The Frequently Used Industrial Food Process Additive, Microbial Transglutaminase: Boon or Bane.

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.

Utilizing Telemedicine Applications in Celiac Disease and Other Gluten-Free-Diet-Dependent Conditions: Insights from the COVID-19 Pandemic.

BACKGROUND: Globally, approximately 1.4% of people have celiac disease (CD), induced by gluten sensitivity. If left untreated, it causes small intestinal inflammation and villous atrophy, which can result in failure to thrive, anemia, osteoporosis, malabsorption, and even malignancy. The only treatment option available is a gluten-free diet (GFD). Few studies have looked at the role and perception of telehealth in relation to CD and selective nutrition both before and after the COVID-19 pandemic. AIM: Our goal was to screen and investigate the research conducted both before and after the COVID-19 pandemic concerning the utilization of telehealth applications and solutions in CD and other GFD-dependent circumstances. METHODS: We employed a narrative review approach to explore articles that were published in scholarly journals or organizations between the years 2000 and 2024. Only English-language publications were included. PubMed and Google Scholar searches were mainly conducted using the following keywords: telemedicine, telehealth, telecare, eHealth, m-health, COVID-19, SARS-CoV-2, celiac disease, and gluten-free diet (GFD). Manual searches of the references in the acquired literature were also carried out, along with the authors' own personal contributions of their knowledge and proficiency in this field. RESULTS: Only a few studies conducted prior to the COVID-19 outbreak examined the viewpoints and experiences of adult patients with CD with relation to in-person clinic visits, as well as other options such as telehealth. The majority of patients believed that phone consultations were appropriate and beneficial. Video conferencing and telemedicine became more popular during the COVID-19 pandemic, demonstrating the effectiveness of using these technologies for CD on a global basis. In recent years, urine assays for gluten identification have become accessible for use at home. These tests could be helpful for CD monitoring with telemedicine assistance. CONCLUSIONS: The extended knowledge gathered from the COVID-19 pandemic is expected to complement pre-COVID-19 data supporting the usefulness of telemedicine even after the emergent pandemic, encouraging its wider adoption in standard clinical practice. The monitoring and follow-up of CD patients and other GFD-dependent conditions can greatly benefit from telemedicine.

The Potential Harmful Effects of Genetically Engineered Microorganisms (GEMs) on the Intestinal Microbiome and Public Health.

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.

Natural Killer Cells and Cytotoxic T Cells: Complementary Partners against Microorganisms and Cancer.

Natural killer (NK) cells and cytotoxic T (CD8+) cells are two of the most important types of immune cells in our body, protecting it from deadly invaders. While the NK cell is part of the innate immune system, the CD8+ cell is one of the major components of adaptive immunity. Still, these two very different types of cells share the most important function of destroying pathogen-infected and tumorous cells by releasing cytotoxic granules that promote proteolytic cleavage of harmful cells, leading to apoptosis. In this review, we look not only at NK and CD8+ T cells but also pay particular attention to their different subpopulations, the immune defenders that include the CD56+CD16dim, CD56dimCD16+, CD57+, and CD57+CD16+ NK cells, the NKT, CD57+CD8+, and KIR+CD8+ T cells, and ILCs. We examine all these cells in relation to their role in the protection of the body against different microorganisms and cancer, with an emphasis on their mechanisms and their clinical importance. Overall, close collaboration between NK cells and CD8+ T cells may play an important role in immune function and disease pathogenesis. The knowledge of how these immune cells interact in defending the body against pathogens and cancers may help us find ways to optimize their defensive and healing capabilities with methods that can be clinically applied.

HLA-DQ2/8 and COVID-19 in Celiac Disease: Boon or Bane.

The SARS-CoV-2 pandemic continues to pose a global threat. While its virulence has subsided, it has persisted due to the continual emergence of new mutations. Although many high-risk conditions related to COVID-19 have been identified, the understanding of protective factors remains limited. Intriguingly, epidemiological evidence suggests a low incidence of COVID-19-infected CD patients. The present study explores whether their genetic background, namely, the associated HLA-DQs, offers protection against severe COVID-19 outcomes. We hypothesize that the HLA-DQ2/8 alleles may shield CD patients from SARS-CoV-2 and its subsequent effects, possibly due to memory CD4 T cells primed by previous exposure to human-associated common cold coronaviruses (CCC) and higher affinity to those allele's groove. In this context, we examined potential cross-reactivity between SARS-CoV-2 epitopes and human-associated CCC and assessed the binding affinity (BA) of these epitopes to HLA-DQ2/8. Using computational methods, we analyzed sequence similarity between SARS-CoV-2 and four distinct CCC. Of 924 unique immunodominant 15-mer epitopes with at least 67% identity, 37 exhibited significant BA to HLA-DQ2/8, suggesting a protective effect. We present various mechanisms that might explain the protective role of HLA-DQ2/8 in COVID-19-afflicted CD patients. If substantiated, these insights could enhance our understanding of the gene-environment enigma and viral-host relationship, guiding potential therapeutic innovations against the ongoing SARS-CoV-2 pandemic.

Resveratrol in Rheumatological Diseases: A Systematic Review.

Resveratrol is an antioxidant with anti-inflammatory and cell-protective properties. The aim of our article is to review the use of resveratrol in rheumatic diseases. PubMed/Medline, Embase, and Scielo were screened for articles on resveratrol and rheumatic diseases in the period between of January 1966 and March 2023. Five articles were depicted, including 481 patients. The included diseases were osteoarthritis (n=3), rheumatoid arthritis (n=1), and Takayasu arteritis (n=1). The age varied from 32 to 58.2 years, and the female gender ranged from 62% to 74% in the studies. Disease duration ranged from 3.5 ± 3.2 to 9.4 ± 5.8 years. The resveratrol dosage went from 250 mg to 1000 mg/day. All those articles demonstrated improvements in the diverse rheumatic diseases, including pain intensity, function, disease activity (DAS 28), swelling joints, and reduced inflammation markers (erythrocyte sedimentation rate, C-reactive protein, interleukinIL-1, IL-6, and tumor necrosis factor). No side effects were detected in all studies. In conclusion, resveratrol seems to be a safe therapy for various rheumatic diseases, although the evidence is very limited. The improved subjective and objective complaints and laboratory parameters are promising. However, there is a need to reconfirm, reproduce, and investigate the topic in more extensive, well-controlled, double-blind, cross-over studies.

Cross-reactivity and sequence similarity between microbial transglutaminase and human tissue antigens.

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.

SARS-CoV-2 Gut-Targeted Epitopes: Sequence Similarity and Cross-Reactivity Join Together for Molecular Mimicry.

The gastrointestinal tract can be heavily infected by SARS-CoV-2. Being an auto-immunogenic virus, SARS-CoV-2 represents an environmental factor that might play a role in gut-associated autoimmune diseases. However, molecular mimicry between the virus and the intestinal epitopes is under-investigated. The present study aims to elucidate sequence similarity between viral antigens and human enteric sequences, based on known cross-reactivity. SARS-CoV-2 epitopes that cross-react with human gut antigens were explored, and sequence alignment was performed against self-antigens implicated in enteric autoimmune conditions. Experimental SARS-CoV-2 epitopes were aggregated from the Immune Epitope Database (IEDB), while enteric antigens were obtained from the UniProt Knowledgebase. A Pairwise Local Alignment tool, EMBOSS Matcher, was employed for the similarity search. Sequence similarity and targeted cross-reactivity were depicted between 10 pairs of immunoreactive epitopes. Similar pairs were found in four viral proteins and seven enteric antigens related to ulcerative colitis, primary biliary cholangitis, celiac disease, and autoimmune hepatitis. Antibodies made against the viral proteins that were cross-reactive with human gut antigens are involved in several essential cellular functions. The relationship and contribution of those intestinal cross-reactive epitopes to SARS-CoV-2 or its potential contribution to gut auto-immuno-genesis are discussed.

Infantile-onset inflammatory bowel disease has variable long-term outcomes.

Objective and aim: Infantile-onset inflammatory bowel disease (IO-IBD), defined as IBD diagnosed at age 2 years or younger, tends to be more severe and refractory to conventional treatment than IBD diagnosed at a later age. However, data about IO-IBD and its long-term follow up are limited. We thus aimed to evaluate the presentation and long-term outcomes of patients with IO-IBD in a retrospective multicenter study. Methods: Medical records of patients diagnosed with IO-IBD in eight medical centers during 2000-2017 with at least 1-year follow up were reviewed. Demographics and disease characteristics at diagnosis including age of onset, disease phenotype and location, surgeries, medical therapy, and comorbid conditions were recorded. Results: Twenty-three patients with IO-IBD (16 males, 70%) were identified and followed for a median (range) of 51.2 (26.0-110.3) months. The mean ages at presentation and at the last follow up were 14 ± 9.8 and 101 ± 77 months, respectively. Six (26%) patients needed ileostomy already at the time of diagnosis and 20 (87%) were treated with corticosteroids. During long-term follow up, remission was achieved in 16 (73%) patients; of whom, 3 (14%) were without medications and 7 (32%) were in remission with the use of 5-aminosalicylic acid only. One patient needed hemicolectomy and one developed a severe EBV related infection. Conclusion: The majority of patients with IO-IBD achieved long-term remission, despite a severe disease presentation at diagnosis. Surgery rate however is high, mainly during the first months from diagnosis.

Nutraceutical strategies for alleviation of UVB phototoxicity.

Ultraviolet B exposure to keratinocytes promotes carcinogenesis by inducing pyrimidine dimer lesions in DNA, suppressing the nucleotide excision repair mechanism required to fix them, inhibiting the apoptosis required for the elimination of initiated cells, and driving cellular proliferation. Certain nutraceuticals - most prominently spirulina, soy isoflavones, long-chain omega-3 fatty acids, the green tea catechin epigallocatechin gallate (EGCG) and Polypodium leucotomos extract - have been shown to oppose photocarcinogenesis, as well as sunburn and photoaging, in UVB-exposed hairless mice. It is proposed that spirulina provides protection in this regard via phycocyanobilin-mediated inhibition of Nox1-dependent NADPH oxidase; that soy isoflavones do so by opposing NF-κB transcriptional activity via oestrogen receptor-beta; that the benefit of eicosapentaenoic acid reflects decreased production of prostaglandin E2; and that EGCG counters UVB-mediated phototoxicity via inhibition of the epidermal growth factor receptor. The prospects for practical nutraceutical down-regulation of photocarcinogenesis, sunburn, and photoaging appear favourable.

Management of Hyperhomocysteinemia, Low Vitamin Levels, and Low Cortisol in Cannabis Users: A Report of 2 Cases.

Objective: The purpose of this study was to describe the management of 2 long-term users of cannabis with nutrition and psychotherapy. Clinical Features: A 28-year-old man presented with a medical history of asthma, depression, anxiety, and smoking, and was a long-term user of cannabis for 9 years (usually 3 times a week). A 39-year-old man presented with a medical history of anxiety and fatigue, and was a long-term user of cannabis for 14 years (usually twice a week). Laboratory tests showed altered blood levels of homocysteine, vitamins, and cortisol. Intervention and Outcome: Both patients were given supplements of vitamins (folic acid, methylcobalamin, and pyridoxine), vitamin D, Rhodiola rosea, and L-tyrosine. Psychotherapy also was provided to both patients. After 2 months of treatment, both patients improved and reduced their cannabis consumption. Conclusion: This study describes vitamin deficiencies, low cortisol levels, and hyperhomocysteinemia in 2 cannabis users who were managed with a combination of nutritional supplements and psychotherapy.

Checkpoint Inhibitors and Induction of Celiac Disease-like Condition.

Immune checkpoint inhibitors herald a new era in oncological therapy-resistant cancer, thus bringing hope for better outcomes and quality of life for patients. However, as with other medications, they are not without serious side effects over time. Despite this, their advantages outweigh their disadvantages. Understanding the adverse effects will help therapists locate, apprehend, treat, and perhaps diminish them. The major ones are termed immune-related adverse events (irAEs), representing their auto-immunogenic capacity. This narrative review concentrates on the immune checkpoint inhibitors induced celiac disease (CD), highlighting the importance of the costimulatory inhibitors in CD evolvement and suggesting several mechanisms for CD induction. Unraveling those cross-talks and pathways might reveal some new therapeutic strategies.

The intestinal luminal sources of α-synuclein: a gastroenterologist perspective.

Parkinson's disease is characterized by nonmotor/motor dysfunction, midbrain dopaminergic neuronal death, and α-synuclein (aSN) deposits. The current hypothesis is that aSN accumulates in the enteric nervous system to reach the brain. However, invertebrate, vertebrate, and nutritional sources of aSN reach the luminal compartment. Submitted to local amyloidogenic forces, the oligomerized proteins' cargo can be sensed and sampled by a specialized mucosal cell to be transmitted to the adjacent enteric nervous system, starting their upward journey to the brain. The present narrative review extends the current mucosal origin of Parkinson's disease, presenting the possibility that the disease starts in the intestinal lumen. If substantiated, eliminating the nutritional sources of aSN (eg, applying a vegetarian diet) might revolutionize the currently used dopaminergic pharmacologic therapy.

Gluten-free diet can ameliorate the symptoms of non-celiac autoimmune diseases.

CONTEXT: 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). OBJECTIVE: The current systematic review summarizes those entities and discusses the logic behind using a GFD in classical non-gluten-dependentADs. DATA SOURCES: 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. DATA EXXTRACTION: Eight-three articles were included in the systematic review (using PRISMA guidelines). DATA ANALYSIS: 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. CONCLUSION: A GFD might represent a novel nutritional therapeutic strategy for classical non-gluten-dependent autoimmune conditions.

Plummer-Vinson syndrome in primary Sjögren syndrome: a case-based review.

This study aimed to describe a patient with Sjögren syndrome who developed Plummer-Vinson syndrome, and to review the literature and describe shared aspects of this rare association. A systematic screening of articles was conducted in PubMed/MEDLINE, LILACS, SciELO, Scopus, Web of Science, and Cochrane, dating 1940 to 2020. All the articles included the association between Sjögren syndrome and Plummer-Vinson syndrome. No language restriction was applied. The following terms were used: "Sjögren syndrome" or "sicca syndrome" and "Plummer-Vinson syndrome" or "Paterson-Kelly syndrome." We performed our analysis by adding our present case, with a total of 4 cases. Three out of four were female (75%), age varied from 56 to 58 years old. In 2 cases, Sjögren syndrome preceded Plummer-Vinson syndrome diagnosis, and in 1 report, Plummer-Vinson syndrome appeared before Sjögren syndrome. Disease duration varied from 7 to 20 years. In two cases, autoantibodies were available, and antinuclear antibodies and anti-Ro/SS-A were positive in both, and anti-La/SS-B in one of them was associated with anti-dsDNA; however, no data regarding lupus was available in the article. Treatment involved iron supplementation in 3/3. Two out of three received parenteral iron supplementation, and in these two cases, mechanical esophageal dilatation was needless. In the other case, an additional endoscopic esophageal dilatation was necessary to receive the oral iron supplement. All 3 cases had a good outcome. This case illustrates a patient with Sjögren syndrome who developed the rare Plummer-Vinson syndrome. In Sjögren syndrome, the presence of iron-deficiency anemia, dysphagia, and weight loss should alert the physician to search for associated Plummer-Vinson syndrome.

Nutraceutical Aid for Allergies - Strategies for Down-Regulating Mast Cell Degranulation.

Interactions of antigens with the mast cell FcεRI-IgE receptor complex induce degranulation and boost synthesis of pro-inflammatory lipid mediators and cytokines. Activation of spleen tyrosine kinase (Syk) functions as a central hub in this signaling. The tyrosine phosphatase SHP-1 opposes Syk activity; stimulation of NADPH oxidase by FcεRI activation results in the production of oxidants that reversibly inhibit SHP-1, up-regulating the signal from Syk. Activated AMPK can suppress Syk activation by the FcεRI receptor, possibly reflecting its ability to phosphorylate the FcεRI beta subunit. Cyclic GMP, via protein kinase G II, enhances the activity of SHP-1 by phosphorylating its C-terminal region; this may explain its inhibitory impact on mast cell activation. Hydrogen sulfide (H2S) likewise opposes mast cell activation; H2S can boost AMPK activity, up-regulate cGMP production, and trigger Nrf2-mediated induction of Phase 2 enzymes - including heme oxygenase-1, whose generation of bilirubin suppresses NADPH oxidase activity. Phycocyanobilin (PCB), a chemical relative of bilirubin, shares its inhibitory impact on NADPH oxidase, rationalizing reported anti-allergic effects of PCB-rich spirulina ingestion. Phase 2 inducer nutraceuticals can likewise oppose the up-regulatory impact of NADPH oxidase on FcεRI signaling. AMPK can be activated with the nutraceutical berberine. High-dose biotin can boost cGMP levels in mast cells via direct stimulation of soluble guanylate cyclase. Endogenous generation of H2S in mast cells can be promoted by administering N-acetylcysteine and likely by taurine, which increases the expression of H2S-producing enzymes in the vascular system. Mast cell stabilization by benifuuki green tea catechins may reflect the decreased surface expression of FcεRI.

Microbial Transglutaminase Is a Very Frequently Used Food Additive and Is a Potential Inducer of Autoimmune/Neurodegenerative Diseases.

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.

Celiac disease in the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has had an impact on global health. DESIGN: The impact of the COVID-19 pandemic on patients with coeliac disease was assessed in the present review. RESULTS: The incidence of coeliac disease and the problems associated with coeliac disease increased during the COVID-19 pandemic. Adherence to the diet is crucial for the patient's health and quality of life since the only approved therapy for coeliac disease is a gluten withdrawal. CONCLUSIONS: A gluten-free diet should be promoted by the therapeutic team and implemented among these categories of patients.