Early Life Stress and Corticotropin Releasing Hormone / Gut Flora / Immune System Theory

Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro

Abstract

Objective: Persistent stress and life events affect the course of ulcerative colitis and irritable bowel syndrome by largely unknown mechanisms. Corticotropin-releasing hormone (CRH) has been implicated as an important mediator of stress-induced abnormalities in intestinal mucosal function in animal models, but to date no studies in human colon have been reported. The aim was to examine the effects of CRH on mucosal barrier function in the human colon and to elucidate the mechanisms involved in CRH-induced hyper-permeability.

Design: Biopsies from 39 volunteers were assessed for macromolecular permeability (horseradish peroxidise (HRP), 51Cr-EDTA), and electrophysiology after CRH challenge in Ussing chambers. The biopsies were examined by electron and confocal microscopy for HRP and CRH receptor localisation, respectively. Moreover, CRH receptor mRNA and protein expression were examined in the human mast cell line, HMC-1.

Results: Mucosal permeability to HRP was increased by CRH (2.8±0.5 pmol/cm2/h) compared to vehicle exposure (1.5±0.4 pmol/cm2/h), p = 0.032, whereas permeability to 51Cr-EDTA and transmucosal electrical resistance were unchanged. The increased permeability to HRP was abolished by α-helical CRH (9-41) (1.3±0.6 pmol/cm2/h) and the mast cell stabiliser, lodoxamide (1.6±0.6 pmol/cm2/h). Electron microscopy showed transcellular passage of HRP through colonocytes. CRH receptor subtypes R1 and R2 were detected in the HMC-1 cell line and in lamina propria mast cells in human colon.

Conclusions: Our results suggest that CRH mediates transcellular uptake of HRP in human colonic mucosa via CRH receptor subtypes R1 and R2 on subepithelial mast cells. CRH-induced macromolecular uptake in human colon mucosa may have implications for stress-related intestinal disorders.

Abstract
Background—Corticotropin-releasing hormone
(CRH) plays a key role in modulating
intestinal motility in stressed animals.
Aims—To evaluate the effect of CRH on
intestinal motility in humans and to
determine whether patients with irritable
bowel syndrome (IBS) have an exaggerated
response to CRH.
Subjects—Ten IBS patients diagnosed by
Rome criteria and 10 healthy controls.
Methods—CRH (2 μg/kg) was intravenously
administered during duodenal and
colonic manometry and plasma adrenocorticotropic
hormone (ACTH) was
measured by radioimmunoassay.
Results—CRH induced motility of the
descending colon in both groups (p<0.001)
and induced greater motility indexes in
IBS patients than in controls (p<0.05).
CRH produced duodenal phase III motor
activity in 80% of the subjects and duodenal
dysmotility in 40% of IBS patients.
Abdominal symptoms evoked by CRH in
IBS patients lasted significantly longer
than those in controls (p<0.05). CRH
induced significant increases in plasma
ACTH levels in both groups (p<0.001) and
produced significantly higher plasma
ACTH levels in IBS patients than in
controls (p<0.001).
Conclusion—Human intestinal motility is
probably modulated by exogenous CRH.
The brain-gut in IBS patients may have an
exaggerated response to CRH.

The role of microbiota and probiotics in stress-induced gastro-intestinal damage.

Stress has a major impact on gut physiology and may affect the clinical course of gastro-intestinal diseases. In this review, we focus on the interaction between commensal gut microbiota and intestinal mucosa during stress and discuss the possibilities to counteract the deleterious effects of stress with probiotics. Normally, commensal microbes and their hosts benefit from a symbiotic relationship. Stress does, however, reduce the number of Lactobacilli, while on the contrary, an increased growth, epithelial adherence and mucosal uptake of gram-negative pathogens, e.g. E. coli and Pseudomonas, are seen. Moreover, intestinal bacteria have the ability to sense a stressed host and up-regulate their virulence factors when opportunity knocks. Probiotics are "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host", and mainly represented by Lactic Acid Bacteria. Probiotics can counteract stress-induced changes in intestinal barrier function, visceral sensitivity and gut motility. These effects are strain specific and mediated by direct bacterial-host cell interaction and/or via soluble factors. Mechanisms of action include competition with pathogens for essential nutrients, induction of epithelial heat-shock proteins, restoring of tight junction protein structure, up-regulation of mucin genes, secretion of defensins, and regulation of the NFkappaB signalling pathway. In addition, the reduction of intestinal pain perception was shown to be mediated via cannabinoid receptors. Based on the studies reviewed here there is clearly a rationale for probiotic treatment in patients with stress-related intestinal disorders. We are however far from being able to choose the precise combination of strains or bacterial components for each clinical setting.

Previous studies have shown that gastrointestinal flora have a role in stress, anxiety, and depression. A French team has found that specific strains of Lactobacillus and Bifidobacterium, two probiotic compounds, yield beneficial psychological effects. Michael Messaoudi and colleagues investigated the effects of probiotics on anxiety-type symptoms in rats, and also on anxiety, depression, and stress in healthy human volunteers. In the rat study, animals were given daily supplements of probiotics for two weeks and then subjected to a test challenge. The probiotic-supplemented animals had lower stress and anxiety scores, as compared with control animals. In the human study, subjects either randomly received a probiotic supplement (containing Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) or placebo for 30 days, and then tested using a battery of stress and anxiety assessments. Among the probiotic-supplemented subjects. psychological distress, including measures of depression, anger-hostility, anxiety, and problem solving, were significantly improved, as compared with the placebo group. The researches conclude that: “[Lactobacillus and Bifidobacterium] taken in combination display ... beneficial psychological effects in healthy human volunteers.”

LittleFighter wrote:damn! I lost everything in my reply

Crap #"$"# I'll reply in a "lighter" way...

Not a load of crap, it is proven, and the evidence is piling up (see http://evolutionarypsychiatry.blogspot.com). Evidence exists that stress alters permeability and changes gut flora for the bad (ie less lactobacilli). The consequences are constant inflammation, toxins, oxidative stress, nutrient depletion, etc.

The evidence certainly is piling up ... very exciting times. As for nutrient depletion, our gut flora if not compromised pump out tons of Vitamin K and the B's, the one's that MPB sufferers have to supplement most strongly. Vit D has a HUGE affect on the gut flora as well.

Damage to the brain induces intestinal permeability instantly and pathogenic bacteria do the same, they also influence your behaviour (stress).

So gut flora can make us stressed and leaves us hypersensitive to stress; this is what I believe based on evidence we've been reviewing lately. Gut flora is one very significant factor, early trauma might be other one.

My GF recently made a connection with stress, dental and gut problems. She's a dentist. People with colitis where anxious, stressed and had acute dental problems.

Bacteria in the mouth end up in the gut, gut bacteria end up everywhere depending on the person, no surprises here, in fact most of my health issues really became pronounced after four teeth extractions, chronic fatigue tripled in intensity, hair loss sped up, state of mind dropped like a stone, skin went to shit, really pretty obvious. Don't have the study on me but the bacteremia that comes from oral pathology and the excavation of such even by brushing the teeth daily, is massive.

I went to eat with a friend and noticed he started to lose his hair, barely noticeable but I sensed something different. Eventually he told me he went through very stressful times. I assured him that it was due to stress and recommended rhodiola. I forgot to ask if he noticed GI changes. Previously he was very very healthy, he's young and had a muscular body, 100% clear skin, perfect digestion and tolerance to everything.

This has to be attacked at the source (gut) and the consequences (herbs and nutrients).


This just came out:

http://www.hairloss-research.org/UpdateUCLA-Stumbles-on-Cure-for-Hairloss4-11.html

I saw this recently, amazing stuff!

It mentions rhodiola, which I'm currently focusing on.

Adult Acne Caused By Stress

Acne forms when oily secretions from the sebaceous glands beneath the skin plug up the pores. But what causes the oil to form in the first place? The German researchers found that a stress hormone called corticotropin-releasing hormone (CRH) is released in the sebaceous gland -- producing oily skin, which sets the stage for acne.

http://www.greatestherbsonearth.com/articles/acne_adult.htm


Michael Ash from nutrilink explains how the gut flora communicates with the gut and influences the brain, to cause depression.

mphat was looking into something to counteract CRH at the follicle level.

mphat was looking into something to counteract CRH at the follicle level.

Abstract

Quercetin is a bioflavonoid reported to produce variety of behavioral effects like anxiolytic, antidepressant, etc. Recent gathering evidences indicated that quercetin attenuates stress-induced behavioral and biochemical effects. It also decreases CRF expression in the brain. As CRF is commonly implicated in the high-anxiety and depression, we hypothesized that quercetin may involve CRF in its anxiolytic- and antidepressant-like effects. To support such possibility, we investigated the influence of quercetin on CRF or CRF antagonist (antalarmin) induced changes in social interaction time in social interaction test, and immobility time in forced swim test. Results indicated that quercetin (20–40 mg/kg, p.o.) or antalarmin (2–4 µg/mouse, i.c.v.) dose dependently increased social interaction time and decreased immobility time indicating anxiolytic- and antidepressant-like effect. These effects were comparable with the traditional anxiolytic (diazepam, 1-2 mg/kg, i.p.) and antidepressant (fluoxetine, 10–20 mg/kg, i.p.) agents. Administration of CRF (0.1 and 0.3 nmol/mouse, i.c.v.) produced just opposite effects to that of quercetin on these parameters. Further, it was seen that pretreatment with quercetin (20 or 40 mg/kg, p.o.) dose dependently antagonized the effects of CRF (0.1 or 0.3 nmol/mouse, i.c.v.) in social interaction and forced swim test. The sub-effective dose of antalarmin (1 µg/mouse) when administered along with the sub-effective dose of quercetin (10 mg/kg) produced significant anxiolytic-and antidepressant-like effect. These observations suggest reciprocating role of quercetin on the CRF-induced anxiogenic and depressant-like effects.

The skin and its major appendages are prominent target organs and potent sources of key players
along the classical hypothalamic-pituitary axis, such as corticotropin releasing hormone (CRH),
adrenocorticotropic hormone (ACTH), and α melanocyte stimulating hormone (α-MSH), and
even express key steroidogenic enzymes. Therefore, it may have established local stress response
systems that resemble the hypothalamic-pituitary-adrenal (HPA) axis.

The present study evaluated the potential of a w/o microemulsion as a topical carrier system for delivery of the antioxidant quercetin. Topical and transdermal delivery of quercetin were evaluated in vitro using porcine ear skin mounted on a Franz diffusion cell and in vivo on hairless-skin mice. Skin irritation by topical application of the microemulsion containing quercetin, and the protective effect of the formulation on UVB-induced decrease of endogenous reduced glutathione levels and increase of cutaneous proteinase secretion/activity were also investigated. The w/o microemulsion increased the penetration of quercetin into the stratum corneum and epidermis plus dermis at 3, 6, 9 and 12 h post-application in vitro and in vivo at 6 h post-application. No transdermal delivery of quercetin occurred. By evaluating established endpoints of skin irritation (erythema formation, epidermis thickening and infiltration of inflammatory cells), the study demonstrated that the daily application of the w/o microemulsion for up to 2 days did not cause skin irritation. W/o microemulsion containing quercetin significantly prevented the UVB irradiation-induced GSH depletion and secretion/activity of metalloproteinases.

Onion is a major source of flavonoids and is cooked in various ways in the world. The major flavonoids in onion are two quercetin glycosides, quercetin 4'-O-beta-glucoside (Q4'G) and quercetin 3,4'-O-beta-diglucosides (Q3,4'G), which are recognized as bioactive substances that are good for our health. We have investigated the effect of cooking procedures on the content of antioxidants. We selected quercetin conjugates, total phenol compounds, and ascorbic acid to estimate the amount of flavonoid ingestion from onion. We examined the following cooking methods: boiling, frying with oil and butter, and microwave cooking. Various cooking methods do not consider the degradation of quercetin conjugates when cooking onion. Microwave cooking without water better retains flavonoids and ascorbic acid. Frying does not affect flavonoid intake. The boiling of onion leads to about 30% loss of quercetin glycosides, which transfers to the boiling water. At that time, the effect of additives on the quercetin conjugates is different according to the compounds. The hydrolysis of quercetin glycosides for daily cooking might occur with the addition of seasonings such as glutamic acid. Additional ferrous ions accelerated the loss of flavonoids.

LittleFighter wrote:damn! I lost everything in my reply

Crap #"$"# I'll reply in a "lighter" way...

Not a load of crap, it is proven, and the evidence is piling up (see http://evolutionarypsychiatry.blogspot.com). Evidence exists that stress alters permeability and changes gut flora for the bad (ie less lactobacilli). The consequences are constant inflammation, toxins, oxidative stress, nutrient depletion, etc.

Damage to the brain induces intestinal permeability instantly and pathogenic bacteria do the same, they also influence your behaviour (stress).

So gut flora can make us stressed and leaves us hypersensitive to stress; this is what I believe based on evidence we've been reviewing lately. Gut flora is one very significant factor, early trauma might be other one.

My GF recently made a connection with stress, dental and gut problems. She's a dentist. People with colitis where anxious, stressed and had acute dental problems.

I went to eat with a friend and noticed he started to lose his hair, barely noticeable but I sensed something different. Eventually he told me he went through very stressful times. I assured him that it was due to stress and recommended rhodiola. I forgot to ask if he noticed GI changes. Previously he was very very healthy, he's young and had a muscular body, 100% clear skin, perfect digestion and tolerance to everything.

This has to be attacked at the source (gut) and the consequences (herbs and nutrients).


This just came out:

http://www.hairloss-research.org/UpdateUCLA-Stumbles-on-Cure-for-Hairloss4-11.html

It mentions rhodiola, which I'm currently focusing on.

Adult Acne Caused By Stress

Acne forms when oily secretions from the sebaceous glands beneath the skin plug up the pores. But what causes the oil to form in the first place? The German researchers found that a stress hormone called corticotropin-releasing hormone (CRH) is released in the sebaceous gland -- producing oily skin, which sets the stage for acne.

http://www.greatestherbsonearth.com/articles/acne_adult.htm


Michael Ash from nutrilink explains how the gut flora communicates with the gut and influences the brain, to cause depression.

mphat was looking into something to counteract CRH at the follicle level.

Abstract
Aims/hypothesis Accumulating data suggest that the gut
immune system plays a role in the development of type 1
diabetes. The intestinal flora is essential for the development
of the (gut) immune system and the establishment of
tolerance. It has been reported that oral administration of
food and bacterial antigens early in life suppresses later
development of diabetes in the Bio-Breeding diabetesprone
(BB-DP) rat. This study was designed to investigate
the possible relationship between the development of
diabetes and the composition of intestinal flora.
Materials and methods The intestinal flora of BB-DP rats,
a rat model for type 1 diabetes, was characterised long
before the clinical onset of diabetes by fluorescent in situ
hybridisation. In a separate experiment, BB-DP rats were
treated with antibiotics and the effect on diabetes incidence
and level of insulitis was analysed.
Results We observed a difference in bacterial composition
between rats that eventually did and those that did not
develop diabetes. This difference was detectable long
before clinical onset of the disease. Rats that did not
develop diabetes at a later age displayed a lower amount of
Bacteroides sp. Modulation of the intestinal flora through
antibiotic treatment decreased the incidence and delayed the
onset of diabetes. A combination of antibiotic treatment and
a protective hydrolysed casein diet completely prevented
diabetes in the BB-DP rat.
Conclusions/interpretation Our data suggest that the intestinal
flora is involved in the development of type 1
diabetes. Factors influencing composition of the intestinal
flora could be a target for therapeutic intervention.

aabc - Interesting studies ... generally from what I've seen the body can bounce back from natural substances effects fairly well, but playing with brain chemistry for an extended period of time, especially when its just a cover for another problem, isn't something I personally would advise. I took antidepressants for four years, and now two years clean I'm still feeling negative effects, very different substance, but you never know.

Analysis of Intestinal Flora Development in Breast-Fed and Formula-Fed Infants by Using Molecular Identification and Detection Methods


Abstract

Background: An obvious difference between breast-fed and formula-fed newborn infants is the development of the intestinal flora, considered to be of importance for protection against harmful micro-organisms and for the maturation of the intestinal immune system. In this study, novel molecular identification methods were used to verify the data obtained by traditional culture methods and to validate the culture independent fluorescent in situ hybridization (FISH) technique.

Methods: From each of six breast-fed and six formula-fed newborn infants, six fecal samples were obtained during the first 20 days of life. The microbial compositions of the samples were analyzed by culturing on specific media and by FISH, by using specific 16S rRNA-targeted oligonucleotide probes. The colonies growing on the media were identified by random amplified polymorphic DNA pattern analysis and by polymerase chain reaction amplification and subsequent analysis of the 16S rRNA gene.

Results: Molecular identification of the colonies showed that the selective media are insufficiently selective and unsuitable for quantitative analyses. Qualitative information from the culturing results combined with the data obtained by the FISH technique revealed initial colonization in all infants of a complex (adult-like) flora. After this initial colonization, a selection of bacterial strains began in all infants, in which Bifidobacterium strains played an important role. In all breast-fed infants, bifidobacteria become dominant, whereas in most formula-fed infants similar amounts of Bacteroides and bifidobacteria (∼40%) were found. The minor components of the fecal samples from breast-fed infants were mainly lactobacilli and streptococci; samples from formula-fed infants often contained staphylococci, Escherichia coli, and clostridia.

Conclusions: This study confirms the differences in development of intestinal flora between breast-fed and formula-fed infants. The results obtained from the FISH technique were consistent. Although the repertoire of probes for this study was not yet complete, the FISH technique will probably become the method of reference for future studies designed to develop breast-fed-like intestinal flora in formula-fed infants.

Paradox wrote:

a<r wrote:abc - Interesting studies ... generally from what I've seen the body can bounce back from natural substances effects fairly well, but playing with brain chemistry for an extended period of time, especially when its just a cover for another problem, isn't something I personally would advise. I took antidepressants for four years, and now two years clean I'm still feeling negative effects, very different substance, but you never know.

There could be a question of what is "natural" and what isn't, but without even going there- Are you sure the body bounces back better from natural substances? Some examples come to mind of natural substances (elements even) that are (can be) very damaging: Mercury, Fluoride, arsenic, lead, chlorine. The natural venom of many species is extremely toxic/fatal. Certain mushrooms, berries, and other "foods" can be deadly. I know what you are getting at- just playing devil's advocate because I asked myself that question just now.

As far as where I said I wasn't going to go....ah what the hell... Human beings and even the "synthetic" substances they create cannot really be said to be unnatural. WHy? Because human beings are one manifestation of nature or "the whole". We ARE nature itself in human form, like a tree is nature manifested in tree form. Logically if we are part of nature (how could we not be?) and therefor ARE nature.... then it is actually nature itself (manifest in human form) that is creating these quote unquote unnatural or synthetic substances. Does that make sense? So when that is either seen or understood conceptually- there is an understanding that even the most toxic drugs made by man ARE in fact, or in essence- natural. Another way of saying this is that nature is all that there is; nothing exists outside of nature. Therefor nothing is truly or ultimately unnatural; only relatively so. Another point is that humans cannot create something out of nothing. We must work with the building blocks of life or nature to create drugs and "synthetic" substances. So we are not creating anything new on the most basic level; we're not creating new building blocks... We can only manipulate or mess around with the building blocks. So we can make crazy things out of legos, but we can't make legos. Does that make any sense even conceptually?

abc123 wrote:

Paradox wrote:

aabc - Interesting studies ... generally from what I've seen the body can bounce back from natural substances effects fairly well, but playing with brain chemistry for an extended period of time, especially when its just a cover for another problem, isn't something I personally would advise. I took antidepressants for four years, and now two years clean I'm still feeling negative effects, very different substance, but you never know.

There could be a question of what is "natural" and what isn't, but without even going there- Are you sure the body bounces back better from natural substances? Some examples come to mind of natural substances (elements even) that are (can be) very damaging: Mercury, Fluoride, arsenic, lead, chlorine. The natural venom of many species is extremely toxic/fatal. Certain mushrooms, berries, and other "foods" can be deadly. I know what you are getting at- just playing devil's advocate because I asked myself that question just now.

As far as where I said I wasn't going to go....ah what the hell... Human beings and even the "synthetic" substances they create cannot really be said to be unnatural. WHy? Because human beings are one manifestation of nature or "the whole". We ARE nature itself in human form, like a tree is nature manifested in tree form. Logically if we are part of nature (how could we not be?) and therefor ARE nature.... then it is actually nature itself (manifest in human form) that is creating these quote unquote unnatural or synthetic substances. Does that make sense? So when that is either seen or understood conceptually- there is an understanding that even the most toxic drugs made by man ARE in fact, or in essence- natural. Another way of saying this is that nature is all that there is; nothing exists outside of nature. Therefor nothing is truly or ultimately unnatural; only relatively so. Another point is that humans cannot create something out of nothing. We must work with the building blocks of life or nature to create drugs and "synthetic" substances. So we are not creating anything new on the most basic level; we're not creating new building blocks... We can only manipulate or mess around with the building blocks. So we can make crazy things out of legos, but we can't make legos. Does that make any sense even conceptually?

I'm a fan of debunking that narutalistic fallacy so nice post but you can obviously tell he was just talking about man made drugs vs non-man made substances.

aOn a completely unrelated note, the new Chili Peppers song is bangin'.