What's Behind the Rise in Gluten Toxicity? hypothesIs 1 – the role of antibiotics

This short series considers the latest ideas from coeliac researchers as they try to explain the rising tide of gluten-related disorders. We start by reviewing the current hypotheses before focusing on the possible role of antibiotics… 

TL;DR

• There has been a 20 fold rise in the incidence of coeliac disease and other gluten-related disorders in the past 30 years.
• Researchers are homing in on the interplay of genetics, gut dysbiosis and leaky gut as a likely mechanism.
• Antibiotic use and childhood infection are suggested as possible causes for the rise.

Read time 6 minutes (1200 words)

Introduction

Coeliac disease is an autoimmune gut disease which can only be treated by lifelong adherence to a gluten-free diet. Once considered a rare condition of childhood, the incidence of coeliac has undergone a dramatic increase in the last thirty years. By way of example, one centre in Derby, UK, has seen diagnosis rates increase by 2000% since the late 1970s (see graph below).

Alongside this, there has been a shift in the age of diagnoses towards older people, with the greatest increase in diagnosis occurring among the over 60s. Furthermore, over the last three decades, new gluten-related disorders have been identified, such as non-coeliac gluten sensitivity (NCGS), which appears to affect up to 6% of the population.

Coeliac disease is an autoimmune enteropathy (gut disease) caused by exposure to gluten amongst genetically susceptible individuals. However, although 35-40% of the population carry these genes, only 1% go on to develop coeliac disease indicating that other environmental factors are at play.

More and more data is accumulating on the detrimental effects of gluten to human health.

Aaron & Torsten, Clinical Immunology, Dec 2018

Existing hypotheses

There have been many hypotheses put forward to explain the remarkable changes observed over the last half-century, many of which we have written about elsewhere. Here are a few of the most common:

1) Increased awareness and improved diagnoses rates

While it is widely recognised that awareness and diagnosis rates indeed have increased, researchers are clear that this only accounts for a small part of the observed rise.

2) We are eating more wheat these days

It is true that rates of coeliac disease often mirror levels of dietary gluten in the habitual diets of populations, for example, Northern India has much lower rates than Southern India in line with gluten consumption (Ramakrishna, 2016). However, in the USA and UK, consumption of wheat has remained fairly constant over the last 50 years at around 20% of calories, yet rates of coeliac disease have increased twenty-fold.

3) Modern strains of wheat, developed in the 1960s, are more toxic than older strains

Studies have confirmed there is truth in this statement and we have written about this before. See our posts:

• Modern Strains of Wheat are More Toxic than Ancient Varieties Study Finds
• Ten More Reasons to Avoid Wheat

Despite these differences, however, it seems unlikely that this alone can explain the dramatic increase in incidence. One reason to be sceptical is that all varieties, old and new, are nevertheless sufficiently immunogenic that cannot safely be consumed by people who are either coeliac or have NCGS.

4) Increased leaky gut

For coeliac disease to develop, gluten peptides (the digested fragments of gluten) need to cross the gut wall and be detected by the immune system. In a healthy gut, the most toxic peptides of gluten (gliadin) should not normally cross the gut wall. ‘Leaky gut’ is the name given to the condition in which the gut lining becomes more permeable allowing large proteins (gluten peptides) to cross into the body.

This is a highly plausible explanation, although it begs the question as to what is causing the increase in leaky gut. Although gluten itself has this ability to open tight-junctions in the wall of the gut, and modern strains seem to increase permeability more than older strains, it would appear that there need to be additional factors at play.

5) Dysbiosis, a disordered balance of gut microbes, increases gluten toxicity

Coeliac disease is associated with a disordered gut profile with lower species diversity and a more inflammatory profile (Nouvenne et al, 2018). What is less clear is if this dysbiosis is caused by the disease, or whether it was present before the disease started and contributed to breakdown of immune tolerance.

However, it seems plausible that dysbiosis might contribute to disease initiation as it can affect the mucous layer and increase gut permeability. Indications are those coeliac genes and dysbiosis “have a certain role in the pathogenesis of coeliac disease” (Girbovan et al, Dysbiosis a risk factor for celiac disease, 2017)

Common Ground Hypothesis

How leaky gut, dysbiosis and genetics work together

Building on the hypotheses above, a new paper pulls together several strands:

The diagram above illustrates a healthy gut mucosa (a) (left-hand side) in which a healthy colonisation of ‘good’ bacteria help maintain the integrity of the mucus layer, brush border (b) and tight junctions. When this protective state is lost (right-hand side) the mucus layer becomes disrupted, opportunistic bacteria invade and tight junction integrity is lost allowing bacteria (and incompletely digested food proteins) to enter. The adjacent micrographs show the damage caused to the mucosa (c) and microvilli (d) typical of pathological conditions.

Although the above review was looking at Crohn’s disease and Ulcerative Colitis the basic mechanism is similar for coeliac diseae. Indeed, Girbovan et al, lay out an almost identical hypothesis specifically for Coeliac Disease in their paper Dysbiosis a risk factor for celiac disease (2017), which unfortunately is only available as a full text if you have institutional access.

Here are some key points from their paper:

• The coeliac genes (HLA-DQ2/8) influence gut colonisation, and changes to gut microbe composition contributes to the risk of developing coeliac disease.
• Both duodenal and colon dysbiosis is associated with coeliac disease.
• Micobes from Coeliac gut tend to express higher virulence factors.

All of the above provide us with a mechanism in which dysbiosis

Is the increase in coeliac disease due to childhood infections and antibiotic use?

A review paper, Cross-Talk Between Gluten, Intestinal Microbiota and Intestinal Mucosa in Celiac Disease: Recent Advances and Basis of Autoimmunity (Chander, Frontiers in Microbiology, Nov 2018), makes a strong case for early childhood infections combined with antibiotic use.

This builds on earlier observations that diagnoses of coeliac disease in children often occur soon after childhood gastrointestinal (GI) infection. Such anecdotal evidence was recently confirmed by researchers (Kemppainen et al, 2017) who tracked 6327 children (1-4 years of age) in the United States and Europe who carried HLA risk genes for celiac disease. Those who had a GI infection within three months of diagnosis had an increased incidence of coeliac disease.

Another study (Canova, 2014) found a similar pattern, but also that the risk of developing coeliac was related in a dose-dependent way to antibiotic use, especially in the case of cephalosporin use.

A similar, Swedish study which included adults, as well as children, found similar results to the two studies above: Antibiotic use was associated with a 30 to 40% relative increase in risk of developing coeliac disease. This is actually quite a modest risk increase, meaning that antibiotics raise the risk from 3 people who develop coeliac where no antibiotics were used

Use of antibiotics (supported by the dose-response relationship) and gastrointestinal infections in the first year of life may facilitate the early onset of CD by altering intestinal microflora and the gut mucosal barrier. 

Canova, 2014

In their new paper, Chander et al develop this theme and describe a possible mechanism.

The basic idea is that an infection at a young age sets up an initial dysbiosis. Oral antibiotic treatment pushes the imbalance further out of whack: Gut permeability increases, so gluten peptides are able to cross over and activate the immune system. Gluten intolerance ensues.

Points in favor

• The role of antibiotics fits naturally into our understanding of the link dysbiosis, leaky gut and gluten intolerance.
• Accounts for the observation that childhood gastrointestinal infections and antibiotic use often precede the onset of coeliac disease.
• On average adults in the UK and US use antibiotics for 9 days each year. Half of all children in many Western countries receive antibiotics at least once a year [ref]

Points against

The gastrointestinal infection / antibiotic use hypothesis does not provide a compelling explanation for the 20 fold increase in coeliac disease that has occurred in the last three decades for several reasons:

• The increase in risk was modest, contributing only 1/4 of the risk factor, meaning 3/4 is due to other factors. It seems improbable that this could account for the dramatic rise in coeliac disease.
• Antibiotic use began in the 1950s without any obvious increase in coeliac disease. The major increase in coeliac disease started in the 1980s, yet, as shown below, antibiotic use was fairly constant from 1974 to 2011

Antibiotics probably do not explain the remarkable rise in gluten-related disorders, however, they do seem to increase risk, so are probably part of a bigger multifactorial picture.

Additional technical details

Just in case you were wondering…

Common Ground Hypothesis

Role of Infections and Antibiotics