Leaky Gut May Be The Primary Mechanism For Autoimmune Activation?

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In January 2011 a very interesting paper was published in Physiological Reviews, exploring the role of gastrointestinal permeability, genetics and risk of development of autoimmune diseases.[1]

This abstract explores some of the principle messages in the paper which is also available as a full free text.

It is generally accepted that it is the interplay between environmental factors and specific susceptibility genes that underlies the aberrant immune response responsible for the onset of these diseases. Less than 10% of those with increased genetic susceptibility progress to clinical disease, suggesting a strong environmental trigger in the predisease state.

Environmental factors are also likely affecting the outcome of the process and the rate of progression to disease in those who develop pathological outcomes. One theory is that antigens absorbed through the gut may be involved.[2]

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.[3]

Mucosal surfaces are lined by epithelial cells. These cells establish a barrier between sometimes hostile external environments and the internal milieu. However, mucosae are also responsible for nutrient absorption and waste secretion, which require a selectively permeable barrier. These functions place the mucosal epithelium at the centre of interactions between the mucosal immune system and luminal contents, including dietary antigens and microbial products.

A variety of food substances affect the key transporter activities, impacting on tight junction permeability, metabolic enzyme expression, immune functions and so on. Modulation of the intestinal functions by dietary substances is therefore essential to promote health and recovery from related diseases.

Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer.


The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. 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 physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. 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.


[1] Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011 Jan;91(1):151-75. Review. View Full Paper

[2] Fasano A. Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol. 2012 Feb;42(1):71-8. doi: 10.1007/s12016-011-8291-x. View Abstract

[3] Turner JR (2009) Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 9:799–809 View Abstract

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4 Comments. Leave new

  • Excellent! I am so pleased to see this here.

    I work with some eminent US Naturopathic Doctors who have quelled or seemingly cured autoimmune diseases for at least 15 years by addressing intestinal barrier targets, and comprehensively repairing the integrity of the intestinal mucosal barrier. Michael Ash is of the few people in the UK who has a really cutting-edge approach to medicine, and who can (and does!) appraise new science to create additional possibilities and applications. You are a great follow, and a great inspiration!

    I don’t though believe that this quite the correct use of the term ‘new paradigm’, given that a ‘new paradigm’ is something that seems almost inconceivable given the current dominant way of thinking (about something huge that underpins many other things – like Medicine, or Physics). Like saying the world is hexagonal when we all think it’s round.

    Here we are simply (but excitingly!) talking about a *new *model of autoimmune disease, with defined putative mechanisms, and defined interventional targets. That fits within the *current paradigm of thinking that addressing mechanisms involved in disease can lead to improvement in some facet of health and wellness.

    This is an radical advancement in the understanding of how autoimmune disease arises, and therefore how it can be treated – and thus groundbreaking! – but not a new paradigm.

    I would be glad if we could reserve the term ‘new paradigm’ for the complete upturn in the current way of thinking in mainstream medicine that we will achieve by fundamentally re-organising how disease is approached, by radically changing how most people in the medical industry think, how we train, how we are regulated, how we diagnose, how we decide on interventions, how we use complexity modelling and systems theory, how we revolutionise research & development to evaluate and properly validate personalised/individualistic approaches and so on.

    That said, the understanding and utilisation of such exquisite mechanistic approaches as Michael Ash explains here, provides leading-edge working models that are pivotal within the New Paradigm… and enable us to begin to better integrate science that is currently redundant into working solutions at the point of practice.

    I am commencing a international web-hosted radio show (www.dr-concorde-trusted-voice.com – noting the site is being upgraded) to discuss these sorts of key developments, and hope that Michael can join us on the show. Material from the show, and other expert inputs, is made available to subscribers worldwide.

    I also hope that we can feature some of the truly exceptional approaches and commentaries provided in this educational section of Nutri-Link on http://www.new-paradigmmedicine.blogspot.com. This is starting this month, and is being followed & contributed to by spokespersons/eminent practitioners of several international networks, including US NDs.

    The aim of this and other elements of the major New Paradigm Initiative is to advance New Paradigm Medicine in a way that is cohesive across nations and inclusive of all relevant contributions…

    Please can we feature a link to this site on the NP-Medicine Blogspot?!

  • Michael Ash
    April 1, 2012 5:11 pm

    Hello Alex

    Thank you for your kind comments and suggestions. I understand your disquiet about the use of the ‘paradigm’ message – it is perhaps overused in situations where the context may be considered as simply an extension of an existing model.

    I sneaked it in here, as I suspect that in the majority of primary care clinics and secondary care centres here in the UK the idea that a zonulin mediated causal factor for the promotion and development of autoimmune disease exists and should be evaluated and treated, is a step to far….

    Not only are the mechanisms described novel to most NHS physicians more familiar with symptom control than recovery, but how do they fix it – it is not managed by drug based therapies very well – as we know many medications designed to alleviate the progressive damage wrought by an over activated immune system contribute to further barrier complications either directly or indirectly and lead to increasingly complex post therapeutic secondary symptom driven pharmaceutical recommendations.

    In the same frame the concept of RA being a pathogen induced process (P.mirabilis) is also seen by many to be a step to far – despite Prof. Ebringers obvious rigour and related clinical benefits.

    So I take your comments in the context they were meant, but if we introduced this concept to a group of clinicians unfamiliar with the principles well presented by functional medicine, and then demonstrated the existence of barrier changes and post treatment demonstrated objective findings that Sx had diminished or resolved – some of them may be tempted to favour the concept!

    In term of linking to my site – please feel free, and if an interview is something you favour, then do contact me.

  • Thank you Michael. As always, you make your points so very well… and in your reply to my comment elegantly & succinctly illustrate the difference between the current/dominant and emergent/new paradigm.

    The fact that we are even toggling between the two in this commentary – with such scientifically-solid illustrations of possible/actual clinical applications – itself indicates that the transition to new-paradigmic medicine is not just in sight, but already happening. 🙂

    I will indeed contact you regards an interview – many thanks.

    I am wholly committed to helping to drive these transitions… through broadcast & cohesion, and by creating a solid working platform that is ‘universally-robust’,

    If I may, I would also like to feature some excerpts – author-attributed & with linkbacks, of course – of your leaky-gut/autoimmunity articles on the blogspot, and your commentary above, as an illustrative example of where this is is all heading. Which I can marry with case histories from US NDs.

    We disseminate all this through our established international platform, reaching upto 1 million people, and via our 30000 followers on twitter.

    Do let me know if that works for you (via here or LinkedIn).

    Again my thanks for your interesting and inspiring articles – and your remarkable case-based Professional Education Group on Linked In (Nutri Link Clinical Education). Anyone who is serious about their science in integrative medicine, naturopathy and/or nutritional therapy should join and check that out daily [& feel free to quote me! 🙂 ].


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