Celiac disease is on the rise, and the population-wide overuse of antibiotics could play a key role in triggering disease onset.
There’s no denying that celiac disease (CD) is more prevalent now than ever. In the US, rates of CD have increased at least 5-fold over the past few decades, and prevalence in Finland has doubled. (1, 2, 3) The incidence of CD has also increased four-fold in the UK and three-fold in the Netherlands in the past 20 years, and the incidence of pediatric CD in Scotland has increased 6.4-fold. (4, 5, 6)
So naturally, everyone is wondering – why? We know that there’s a strong genetic component to celiac disease (and our ability to detect the disease has vastly improved), but the rising rates have occurred too quickly to be explained by a genetic shift in the population.
Besides, the genes that predispose an individual to CD are actually relatively common in the population, but only a very small percentage of those people actually develop the disease. In other words, genetics appear to be necessary – but not sufficient – for someone to develop CD.
Can the overuse of #antibiotics trigger celiac disease?
Antibiotics can cause intestinal dysbiosis and infection
Clearly, something has changed in the environment to trigger celiac disease in a higher proportion of genetically susceptible people. Multiple factors probably play a role, but evidence indicates that one big factor is the intestinal microbiota. And a major contributor to disordered intestinal microbiota is antibiotic overuse.
In my previous article on the effects of antibiotics, I reviewed several studies that demonstrate how drastically antibiotics can alter the gut microbiome. Just a single course of antibiotics can reduce the richness and diversity of the intestinal microbiota, and in many cases, people never completely regain the diversity they lost.
Even if a person doesn’t develop an overt, clinically-diagnosable infection such as C. difficile, imbalances in the types of bacteria that colonize the gut can still cause serious problems. But to understand how antibiotic-induced gut dysbiosis could trigger celiac disease in genetically-susceptible individuals, it helps to first understand some of the basic mechanisms behind celiac disease.
Celiac disease involves an immune reaction to both gliadin and tissue transglutaminase
The biological mechanisms behind celiac disease are complicated and still not fully understood, but the general idea is that gluten – a group of proteins found in wheat, rye, and barley – triggers an autoimmune response that results in severe damage to the epithelial lining of the intestine.
Gliadins and glutenins are the two main components of gluten, with gliadins being the primary trigger for celiac disease. These proteins are very difficult for the body to digest fully, but in most people, this isn’t a problem. However, in people with celiac disease, certain cells (known as “antigen-presenting cells”) get a hold of these large, undigested fragments of protein and present them to T-cells, triggering an immune response. (7, 8)
An enzyme called tissue transglutaminase (TG2) is also important in the development of CD. This is because antigen-presenting cells only bind certain types of proteins, and they don’t usually bind normal gliadin fragments. (9) On the other hand, TG2 readily binds gliadin, and actually modifies it to make the gliadin much more attractive to antigen-presenting cells. This vastly increases the likelihood of an immune response.
Once this happens, the body starts creating antibodies against gliadin. But because the gliadin is usually bound to TG2, the body also creates antibodies against TG2, its own enzyme. This attack of “self” is what earns CD the classification of “autoimmune.”
Intestinal dysbiosis and infection can lead to up-regulation of tissue transglutaminase
In healthy individuals, TG2 plays a role in tissue repair, as well as in other processes such as regulation of cell death; it’s not an enzyme that’s “supposed” to interact with gluten. (Interestingly, TG2 also plays a role in other diseases, such as Parkinson’s and Huntington’s, by modifying proteins that it isn’t supposed to modify.) (10)
Most TG2 appears to be either stored safely inside cells or inactive under normal conditions, and is only activated in the event of tissue injury, bacterial or viral infection, or another source of inflammation. (11, 12) This indicates that tissue damage or inflammation in the intestine (and subsequent TG2 up-regulation) might actually be necessary for the development of CD.
Without substantial TG2 activity, it’s unlikely that the antigen-presenting cells would bind and present enough gluten fragments to provoke a major immune response. But a bacterial or viral infection could create inflammation and tissue damage that would activate TG2, and thus trigger the cascade of events eventually leading to celiac disease.
Intestinal dysbiosis and infection can contribute to leaky gut
Another factor to consider is the location of tissue transglutaminase. Nearly all TG2 is found in the sub-epithelial region of the intestine, a place that gluten shouldn’t have access to. This means the intestinal barrier would need to be compromised in some way for gluten proteins to significantly interact with TG2. (13)
This fits with previous work done by researchers such as Alessio Fasano, who have hypothesized that a person cannot develop an autoimmune condition such as CD if they don’t have leaky gut. If the intestinal barrier is intact, the immune system will never “see” the antigens, so it won’t mount an immune response.
But one big risk factor for developing leaky gut is intestinal dysbiosis or infection. Bacterial components such as lipopolysaccharides can induce inflammation and increase intestinal permeability, which would allow gluten into the sub-epithelial region of the intestine where it could be modified by TG2 and trigger CD. (14)
Candida infection may trigger celiac disease through cross-reactivity
So far, we’ve been talking about dysbiosis in a general sense, but there’s evidence that specific microbes could trigger celiac disease as well. A recent study (hat tip to Questioning Answers for the find) found that an overabundance of the yeast Candida albicans could contribute to the development of CD, and unfortunately, antibiotic use is a big risk factor for developing a candida infection. (15)
Candida is a normal part of the intestinal microbiome of healthy individuals, but problems can arise when it overgrows relative to other inhabitants of the intestine. Remember how tissue transglutaminase (TG2) readily binds gliadin? Well, it turns out that candida expresses a protein named Hwp1 that also binds TG2, potentially leading to immune activation and cross-reactivity with gluten.
The study found that people without CD who had candida infections produced anti-gliadin antibodies, as well as the expected anti-Hwp1 antibodies. People with CD produced antibodies to both proteins as well. This means that in theory, a person who is genetically susceptible to CD but who doesn’t have the disease could develop the disease in response to a candida infection.
So, what does this mean for you?
As you can see, there are several ways in which antibiotic overuse and subsequent intestinal dysbiosis or infection could lead to the development of celiac disease. As I’ve said before, antibiotics can be lifesaving and are necessary in some situations, but that doesn’t mean they’re free of consequences.
It’s becoming more and more clear how vitally important it is to use antibiotics responsibly, whether that’s not using them at all, or properly rehabilitating the gut during and after a course when they’re deemed necessary.
Now I’d like to hear from you. If you have Celiac disease, do you have a history of antibiotic use prior to the expression of the disease? What do you think about this theory? Share your opinion in the comments below.
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