Microbial transglutaminase (mTG) is a frequently consumed processed food additive, and use of its cross-linked complexes is expanding rapidly. It was designated as a processing aid and was granted the generally recognized as safe (GRAS) classification decades ago, thus avoiding thorough assessment according to current criteria of toxicity and public health safety. In contrast to the manufacturer's declarations and claims, mTG and/or its transamidated complexes are proinflammatory, immunogenic, allergenic, pathogenic, and potentially toxic, hence raising concerns for public health. Being a member of the transglutaminase family and functionally imitating the tissue transglutaminase, mTG was recently identified as a potential inducer of celiac disease. Microbial transglutaminase and its docked complexes have numerous detrimental effects. Those harmful aspects are denied by the manufacturers, who claim the enzyme is deactivated when heated or by gastric acidity, and that its covalently linked isopeptide bonds are safe. The present narrative review describes the potential side effects of mTG, highlighting its thermostability and activity over a broad pH range, thus, challenging the manufacturers' and distributers' safety claims. The national food regulatory authorities and the scientific community are urged to reevaluate mTG's GRAS status, prioritizing public health protection against the possible risks associated with this enzyme and its health-damaging consequences.

Microbial transglutaminase (mTG) is a bacterial survival factor, which is frequently used as a food additive. This results in the formation of immunogenic epitopes that may cause autoimmunity. Primary biliary cholangitis (PBC) is a cholestatic, autoimmune liver disease characterized by the presence of characteristic autoantibodies. The aim of this work was to determine epitope similarity and cross-reactivity between mTG- and PBC-specific antigens and to investigate whether the microbial enzyme may be associated with the induction of autoimmunity due to epitope similarity and cross-reactivity. Monoclonal and polyclonal antibodies against mTG were applied to nine different PBC-specific antigens using ELISA technique. They reacted significantly with four out of nine antigens. This reaction was most pronounced for gp210 and PML protein. We also performed in vitro studies on the impact of the mTG on the specific antigen-antibody binding using sera of PBC patients. We found four PBC-specific antigens that share homology with mTG sequences. We noticed inhibition of this specific binding by the mTG to the PDC M2, gp210, PML, and KLHL12 protein. Microbial mimics may be the major targets of cross-reactivity with human-specific antigens. Cross-reactivity may indicate a link between mTG and the development of autoimmune diseases.

We have identified a decreased abundance of microbial species known to have a potential anti-inflammatory, protective effect in subjects that developed Celiac Disease (CeD) compared to those who did not. We aim to confirm the potential protective role of one of these species, namely Bacteroides vulgatus, and to mechanistically establish the effect of bacterial bioproducts on gluten-dependent changes on human gut epithelial functions.

We identified, isolated, cultivated, and sequenced a unique novel strain (20220303-A2) of B. vulgatus found only in control subjects. Using a human gut organoid system developed from pre-celiac patients, we monitored epithelial phenotype and innate immune cytokines at baseline, after exposure to gliadin, or gliadin plus B. vulgatus cell free supernatant (CFS).

Following gliadin exposure, we observed increases in epithelial cell death, epithelial monolayer permeability, and secretion of pro-inflammatory cytokines. These effects were mitigated upon exposure to B. vulgatus 20220303-A2 CFS, which had matched phenotype gene product mutations. These protective effects were mediated by epigenetic reprogramming of the organoids treated with B. vulgatus CFS.

We identified a unique strain of B. vulgatus that may exert a beneficial role by protecting CeD epithelium against a gluten-induced break of epithelial tolerance through miRNA reprogramming.

Gut dysbiosis precedes the onset of celiac disease in genetically at-risk infants. This dysbiosis is characterized by the loss of protective bacterial strains in those children who will go on to develop celiac disease. The paper reports the mechanism by which one of these protective strains, B. vulgatus, ameliorates the gluten-induced break of gut epithelial homeostasis by epigenetically re-programming the target intestinal epithelium involving pathways controlling permeability, immune response, and cell turnover.

Gut luminal dysbiosis and pathobiosis result in compositional and biodiversified alterations in the microbial and host co-metabolites. The primary mechanism of bacterial evolution is horizontal gene transfer (HGT), and the acquisition of new traits can be achieved through the exchange of mobile genetic elements (MGEs). Introducing genetically engineered microbes (GEMs) might break the harmonized balance in the intestinal compartment. The present objectives are: 1. To reveal the role played by the GEMs' horizontal gene transfers in changing the landscape of the enteric microbiome eubiosis 2. To expand on the potential detrimental effects of those changes on the human genome and health. A search of articles published in PubMed/MEDLINE, EMBASE, and Scielo from 2000 to August 2023 using appropriate MeSH entry terms was performed. The GEMs' horizontal gene exchanges might induce multiple human diseases. The new GEMs can change the long-term natural evolution of the enteric pro- or eukaryotic cell inhabitants. The worldwide regulatory authority's safety control of GEMs is not enough to protect public health. Viability, biocontainment, and many other aspects are only partially controlled and harmful consequences for public health should be avoided. It is important to remember that prevention is the most cost-effective strategy and primum non nocere should be the focus.

Microbial transglutaminase (mTG) is a bacterial survival factor, frequently used as a food additive to glue processed nutrients. As a result, new immunogenic epitopes are generated that might drive autoimmunity. Presently, its contribution to autoimmunity through epitope similarity and cross-reactivity was investigated. Emboss Matcher was used to perform sequence alignment between mTG and various antigens implicated in many autoimmune diseases. Monoclonal and polyclonal antibodies made specifically against mTG were applied to 77 different human tissue antigens using ELISA. Six antigens were detected to share significant homology with mTG immunogenic sequences, representing major targets of common autoimmune conditions. Polyclonal antibody to mTG reacted significantly with 17 out of 77 tissue antigens. This reaction was most pronounced with mitochondrial M2, ANA, and extractable nuclear antigens. The results indicate that sequence similarity and cross-reactivity between mTG and various tissue antigens are possible, supporting the relationship between mTG and the development of autoimmune disorders 150W.

Microbial transglutaminases (mTGs) belong to the family of global TGs, isolated and characterised by various bacterial strains, with the first being Streptomyces mobaraensis. This literature review also discusses TGs of animal and plant origin. TGs catalyse the formation of an isopeptide bond, cross-linking the amino and acyl groups. Due to its broad enzymatic activity, TG is extensively utilised in the food industry. The annual net growth in the utilisation of enzymes in the food processing industry is estimated to be 21.9%. As of 2020, the global food enzymes market was valued at around $2.3 billion USD (mTG market was estimated to be around $200 million USD). Much of this growth is attributed to the applications of mTG, benefiting both producers and consumers. In the food industry, TG enhances gelation and modifies emulsification, foaming, viscosity, and water-holding capacity. Research on TG, mainly mTG, provides increasing insights into the wide range of applications of this enzyme in various industrial sectors and promotes enzymatic processing. This work presents the characteristics of TGs, their properties, and the rationale for their utilisation. The review aims to provide theoretical foundations that will assist researchers worldwide in building a methodological framework and furthering the advancement of biotechnology research.

Stabilization and reusability of enzyme transglutaminase (TGM) are important goals for the enzymatic process since immobilizing TGM plays an important role in different technologies and industries. TGM can be used in many applications. In the food industry, it plays a role as a protein-modifying enzyme, while, in biotechnology and pharmaceutical applications, it is used in mediated bioconjugation due to its extraordinary crosslinking ability. TGMs (EC 2.3.2.13) are enzymes that catalyze the formation of a covalent bond between a free amino group of protein-bound or peptide-bound lysine, which acts as an acyl acceptor, and the γ-carboxamide group of protein-bound or peptide-bound glutamine, which acts as an acyl donor. This results in the modification of proteins through either intramolecular or intermolecular crosslinking, which improves the use of the respective proteins significantly.

Microbial transglutaminase (mTG) is a heavily used food additive and its industrial transamidated complexes usage is rising rapidly. It was classified as a processing aid and was granted the GRAS (generally recognized as safe) definition, thus escaping full and thorough toxic and safety evaluations. Despite the manufacturers claims, mTG or its cross-linked compounds are immunogenic, pathogenic, proinflammatory, allergenic and toxic, and pose a risk to public health. The enzyme is a member of the transglutaminase family and imitates the posttranslational modification of gluten, by the tissue transglutaminase, which is the autoantigen of celiac disease. The deamidated and transamidated gliadin peptides lose their tolerance and induce the gluten enteropathy. Microbial transglutaminase and its complexes increase intestinal permeability, suppresses enteric protective pathways, enhances microbial growth and gliadin peptide's epithelial uptake and can transcytose intra-enterocytically to face the sub-epithelial immune cells. The present review updates on the potentially detrimental side effects of mTG, aiming to interest the scientific community, induce food regulatory authorities' debates on its safety, and protect the public from the mTG unwanted effects.

A gluten-free diet (GFD) is the recommended treatment for gluten-dependent disease. In addition, gluten withdrawal is popular and occasionally is suggested as a treatment for other autoimmune diseases (ADs).

The current systematic review summarizes those entities and discusses the logic behind using a GFD in classical non-gluten-dependentADs.

A search for medical articles in PubMed/MEDLINE, Web of Sciences, LILACS, and Scielo published between 1960 and 2020 was conducted, using the key words for various ADs and GFDs.

Eight-three articles were included in the systematic review (using PRISMA guidelines).

Reduction in symptoms of ADs after observance of a GFD was observed in 911 out of 1408 patients (64.7%) and in 66 out of the 83 selected studies (79.5%). The age of the patients ranged from 9 months to 69 years. The duration of the GFD varied from 1 month to 9 years. A GFD can suppress several harmful intraluminal intestinal events. Potential mechanisms and pathways for the action of GFD in the gut - remote organs' axis have been suggested.

A GFD might represent a novel nutritional therapeutic strategy for classical non-gluten-dependent autoimmune conditions.

This study has investigated the characteristics of dry noodles made with Korean domestic wheat flours using enzyme treatment for reducing water absorption to improve noodle-making performance. The water solvent retention capacity (SRC) values of flour treated with α-amylase and xylanase significantly decreased with increasing enzyme concentrations up to 0.025% (flour weight basis), which confirmed the enzyme effect on reducing the water absorption capacity of damaged starches and arabinoxylans. Enzyme-treated cooked noodles showed changes in textural characteristics, depended on the enzyme type, water amount, and drying method. Applying α-amylase for reducing the water absorption capacity of flour could mitigate the issue of inferior dry-noodle-making performance. Sensory evaluation showed improved preference attributes of cooked noodles with α-amylase treatment. In conclusion, the α-amylase application could improve the quality of dry-noodle made of Korean domestic wheat flour by diminishing the undesirable effect of damaged starch in flour related to noodle quality.

Recent studies suggest that the beneficial properties provided by sourdough fermentation may be translated to the development of new GF products that could improve their technological and nutritional properties. The main objective of this manuscript is to review the current evidence regarding the elaboration of GF baked goods, and to present the latest knowledge about the so-called sourdough biotechnology. A bibliographic search of articles published in the last 12 years has been carried out. It is common to use additives, such as hydrocolloids, proteins, enzymes, and emulsifiers, to technologically improve GF products. Sourdough is a mixture of flour and water fermented by an ecosystem of lactic acid bacteria (LAB) and yeasts that provide technological and nutritional improvements to the bakery products. LAB-synthesized biopolymers can mimic gluten molecules. Sourdough biotechnology is an ecological and cost-effective technology with great potential in the field of GF products. Further research is necessary to optimize the process and select species of microorganisms robust enough to be competitive in any circumstance.

Numerous dough improvers are used alone or in combination to enhance the quality of baked goods such as breads. While modern consumers demand consistent quality, the expectations for ingredients have changed over the past few years, and reformulations have taken place to provide "clean label" options. However, the effects and mechanisms of blended dough conditioners suitable for such baked products have not been systematically summarized. In this review, dough and bread properties as affected by different improver combinations are examined, with a focus on additive or synergistic interactions between enzymes or between enzymes and ascorbic acid. The combination of enzymes that hydrolyze starch and cell wall polysaccharides has been shown to reduce textural hardness in fresh and stored bakes goods such as breads. Enzymes that hydrolyze arabinoxylans, the main nonstarch polysaccharide in wheat, have synergistic effects with enzymes that result in cross-linking of wheat flour biopolymers. In some studies, the effects of bread improvers varied for wheat flours of different strength. Overall, bread products in which wheat is used in whole grain form or in a blend with other flours especially benefit from multiple improvers that target different flour constituents in doughs.

Wheat is a most favored staple food worldwide and its major protein is gluten. It is involved in several gluten dependent diseases and lately was suggested to play a role in non-celiac autoimmune diseases. Its involvement in neurodegenerative conditions was recently suggested but no cause-and-effect relationship were established. The present narrative review expands on various aspects of the gluten-gut-brain axes events, mechanisms and pathways that connect wheat and gluten consumption to neurodegenerative disease. Gluten induced dysbiosis, increased intestinal permeabillity, enteric and systemic side effects, cross-reactive antibodies, and the sequence of homologies between brain antigens and gluten are highlighted. This combination may suggest molecular mimicry, alluding to some autoimmune aspects between gluten and neurodegenerative disease. The proverb of Hippocrates coined in 400 BC, "let food be thy medicine," is critically discussed in the frame of gluten and potential neurodegeneration evolvement.

Microbial transglutaminase (mTG) catalyses the formation of protein crosslinks, deamidating glutamine in a side-reaction. Gluten deamidation by human tissue transglutaminase is critical to activate celiac disease pathogenesis making the addition of mTG to wheat-based products controversial. The ability of mTG (0-2000 U.kg^-1) to alter gluten's structure, digestibility and the deamidation state of six immunogenic gluten peptides within bread was investigated. Gluten's structure was altered when mTG exceeded 100 U.kg^-1, determined by confocal microscopy, extractability and free sulfhydryl assays. The effect of mTG on six immunogenic peptides was investigated by in vitro digestion (INFOGEST) and mass spectrometry. The addition of mTG to bread (0-2000 U.kg^-1) did not alter the deamidation state or digestibility of the immunogenic peptides investigated. Overall, this investigation indicated that the addition of mTG to bread does not create activated gluten peptides. This analysis provides evidence for risk assessments of mTG as a food processing aid.

Despite the progress in the development of novel treatment modalities, a significant portion of patients with psoriasis remains undertreated relative to the severity of their disease. Recent evidence points to targeting the glucose transporter 1 and sugar metabolism as a novel therapeutic strategy for the treatment of psoriasis and other hyperproliferative skin diseases. In this review, we discuss glycoconjugation, an approach that facilitates the pharmacokinetics of cytotoxic molecules and ensures their preferential influx through glucose transporters. We propose pathways of glycoconjugate synthesis to increase effectiveness, cellular selectivity, and tolerability of widely used antipsoriatic drugs. The presented approach exploiting the heightened glucose requirement of proliferating keratinocytes bears the potential to revolutionize the management of psoriasis. SIGNIFICANCE STATEMENT: Recent findings concerning the fundamental role of enhanced glucose metabolism and glucose transporter 1 overexpression in the pathogenesis of psoriasis brought to light approaches that proved successful in cancer treatment. Substantial advances in the emerging field of glycoconjugation highlight the rationale for the development of glucose-conjugated antipsoriatic drugs to increase their effectiveness, cellular selectivity, and tolerability. The presented approach offers a novel therapeutic strategy for the treatment of psoriasis and other hyperproliferative skin diseases.

The recent scientific progresses on the use of enzyme-mediated reactions in organic, non-aqueous and aqueous media have significantly supported the growing demand of new biotechnological and/or pharmacological products. Today, a plethora of microbial enzymes, used as biocatalysts, are available. Among these, microbial transglutaminases (MTGs) are broadly used for their ability to catalyse the formation of an isopeptide bond between the γ-amide group of glutamines and the ε-amino group of lysine. Due to their promiscuity towards primary amine-containing substrates and the more stringent specificity for glutamine-containing peptide sequences, several combined approaches can be tailored for different settings, making MTGs very attractive catalysts for generating protein-protein and protein small molecule's conjugates. The present review offers a recent update on the modifications attainable by MTG-catalysed bioreactions as reported between 2014 and 2019. In particular, we present a detailed and comparative overview on the MTG-based methods for proteins and antibodies engineering, with a particular outlook on the synthesis of homogeneous antibody-drug conjugates.

Tissue transglutaminase (tTG) and microbial transglutaminase (mTG) cross-link gliadins to form complexes that expose immunogenic neo-epitopes to produce tTG and mTG-neo-epitope antibodies. The aim of this study was to test the diagnostic performance of antibodies against non-complexed and complexed forms of transglutaminases, to correlate their activities to the intestinal damage and to explore age group dependency in celiac disease (CD). A total of 296 children with untreated CD and 215 non-celiac disease controls were checked by in-house enzyme-linked immunosorbent assays detecting immunoglobulin (Ig)A, IgG or combined detection of IgA and IgG (check) against tTG, AESKULISA® tTG New Generation (tTG-neo) and mTG-neo (RUO), IgA and IgG antibodies against deamidated gliadin peptide (DGP) and human IgA anti-endomysium antibodies (EMA) using AESKUSLIDES® EMA. Intestinal pathology was graded according the revised Marsh criteria, and age dependencies of the antibody activities were analysed. Using cut-offs estimated from receiver operating characteristic (ROC) curves, the highest area under curve (AUC) of the TG assays was 0·963 for tTG-neo check, followed by tTG check (0·962) when the diagnosis was based on enteric mucosal histology. tTG-neo check was the most effective to reflect the intestinal abnormalities in CD (r = 0·795, P < 0·0001). High levels of anti-mTG-neo IgG and anti-tTG-neo IgG appeared in the earlier age groups, as compared to anti-tTG IgG (P < 0·001). Considering antibody diagnostic performance based on AUC, enteric damage reflection and predictability at an early age, the anti-neo tTG check was the most effective diagnostic biomarker for pediatric CD. The mTG neo check might represent a new marker for CD screening, diagnosis and predictability.

Microbial transglutaminase (mTG) is a survival factor for microbes, but yeasts, fungi, and plants also produce transglutaminase. mTG is a cross-linker that is heavily consumed as a protein glue in multiple processed food industries. According to the manufacturers' claims, microbial transglutaminase and its cross-linked products are safe, i.e., nonallergenic, nonimmunogenic, and nonpathogenic. The regulatory authorities declare it as "generally recognized as safe" for public users. However, scientific observations are accumulating concerning its undesirable effects on human health. Functionally, mTG imitates its family member, tissue transglutaminase, which is the autoantigen of celiac disease. Both these transglutaminases mediate cross-linked complexes, which are immunogenic in celiac patients. The enzyme enhances intestinal permeability, suppresses mechanical (mucus) and immunological (anti phagocytic) enteric protective barriers, stimulates luminal bacterial growth, and augments the uptake of gliadin peptide. mTG and gliadin molecules are cotranscytosed through the enterocytes and deposited subepithelially. Moreover, mucosal dendritic cell surface transglutaminase induces gliadin endocytosis, and the enzyme-treated wheat products are immunoreactive in CD patients. The present review summarizes and updates the potentially detrimental effects of mTG, aiming to stimulate scientific and regulatory debates on its safety, to protect the public from the enzyme's unwanted effects.

The prevalence of celiac disease (CD) has increased significantly in some developed countries in recent decades. Potential risk factors that have been considered in the literature do not appear to provide a convincing explanation for this increase. This has led some researchers to hypothesize that there is a "missing environmental factor" that increases the risk of CD. Based on evidence from the literature, the author proposes that elevation in plasma levels of 1,25-dihydroxyvitamin D [1,25(OH)₂D] is a missing risk factor for CD, and relatedly that significant oral vitamin D exposure is a "missing environmental factor" for CD. First, elevated plasma levels of 1,25(OH)₂D are common in CD, especially in the newly diagnosed. Second, nine distinct conditions that increase plasma levels of 1,25(OH)₂D are either associated with CD or have indications of such an association in the literature. Third, a retrospective study shows that sustained oral vitamin D supplementation in infancy is associated with increased CD risk, and other studies on comorbid conditions support this association. Fourth, large doses of oral vitamin D upregulate many of the same cytokines, chemokines, and toll-like receptors that are upregulated in CD. Fifth, epidemiological evidence, such as the timing of the inception of a CD "epidemic" in Sweden, the increased prevalence of CD in Finland and the United States in recent decades, the unusually low prevalence of CD in Germany, and the differential in prevalence between Finnish Karelians and Russian Karelians, may all be explained by oral vitamin D exposure increasing CD risk. The same is true of some seemingly contradictory results in the literature on the effects of breastfeeding on CD risk. If future research validates this hypothesis, adjustments to oral vitamin D consumption among those who have genetic susceptibility may decrease the risk of CD in these individuals.

Because of their protein cross-linking properties, transglutaminases are widely used in several industrial processes, including the food and pharmaceutical industries. Transglutaminases obtained from animal tissues and organs, the first sources of this enzyme, are being replaced by microbial sources, which are cheaper and easier to produce and purify. Since the discovery of microbial transglutaminase (mTGase), the enzyme has been produced for industrial applications by traditional fermentation process using the bacterium Streptomyces mobaraensis. Several studies have been carried out in this field to increase the enzyme industrial productivity. Researches on gene expression encoding transglutaminase biosynthesis were performed in Streptomyces lividans, Escherichia coli, Corynebacterium glutamicum, Yarrowia lipolytica, and Pichia pastoris. In the first part of this review, we presented an overview of the literature on the origins, types, mediated reactions, and general characterizations of these important enzymes, as well as the studies on recombinant microbial transglutaminases. In this second part, we focus on the application versatility of mTGase in three broad areas: food, pharmacological, and biotechnological industries. The use of mTGase is presented for several food groups, showing possibilities of applications and challenges to further improve the quality of the end-products. Some applications in the textile and leather industries are also reviewed, as well as special applications in the PEGylation reaction, in the production of antibody drug conjugates, and in regenerative medicine.

Due to the recent interest in food additives that can act as triggering factors in autoimmune diseases including celiac disease (CD), the present letter to the editor expands on the microbial transglutaminase (mTG). It is heavily consumed by a plethora of food processing industries as "glue of proteins" thus improving product's stability, texture and shelf life. However, more and more information is accumulated lately, questioning its safety. Its cross-linked gliadin complexes are immunogenic in CD. The enzyme increases gliadin uptake, is transported in a trans-epithelial way and deposited below the enterocyte's line, has anti- phagocytic activity, enhances intestinal permeability and creates luminal resistant isopeptide bonds. No doubt that mTG is beneficial to food industries but a caveat to public health is highly recommended.

In gluten dependent conditions the gluten free diet is the cornerstone of therapy, decreasing disease activity, improving health and quality of life and treating or preventing the associated complications. Gluten withdrawal implies strict and lifelong elimination not only of wheat, barley, rye, and wheat-contaminated oats, but also of numerous non-nutritional products where components of wheat are often added. Due to multiple reasons the diet is difficult to follow and the long-term adherence is decreased with time. The present review summarizes the dark side of gluten restriction where nutritional deficiencies, toxicity, morbidity, mortality, and mental health problems are reported. The aim being to increase awareness, avoid, detect and treat the side effects and to promote a healthier nutrition, for the patient's benefits.

Most patients affected by celiac disease (CD) are asymptomatic or hyposymptomatic and undiagnosed, and are at risk of preventable complications. Therefore, early diagnosis is highly recommended. Multiple diagnostic antibodies are available; the most frequently used is IgA to tissue transglutaminase (IgA-tTg). It may yield false results and, alone, does not address IgA deficiency. Recently, a new generation of anti-neo-epitope tTg check (IgG + IgA) has become available. It is highly sensitive and specific, covers IgA-deficient patients with CD, reflects intestinal damage, and has predictive potential in the diagnosis of CD.

Probiotics per definition should have beneficial effects on human health, and their consumption has tremendously increased in the last decades. In parallel, the amount of published material and claims for their beneficial efficacy soared continuously. Recently, multiple systemic reviews, meta-analyses, and expert opinions expressed criticism on their claimed effects and safety. The present review describes the dark side of the probiotics, in terms of problematic research design, incomplete reporting, lack of transparency, and under-reported safety. Highlighted are the potential virulent factors and the mode of action in the intestinal lumen, risking the physiological microbiome equilibrium. Finally, regulatory topics are discussed to lighten the heterogeneous guidelines applied worldwide. The shift in the scientific world towards a better understanding of the human microbiome, before consumption of the probiotic cargo, is highly endorsed. It is hoped that better knowledge will extend the probiotic repertoire, re-confirm efficacy or safety, establish their efficacy and substantiate their beneficial effects.

Celiac disease is an autoimmune condition of the small intestine caused by prolamins in genetically susceptible individuals evoked by multiple environmental factors. The pathological luminal intricate eco-events produce multiple signals that irradiate the entire body, resulting in a plethora of extra-intestinal manifestations. Nutrients, dysbiosis, dysbiotic components and their mobilome, post-translational modification of naive proteins, inter-enterocyte's tight junction dysfunction resulting in a leaky gut, microbial lateral genetic transfer of virulent genes, the sensing network of the enteric nervous systems and the ensuing pro-inflammatory messengers are mutually orchestrating the autoimmune interplay. Genetic-environmental-luminal events-mucosal changes are driving centrifugally the remote organs autoimmunity, establishing extra-intestinal multi organ injury. Exploring the underlying intestinal eco-events, the sensing and the delivery pathways and mechanisms that induce the peripheral tissues' damages might unravel new therapeutical strategies to prevent and help the gluten affected patients.

Celiac disease (CD) is a systemic inflammatory disorder, characterized by the destruction of duodenal epithelium. The CD8 T cells involved are associated with cross-presentation. In addition to other factors, the rising prevalence of CD might be induced by microbial transglutaminase (mTG) an enzyme frequently used in food production that shares enzymatic and antigenic properties of tissue transglutaminase (TG2), the autoantigen in CD. We hypothesized that mTG and gliadin are transported into the endoplasmic reticulum (ER), indicating cross-presentation of both antigens.

Apical incubation of duodenal biopsies from CD and control patients was performed with mTG alone or with mTG and simultaneously with Frazer's fraction. Evaluation was carried out by immunofluorescence and electron microscopy.

Approximately 6% to 9% of the intracellular mTG and gliadin were transported to the ER of enterocytes. RACE cells (Rapid uptake of Antigen into the Cytosol of Enterocytes) displayed an enhanced antigen uptake into a dilated ER. mTG strongly localized at the basolateral membrane and the lamina propria.

mTG and gliadin are transported to the ER of enterocytes and to a greater extent to the ER of RACE cells, suggesting cross-presentation of exogenous antigens. The strong localization of mTG at the basolateral membrane and the lamina propria may also indicate a potential antigenic interaction with cells of the immune system. Since mTG may not only been taken up with food stuffs but could also be released by bacteria within the intestinal microbiota, further investigations are needed regarding the role of mTG in CD pathogenesis.

The enzyme microbial transglutaminase is heavily used in the food processing industries to ameliorate food qualities and elongate the products' shelf life. As a protein's glue, it cross-links gliadin peptides, creating neo-complexes that are immunogenic and potentially pathogenic to celiac disease communities. Even lacking sequence identity, it imitates functionally the endogenous tissue transglutaminase, known to be the autoantigen of celiac disease and representing an undisputable key player in celiac disease initiation and progress. The present review expend on the enzyme characteristics, exogenous intestinal sources, its cross-linking avidity to gluten or gliadin, turning naïve protein to immunogenic ones. Several observation on microbial transglutaminase cross linked complexes immunogenicity in celiac patients are reviewed and its pathogenicity is summarized. Warnings on its potential risks for the gluten dependent conditions are highlighted. When substantiated, it might represent a new environmental factor of celiac disease genesis. It is hoped that the presented knowledge will encourage further research to explore the mechanism and the pathogenic pathways taken by the gliadin cross linked enzyme in driving celiac disease.

Microbial transglutaminase is heavily used in the food processing industries to improve food qualities. Being a protein's glue, by cross-linking it creates neoepitope complexes that are immunogenic and potentially pathogenic in celiac disease. Despite low sequence identity, it imitates functionally its family member, the endogenous tissue transglutaminase, which is the autoantigen of celiac disease. The present comprehensive review highlights the enzyme characteristics, endogenous and exogenous intestinal sources, its cross-talks with gluten and gliadin, its immunogenicity and potential pathogenicity and risks for the gluten induced conditions. If substantiated, it might represent a new environmental inducer of celiac disease. The present findings might affect nutritional product labeling, processed food additive policies and consumer health education.

Recent studies suggest that the prevalence of celiac disease is rising. We previously established the prevalence of celiac disease in healthy blood donors in 2002.

The purpose of this study was to examine whether the prevalence of celiac disease and celiac disease autoimmunity has changed over time by performing a similar prospective study.

Healthy blood donors (n = 1908) were tested for tissue transglutaminase antibodies and for anti-endomysial antibodies when positive. Further evaluation followed accepted criteria for diagnosis.

Overall, 32 donors had abnormal tissue transglutaminase antibodies (1.68%). Eight donors had tissue transglutaminase antibodies >3 × upper limit of normal (0.42%), two of them with tissue transglutaminase antibodies >10 × upper limit of normal, while 24 donors had tissue transglutaminase antibodies <3 × upper limit of normal (1.26%). Most of the donors with positive tissue transglutaminase antibodies <3 × upper limit of normal had negative tissue transglutaminase antibodies levels on repeated testing (18/19). Celiac disease was diagnosed in four donors with positive tissue transglutaminase antibodies, establishing a prevalence of 1.68% (95% confidence interval 1.15-2.3) for celiac disease autoimmunity and 0.21% for celiac disease (95% confidence interval 0.07-0.5%).

The prevalence of celiac disease in blood donors in Israel did not rise in the last 15 years, suggesting that the increased prevalence of diagnosed celiac disease is mainly due to increased awareness. As most of the donors with elevated tissue transglutaminase antibodies <3 × upper limit of normal were endomysial antibody negative and had a negative tissue transglutaminase antibodies result upon re-testing, repeated tissue transglutaminase antibodies testing is required when screening asymptomatic populations for celiac disease.

If the transmission of biological information from one generation to the next is based on DNA, most heritable phenotypic traits such as chronic metabolic diseases, are not linked to genetic variation in DNA sequences. Non-genetic heritability might have several causes including epigenetic, parental effect, adaptive social learning, and influence of the ecological environment. Distinguishing among these causes is crucial to resolve major phenotypic enigmas. Strong evidence indicates that changes in DNA expression through various epigenetic mechanisms can be linked to parent-offspring resemblance in terms of sensitivity to metabolic diseases. Among non-genetic heritable traits, early nutrition could account for a long term deviant programming of genes expression responsible for metabolic diseases in adulthood. Nutrition could shape an inadequate gut microbiota (dysbiosis), triggering epigenetic deregulation of transcription which can be observed in chronic metabolic diseases. We review herein the evidence that dysbiosis might be a major cause of heritable epigenetic patterns found to be associated with metabolic diseases. By taking into account the recent advances on the gut microbiome, we have aggregated together different observations supporting the hypothesis that the gut microbiota could promote the molecular crosstalk between bacteria and surrounding host cells which controls the pathological epigenetic signature. We introduce for the first time the concept of "microbiological memory" as the main regulator of the epigenetic signatures, thereby indicating that different causes of non-genetic heritability can interact in complex pathways to produce inheritance.

In light of the coincident surge in overall gluten intake and the incidence of autoimmune diseases, the possible biological adverse effects of gluten were explored. PubMed, MEDLINE, and the Cochrane Library databases were screened for reports published between 1964 and 2016 regarding the adverse effects of gluten as well as the effects of a gluten-free diet on autoimmune diseases. In vitro and in vivo studies describing gluten intake in animal models or cell lines and gluten-free diets in human autoimmune diseases were reviewed. Multiple detrimental aspects of gluten affect human health, including gluten-dependent digestive and extradigestive manifestations mediated by potentially immunological or toxic reactions that induce gastrointestinal inadequacy. Gluten affects the microbiome and increases intestinal permeability. It boosts oxidative stress and affects epigenetic behavior. It is also immunogenic, cytotoxic, and proinflammatory. Gluten intake increases apoptosis and decreases cell viability and differentiation. In certain nonceliac autoimmune diseases, gluten-free diets may help curtail the adverse effects of gluten. Additional in vivo studies are needed to unravel the puzzle of gluten effects in humans and to explore the potential beneficial effects of gluten-free diets in autoimmune diseases.

Many essential functions of the human body are dependent on the symbiotic microbiota, which is present at especially high numbers and diversity in the gut. This intricate host-microbe relationship is a result of the long-term coevolution between the two. While the inheritance of mutational changes in the host evolution is almost exclusively vertical, the main mechanism of bacterial evolution is horizontal gene exchange. The gut conditions, with stable temperature, continuous food supply, constant physicochemical conditions, extremely high concentration of microbial cells and phages, and plenty of opportunities for conjugation on the surfaces of food particles and host tissues, represent one of the most favorable ecological niches for horizontal gene exchange. Thus, the gut microbial system genetically is very dynamic and capable of rapid response, at the genetic level, to selection, for example, by antibiotics. There are many other factors to which the microbiota may dynamically respond including lifestyle, therapy, diet, refined food, food additives, consumption of pre- and probiotics, and many others. The impact of the changing selective pressures on gut microbiota, however, is poorly understood. Presumably, the gut microbiome responds to these changes by genetic restructuring of gut populations, driven mainly via horizontal gene exchange. Thus, our main goal is to reveal the role played by horizontal gene exchange in the changing landscape of the gastrointestinal microbiome and potential effect of these changes on human health in general and autoimmune diseases in particular.

Objectives: To comprehensively review the scientific knowledge on the gut-brain axis. Methods: Various publications on the gut-brain axis, until 31 July 2017, were screened using the Medline, Google, and Cochrane Library databases. The search was performed using the following keywords: "gut-brain axis", "gut-microbiota-brain axis", "nutrition microbiome/microbiota", "enteric nervous system", "enteric glial cells/network", "gut-brain pathways", "microbiome immune system", "microbiome neuroendocrine system" and "intestinal/gut/enteric neuropeptides". Relevant articles were selected and reviewed. Results: Tremendous progress has been made in exploring the interactions between nutrients, the microbiome, and the intestinal, epithelium-enteric nervous, endocrine and immune systems and the brain. The basis of the gut-brain axis comprises of an array of multichannel sensing and trafficking pathways that are suggested to convey the enteric signals to the brain. These are mediated by neuroanatomy (represented by the vagal and spinal afferent neurons), the neuroendocrine-hypothalamic-pituitary-adrenal (HPA) axis (represented by the gut hormones), immune routes (represented by multiple cytokines), microbially-derived neurotransmitters, and finally the gate keepers of the intestinal and brain barriers. Their mutual and harmonious but intricate interaction is essential for human life and brain performance. However, a failure in the interaction leads to a number of inflammatory-, autoimmune-, neurodegenerative-, metabolic-, mood-, behavioral-, cognitive-, autism-spectrum-, stress- and pain-related disorders. The limited availability of information on the mechanisms, pathways and cause-and-effect relationships hinders us from translating and implementing the knowledge from the bench to the clinic. Implications: Further understanding of this intricate field might potentially shed light on novel preventive and therapeutic strategies to combat these disorders. Nutritional approaches, microbiome manipulations, enteric and brain barrier reinforcement and sensing and trafficking modulation might improve physical and mental health outcomes.

Celiac disease (CD) is an autoimmune and multisystem gluten-related disorder that causes symptoms involving the gastrointestinal tract and other organs. Pathogenesis of CD is only partially known. It had been established that ingestion of gluten proteins present in wheat and other cereals are necessary for the disease and develops in individuals genetically predisposed carrying the DQ2 or DQ8 human leukocyte antigen haplotypes. In this review, we had pay specific attention on the last discoveries regarding the three cellular components mainly involved in the development and maintenance of CD: T-cells, B-cells, and microbioma. All of them had been showed critical for the interaction between inflammatory immune response and gluten peptides. Although the mechanisms of interaction among overall these components are not yet fully understood, recent proteomics and molecular studies had shed some lights in the pathogenic role of tissue transglutaminase 2 in CD and in the alteration of the intestinal barrier function induced by host microbiota.

The effect of standard bakery concentrations of microbial transglutaminase (MTG) in wheat bread preparation on the immunoreactivity of sera of celiac disease (CD) patients was investigated. Immunoblotting using monoclonal antibodies specific to unmodified and/or deamidated gliadin showed no differences between control bread and MTG bread. Deamidation of gliadin could not be detected at standard MTG concentrations. Sera of CD patients were characterized using anti-gliadin and anti-deamidated gliadin peptide (DGP) enzyme-linked immunosorbent assay and grouped into DGP high- and low-titer pools. The recognition pattern obtained after using both CD sera pools for immunoblotting did not reveal differences between control and MTG-treated bread protein extracts. Our results indicate that MTG treatment of wheat bread prepared with typical MTG concentrations used in standard bakery processes does not lead to immunodetectable amounts of CD immunotoxic deamidated gliadins.

A GQD/PAMAM nanohybrid modified on gold nanoparticles (AuNP) embedded in multiwalled carbon nanotubes (MWCNT) based immunosensor was developed for detection of celiac disease in human. The AuNP embedded in MWCNT were linked with thiol groups of cysteine and amino groups were further coupled with carboxyl moieties of graphene quantum dots (GQDs) using EDC-NHS cross-linking chemistry. To enhance the sensitivity of the sensor, polyamidoamine (PAMAM) dendrimer was attached with GQDs through carbodiimide coupling. The tissue transglutaminase (tTG) antigen was immobilized on PAMAM to form nanoprobe for sensing specific anti-tissue transglutaminase (anti-tTG) antibodies (immunoglobin A isotype) in human serum. The electrochemical changes after specific binding of antibody with antigen was measured cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The modifications in sensor surface were characterized using FE-SEM. The sensor is highly specific to anti-tissue transglutaminase antibodies and showed negligible response to non-specific serum proteins. The sensitivity of the sensor was 1297.14μA/cm²/pg with DPV and lower limit of detection of anti-tissue transglutaminase antibody was found 0.1fg per 6μl.

Celiac disease, also known as "celiac sprue", is a chronic inflammatory disorder of the small intestine, produced by the ingestion of dietary gluten products in susceptible people. It is a multifactorial disease, including genetic and environmental factors. Environmental trigger is represented by gluten while the genetic predisposition has been identified in the major histocompatibility complex region. Celiac disease is not a rare disorder like previously thought, with a global prevalence around 1%. The reason of its under-recognition is mainly referable to the fact that about half of affected people do not have the classic gastrointestinal symptoms, but they present nonspecific manifestations of nutritional deficiency or have no symptoms at all. Here we review the most recent data concerning epidemiology, pathogenesis, clinical presentation, available diagnostic tests and therapeutic management of celiac disease.