8 replies to this topic

[CaptainFuture]

This is one of the greatest studies for a long time. I suffer from intolerance reactions (including IBS) to nearly all foods. An elimination diet brought no solution and in my eyes the problem goes beyond the current understanding of allergies/inflammation. If you brought up or bring up "Leaky Gut" in a conversation with most doctors (who are likely to not follow the latest science) they may think you are crazy. Intestinal permeability is very real unfortunately but hasn't reached the medial mainstream yet. I have no idea how some people can be so backward in order to claim that everything which reaches your intestines is filtered so perfectly that only the good stuff penetrates the intestinal wall. We still have no idea how far reaching a better understanding of gut integrity is, but we can say for sure that it could be connected to cancer and inflammation. This study sheds more light onto intestinal permeability and makes hope by stating that the first drug that contains GC-C is about to hit the market and could be the first treatment to increase gut integrity.


http://www.scienceda...20221212345.htm

ScienceDaily (Feb. 21, 2012) — A leaky gut may be the root of some cancers forming in the rest of the body, a new study published online Feb. 21 in PLoS ONE by Thomas Jefferson University researchers suggests.

It appears that the hormone receptor guanylyl cyclase C (GC-C) -- a previously identified tumor suppressor that exists in the intestinal tract -- plays a key role in strengthening the body's intestinal barrier, which helps separate the gut world from the rest of the body, and possibly keeps cancer at bay. Without the receptor, that barrier weakens.
A team led by Scott Waldman, M.D., Ph.D., chair of the Department of Pharmacology and Experimental Therapeutics at Jefferson and director of the Gastrointestinal Cancer Program at Jefferson's Kimmel Cancer Center, discovered in a pre-clinical study that silencing GC-C in mice compromised the integrity of the intestinal barrier. It allowed inflammation to occur and cancer-causing agents to seep out into the body, damaging DNA and forming cancer outside the intestine, including in the liver, lung and lymph nodes.
Conversely, stimulating GC-C in intestines in mice strengthened the intestinal barrier opposing these pathological changes.
A weakened intestinal barrier has been linked to many diseases, like inflammatory bowel disease, asthma and food allergies, but this study provides fresh evidence that GC-C plays a role in the integrity of the intestine. Strengthening it, the team says, could potentially protect people against inflammation and cancer in the rest of the body.
"If the intestinal barrier breaks down, it becomes a portal for stuff in the outside world to leak into the inside world," said Dr. Waldman. "When these worlds collide, it can cause many diseases, like inflammation and cancer."
The role of GC-C outside the gut has remained largely elusive. Dr. Waldman and his team have previously shown its role as a tumor suppressor and biomarker that reveals occult metastases in lymph nodes. They've used to it better predict cancer risk, and have even shown a possible correlation with obesity.
Reporting in the Journal of Clinical Investigation, Dr. Waldman colleagues found that silencing GC-C affected appetite in mice, disrupting satiation and inducing obesity. Conversely, mice who expressed the hormone receptor knew when to call it quits at mealtime.
However, its role in intestinal barrier integrity, inflammation, and cancer outside the intestine is new territory in the field.
A new drug containing GC-C is now on the verge of hitting the market, but its intended prescribed purpose is to treat constipation.
This study helps lays the groundwork, Dr. Waldman said, for future pre-clinical and clinical studies investigating GC-C's abilities beyond those treatments in humans, including prevention and treatment of inflammatory bowel disease and cancer.
"We've shown that when you pull away GC-C in animals, you disrupt the intestinal barrier, putting them at risk for getting inflammatory bowel disease and cancer. And when you treat them with hormones that activate GC-C it helps strengthen the integrity of the intestinal barrier," Dr. Waldman said. "Now, if you want to prevent inflammation or cancer in humans, then we need to start thinking about feeding people hormones that activate GC-C to tighten up the barrier.

[niner]

Is this the new drug? It doesn't "contain" GC-C, rather it's an agonist, which makes a lot more sense. Here's the abstract:

Constipation-predominant irritable bowel syndrome (IBS-C) and chronic constipation affect millions of Americans. Patients diagnosed with these conditions experience adverse symptoms that can have a negative impact on their quality of life. Use of agents currently available for treatment is not supported by well-controlled clinical studies. A new drug application for linaclotide, an orally administered guanylate cyclase type-C receptor agonist for treatment of IBS-C and chronic constipation, was submitted to the US Food and Drug Administration (FDA) with a target action date of June 2012. In clinical trials, linaclotide was dosed once daily, had minimal systemic absorption, lacked major drug interactions, and did not require dosage adjustment in patients with renal or hepatic impairment. Studies demonstrated linaclotide to be superior to placebo in achieving primary efficacy end points of at least 30% abdominal pain reduction, at least 3 complete spontaneous bowel movements, and an increase of at least 1 complete spontaneous bowel movement per week compared with baseline. The most common adverse effect was diarrhea. Linaclotide seems to be a promising new agent for the management of IBS-C and chronic constipation. (Formulary. 2012; 47:15-22.)

[CaptainFuture]

It's an agonist, I quoted sciencedaily: "A new drug containing GC-C is now on the verge of hitting the market, but its intended prescribed purpose is to treat constipation."

[Alec]

What about glutamine and whey? Here is some research on both. There's more if you search PubMed.

Glutamine improves intestinal barrier function in experimental biliary obstruction.
White JS, Hoper M, Parks RW, Clements WD, Diamond T.
SourceDepartment of Surgery, School of Medicine, Queen's University of Belfast, Belfast, UK.

OBJECTIVE: To determine the effects of enteral administration of glutamine on intestinal barrier function in experimental biliary obstruction.

BACKGROUND: Extrahepatic biliary obstruction is associated with the failure of intestinal barrier function, allowing bacteria and other substances from the intestine to enter the circulation and initiate a systemic inflammatory response, causing impairment of multiple organs. The amino acid glutamine has been shown to improve intestinal barrier function in other conditions, but its effects in biliary obstruction have not been fully examined.

METHODS: This study examined the effects of enteral administration of glutamine on intestinal permeability and on bacterial translocation from the intestine in a rodent model of biliary obstruction.

RESULTS: Glutamine was shown to reduce intestinal permeability measured as percentage excretion of 14C 7 days after biliary obstruction (0.35+/-0.03 vs. 0.56+/-0.085% in controls, p=0.028), and glutamine administration was also associated with a decreased incidence of bacterial translocation to extra-intestinal sites (p=0.03). Radiolabelled bacterial studies also demonstrated reduced translocation of bacterial fragments to extra-intestinal sites in glutamine-treated animals (p=0.01). There was also some evidence of decreased exposure to endotoxin, reduced systemic inflammation and increased bacterial killing by the immune system in glutamine-treated animals.
CONCLUSIONS: Glutamine modulates intestinal permeability and reduces bacterial translocation in an animal model of experimental biliary obstruction and may increase bacterial killing by the immune system.

Transforming growth factor-β, a whey protein component, strengthens the intestinal barrier by upregulating claudin-4 in HT-29/B6 cells.
Hering NA, Andres S, Fromm A, van Tol EA, Amasheh M, Mankertz J, Fromm M, Schulzke JD.
SourceDepartment of Gastroenterology, Charité, Campus Benjamin Franklin, Berlin 12200, Germany.

TGFβ (isoforms 1-3) has barrier-protective effects in the intestine. The mechanisms involved in regulating tight junction protein expression are poorly understood. The aim of this study was to elucidate TGFβ-dependent protective effects with special attention to promoter regulation of tight junction proteins using the HT-29/B6 cell model. In addition, the effects of whey protein concentrate 1 (WPC1), a natural source of TGFβ in human nutrition, were examined. For this purpose, the claudin-4 promoter was cloned and tested for its activity. It exhibited transactivation in response to TGFβ1, which was intensified when Smad-4 was cotransfected, indicating a Smad-4-dependent regulatory component. Shortening and mutation of the promoter altered and attenuated this effect. WPC1 induced an increase in the claudin-4 protein level and resistance of HT-29/B6 cell monolayers. Anti-TGFβ(1-3) antibodies blocked these whey protein effects, suggesting that a main part of this function was mediated through TGFβ. This effect was observed on intact monolayers as well as when barrier function was impaired by preexposure to IFNγ. In conclusion, TGFβ1 affects claudin-4 gene expression via Smad-4-dependent and -independent transcriptional regulation, resulting in barrier protection, a cytokine effect that is also found in whey protein concentrates used in enteral nutrition.

[CaptainFuture]

Glutamine, whey, carnitine and certain probiotics all seem to reduce intestinal permeability but I'm not sure about their effectiveness. I know of other people and I know from personal experience that glutamine can cause glutamate like effects in prone individuals, some people are allergic to whey (including me) and probiotics can cause a huge variety of symptoms including bacterial translocation in the worst case. The question moreover is if Th2 mediated reactions to leaky gut supplements worsen a "leaky gut" so much that the beneficial effects are outweighed. If you tolerate the supplements that's very good, otherwise you would have to wait for a stronger and more specific treatment option which Linaclotide hopefully will be.

[niner]

Glutamine, whey, carnitine and certain probiotics all seem to reduce intestinal permeability but I'm not sure about their effectiveness. I know of other people and I know from personal experience that glutamine can cause glutamate like effects in prone individuals, some people are allergic to whey (including me) and probiotics can cause a huge variety of symptoms including bacterial translocation in the worst case. The question moreover is if Th2 mediated reactions to leaky gut supplements worsen a "leaky gut" so much that the beneficial effects are outweighed. If you tolerate the supplements that's very good, otherwise you would have to wait for a stronger and more specific treatment option which Linaclotide hopefully will be.

Glutamine only needs a pH change to turn into glutamate, so if you're MSG sensitive, it isn't for you. Whey allergy makes sense, but what's up with probiotics? I've never heard of problems with normal (no FOS) probiotics. What's bacterial translocation, exactly? Is this bacteria leaking out of the gut? I think if someone's gut is that leaky, they have a major problem. How common is this?

[CaptainFuture]

Glutamine only needs a pH change to turn into glutamate, so if you're MSG sensitive, it isn't for you. Whey allergy makes sense, but what's up with probiotics? I've never heard of problems with normal (no FOS) probiotics. What's bacterial translocation, exactly? Is this bacteria leaking out of the gut? I think if someone's gut is that leaky, they have a major problem. How common is this?

Invasive Infection occurs by taking probiotics which then translocate into the blood stream. The reported cases where invasive infection occurs after taking probiotics are low but they exist:

*Transpl Infect Dis. 2010 Oct 7. doi: 10.1111/j.1399-3062.2010.00580.x. [Epub ahead of print]
Lactobacillus probiotic use in cardiothoracic transplant recipients: a link to invasive Lactobacillus infection?

*http://chemistry-tod....20AGRO4-08.pdf

CONCLUSIONS

Overall, we conclude that use of probiotics by most
people is safe, based on a comparison of to the large
number of people who have consumed them, and the
small number of people in whom serious adverse
events have been reported. However, probiotics can
cause invasive infection and, based on laboratory and
animal studies, there is a possibility of translocation
from the gut. Based on these data and available case
reports, we recommend that probiotics be used with caution in
individuals who have an abnormal gastrointestinal mucosal barrier,
and should be avoided in children with short gut syndrome. Probiotics
should also be avoided or used with care in patients with central
venous catheters, particularly when lyophilized formulations are being
handled prior to administration. We also recommend against use of
probiotics in severely immunocompromised patients and critically ill
patients in intensive care units. Similarly, patients with co morbid
conditions that place them at increased risk of invasive infection
should avoid probiotics.
We also conclude that there is a theoretical risk of transfer of
antibiotic resistance plasmids from some but not all probiotic
organisms. However the risk appears to be very low. Probiotics do not
appear to cause adverse immunologic, toxic or metabolic effects in
the gastrointestinal tract or systemically.

http://books.google.....ection&f=false

Page 875: All 14 people, where invasive infection was attributed to probiotics, were immune compromised.

http://books.google.....fection&f=true

Page 259: Saccharomyces infection is clinically indistinguishable from invasive candidasis.
Page 260: Saccharomyces boulardii administration is contraindicated for patients of fragile health.

[CaptainFuture]

Increased intestinal permeability could play a part in many diseases. I know that several doctors in the US and Europe test their autism and CFS patients for intestinal bacteria LPS in their blood. Many tests come back positive. A immune system involvement in CFS seems to be very likely and a recent study also points into this direction. It would be very interesting to know if a GCC agonist could be used as a treatment for a subgroup of CFS patients.

http://www.ncbi.nlm....pubmed/17007934

It is suggested that all patients with CFS should be checked by means of the IgA panel used in the present study and accordingly should be treated for increased gut permeability.

http://www.ncbi.nlm....pubmed/21967891

Conclusion: The findings show that increased IgA responses to commensal bacteria in ME/CFS are associated with inflammation and CMI activation, which are associated with symptom severity. It is concluded that increased translocation of commensal bacteria may be responsible for the disease activity in some ME/CFS patients.

http://www.ncbi.nlm....33/?tool=pubmed
Loss of Guanylyl Cyclase C (GCC) Signaling Leads to Dysfunctional Intestinal Barrier
Furthermore, upon increasing the LPS dose to 4 mg/kg, we found that 90% of the GCC−/− mice did not survive by 24 hrs after LPS challenge, (p<0.05, see Fig 2 C), suggesting that loss of GCC leads to catastrophic intestinal barrier failure and results in death due to LPS-induced sepsis.

[Luminosity]

I agree with your assessment of the problem. The solution, however, is not likely a drug.

MSM will help with this problem. Take the plain powder dissolved in room temperature water along with vitamin C or juice containing vitamin C on an empty stomach. Wait at least twenty minutes to eat. Source Naturals is the best brand. Jarrow or UltraBotanicals are also fine. Collagen might help also. Type II or types I & III may both help. Take them just as the MSM but separately. Drinking hot plain green tea or room temperature green matcha tea may also help. Eating a steamed green vegetable each day would probably help. Pick one that the individual can digest without problems. Sugar snap peas, green beans, and zucchini are some possibilities. Taking a tolerated vitamin C supplement each day will help as well as a diet high in fruits and vegetables the person can tolerate. Eat enough protein that is digestible to YOU. For some people, too many plant proteins can be irritants because they can't break them down well. For some people, a chicken breast is healthier than a veggie burger. All of the above can help building the relevant tissue.

Avoiding allergens and irritants will help. For some people, too many acidic food and drinks are not helpful.

In Chinese medicine, avoiding cold food and drink is important. They would advise taking all food hot or brought to room temperature. Some foods which are hard to digest cold become more digestible when heated.

If pro-biotics cause problems they must be rare because I've never heard of those problems. It sounds like they are confined to some very small groups. On the other hand, if you don't lack the intestinal flora in that particular pro-biotic, or if the brand you use isn't viable, or can't make it through your system in good enough condition, then that pro-biotic will not help you. I took a lot of them, including expensive ones kept in the refrigerator, but they did nothing. Once I happened to buy some yogurt at Subway that was supposed to have a particular strain that was supposed to prevent flu, somehow, but it helped my digestion. I never was able to find it again.

Edited by Luminosity, 03 March 2012 - 02:39 AM.