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Posts Tagged ‘Leaky-Gut’

Framework Matters: Study Links for Safe & Effective Crohn’s Strategies

June 5, 2012 8 comments

This post is really a reference guide that includes an outline and framework for thinking about Crohn’s strategies in a differnent way, along with links to a series of studies that go into depth about each area. This is a good place to start research, and a good resource to share with your doctor.

 
Nothing in biology (nutrition or medicine) makes sense except in the light of evolution. Dr. Loren Cordain

Intestinal Barrier Function & Leaky Gut:

These studies provide the framework for all the rest. Essentially all modern diseases of inflammation can be linked to a series of mismatches between our genes and environmental factors. The origin of this inflammation starts in the gut with a breakdown in intestinal barrier function.

  • The Western diet and lifestyle and diseases of civilization: Cordain, Research Reports in Clinical Cardiology: 2011 March
  • Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Fasano Nat Clin Pract Gastroenterol Hepatol. 2005 Sep
    Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer Alessio Fasano Physiol Rev 2011 Jan
  • Leaky Gut and Autoimmune Diseases Fasano Clinic Rev Allerg Immunol 2011 Nov

  

Below is a simple chart that list the stressors/environmental factors that either increase intestinal permeability directly or damage the balance of the gut flora, all leading to inflammation.

Increasing Intestestinal Permeability

Gluten/Prolamines

Casein

HBC

Stress

Lectins & Saponins

Low Vitamin D

PPI

Sleep Deprivation

Omega 6 Fats

Antibiotics

Alcohol

Endurance Exercise

FODMAPs

NSAIDs

Capsaicin

 

 

Below is a simple chart that list the environmental factors that either decrease intestinal permeability directly or improve the balance of the gut flora, all leading to reduced inflammation and healing.

Improving Intestestinal Permeability

IBD Diet

Krill Oil

Probiotics & Fermented Food

Colostrum

Proline (Broth & Gelatin)

Curcumin — BCM95

Mutaflor, VSL#3, Lactobacillus paracasei

LDN

CLA (Bones & Butter)

Boswellia — 5Loxin

S. Boulardii,  B. Coagulans

Cannaboids (CBD)

D3 & K2

L. Glutamine & Arginine

Sleep, Meditation/Yoga, Acupuncture

IF & HIIT = Growth Hormone

Diet:

  

 Fat Balance:

  • Linoleic Acid, a Dietary N-6 Polyunsaturated Fatty Acid, and the Aetiology of Ulcerative Colitis – A European Prospective Cohort Study. Gut 2009 July
  • The Type of Dietary Fat Modulates Intestinal Tight Junction Integrity, Gut Permeability, and Hepatic Toll-Like Receptor Expression. Alcohol Clin Exp Res. 2011
  • Conjugated linoleic acid modulates immune responses in patients with Mild to Moderately active Crohn’s disease. Clinical Nutrition 2012 March.
  • Lipid based therapy for ulcerative colitis-modulation of intestinal mucus membrane phospholipids as a tool to influence inflammation. Int J Mol Sci. 2010 Oct
  • Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr. 2009


   

Microbiota & Probiotics:

  • Gut Microbiota and Pediatric Disease Dig Dis 2011
  • Association between the use of antibiotics and new diagnoses of Crohn’s disease and ulcerative colitis. Am J Gastroenterol. 2011 Dec
  • Association of Repeated Exposure to Antibiotics With the Development of Pediatric Crohn’s Disease–A Nationwide, Register-based Finnish Case-Control Study. Am J Epidemiol. 2012 Apr
  • Influence of Saccharomyces boulardii (Florastor) on the intestinal permeability of patients with Crohn’s disease in remission. Scand J Gastroenterol. 2008
  • Anti-inflammatory effects of Saccharomyces boulardii mediated by myeloid dendritic cells from patients with Crohn’s disease and ulcerative colitis. Am J Physiol Gastrointest Liver Physiol. 2011 Dec
  • The probiotic Escherichia coli Nissle 1917 (Mutaflor) reduces pathogen invasion and modulates cytokine expression in Caco-2 cells infected with Crohn’s disease-associated E. coli LF82. Trop Med Int Health. 2011 May
  • Probiotic Bacteria Produce Conjugated Linoleic Acid Locally in the Gut That Targets Macrophage PPAR γ to Suppress Colitis. PLoS One. 2012
  • Lactocepin Secreted By Lactobacillus Exerts Anti-Inflammatory Effects By Selectively Degrading Proinflammatory Chemokines Cell Host & Microbe 2012 April
  • Helminthic therapy: improving mucosal barrier function. Trends Parasitol. 2012 Mar 

Supplements:

  • Vitamin D and gastrointestinal diseases: inflammatory bowel disease and colorectal cancer.Therap Adv Gastroenterol. 2011 Jan 
  • Curcumin Ameliorates Hydrogen Peroxide-Induced Epithelial Barrier Disruption. Dig Dis Sci. 2012 March.
  • Therapy of active Crohn disease with Boswellia. Z Gastroenterol. 2001 Jan
  • Dietary supplementation of krill oil attenuates inflammation and oxidative stress in experimental ulcerative colitis. Scand J Gastroenterol. 2012 Jan
  • Glutamine and Whey Protein Improve Intestinal Permeability and Morphology in Patients with Crohn’s Disease: A Randomized Controlled Trial. Dig Dis Sci. 2011 Oct
  • Combined Glutamine and Arginine Decrease Proinflammatory Cytokine Production by Biopsies from Crohn’s Patients J Nutrition 2008
  • Zinc supplementation tightens “leaky gut” in Crohn’s. Inflamm Bowel Dis. 2001 May
  • Intestinal immune system influenced by cocoa-enriched diet. J Nutr Biochem. 2008 Aug 

Drugs:

  • Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn’s disease: a randomized placebo-controlled trial. Dig Dis Sci. Smith & Zagon 2011 Jul 

  

  • Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn’s disease. Gastroenterology. 2012 May
  • Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression. Immunobiology. 2010 Aug
  • Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability British Journal of Pharmacology 2011
  • Linaclotide in the management of gastrointestinal tract disorders. Drugs Today (Barc). 2012 Mar
  • 5-aminosalicylate is not chemoprophylactic for colorectal cancer in IBD: a population based study. Am J Gastroenterol. 2011 Apr
  • Efficacy of 5-aminosalicylates in Crohn’s disease: systematic review and meta-analysis. Am J Gastroenterol. 2011 Apr

Vassar College, Paradigm Shifts, and Crohn’s Disease

April 15, 2012 12 comments

You can’t make this stuff up…so here goes:

In 1978 I was a junior at Vassar College. One of my favorite classes was “The History of Science” taught by James Challey. This was a high level seminar type class where about a dozen students sat around a table and had critical conversations about the books we were reading. The most important book we discussed in detail was The Structure of Scientific Revolutions (1962), by Thomas Kuhn. The core concept was the idea of Paradigm Shifts that have occurred marking the often rocky transition from one way of thinking about science to another. Key examples included the transitions from thinking that the world was flat…to round, that the earth was the center of our universe…to the sun. A modern example would be ulcers being caused not by stress, but by a bacterial infection. Deeply entrenched scientific thinking about the way the world actually works has been dead wrong before…and often.


These were interesting ideas and ways of thinking about the world that I had stuck somewhere in the back of my mind for decades. Then when my daughter was diagnosed with Crohn’s in 2004 and I read Elaine’s book, Breaking The Vicious Cycle….and learned that the medical standard of care for Crohn’s didn’t even consider diet all, I was conflicted. I wondered, could it be possible that Elaine was ushering in some kind of Paradigm Shift in medicine? Unfortunately, I couldn’t find much real scientific evidence at the time but her argument sounded logical…so we tried SCD, and it worked! From there I became an SCD evangelist, but much of it was on faith.

About 2 years ago I stumbled into the Paleo Diet world of Loren Cordain and Robb Wolf. Their diet plan was very similar to SCD, but their argument about why diet mattered was different. It was deeper. It was couched in the framework of evolutionary biology. The very idea that diet is a critical part of the evolution of humans and that key changes in diet since the agricultural revolution…and in the last 50 years, are the underpinnings for most chronic diseases was intriguing. Robb Wolf reminded us, with a great post he called “Framework Matters” that it was more than strange that modern medicine & nutrition is not viewed within the framework of evolutionary biology. He quoted Cordain who argueed:

“In mature and well-developed scientific disciplines there are universal paradigms that guide scientists to fruitful end points as they design their experiments and hypotheses. For instance, in cosmology (the study of the universe) the guiding paradigm is the “Big Bang” concept showing that the universe began with an enormous explosion and has been expanding ever since. In geology, the “Continental Drift” model established that all of the current continents at one time formed a continuous landmass that eventually drifted apart to form the present-day continents. These central concepts are not theories for each discipline, but rather are indisputable facts that serve as orientation points for all other inquiry within each discipline. Scientists do not know everything about the nature of the universe, but it is absolutely unquestionable that it has been and is expanding. This central knowledge then serves as a guiding template that allows scientists to make much more accurate and informed hypotheses about factors yet to be discovered.

The study of human nutrition remains an immature science because it lacks a universally acknowledged unifying paradigm (11). Without an overarching and guiding template, it is not surprising that there is such seeming chaos, disagreement and confusion in the discipline. The renowned Russian geneticist Theodosius Dobzhansky (1900-1975) said, “Nothing in biology makes sense except in the light of evolution” (12). Indeed, nothing in nutrition seems to make sense because most nutritionists have little or no formal training in evolutionary theory, much less human evolution. Nutritionists face the same problem as anyone who is not using an evolutionary model to evaluate biology: fragmented information and no coherent way to interpret the data.”

I was impressed. Not only in that concept of Paradigms discussed, but in holding up the framework of evolution as a guiding theory, it also calls into question the answers that come out of modern medicine that ignores it.  A plausible explanation of how and why modern medicine could be dead wrong about how chronic disease works…and how Elaine could have been right all along.

Then Robb Wolf introduced me/us to Alessio Fasano of UMaryland. For about a decade, Fasano, who focuses on Celiac disease, has been using the model of Celiac and the role of intestinal barrier function to explain the biologic door to not only Celiac, but virtually all chronic diseases. Fasano’s work is really blockbuster stuff. He makes his case using evolutionary biology as a key part of his framework…but he goes further. In his critical paper on Intestinal Barrier Function he reaches back to Kuhn and uses his language of paradigms to explain what is going on.

“Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer. — Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens.  When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function. This review is timely given the increased interest in the role of a “leaky gut” in the pathogenesis of several pathological conditions targeting both the intestine and extraintestinal organs.”

I knew with this study that we really were witnessing a true paradigm shift in the understanding of chronic disease. I knew that with this new line of research that I could be confident that the “standard of care” really is simply wrong and dangerous. And that I could be confident even when arguing with GIs about what is really going on and what to do about it. It really is amazing how much supporting research there is that explains the connections between intestinal barrier function and disease.

The next twist in the ongoing story is the fun part. We’ve been going through the college search process for our daughter for the last 2 years now. And last week, the decision was Vassar, class of 2016. When we visited Vassar last week she got to meet Jim Challey who is retiring next year – He’ll still be there for her Freshman year.  It turns out that Jim Challey was not only that professor that introduced me to the possibility of Paradigm Shifts, but he was a direct protege of Thomas Kuhn himself at Princeton. Like I said, you can’t make this stuff up.

Fasano’s Spectrum of Gluten-related disorders

March 11, 2012 Leave a comment

In February 2012, Alessio Fasano published a new study – Spectrum of gluten-related disorders: consensus on new nomenclature and classification – in it he and his team lay out the broad range of gluten related disorders, including Celiac(CD)/Autoimmune and Wheat Allergy (WA)/Allergic, but not autoimmune.  He also discusses at some length what he calls Gluten Sensitivity (GS) “The symptoms in GS may resemble those associated with CD but with a prevalence of extraintestinal symptoms, such as behavioral changes (depression, foggy-mind, headache), abdominal pain/diarrhea,  eczema, bone or joint pain, muscle cramps, leg numbness, weight loss, anemia and chronic fatigue.”

[GRAIN-0314]

Conclusions
“It is now becoming apparent that reactions to gluten are not limited to CD, rather we now appreciate the existence of a spectrum of gluten-related disorders. The high frequency and wide range of adverse reactions to gluten raise the question as to why this dietary protein is toxic for so many individuals in the world. One possible explanation is that the selection of wheat varieties with higher gluten content has been a continuous process during the last 10,000 years, with changes dictated more by technological rather than nutritional reasons.
Wheat varieties grown for thousands of years and mostly used for human nutrition up to the Middle Ages contain less quantities of the highly toxic 33-mer gluten peptide. Apparently the human organism is still largely vulnerable to the toxic effects of this protein complex, particularly due to a lack of adequate adaptation of the gastrointestinal and immunological responses.
Additionally, gluten is one of the most abundant and diffusely spread dietary components for most populations, particularly those of European origin.  All individuals, even those with a low degree of risk, are therefore susceptible to some form of gluten reaction during their life span. Therefore, it is not surprising that during the past 50 years we have witnessed an ‘epidemic’ of CD and the surging of new gluten-related disorders, including the most recently described GS.”

The point is that gluten is toxic…even if you don’t have Celiac Disease.  Fasano notes that Gluten Sensitivity may be at play in a wide variety of disorders including: eczema, Autism & Autism Spectrum Disorders, Neuropsychiatric disorders/Schizophrenia, IBS, Diabetes, MS and Dimentia to name a few.

Vitamin D and Crohn’s Disease

February 2, 2012 10 comments
Target Vitamin D Levels 25(OH)D
Dr. Jaquelyn McCandless 65 – 90
Robb Wolf 60 – 80
www.VitaminDCouncil.org 50 – 80
www.GrassRootsHealth.net 40 – 60
Vitamin D IBD Study 30 – 60

There is alot of talk about Vitamin D and its relationship to autoimmune disease and cancer. It appears that those with these diseases have very low levels of Vitamin D. And although its hard to tell which came first, Vitamin D deficiency or the disease, we know it plays an important role on a number of dimensions.

Genetic ExpressionResearch shows that (NOD2) gene insufficiency contributes to the development of the disease. Vitamin D signalling is a direct inducer of NOD2 expression arguing strongly that vitamin D deficiency plays a causative role in Crohn’s Disease.

Vitamin D plays a critical role in preventing and healing leaky-gut –  maintenance of the epithelial barrier integrity of the large intestine by vitamin D is critical in preventing IBD.  The VDR (vitamin D receptor)  is required for mucosal repair andVDR expression suggesting that Vitamin D is involved in the regulation of epithelial wound healing.

Vitamin D controls Zonulin – the molecule that is the glue of tight junctions in the gut lining. If you are deficient in D, the gates will stay open.

Vitamin D acts as an anti-inflammatory immunomodulator in IBD -Vitamin D downregulated Th1 (acting as a natural TNF-a suppressor) and upregulated Th2 responses (increased IL-4 anti-inflammatory cytokines). Th17 responses – a primary driver of  inflammation – were also downregulated.

Those with IBD are also prone to vitamin D intestinal malabsorption so we know that it is difficult to get enough. And that is the key question? How much Vitamin D is enough to help with healing? There are no clear answers but there are some good guidelines available.

Vitamin D

Test Your Vitamin D 25(OH)D Levels

Just as you would test you blood levels for key inflammation markers like CRP & ESR, you should be testing for Vitamin D or 25(OH)D. And while there is no clear theraputic range to target, the above chart gives some good guidance. Dr. Jaquelyn McCandless is a pioneer in treating Autism using LDN and diet. She also treats patients with IBD and suggests the highest target of 65 – 90. The above chart from Mercola is in agreement with her. Robb Wolf and the Vitamin D Council are pretty close in the 60 – 80 range.

How Much Vitamin D Do You Need?

 How much vitamin D3  (and yes you want D3) you supplement with – to get up to the target levels – depends on your situation. Where do you live? How much time do you spend in the sun? How much damage do you have to your ileum? As a result, everyone has to determine their own dosage based on their actual blood level results. For some that may mean 1,000 iu/day. Others may need 5,000 or 10,000 iu/day. Preliminary studies show that  high-dose Vitamin D3 Improves Clinical Activity in Crohn’s Disease.

What kind should I take?

Vitamin D is best assimilated when it is taken with fat, so the D3 you take should be in either an MCT oil or olive oil base.

I know that I’ve just scratched the surface on Vitamin D here. In addition to the Vitamin D Council and Grass Roots Health, the Vitamin D wiki is also a great resource – www.vitamindwiki.com for further research. There are also some interesting discussions on other supplements that support vitamin d such as magnesium, zinc and K2. Making sure you get your Vitamin D levels up to theraputic levels does not insure that you’ll be cured (I wish it was that easy), but it’s cheap, safe and easy to do. So don’t wait! Get your blood levels checked and catch some rays!

“Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-beta defensin 2 innate pathway defective in Crohn’s disease” The Journal of Biological Chemistry, January, 2010 .

Vitamin D and gastrointestinal diseases: inflammatory bowel disease and colorectal cancerTheraputic Advances in Gastroenterol,  January, 2011

“US research confirms latitude variation in incidence of chronic digestive diseases.”  American College of Gastroenterology, October, 2011

Robb Wolf: Paleo & Autoimmune Disease

January 30, 2012 7 comments

In August of 2011 I attended Robb Wolf’s final day-long Paleo Solution seminar. Even after reading his book, I must say that I was very impressed. Robb did a masterful job of explaining how putting diet into an evolutionary biology framework allows for a deeper understanding how diet impacts chronic diseases. It turns out that Robb has UC, and his whole journey into the Paleo diet was motivated by his desire to find a better way to treat his own autoimmune disease.

I found this video of Robb giving an overview and he covers it all, with a focus on autoimmune disease starting about 22 minutes in. He references Cordain, Fasano, Leaky-gut, and vitamin D. There is even a nice overview on the importance of omega 3:6 balance and its connection to inflammation that is often overlooked.  Watch the video and also check out his blog at www.robbwolf.com

Glutens Impact Goes Beyond Celiac – An interview with Dr. Fasano

January 12, 2012 2 comments

Here is a blog post by Tender Foodie that includes a recent interview with Dr. Alessio Fasano and thought it was important enough to link to. I hope he doesn’t mind. What is critical here is that gluten has impacts on leaky-gut beyond celiac disease. If you have an autoimmune disease, grains are central to the problem.

How many forms of gluten reactions are there?
Dr. Fasano:  There are 3 forms.  Celiac Disease, and Gluten Sensitivity, and Gluten/Wheat Allergy – and there are four different types of wheat allergy that all behave differently.

What is behind all of these reactions?
Dr Fasano:  Gliadin.  Gliadin is one of the proteins found in gluten.  When someone has a reaction, it’s because gliadin cross talks with our cells, causes confusion, and as a result, causes the small intestine to leak.  Gliadin is a strange protein that our enzymes can’t break down from the amino acids (glutamine and proline) into elements small enough for us to digest.  Our enzymes can only break down the gliadin into peptides.  Peptides are too large to be absorbed properly through the small intestine.  Our intestinal walls or gates, then, have to separate in order to let the larger peptide through.  The immune system sees the peptide as an enemy and begins to attack.  The difference is that in a normal person, the intestinal walls close back up, the small intestine becomes normal again, and the peptides remain in the intestinal tract and are simply excreted before the immune system notices them.   In a person who reacts to  gluten, the walls stay open as long as you are consuming gluten.  How your body reacts (with a gluten sensitivity, wheat allergy or Celiac Disease) depends upon how long the gates stay open, the number of “enemies” let through and the number of soldiers that our immune system sends to defend our bodies.  For someone with Celiac Disease, the soldiers get confused and start shooting at the intestinal walls.

 That sounds like everyone is gluten intolerant in some way.  Is that true?  Everyone?
Dr Fasano: Yes.  No one can properly digest gluten.  We do not have the enzymes to break it down.  It all depends upon how well our intestinal walls close after we ingest it and how our immune system reacts to it.

Leaky Gut and Autoimmune Diseases

December 8, 2011 6 comments

 Alessio Fasano continues to lead the charge with the latest research on the connection between  “leaky-gut” and all autoimmune diseases. It won’t be easy to create what really is a “Paradigm Shift” in the medical world but this is the kind of serious science we need to get there. What Fasano does here is take the next step in not only showing how leaky gut is behind these diseases, but that it is possible to heal from these diseases by repairing leaky gut.

AbstractFull Study

Chris Kresser in his latest article & podcast – Can Autoimmune Disease Be Prevented And Reversed? http://chriskresser.com/rhr-can-autoimmune-disease-be-prevented-and-reversed discusses Fasano’s article. Worth listening to!

Mucosal Biology Research Center, University of Maryland School of Medicine, 20 Penn Street HSF II Building, Room S345, Baltimore, MD, 21201, USA, afasano@mbrc.umaryland.edu.

Abstract

Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on the role of impaired intestinal barrier function on autoimmune pathogenesis. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiologic modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the zonulin pathway is deregulated in genetically susceptible individuals, autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing the zonulin-dependent intestinal barrier function. Both animal models and recent clinical evidence support this new paradigm and provide the rationale for innovative approaches to prevent and treat autoimmune diseases.