[Breakthrough] This could be the cure/treatment for Leaky Gut (PLoS ONE study)

This is the first time for a long time now that I have hope again. You won't believe it but leaky gut is also implicated in cancer and science seems to catch up on it. This will not be a cure for CFS but it could mean tremendous improvement for a subgroup of PWCs who suffer from an increased intestinal permeability/leaky gut. In order to treat increased intestinal permeability (which is connected to cancer, allergies etc.) we probably have to focus on the guanylyl cyclase C receptor. The best thing about this study is that a new drug is about to hit the market which seems to do this exactly, it contains GC-C but was only intended to treat constipation. It therefore could be the first effective treatment for leaky gut.


http://www.sciencedaily.com/releases/2012/02/120221212345.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."

Yes, this could turn out to be a big thing. Let us know if you find out what the drug is called, and where exactly in the pipeline it is.

Thanks Wave, inspiring for sure. This is one to follow closely.

I suppose it might be helpful for autism as well.

We were having a chat about this sort of thing on this thread:
http://phoenixrising.me/forums/show...Lyme-disease-the-culprit-energy-levels-lifted

The drug is called Linaclotide and is manufactured by Ironwood Pharmaceuticals (http://www.ironwoodpharma.com/gastrointestinal.php)
I don't know when it will hit the market but it must be soon. Phase III studies have been done:

"Full results from two Phase III linaclotide trials involving over 1,600 patients with irritable bowel syndrome with constipation (IBS-C) presented at the European Gastroenterology Week (UEGW) congress in Stockholm"

"In August 2011, Ironwood and Forest submitted a New Drug Application (NDA) with the Food and Drug Administration (FDA) seeking approval to market linaclotide to IBS-C and CC patients ages 18 and older in the U.S.

In September 2011, our European partner, Almirall S.A. submitted a Market Authorization Application (MAA), with the European Medicines Agency (EMA), seeking approval to market linaclotide to IBS-C patients in the E.U."

Thanku for all the info Waverunner.

Like Tristen said, we'll have to keep an eye on this drug. (I think i'll set up a google alert.)

This is posted in the comment section of Amy's latest article. Wonder if the drugs work similarly.

http://blogs.wsj.com/health/2012/02...mes-to-chronic-fatigue-syndrome/tab/comments/



12:03 pm February 23, 2012
Esther Siebert wrote :
.Dear Amy Dockser Marcus and all ME/CFS doctors and patients,

Something amazing has happened to me using a repurposed drug that Id like to share with you. After 25+ years of severe ME/CFS, by a fluke of fatea miraculous accident reallyI have apparently recovered from ME/CFS!

Much like the accidental discovery in Norway, I was given Xifaxan, a gastric system antibiotic that doesnt go into the bloodstream, by my gastroenterologist to treat undiagnosed stomach symptoms. He suggested I try it because it doesnt cause side effects and he said there was a 50-50 chance that it would create a miracle in terms of my gastrointestinal symptoms. ( Later. after more symptoms presented themselves, he diagnosed me with gastroparesis which causes overgrowth of bacteria in the stomach and small intestine. These bacteria send toxins to the brain which Im guessing cause the ME/CFS symptoms which have resolved.)

So my gastrointestinal symptoms were treated with a short course of Xifaxan (Rifaxamin). In a couple of days, my ME/CFS symptoms disappeared, only to reappear when I stopped the medicine. I used the short-term treatment dose three times, getting better each time, only to relapse when I went off of it. Though the treatment had no effect on my gastrointestinal symptoms, it unexpectedly treated my ME/CFS.

I did some research and discovered that indeed Xifaxan was used on a maintenance basis for one condition. Now I use a maintenance dose every day. And my ME/CFS symptoms both physical and cognitivehave disappeared. Some ME/CFS doctors are using Xifaxan on their patients but I believe only on a short term treatment dose. Apparently these patients are relapsing as I did before using the maintenance dose. I would love to get the word out for doctors to try the maintenance dose on these relapsing patients.

The short course treatment dose is 550 mg of Xifaxan or Rifaximin, 3X a day, for something like 10 days as I recall. The maintenance dose is 550 mg 2X a day indefinitely. Gastrointestinal symptoms were never a hallmark of my ME/CFS.

This has been an amazing experience that Id like to share with others. Perhaps what helped me will have wider applicability to other victims with gastrointestinal symptoms. I would hate to be the only one to benefit. There are so many of us suffering in desperate isolation with no hope.

@shannah: Rifaximin is an antibiotic. Several PWCs made good experiences with it. I took it myself. Rifaximin has be around for some time now but the way it works has nothing to do with Linaclotide although both reduce inflammation.

Thanks for sharing shannah.

I think you should post that as a new thread, if you haven't already?

Maybe in the general treatment section or antiviral/antibiotic section?

Hi Bob,

I think this post was mentioned by Esther here on the thread that Cort did about Corrine taking questions to Dr Peterson. Here, at post #7. I agree, a new thread would be nice, to discuss it further. Although any attempt to talk about a possible d-lactate connection seems to go down like a lead balloon!!

http://forums.phoenixrising.me/show...erson-6-Including-Picking-Dr-Peterson-s-Brain!

Thanks Glynis.

I see that Corinne talks about Xifaxan on her blog as well:
http://forums.phoenixrising.me/content.php?535-Corinne-At-Dr-Peterson-6-Picking-Dr-Peterson-s-Brain!

Thanks Wave, Glynis and Bob.

I posted the info into the Antibiotic section before reading that it had been discussed in Corrine's thread.

Great idea!!

I thought IBS belonged within the group of 'Functional Somatic Disorders'

http://www.meactionuk.org.uk/In_Debate_Wessely_Sharpe_and_White.pdf

Intestinal permeability that can be pharmacologically treated doesn't sound very 'functional' to me.

If IBS isn't functional, what faith can you have in a diagnosis of 'functional' in these other disorders or, more fundamentally, the very existence of any such thing as a 'functional disorder'?

The problem with "functional" is that some scientists will always claim, that even acid reflux is real, the cause is stress or depression. It's a chicken and egg discussion but the more we understand the better we can describe he causative agents of illnesses.

Linaclotide is a GCC agonist and should help to protect the intestinal barrier. What happens if the GCC receptor is removed?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031533/?tool=pubmed

Loss of Guanylyl Cyclase C (GCC) Signaling Leads to Dysfunctional Intestinal Barrier

GCC?/? mice are predisposed to LPS-induced intestinal injury
To further determine the function of GCC signaling in intestinal barrier, we challenged wild type (GCC+/+) mice and GCC?/? mice with a non-lethal dose of LPS (1 mg/kg), which has been reported to cause a mild and reversible alteration in intestinal barrier function by promoting bacterial translocation and cytokine secretion [24]. LPS challenge (12 hr) did not increase permeability in the jejunum of GCC+/+ mice or the already elevated permeability in GCC?/? mice (Fig 1B); however, we found there was remarkably elevated permeability in the ileum of both genotypes after 12-hr LPS challenge and the increase was significantly higher in GCC?/? mice compared to baseline (Fig 1B & C). Consistently, a significantly higher amount of bacteria translocated to mesenteric lymph nodes (MLN) in GCC?/? mice relative to GCC+/+ mice after 12-hr LPS challenge (Fig 2A), demonstrating that loss of GCC leads to ileal barrier dysfunction after LPS challenge; also, GCC?/? mice consequently lost a significantly higher percentage of body weight than WT mice (p<0.01, Fig 2 B). 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.

Fascinating waverunner. Thanks for posting.

There are many people with ME/CFS who have LPS in their blood and the studies by Maes et al. all point into this direction. The question is whether our current treatment options reduce intestinal permeability (IP) so much that it does not contribute to CFS anymore. In this case there would be not much improvement through new drugs on improving gut integrity. On the other side however, if our current treatment options DO NOT improve IP enough, this could be a great treatment target.

I find this particularly interesting as I was diagnosed with coeliac after tests to try to establish the cause of my symptoms. As I understand it leaky gut is a possible candidate in coeliac also, at least in some theories. Would it be reasonable to think that if this was likely to help it would be most likely to help a sub-set of PwME with co-morbid coeliac/IBS/other gut issues?

I was not aware we had such options, most of what I found when following leaky gut trail online was dietary exclusion and/or dietary supplements, but none seemed to have much research behind them - is that what you are referring to, or am I woefully ignorant of other options (entirely possible ) .

While I am sure gut issues are not causative for all PwME in my particular case I do have a gut feeling (obvious pun intended) that it is a good avenue of attack in my case.

Once this drug is available what do you think the odds are that I/we would get access to it (in UK in my case)? I appreciate the answer may depend on side-effects etc. but is it going to be a case of something no GP would ever give me against a coeliac and possibled ME/CFS diagnosis, or do you think there would be a good chance of persuading my GP it is suitable?

Presumably (am I guilty of trivialising here?) if the drug is to be prescribed for constipation it cannot have too serious a set of side-effects?

Dammit, I want some now...

Hi DaiWelsh,

Linaclotide should be available soon, also in the UK. However I don't know the exact point of time, I hope in the next few months. The drug could help with coeliac disease but even if it does not, another new drug called Larazotide will be available in a few years and it should definitively help with coeliac disease. It also improves the intestinal barrier. Both are backed up by quite a bit research and this is what makes me optimistic.

Best of luck to all of us.

EDIT: The FDA decision about Linaclotide will be in June this year.