Leaky Gut & Food Reactivity – What’s the Mechanism?

Michael Ash looks at leaky gut with a contemporary approach to investigation, relevance and restoration. It is quite clear that in order to extract nutrients and other sentinel information carrying agents the barrier that divides the contents of the gastric lumen from the host must be permeable. The question that has interested clinicians for many years is – when is it too permeable and what does that mean in terms of health and illness.

A paper in the March edition of Mucosal Immunology explores this concept in some detail and delivers some much needed information and potential direction in terms of dietary management and risk.[1]

Most intestinal antigens consist of food substances and large numbers of resident bacteria, known as commensal microbiota, which must be tolerated because their presence is necessary for the normal function of the organism. Food antigens are crucial for survival and induce oral tolerance. Commensal bacteria, similarly, have an integral part in host metabolism, physiology, and immunity, and thus need to be preserved.[2]

The mucosal tissues provide an elegant adaptation of intestinal immune cells crucial for the maintenance of immune homeostasis and health. A change to the barrier integrity and immune balance in the intestine can lead to aberrant immune responses, to previously regarded innocuous substances. A loss of balance not only of barrier capability but of inflammatory and anti-inflammatory cells has been linked to a number of quite disparate disorders. These include IBD³, food allergies[3] and auto immune diseases such as coeliac[4] and type 1 diabetes[5] as well as chronic fatigue[6] and depression.[7] Apart from the selective barrier function, the production of SIgA is required to prevent pathogenic and commensal bacteria from entering internal immunogenic compartments.[8]

Mechanism of Food Reactions

Most foods are broken down by the digestive enzymes and absorbed as nutrients; some however are resistant due to their makeup and or diminished digestive degradation potential. One common trigger for this failure is the concomitant use of anti ulcer medication which is linked to increased food allergy.[9] Others food agents may bind to IgE or IgG proteins and provoke additional reactivity.

Investigation

Intestinal permeability (expressed in cm s⁻¹) is an intrinsic property of the intestine and is defined as “the facility with which intestinal epithelium allows molecules to pass through by non-mediated passive diffusion.[10]

There are two recognised routes through the mucosal barrier:

1. Paracellular diffusion through tight junctions (TJs) between adjacent intestinal epithelial cells (IECs) and
2. Transcellular transport involving endocytosis/exocytosis (transcytosis) mediated or not by membrane receptors.

A number of structural and regulatory molecules controls the plasticity and permeability of TJ, which are mainly composed of proteins, including occludin, claudins, JAM-A (junctional adhesion molecule A), and tricellulin.

Whilst permeability to small molecules is mainly through the paracellular transport pathway, larger antigenic molecules use the transcellular transport pathway to gain access to the submucosal tissues and interact with local immune cells directly without the need for addition immune complexes..

Measurement

Permeability is measured by the differential absorption of lactulose and mannitol in clinical studies, the intestinal permeability test (IPT) discriminates between paracellular (lactulose) and transcellular (mannitol) pathways.[11] It is a useful test in clinical studies, giving information on the overall status of the digestive tract (villous atrophy, inflammation).

Growing Awareness

Food antigens have two main routes through the barrier:

1. By a fluid-phase endocytosis of proteins at the apical membrane of enterocytes. During transcytosis, full-length peptides or proteins are partly degraded in acidic and lysosomal compartments and released in the form of amino acids (total degradation) or breakdown products (partial degradation) at the base layer of the intestinal cells.
2. Through the expression of Ig receptors at the apical surface of enterocytes, thereby allowing their entry in the form of immune complexes (ICs).

SIgA whilst predominately a protective and expelling antibody, may in certain cases import food antigens as sometimes found in coeliac disease.[12] Suggesting that gluten avoidance is necessary even in healthy mucosal immune SIgA production where coeliac is suspected and especially where diagnosed.

With reference to food antigens, immune complexes seem to mostly induce deleterious immune responses, as exemplified in coeliac disease (IgA) and food allergy (IgE) although IgG may also be involved it will depend mainly on the nature and the polarised expression of epithelial Ig receptors.

Best understood is the relationship between IBD and increased permeability although other environmental factors or disease have been shown to affect these tissues. These include acute stress, food reactivity, nutritional depletion, infection, post antibiotic bacterial dysbiosis and medication induced damage amongst others.

Nutritional Therapy

The question for clinicians is does it have any direct effect on disease manifestation, and this remains something of a controversial area. There are numerous papers suggesting that well defined GI diseases can be related to permeability and an increasing number relating it to other often quite varied diseases. There appears as always to be a mix of environmental and genetic factors that determine magnitude of severity. This will be reflected in various ways including different levels of reactivity to proposed food based antigens.

The Nutritional Therapist will need to identify food triggers, here there are various methods including IgE and IgG tests, the latter of which is seen by immunologists as being less reliable and by Nutritional Therapists as a useful indicator of food groups to either rotate or exclude.

Comment

It is becoming clear that the gut is a major player in the aetiology of autoimmune diseases. Increased gut permeability enables gastro related antigens, both friend and foe, to interact with the mucosal immune system. Such antigenic stress can overwhelm this intricate network and lead to the development of chronic inflammation and autoimmunity in genetically susceptible.

When there are defects in resident regulatory antigen presenting cells (Dendritic cells) and T cells in the gut associated lymphoid tissues, inappropriate immune responses can occur, even against harmless food antigens or commensal bacteria, promoting chronic inflammation and epithelial damage as in coeliac disease. The resulting gut leakiness exposes the already inflamed mucosa to large amounts of foreign antigens setting up a vicious cycle of inflammation and increasing the risk of activating autoreactive cells and causing a wide range of inflammatory conditions.

Treatment Strategies

Reinforcement of the intestinal barrier and management of the bacterial colonies represent current and evolving strategies available to Nutritional Therapists. It has been proposed that maintenance of a healthy and balanced commensal microbiota closely corresponds to the correct balance between reactive T cells and regulatory T cells.[13] This is the basis of the “old friends” hypothesis, which states that the presence of normal microbes (i.e., old friends) stimulates a low-grade upregulation of regulatory T-cells that produce IL-10 and TGF-β, diminishing the effects of pro-inflammatory processes.

This is likely to be one of the critical mechanisms underlying the benefits of maintaining gastrointestinal commensal microorganisms as well as supplementation with probiotics such as LGG.[14]

The use of Saccharomyces Boulardii to modify epithelial carbohydrate metabolism and manage a healthy SIgA production which in turn supports bacterial processing and commensal communities is also useful.[15]

Barrier repair has been shown to respond to the use of the amino acid glutamine[16], as well as the growth factor – epithelial growth factor[17], and the antioxidant herb slippery elm.[18] MSM has also been proposed as a beneficial agent in the restoration of barrier integrity through its ability to regenerate vital antioxidants depleted by local inflammation.[19]

It is notable that dietary interventions may not only modulate the immune response to dietary exposure but also immunity in general by changes in microbiota and permeability of the delicate mucosal barrier.

Antigen removal, nutrient supplementation and suitable investigations will permit a reasonable approach to patients with an increased mucosal barrier and may add significantly to the restoration of immune tolerance and a down regulation of aberrant inflammation – a nutritional strategy worthy of application.

References

[1] Ménard S, Cerf-Bensussan N, & Heyman M (2010). Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal immunology, 3 (3), 247-59 PMID: 20404811

[2] Ivanov II, & Littman DR (2010). Segmented filamentous bacteria take the stage. Mucosal immunology, 3 (3), 209-12 PMID: 20147894

[3] T.T. Macdonald and G. Monteleone. Immunity, inflammation, and allergy in the gut. Science 307: 1920–1925, 2005. View Abstract

[4] C. Catassi and A. Fasano. Celiac disease. Curr Opin Gastroenterol 24: 687–691, 2008. View Abstract

[5] O. Vaarala, M.A. Atkinson, and J. Neu. The “perfect storm” for type 1 diabetes: The complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes 57: 2555–2562, 2008. View Abstract

[6] Maes M, Leunis JC. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria.

Neuro Endocrinol Lett. 2008 Dec;29(6):902-10 View Abstract

[7] Maes M, Kubera M, Leunis JC. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett. 2008 Feb;29(1):117-24. View Abstract

[8] Macpherson, A.J., McCoy, K.D., Johansen, F.E. & Brandtzaeg, P. The immune geography of IgA induction and function. Mucosal Immunol. 1, 11–22 (2008). View Abstract

[9] Diesner, S.C. et al. Dose-dependent food allergy induction against ovalbumin under acid-suppression: a murine food allergy model. Immunol. Lett. 121, 45–51 (2008). View Full Paper

[10] Travis, S. & Menzies, I. Intestinal permeability: functional assessment and significance. Clin. Sci. (Lond) 82, 471–488 (1992).

[11] Bijlsma, P.B. et al. Differential in vivo and in vitro intestinal permeability to lactulose and mannitol in animals and humans: a hypothesis. Gastroenterology 108, 687–696 (1995). View Abstract

[12] Matysiak-Budnik, T. et al. Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. J. Exp. Med. 205, 143–154 (2008). View Abstract

[13] Rook GA, Brunet LR.  Microbes, immunoregulation, and the gut. Gut. 2005 Mar;54(3):317-20. Review. View Full Paper

[14] Pohjavuori E, Viljanen M, Korpela R, Kuitunen M, Tiittanen M, Vaarala O, Savilahti E. Lactobacillus GG effect in increasing IFN-gamma production in infants with cow’s milk allergy. J Allergy Clin Immunol. 2004 Jul;114(1):131-6. View Abstract

[15] Favre, L., Spertini, F. & Corthesy, B. Secretory IgA possesses intrinsic modulatory properties stimulating mucosal and systemic immune responses. J. Immunol. 175, 2793–2800 (2005). View Abstract

[16] Nose K, Yang H, Sun X, Nose S, Koga H, Feng Y, Miyasaka E, Teitelbaum DH. Glutamine prevents total parenteral nutrition-associated changes to intraepithelial lymphocyte phenotype and function: a potential mechanism for the preservation of epithelial barrier function. J Interferon Cytokine Res. 2010 Feb;30(2):67-80. View Abstract

[17] Playford RJ, Woodman AC, Clark P, Watanapa P, Vesey D, Deprez PH, Williamson RC, Calam J.

Effect of luminal growth factor preservation on intestinal growth. Lancet. 1993 Apr 3;341(8849):843-8. View Abstract

[18] Langmead L, Dawson C, Hawkins C, Banna N, Loo S, Rampton DS. Antioxidant effects of herbal therapies used by patients with inflammatory bowel disease: an in vitro study. Aliment Pharmacol Ther. 2002 Feb;16(2):197-205. View Abstract

[19] Parcell S. Sulfur in human nutrition and applications in medicine. Altern Med Rev. 2002 Feb;7(1):22-44. Review. View Paper