Gliadin, the primary protein in gluten, is a particularly difficult protein to break down, because of its enrichment in proline (15%) and glutamine (35%) [5]. Proline in particular requires specialized enzymes in proteolysis. Multiple strains of Lactobacillus species are endowed with many enzymes that are adept at separating proline from the amino acid chain, including prolyl endopeptidyl peptidase, tripeptidase, prolidase, and prolinase [6]. Thus, their colonization in the gut may be significant for assisting the host in the digestion of gluten. In a healthy infant gut, Lactobacillus species dominate the intestinal flora.
There may be a direct link between gut dysbiosis and CD [7]. A nationwide study of children in Denmark and Norway revealed a statistically significant dose-response relationship between the use of antibiotics in the first year of life and later diagnosis with CD [8]. Glyphosate is a patented antimicrobial agent, and it has been shown to disrupt the balance of microbes in the gut in a manner that is similar to the effects of chronic antibiotic use [9]. Plus, glyphosate increases the risk of an intestinal infection with a pathogen requiring antibiotic treatment because beneficial bacteria are more susceptible to glyphosate.
Pseudomonas aeruginosa is a gut pathogen that has recently become a major problem in hospitals due to multiple antibiotic resistance. P. aeruginosa are especially resistant to glyphosate, and in fact, are capable of fully metabolizing it as a source of phosphorus [10]. P. aeruginosa microbes taken from the gut of celiac patients were found to be able to break gluten down into short peptides that are especially immunogenic [11]. Lactobacillus can further metabolize these peptides into individual amino acids, but this species is especially susceptible to glyphosate toxicity. A low population of Lactobacillus in the gut could leave these peptides unmodified, and they could then induce an autoimmune antibody response.
Mice exposed to glyphosate were found to have reduced levels of Lactobacillus in their gut, and these mice also expressed behaviors reflecting anxiety [12]. Anxiety is a common symptom of both CD and non-celiac gluten sensitivity [13]. Thus, glyphosate exposure may be causing a microbial imbalance with an over-representation of the resistant pathogen P. aeruginosa, among others, and an under-representation of sensitive Lactobacillus species, leading to both gluten sensitivity and anxiety mediated by the gut-brain axis.
2 Tissue Transglutaminase Antibodies
In CD, there is an inappropriate immune response to undigested gliaden peptides in gluten. Many people who suffer from CD also have antibodies to a human enzyme called tissue transglutaminase (tTG), and also, in some cases, to collagen, the most common protein in the body. These antibodies cause a chronic inflammatory state that damages the small bowel mucosal lining, flattening the villi and preventing nutrients from getting absorbed.
tTG is a fascinating ubiquitously expressed protein with multiple roles. It has been likened to a swiss army knife, a perfect metaphor [14]. Its unusual enzymatic function is to form cross links between glutamine residues and lysine residues either within a single protein or to link two proteins together. These cross-links make the proteins more resistant to proteolysis, and one of its roles is to promote wound healing by strengthening collagen through cross links.
tTG can also convert glutamine residues to glutamate, which is the first step in the cross-linking process. Since gliadin is enriched in glutamine, it is highly susceptible to modification by tTG. Conversion of glutamine to glutamate introduces a negative charge, which increases its ability to bind to celiac antibodies, enhancing antigenicity [15]. tTG can even bind gliadin peptides to itself through cross-linking, and this may account for the antibodies to tTG that are characteristic of CD [16]. tTG can also bind undigested gliadin peptides to lysine residues in collagen, and it has been argued that this can explain antibodies to collagen associated with CD [17].