Talk:Intestinal permeability/Archive 1

Should MEDRS strictly apply here?

Intestinal permeability seems like a topic that sophisticated health care professionals might also find useful as it's a key feature of the digestive system, so I don't think that WP:MEDRS should strictly apply here. I changed the article to Category:Digestive system, to make this clear. This was inspired by looking at the zonulin article, which only cites primary sources, and is in Category:Digestive system.

There seems to be some conflation of leaky gut syndrome article and this article, as if anyone wanting to learn about intestinal permeability is also searching for leaky gut syndrome, though clearly this article is about a general mechanism, not a GI disorder (as it was previously categorized). My addition of non-controversial biochemistry about a receptor, ligand, and an experimental (and unavailable) peptide drug that targets the interaction aren't about health recommendations, the concern behind a strict application of WP:MEDRS, but rather mostly about biochemistry. This simple summation of a primary source should be allowable -- this isn't the highly scrutinized common cold article, after all -- even though there is a secondary review source in this case.

And even if you do believe that WP:MEDRS should strictly apply in this article, WP:MEDRS only deprecates the usage of primary sources, assigning them "minimal WP:WEIGHT", but that's very different from zero weight. No one disputes that zonulin acts on CXCR3 receptors, which then modulates intestinal permeability. This has been known since 2000. Low weight is still enough to support the conclusion in the absence of any disagreement. Pro crast in a tor (talk) 13:34, 13 May 2014 (UTC)

MEDRS applies to all health-related articles, including any biochemistry or physiology that (as you point) is relevant to health. Please see the the lead of MEDRS. As you say, intestinal permeability is a physiological parameter of the gut; "leaky gut syndrome" is a fake medical condition. They are different. Both are subject to MEDRS and to WP:FRINGE.Jytdog (talk) 13:52, 13 May 2014 (UTC)

btw, we will really learn if the zonulin/CXCR3 axis is relevant to health when there is a drug on the market that targets that interaction that improves patients' health. until then, it is a hypothesis. (well validated for sure but many many well validated hypotheses about targets turn out not to be true - that is one of the reason why Phase III clinical trials are very real scientific experiments. Jytdog (talk) 14:36, 13 May 2014 (UTC)

Seeing a pharma company putting money into targeting the zonulin CXCR3 receptor was a strong factor in my revisiting the leaky gut hypothesis, though clinical trials of a drug is just one possible way to validate the mechanism. Prolamins like gliadin have been shown to trigger zonulin release, increasing intestinal permeability, and simply avoiding these cereals is another way to reduce zonulin expression, reduce intestinal permeability, and reduce IBD severity (or another disease, but IBD is relatively easy to study/measure outcomes). Zonulin can be directly measured in serum, as can intestinal permeability via mannulose/lactulose testing, and the two generally agree. Prospective studies that experimentally reduce gliadin intake in a double blind, placebo controlled fashion, and show a clear health benefit (as well as clear evidence for the proposed mechanism), could also help prove the existence of the clinical concept.

And in fact, a one DBPC prospective study on non-celiac patients with IBD symptoms has been performed, and though it's a primary source, you might find this study in American Journal of Gastroenterology from Sicily compelling. Of the 276 study participants that were diagnosed wheat sensitive via double blind, placebo controlled trial, 80% reported IBD symptoms when taking wheat capsules for two weeks, and none of the wheat sensitive people responded to the placebo. In fact, 50% of them actually told the researchers in advance that they knew they were wheat sensitive - again, this was Sicily, home of pasta. As they said in the discussion, "clinicians might do well to listen to patients" when it comes to IBD suffers that say wheat-free diets are helpful.

The 'leaky gut' hypothesis was certainly a WP:FRINGE theory until perhaps 2010, five years after zonulin was isolated as the hypothesized but unknown permeability factor, well after the 2005 Nature review was released. In the past few years, the hypothesis has had some serious research and exposure, and the evidence, both by elucidated mechanism and by clinical experiments, have shown that it appears to be a clinically useful insight.

• Check out the tens of thousands of citations for Alessio Fasano's work, spread over dozens of journals. He started work on isolating how cholera spread in 1994, which lead to zonulin in 2000, and now he's invited to be a coauthor or write review articles for dozens of journals. Now at Mass. General as chief of pediatric gastroenterology and nutrition, he helped determine the gluten-free FDA standards (20 PPM) that were implemented in August 2013, and take effect in August 2014. He's smack dab in the middle of the establishment, not a reviled fringe figure selling a supplement or book.
• A 2003 review article in Advanced Drug Delivery Reviews, which highlights cholera's exploitation of the zonulin system to bypass the intestinal barrier.
• A 2005 review article in Nature Clinical Practice Gastroenterology & Hepatology with Review criteria:

PubMed was searched in February 2005 and again in July 2005 using the following keywords alone and in combination: "intestinal permeability", "autoimmunity", "tight junctions", "toll", "innate immunity", "occludin", "claudin", "claudins", and "intestinal AND disease AND permeability"

• A 2008 review article in Current Opinion in Gastroenterology November 2008 - Volume 24 - Issue 6 - p 687–691, who note that CD is a relatively easy autoimmune disorder to study, making it a good model for other autoimmune disorders.
• A 2012 review article in Clinical Reviews in Allergy & Immunology is titled "Leaky Gut and Autoimmune Diseases", which I recently added to this article for the uptake route size in angstroms.
• Another 2012 review article in Physiology Review goes so far as to include some cancers as possible results of a leaky gut.
• And of course, the zonulin receptor targeting drug has now been tested with over 1000 people, and is now entering phase III trials.

As everyone here knows, Wikipedia is a lagging medical resource by design, but I think that post-2012, the evidence for the leaky gut hypothesis has built sufficiently to say it's no longer fringe. Evidence isn't overwhelming, Cochrane has yet to weigh in on the topic, and there aren't enough RCTs for a meta-analysis; however, there is enough support for the hypothesis to lay off on the pseudoscience allegations with "no evidence", or to be called a "fake diagnosis". I'm sure snake oil salespeople will continue to oversell the issue, but that doesn't mean that there's no evidence for, or physiological basis behind, the leaky gut hypothesis. Pro crast in a tor (talk) 13:06, 14 May 2014 (UTC)

the article is clear that intestinal permeability appears to be a factor in several medical conditions. "leaky gut syndrome" and the pile of crap dietary supplements peddled to "treat" it remains pure unadulterated FRINGE (as that is defined on wikipdia). Please think clearly. Jytdog (talk) 13:11, 14 May 2014 (UTC)

"Leaky gut" is a term often used in journals to describe high intestinal permeability, and the idea that a leaky gut might cause health problems is referred to as the "leaky gut hypothesis". [www.scirp.org/journal/PaperInformation.aspx?paperID=27948 Exactly one paper] refers to "leaky gut syndrome" as synonymous with "intestinal hyper-permeability", so it seems academia mostly agrees with you that "leaky gut syndrome" is a term not to be used in academia. Pro crast in a tor (talk) 13:51, 14 May 2014 (UTC)

There is some terminological fuzz in this area, but there are two fields: medicine and science (as discussed in this article), and the quackery that says gut problems (e.g. "parasites") causes all kinds of systemic health issues (e.g. multiple sclerosis) - and so buy expensive dietary supplements now! By and large, the term "leaky gut syndrome" is used for the quackery thing, and for consistency Wikipedia follows that, making the distinction clear both here and in the Leaky gut syndrome article. What we don't want to do is to start legitimizing the health fraud by mixing in real science with it. Alexbrn ^{talk|contribs|COI} 14:05, 14 May 2014 (UTC)

amen brother. Pro crast in a tor about this this dif which I reverted, we do want to keep the terminology clear. Please do not re-create the confusion that we just clarified. and again please keep in mind, there are zillions of ideas about disease out there. linus pauling started the whole "antioxidant" hullabaloo which has generated oceans (literally) of basic research papers, dietary supplement sales, and expensive clinical trials. Not a single phase III clinical trial has shown efficacy for anti-oxidants. In fact the SELECT cancer prevention trial showed that taking vitamin E and selenium increases (not decreases) the likelihood of getting cancer, and people were so certain of the antioxidant hypothesis and there was so much preclinical work supporting it that the NIH - which is very risk averse with regard to funding clinical trials - funded the Phase III trial. Again, until there is a diagnostic test on the market (validated by clinical trials) testing some aspect of IP, the ideas that IP is definitely correlated with disease is a hypothesis, and until there is a drug on the market addressing a disease via the zonulin/CXCR3 axis (or some other interaction that is clearly related to IP) the idea that sick people will actually be healthier if we reduce IP is just a medical hypothesis, not a fact. You seem to think both of them are medical facts. This is not true. Jytdog (talk) 14:13, 14 May 2014 (UTC)

Jytdog, dietary clinical trials are just as valid as pharmacology clinical trials. Larazotide acetate is being marketed as an alternative or adjunct to a gluten-free diet, which is undeniably an effective treatment for celiac disease. In CD patients, intestinal permeability has been shown to be a leading indicator, increasing before symptoms are shown. 1000 sick people have been shown to get healthier by reducing intestinal permeability. The antioxidant trials failed to show more than a few percentage point changes in relative risk, where as gluten-free diet helps about 80% of all celiacs with IBD symptoms, more than two degrees of magnitude more effective. Lacman (lactulose/mannitol) tests are widely available, and were correlated with zonulin serum levels in 2000. This is the primary way that intestinal permeability is tested in experiments cited in the review articles, as well as in clinical trials of Larazotide acetate. I'll add a section on testing when I get a chance.

I'm following the lead of multiple review articles that use the term "leaky gut". It's a common tactic of pseudoscience to choose a similar sounding name to hijack reputation, and there's nothing we can do about potential confusion except to help clear it up. A quick search of google scholar shows that the academic literature manages to keep the two separate, with hundreds of articles including the term "leaky gut", but only one using the term "leaky gut syndrome". This confusion is directly addressed by this physician-journalist in The Daily Beast, formerly Newsweek, and includes comments by Fasano where he disparages the leaky gut syndrome preachers as being a cure-all.

Alexbrn, actually, intestinal permeability has been correlated with MS (see B2 in this review, with zonulin expression in RPMS subjects in remission resembling controls, P=0.03, which is impressive for a study with only 62 patients), so yours is a poor example. I haven't seen any leaky gut syndrome supplement ads -- it's outside my filter bubble, I suppose. But as with most pseudoscience, it wouldn't be so pernicious if there were zero truth to it: if it works _sometimes_, it won't be discarded as a completely ineffective fad diet. The adoption rate of paleo/gluten free diets do not resemble the low-fat and low-carb fad diets in adoption rates, which is strong evidence that it is, at least occasionally, helpful. See adoption rate graph here. And bear with me on a thought experiment: if intestinal permeability is causal in CD (1% of the population), most autoimmune disorders (6-8% of the population), and IBD sufferers (another 1% of population), then about 10% of the population might benefit from eating gluten-free or regulating their zonulin levels. And let's say half the population has some kind of malady, from plantar's warts to IBD to stage IV cancer, and is seeking a way to fix it. That means 10/50 = 20% of the time, eating gluten-free will help people with an random ailment, which is higher than placebo effectiveness (and probably more like 30% when placebo is included). I think this thought experiment explains the popularity of "leaky gut syndrome" as a cure-all. I'm not saying the above numbers are accurate, I'm just trying to point out that in surprisingly large fraction of the population, eating gluten-free will actually address real problems. Zonulin expression has been shown as an early warning biomarker for various cancers in C3 of this review, and even to show a role in the pathogenesis of some cancers, with tumors shown to be zonulin-enriched. If these links to cancer stand up to future scrutiny, well, I've read Fasano's name floated as a Nobel candidate, which doesn't seem unwarranted for his 20 years of work on the topic. Pro crast in a tor (talk) 01:34, 16 May 2014 (UTC)

Procrastinator, there is no doubt that if you have celiac, cutting gluten out is dramatically helpful. You are focusing on one thing that gliaden does and not dealing with the immune response. We don't know which is more important to health. We don't know what clinical trials will show - if you take the zonulin antagonist and eat wheat, will your intestine not be destroyed anymore? Will you be healthier? Do you see what I am saying? Jytdog (talk) 03:14, 16 May 2014 (UTC)

I focus on celiac disease because the pathophysiology is well understood, down to the biochemistry of every little step in at least one pathway. See Gluten_immunochemistry, especially the right explanatory panel. Increased intestinal permeability is part of a chain that can impacts health in many ways. We may not know all of the different ways for polypeptides to make it through the gut wall, but we can measure the response to their passage if and when they do. Autoantibodies can only be formed when exposed to epitopes that pass through the gut wall. If the TJs are fully competent, only 3-4 amino acid chain (3-4mers) can pass through. I believe all immunogenic epitopes are at least 10 amino acids long. Do you see how permeability is a physical restriction? Though the text I added talks about zonulin, I was careful to start with "One way in which...". The role of intestinal permeability in pathogenesis is well established, even if all of the possible mechanisms might not be fully known, and a drug validating one pathway isn't required to say that intestinal permeability is a part of pathogenesis of various autoimmune disorders. We also have knockout mice that have been fed alpha-gliadin, and they develop type 1 diabetes at a dramatic rate. No alpha-gliadin, no autoimmune response, no t1d, longer lifespan. Very repeatable. Pro crast in a tor (talk) 10:53, 18 May 2014 (UTC)

we are veering off into "general discussion of the topic" now and we should stop. We don't have to agree on this; we just have to make sure that the text of our article is accurate. Jytdog (talk) 16:52, 18 May 2014 (UTC)

"Leaky gut" terminology

Procrastinator , Wikipedia is about reaching consensus, not about winning. Please continue discussing whether we are going to use the terminology "leaky gut" in the article, and how, instead of just sticking it, which you have done twice now. There is no deadline here so you don't need to rush to insert it. Please. I might be OK with using the term in the article, but it would have to be something like: also known as "leaky gut", which is distinct from "leaky gut syndrome". Am thinking about this. This is a preference-based consideration for all of us, not something based in policy or guideline, so let's just calmly talk this out, in the Wikipedia way. thanks. What do the two of you think of this? Jytdog (talk) 02:56, 16 May 2014 (UTC)

In the LGS article we say: "While a "leaky gut" (or intestinal permeability) is a phenomenon recognized by mainstream science, the existence of a condition called "leaky gut syndrome" is supported mostly by nutritionists and practitioners of alternative medicine.[2]" -- would some kind of mirror of that wording work here? Alexbrn ^{talk|contribs|COI} 05:15, 16 May 2014 (UTC)

thanks alexbrn... that is kind of weak, though. I would support "While a "leaky gut" (or intestinal permeability) is a phenomenon recognized by mainstream science, the existence of a condition called "leaky gut syndrome" is not." And we put this at the start of the paragraph on LGS - it makes a good transition there between science and FRINGE. Would you guys be OK with that? Jytdog (talk) 11:26, 16 May 2014 (UTC)

In my understanding there are (a very few) uses of "leaky gut syndrome" in real medicine, so I think it's worth adding some qualifier: "... the existence, in alternative medicine, of a condition called 'leaky gut syndrome' is not" . Might be worth strengthening the wording in the LGS article too? Alexbrn ^{talk|contribs|COI} 11:40, 16 May 2014 (UTC)

yes and yes. Procrastinator? Jytdog (talk) 12:11, 16 May 2014 (UTC)

There's exactly one result on google scholar for "leaky gut syndrome", so vilify away at that term. And Alexbrn, per the review articles, "leaky gut" is used to refer to _excessive_ intestinal permeability, not just intestinal permeability. The intestines are always permeable, and it's the size of macromolecule that can travel through channels in the membrane that varies with TJ competency. Too much zonulin increases pore size so much that unwanted epitopes (like the 33mer of alpha-glidin) can enter the body through the membrane, stimulating an immune response, hence "leaky gut". At normal levels of zonulin, 33mers can't pass through, only water and shorter polypeptides that aren't immunogenic. Personally, I think there should eventually be a section titled "Leaky gut", but the rest of the article isn't ready yet, so do whatever you want. Also, y'all think about redirecting "leaky gut" straight to this article, rather than to the current disambiguation page? I think this more science-y article could be more helpful to most readers than the pseudoscience debunking LGS article. Pro crast in a tor (talk) 17:30, 16 May 2014 (UTC)

OK, thanks for the greenlight to do whatever. I remain surprised that you are putting so much credence into this hypothesis, that has not yet been validated clinically. It is clear that you find it powerful and persuasive - and I caught how you answered my question above - the hypothesis (as I understand it) is that if the TJ remains tight, gliaden doesn't escape and you wouldn't get an immune response. Not everybody is convinced of this picture (as per PMID 21890812). It appears that the gliadin peptides may directly damage the intestines, and there may be local immune response. And most importantly, there are serious questions as to whether IP is a cause or a consequence. Please don't state hypotheses as facts on WP. Thanks! Jytdog (talk) 17:51, 16 May 2014 (UTC)

Gut flora

An edit of on preliminary evidence for an involvement of gut flora has been reverted (link) citing WP:MEDRS. While I do not find the revert entirely necessary under MEDRS, I do not find it without some merit either, especially as there is something to be said for working exclusively the basis of review articles for such a topic, so I do not object per se.

What I do object to however is that, in a later step, a further edit on contributions of gut flora with an inline reference to a review article that clearly fulfils WP:MEDRS was reverted (link), with a rather rude-sounding comment at that, and for no good reason (citing MEDRS! wheras the reference clearly fulfils MEDRS). Furthermore, the admonition in that edit comment to "stop overselling animal studies" (!?) is rather surprising in this context, given that the article is on intestinal permeability as such (and not only restricted to humans), so wherever applicable adding the words "in animals" is appropriate and sufficient, but not such a deletion.

As the reason for deletion is insufficient, that deletion (link) should be taken back.

--Chris Howard (talk) 18:24, 27 December 2014 (UTC)

MEDRS is very clear that we do not make general claims about health based on animal studies. Jytdog (talk) 18:45, 27 December 2014 (UTC)

Please observe Wikipedia guidelines on discussion pages by not using judgments like "reprehensible", all the less bold-faced - at least you took it back (link). I find your style of edit comments and discussion contributions unnecessarily brings emotions like annoyment etc into the picture which is not helpful. I do think we are all editing in good faith here, so this is not necessary.

Concerning the content of your comment, the article is about a biological phenomenon of intestinal permeability. Very clearly, this also has health impacts, but it is not a health-only topic as such. Therefore, in my view the text as follows (with insertion of "For mice," at the beginning) is not objectionable but rather improves the article:

For mice, it has been shown that an intake of bifidobacterium can improve the gut epithelial barrier.

(Inline reference as follows: [Quote: "The administration of probiotics containing Bifidobacterium is associated to an improvement of gut epithelial barrier, promoted by increased expression of tight-junction proteins […] Consequently, a significant reduction of bacterial translocation, intestinal inflammation and metabolic endotoxemia have been observed". Cited from: Festi, Davide; Schiumerini, Ramona; Eusebi, Leonardo Henry; Marasco, Giovanni; Taddia, Martina; Colecchia, Antonio (2014). "Gut microbiota and metabolic syndrome". World Journal of Gastroenterology : WJG (Review). 20 (43): 16079–16094. doi:10.3748/wjg.v20.i43.16079. PMC 4239493. PMID 25473159. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: unflagged free DOI (link)])

--Chris Howard (talk) 19:15, 27 December 2014 (UTC)

let me ask you, why do you care if mice have intestinal permeability? why does that matter? Jytdog (talk) 19:39, 27 December 2014 (UTC)

because it is science, and science may be an inspiration for further research.

Can we agree that the section, as modified, goes back into the article, but now into the new section on "Rodent research"? --Chris Howard (talk) 21:11, 27 December 2014 (UTC)

and I call "bullshit" on that answer. the only reason experiments are done on animals, and the only reason anybody cares about the results, is that they might give insight into human health. Jytdog (talk) 21:30, 27 December 2014 (UTC)

Look, I do not agree with your style of discussion. If you have your own view on what other persons' motives are and your own judgment about what science is for, then that is your business, but how you discuss with people on Wikipedia is not your business alone.

Again, this section is about a specific issue, not more. Now that your objections against the sentence on gut flora have been addressed, I assume the sentence can go back in. --Chris Howard (talk) 22:07, 27 December 2014 (UTC)

Jytdog, in the mean time I noticed that you simply entirely removed the new section. Please do not do that while the discussion is ongoing.

Just to highlight the relevance of research on rodents, see for example the statement in the review article PMID 21807932 which says: "many agents that affect gut flora/permeability, such as probiotics/prebiotics, also appear to affect obesity and certain forms of liver injury in animal model systems".

So please be constructive on this whole question. --Chris Howard (talk) 22:56, 27 December 2014 (UTC)

i just glanced through your contribs. you seem to be a hard sciences person, moving recently into health-related content. biological sciences are utterly different than dead sciences. animal studies only sometimes reflect what is going on in people. Our goal here is to provide the public with reliable information. There is no end to the baloney we could have in WP articles about diseases, if we fill them with content about animal studies. really. i wrote an essay that still needs a lot of work, called Why MEDRS?... that explains why MEDRS calls us to avoid adding content to health-related articles based on in vitro or animal studies, and to avoid primary sources (I do recognize that you have been using reviews, which is great). please have a look at it. (btw, i acknowledge that I am crabby today - sorry about that.) Jytdog (talk) 01:06, 28 December 2014 (UTC)

I appreciate your message. There's much to say, but given that in Wikipedia we cannot meet up for a beer and talk it through, I'll keep it short, as is appropriate in an article's Talk page. I read your "Why MEDRS" and actually found it exceedingly well-written. Sort of like: this is rather what I meant with "something to be said for", just that you have fully fledged it out.

Back to business: I think much would be gained in the article by having a "Research" section, containing also results on animal models like those discussed so far (and clearly to be marked as such in the article), yet mainly information on which are at present, according to recent review articles, the main questions or research directions on this topic - stating what is under investigation, with a link to the review article making the statement. (Rather similar to the "Research" section that I introduced into the "Gluten sensitivity" article - an article which for the rest still needs quite a workover, but that is another matter.) --Chris Howard (talk) 14:49, 28 December 2014 (UTC)

FYI, still waiting for your answer on the earlier sentence (on mice). In the mean time I intend to further expand the article based on a review article of 2014 (PMID 25473159, clearly meeting WP:MEDRS) which provides an overview that touches upon the intestinal barrier, including studies on animal models and on human clinical trials, and I would appreciate if in case of an objection to the content of such an edit, you would not just delete or revert but rather re-word or re-frame it. --Chris Howard (talk) 10:58, 29 December 2014 (UTC)

well you seem determined to lard WP with a bunch of early stage, unreliable information. All I can do is ask you to be very very clear that the research is just that and not applicable to human health. And please do not give undue weight to the section. Jytdog (talk) 17:11, 29 December 2014 (UTC)

I appreciate the timeliness of your reply. But in my way of seeing things your first sentence contradicts WP:AGF and WP:CIVIL: would you care to put it in strikethrough? --Chris Howard (talk) 18:06, 29 December 2014 (UTC)

you are pushing it. i have agreed to stand down although I don't like it - in my view adding content about animal models of diseases is not information that is helpful to the public, and because it often doesn't match what happens in people, it is indeed often misleading to the public - information gleaned from animal studies (highly artificial, usually conducted on genetically pure strains that don't even resemble WT mice, much less humans) is information that scientists use to try to understand what is going on in people. I will not kiss your ass too. Jytdog (talk) 20:47, 29 December 2014 (UTC)

the thing is that as far as I see it you are pushing it by adding sour remarks to what you say, and I have stood back by not taking offense so far. But we may not agree on how to communicate in WP.

In my view, adding content about animal models is helpful for understanding a biological phenomon as such, also for future research directions. --Chris Howard (talk) 21:52, 29 December 2014 (UTC)

wikipedia is WP:NOT many things, including a textbook and a "guide to future research". But whatever. Jytdog (talk) 22:24, 29 December 2014 (UTC)