogen receptor type will be discovered, my thought is that the homology of estrogens receptors slip in/out of each receptor type, now what influences this reaction between them I don't know yet, it's certainly intriguing though. (Yup, I've lost my mind lol).

Membrane estrogen receptors - is it an alternative way of estrogen action?
Review article
Soltysik K, et al. J Physiol Pharmacol. 2013.
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Abstract
The functions of estrogens are relatively well known, however the molecular mechanism of their action is not clear. The classical pathway of estrogen action is dependent on ERα and ERβ which act as transcription factors. The effects of this pathway occur within hours or days. In addition, so-called, non-classical mechanism of steroid action dependent on membrane estrogen receptors (mER) was described. In this mechanism the effects of estrogen action are observed in a much shorter time. Here we review the structure and cellular localization of mER, molecular basis of non-classical mER action, physiological role of mER as well as implications of mER action for cancer biology. Finally, some concerns about the new estrogen receptor - GPER and candidates for estrogen receptors - ER-X and ERx, are briefly discussed. It seems that mER is a complex containing signal proteins (signalosome), as IGF receptor, EGF receptor, Ras protein, adaptor protein Shc, non-receptor kinase c-Src and PI-3K, what rationalizes production of second messengers. Some features of membrane receptors are almost identical if compared to nuclear receptors. Probably, membrane and nuclear estrogen receptors are not separate units, but rather the components of a complex mechanism in which they both cooperate with each other. We conclude that the image of the estrogen receptor as a simple transcription factor is a far-reaching simplification. A better understanding of the mechanisms of estrogen action will help us to design more effective drugs affecting signal pathways depending on both membrane and nuclear receptors.

PMID 23756388 [PubMed - indexed for MEDLINE]

[Lotus]

Supplemental on cimetidine:

The effects of cimetidine on the oxidative metabolism of estradiol.
Galbraith RA, et al. N Engl J Med. 1989.
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Abstract
Cimetidine, a histamine H2-receptor antagonist widely used to treat peptic ulceration, is known to cause gynecomastia and sexual dysfunction in some men. Since cimetidine inhibits the cytochrome P-450-dependent biotransformation of numerous drugs, we investigated the possibility that it might also inhibit the cytochrome P-450--dependent metabolism of estradiol. Radiometric analysis of urine and serum samples from nine normal male volunteers showed that the extent of 2-hydroxylation of estradiol was significantly reduced from a mean (+/- SEM) of 31.7 +/- 2.3 percent to 19.7 +/- 2.3 percent (P less than 0.0001) after two weeks of oral treatment with cimetidine (800 mg twice a day); the 16 alpha-hydroxylation of estradiol was unaffected. At the same time, the urinary excretion of 2-hydroxyestrone decreased by approximately 25 percent (P less than 0.0002), and the serum concentration of estradiol increased by approximately 20 percent (P less than 0.04). The mean percentage of estradiol 2-hydroxylation was also rapidly reduced, from 36.8 +/- 4.4 percent to 24.5 +/- 3.4 percent in six men after one week of oral cimetidine at a lower dosage (400 mg twice a day; P less than 0.0006). In a separate study of seven men, ranitidine, a second-generation H2-receptor antagonist, was found to have no effect on the 2-hydroxylation of estradiol. This study demonstrates that the administration of cimetidine to men decreases the 2-hydroxylation of estradiol and results in an increase in the serum estradiol concentration. This mechanism may help to account for the signs and symptoms of estrogen excess reported with the long-term use of cimetidine.

[Huggy]

Hiya Lotus.

Got a little update for you. It took a few more days than expected before I got back onto the anti-histamines. The interesting thing is that the delay has inadvertently shown me something.

I have had a touch of oedema and a bout of depression recently. Now this is not particularly unusual and has become almost part of the background noise (think you probably know what I mean by that). But what is really interesting is that once I started back on the anti-histamines the oedema reduced and my depression lifted too! Nothing else had changed but the anti-h. I would also add that I do not have the usual symptoms of allergies or hay fever etc that would normally require anti-h, so something else is going on here. I'm still trying to work out the full implications of this, but you may not be surprised to hear I have now stocked up with an extra supply!

Very interesting links, thanks. I especially like the one talking about allergies causing anxiety and depression. It fits right in with what I am learning!

And what an amazing find with Cimetidine! An anti-h that encourages boobs!? Don't know if I am reading this right (so please correct me) but this seems to read that it will make any oestrogen source more effective? Are we talking pharma or herbal? Understand they tend to go for different receptors. But I also suspect care is needed as this would be using it "off label" and the side effects sound a bit worrisome?

Thanks for your efforts and take care buddy.

Huggy.

[Huggy]

Hiya bud :-)

(Just noticed.... Lotus... Bud.... :-)

Anyway, just done a check and Cimetidine is prescription only in the UK. It seems to have a bad rep for side effects (at least over here).

It might be possible to find it as a minor ingredient in an over the counter med? But as far as I have found so far, that's about it.

Huggs

[Lotus]

Hiya bud :-)

(Just noticed.... Lotus... Bud.... :-)

Anyway, just done a check and Cimetidine is prescription only in the UK. It seems to have a bad rep for side effects (at least over here).

It might be possible to find it as a minor ingredient in an over the counter med? But as far as I have found so far, that's about it.

Huggs

I see, (ok thanks Huggs).

Back to searching then, I do see this study on histamine and exercise-induced fatigue, it's worth a look see, what do ya think?.


Roles of histamine in exercise-induced fatigue: favouring endurance and protecting against exhaustion.
Niijima-Yaoita F, et al. Biol Pharm Bull. 2012.
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Abstract
Exercise necessitates a large supply of O(2) and nutrients and rapid removal of CO(2) and waste products. Histamine is a regulator of the microcirculation (which performs these exchanges), suggesting a possible involvement of histamine in exercise. Histamine is released from either mast cells or non-mast cells. In the latter, histamine is newly formed via the induction of histidine decarboxylase (HDC) in response to an appropriate stimulus, and it is released without being stored. Here, in mice, we examined the role of histamine or HDC induction in exercise. Prolonged walking (PW) (in a cylindrical cage turned electrically) increased HDC mRNA and HDC activity in quadriceps femoris muscles. Mice given a histamine H1-receptor antagonist [fexofenadine (peripherally acting) or pyrilamine (peripherally and centrally acting)] or an irreversible HDC inhibitor (α-fluoromethylhistidine) displayed less PW endurance than control mice. Ranitidine (H2-receptor antagonist) tended to reduce endurance. Other histamine-receptor (H3 and H4) antagonists had no significant effects on endurance. Mice deficient in HDC or histamine H1-receptors displayed markedly less endurance than control mice, and HDC activity in the quadriceps femoris of H1-deficient mice was rapidly elevated by PW. Fexofenadine significantly reduced the muscle levels of nitric oxide (NO) metabolites and glycogen after PW. The results support the ideas that (i) histamine is involved in protecting against exercise-induced fatigue or exhaustion, (ii) histamine exerts its protective effect via H1 receptors and the ensuing production of NO in skeletal muscle, and (iii) histamine is provided, at least in part, by HDC induction in skeletal muscles during prolonged exercise.

PMID 22223343 [PubMed - indexed for MEDLINE]