The importance of the microbiota in the pathogenesis and treatment of coeliac disease

  1. Dr.Schär Institute
  2. Dr. Schär Institute
  3. The importance of the microbiota in the pathogenesis and treatment of coeliac disease

The importance of intestinal microbiota and role of probiotics is well documented in some clinical scenarios and conditions, for example, antibiotic-associated diarrhoea, irritable bowel syndrome. However, there are currently few studies on the relationship between coeliac disease and microbiota. This article looks to address and summarise the current knowledge base within this specific area.

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Man is not a single living being; he lives in a community with trillions of bacteria and other micro-organisms. The gastrointestinal tract is densely populated: it has an estimated 100 trillion (10^14) micro-organisms, which are referred to as intestinal microbiota (formerly intestinal flora). The number of microbial cells in the intestine is ten times greater than the number of human somatic cells; they have about 150 times more genes than the human body which means they have an enormous metabolic activity [Le Chatelier et al. 2013]. Their metabolic products and neurotransmitters have a close interdependency with the somatic cells both inside and outside of the gastrointestinal tract. They support the digestive functions, help ward off pathogenic micro-organisms and contribute to the development and maintenance of the immune system and the intestinal barrier. The intestinal barrier is a complex system that separates the intestinal lumen from the inside of the body and is composed of the following elements [Bischoff et al. 2014]:

  • Mechanical: Epithelial cells with tight junctions, mucus
  • Humoral: Defensins, immunoglobulins, cytokines
  • Immune cells: Specific and non-specific immune cells
  • Muscle cells
  • Nerve cells


The intestinal microbiota are involved in metabolic processes and can modulate the barrier function [Viggiano et al. 2015]. In addition to a balanced microbiota, another important protection mechanism for a functioning intestinal barrier is the regulation of paracellular passage through tight junctions.

In recent years, scientists have achieved great progress in the study of microbiota thanks to the application of methods of analysis from molecular biology. The thousands of different types of bacteria that occur in the intestine can be divided into a total of six different subgroups. Up to 90 % of the intestinal bacteria belong to the groups of firmicutes and bacteroidetes, followed by proteobacteria, actinobacteria, verrucomicrobia and fusobacteria [Blaut 2015].

The majority of micro-organisms are found in every human intestine. These are referred to as the core microbiome [Doré et al. 2013]. Every person also has a variable part. This makes up the individual microbiota. The composition and activity of the microbiota are influenced by several factors, including type of birth (vaginal or C-section), genes, age and lifestyle. Medicines (e.g. antibiotics) and diet play an important role: factors such as quantity and type of fibre and fermented foods are important.

According to recent studies, the composition of the microbiota plays an important role in the maintenance of health, because the different species of bacteria can have both protective and harmful effects [Doré et al. 2013]. Certain pathogenic bacteria can, for example, cause local inflammation, weaken the intestinal barrier and increase permeation of substances including gluten [Moraes L. F. de Sousa, Grzeskowiak L.M. et al 2014, Viggiano et al 2015].

Coeliac disease and microbiota

It is known that missing peptidases in the human intestine mean that gluten is incompletely digested and that gluten peptides are absorbed via the small intestinal mucosa. Furthermore, there is growing evidence that a change in intestinal permeability due to increased permeability of tight junctions (TJ) is a major factor in the pathogenesis of coeliac disease. This makes it simpler for the remaining oligopeptides to be absorbed into the lamina propria and trigger the inflammation typical of coeliac disease.

It is still unclear whether disorders of the intestinal barrier are the primary cause or the consequence of coeliac disease [Sapone et al. 2012, Moraes L. F. de Sousa et al. 2014]. However, it has been possible to demonstrate that in the case of persons suffering from coeliac disease, gliadin is a strong stimulus for the release of zonulin. This protein increases intestinal permeability by facilitating the absorption of macromolecules via TJs [Drago et al. 2006].

On the other hand, there is evidence that changes in the intestinal microbiota can lead to increased intestinal permeability and therefore may be involved in the pathogenesis of coeliac disease and allergic diseases. There are, however, only a few studies on the role of the microbiota in the pathophysiology of coeliac disease. It is believed that in the case of genetically susceptible patients, gram-negative bacteria are involved in the loss of gluten tolerance. Comparative studies between children with coeliac disease and healthy control groups detected a lower number of lactobacilli and bifidobacteria in the former. However, it is unclear whether a change in the microbiota of persons with coeliac disease is the primary cause or the consequence of coeliac disease. In biopsy specimens of the duodenum of untreated children with coeliac disease, more gram-negative bacterial strains were detected compared to treated children and healthy control groups, which suggests a change in the microbiota as a result of this disease [Moraes L. F. de Sousa et al. 2014].

Coeliac disease and probiotics

Currently, the only therapy there is for coeliac disease patients is a strict lifelong gluten-free diet (GFD), which includes avoiding traces of gluten. In the long term, this is difficult for many of those affected, especially without concomitant dietary advice. Despite complaints and the risk of complications and long-term consequences (e.g. malignancies, refractory coeliac disease) 30 % to 50 % of patients do not maintain a strict gluten-free diet [Körner, Schareina 2015]. Given the knowledge of changes in the intestinal microbiota in persons with coeliac disease, the following studies have demonstrated that the use of probiotics may constitute a promising approach to concurrent therapy in the case of coeliac disease:
  

  • In 2006, De Angelis et al. examined combination preparation VSL#3, which contains 8 different probiotic strains (e.g. bifidobacteria and lactobacilli). They demonstrated that compared with isolated strains and other commercially available products that were tested, the combination of these probiotic strains can split gliadin peptides more effectively, i.e. gliadin peptides are easier to digest with the aid of this probiotic combination preparation.
  • In the case of PBMCs*, De Palma's research group (2010) was able to reduce the secretion of interleukin-12 and IFN-gamma (pro-inflammatory cytokines) under the influence of gluten in-vitro, using specific bifidobacteria. This observation suggests an anti-inflammatory effect of the investigated bifidobacteria.
  • Lindfors et al. (2008) demonstrated that the bacterial strain b. lactis can prevent the toxic effect of wheat gliadin on epithelial cell cultures at doses of 106 and 107 CFU** per ml, but not at 105 CFU per ml.
  • In a mouse model by D`Arienzo et al. (2011), a milk product with the l. casei ATCC 9595 strain (Actimel) enhanced the intestinal barrier function and prevented the intake of gliadin in the lamina propria.


            * PBMC: peripheral blood mononuclear cell
           ** CFU: colony-forming units

NCGS and probiotics

As yet there is no practical study on the influence of the microbiota on the pathogenesis of this new disease in the specific case of gluten/wheat sensitivity. Unlike coeliac disease, an innate immune response is suspected in the case of NCGS. This is activated by gluten or wheat, but does not alter the intestinal mucosa or its permeability. However, there are indications of increased intestinal permeability in patients with neurological symptoms such as schizophrenia or autism and suspected NCGS.

The aforementioned studies demonstrate that certain strains of bacteria aid the digestion of gliadin peptides. This may mean that patients with NCGS can as in the case of coeliac disease benefit from a concomitant course of probiotics. Further studies are required for specific recommendations.

In the case of some diseases (e.g., antibiotic-associated diarrhoea, irritable bowel syndrome, ulcerative colitis, pouchitis) there are studies that demonstrate clinically relevant efficacy of probiotics [Bischoff u. Köchling 2012]. However, the underlying mechanisms are still unclear. There are currently few studies on the relationship between coeliac disease and microbiota and the use of probiotics in the managementof coeliac disease. Since many effects of probiotic micro-organisms are strain-specific, evidence that has been obtained with a specific bacterial strain or preparation/product for coeliac disease cannot necessarily be transferred to other strains. Further investigation of the underlying mechanisms of action is necessary. Due to the positive effects reported and relative lack of known side effects, the trial use of probiotics can be considered.

  • Probiotics

    are live micro-organisms that offer the host a health benefit if they are taken in sufficient quantities (FAO/WHO 2002; Hill et al. 2014). These are special types of non-pathogenic bacteria (in particular lactobacilli and bifidobacteria) that are especially resistant to acids and therefore to a large extent survive the passage through the stomach and small intestine. Probiotics are available in the form of medicines, food supplements and foodstuffs. Commercially available foodstuffs with live cultures include yoghurt, drinking yoghurt and mixed milk products. In freeze-dried form, probiotic bacteria can be found in products including cereals and baby food. Although the Health Claims Regulation (Regulation EU No. 432/2012 of the Commission of 16 May 2012) states that these foods may not use the term “probiotic” or claim a health effect, this does not rule out efficacy. Probiotic bacteria temporarily settle in the intestine and produce organic acids (e.g. butyrate). This reduces the pH, which repels pathogenic bacteria. Some probiotic bacteria strengthen the intestinal barrier, e.g. by inducing the formation of defensins from mucosal cells. An intact intestinal barrier ensures that nutrients can cross the intestinal wall, but that pathogenic bacteria and toxins are repelled.

Points to consider in the selection and use of probiotics – Make the correct choice!

  • Benefits are strain-specific
  • Sufficiently high bacterial count of 10 (8) and 10 (9) CFU per day
  • Favour products that also contain bifidobacteria
  • At the beginning of therapy: Take with meals and refrain from products with prebiotics such as inulin and oligofructose; in the case of simultaneous malabsorption of lactose or fructose, also avoid probiotic products with these ingredients where possible.
  • Slowly increase dosage (start with ½ the amount)

Authors

DIPL. OEC. TROPH. UTE KÖRNER
is a qualified Nutritionist specializing in Allergology. Since completing her qualification in Nutritional Science, she has worked as a nutritionist, lecturer, journalist and writer, mainly in the field of Allergology and Gastroenterology. She writes books and speaks at lectures, training seminars and further education courses for doctors on the subject of food allergies and intolerances.

DR. MAIKE GROENEVELD
is a qualified nutritionist and home economist, and has worked as a freelance nutritionist, lecturer and writer for over 20 years. She advises both patients and companies on nutritional issues, and as a professional writer publishes books, brochures, specialist publications and internet articles.

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