Transglutaminases in Dysbiosis As Potential Environmental Drivers of Autoimmunity

Abstract

Protein-glutamine γ-glutamyltransferases (transglutaminases, Tgs) belong to the class of transferases. They catalyze the formation of an isopeptide bond between the acyl group at the end of the side chain of protein- or peptide-bound glutamine residues and the first order 𝜀-amine groups of protein- or peptide-bound lysine. The Tgs are considered to be universal protein cross-linkers, and they play an essential role in a number of human diseases. In this review, we discuss mainly the bacterial Tgs in terms of the functionality of the enzymes and a potential role they may play in bacterial survival. Since microbial transglutaminases (mTgs) are functionally similar to the human homologs, they may be involved in the human disease provocation. We suggest here a potential involvement of Tgs in the pathologies such as autoimmune diseases. In this hypothesis, the endogenous mTgs that are secreted by the gut microbiota, especially in a dysbiotic configuration, are potential drivers of systemic autoimmunity, via the enzymatic posttranslational modification of peptides in the gut lumen. These mTg activities directed toward cross-linking of naïve proteins can potentially generate neo-epitopes that are not only immunogenic but may also activate some immune response cascades leading to the pathological autoimmune processes.

Gluten-free Diet - Tough Alley in Torrid Time

“…The CD population is facing nowadays torrid time due to the actual surge in incidence, wheat content, gluten intake, CD-related T-cell stimulatory epitopes in wheat, usage in the processed food industries, nutritional deficiencies, changing phenotype and the fact that gluten is potentially detrimental to humankind health [36][37][38][39][40][41][42][43][44][45].…”

Are Non-Celiac Autoimmune Diseases Responsive to Gluten-Free Diet?

“…This dynamics paralleled the increased incidence of CD and other ADs [2,4,5,52,53] f. Intestinal post translational modification of protein (PTMP) represents a key regulator in autoimmunity, by transforming naïve/self or non-self-peptides to auto immunogenic ones. [3,39,54]. Gluten is an ideal substrate for enzymatic PTMP, tissue and microbial transglutaminases being typical examples [3,54,55,56].…”

“…[3,39,54]. Gluten is an ideal substrate for enzymatic PTMP, tissue and microbial transglutaminases being typical examples [3,54,55,56].…”

“…Tissue and microbial transglutaminases are extensively distributed in the human body and intestinal lumen, respectively [39,54,57]. Human transglutaminase plays a role in end organ affected ADs.…”

Gut-thyroid axis and celiac disease

“…Several potential mechanisms were suggested for the gut mucosa and luminal ecosystems involvement in the thyroid autoimmunity: (i) Gut dysbiosis might disturb the finely tuned immune balance and break tolerance to self-antigens and non-pathogenic non-self-antigens, by posttranslational modification proteins, inducing autoimmunity; (ii) association of lipopolysaccharide-induced Toll-like receptor (TLR) activation with thyroiditis development or production of anti-thyroglobulin antibody in mice was suggested; (iii) induction of Th1 to Th2 shift, inhibition of Th17 differentiation and oral tolerance induction, by retinoic acid might activate tolerogenic immune responses in the gut; (iv) breaching tight junction integrity, resulting in the leaky gut barrier is a common shared pathway in autoimmunogenesis; (v) not less important is the transcriptomic, proteinomic and the metabolomics changes induced by the gut microbes, being direct messengers between the bugs and us. Changes in microbiota and short chain fatty acids production are clearly related to the pathogenesis of CD, but their role in thyroid autoimmunity induction or protection remains to be investigated (9, 10, 12, 13, 14, 15, 16). …”