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Sindrome dell’intestino irritabile: c’è un ruolo per il glutine?

by luciano

Uno studio molto importante che evidenzia la sovrapposizione dei sintomi della sindrome dell’intestino irritabile con quelli generati dalla sensibilità al glutine non celiaca dalle ATI e da Fodmaps.

“A tight link exists between dietary factors and irritable bowel syndrome (IBS), one of the most common functional syndromes, characterized by abdominal pain/discomfort, bloating and alternating bowel habits. Amongst the variety of foods potentially evoking “food sensitivity”, gluten and other wheat proteins including amylase trypsin inhibitors represent the culprits that recently have drawn the attention of the scientific community. Therefore, a newly emerging condition termed non-celiac gluten sensitivity (NCGS) or nonceliac wheat sensitivity (NCWS) is now well established in the clinical practice. Notably, patients with NCGS/NCWS have symptoms that mimic those present in IBS. The mechanisms by which gluten or other wheat proteins trigger symptoms are poorly understood and the lack of specific biomarkers hampers diagnosis of this condition. The present review aimed at providing an update to physicians and scientists regarding the following main topics: the experimental and clinical evidence on the role of gluten/wheat in IBS; how to diagnose patients with functional symptoms attributable to gluten/wheat sensitivity; the importance of double-blind placebo controlled cross-over trials as confirmatory assays of gluten/wheat sensitivity; and finally, dietary measures for gluten/wheat sensitive patients. The analysis of current evidence proposes that gluten/wheat sensitivity can indeed represent a subset of the broad spectrum of patients with a clinical presentation of IBS. (J Neurogastroenterol Motil 2016;22:547-557). Umberto Volta, Maria Ines Pinto-Sanchez et al.

Extrac from the study:
…..omissis. Experimental Evidence for a Role of Wheat Components in Irritable Bowel Syndrome. Different mechanisms have been proposed to explain how gluten may trigger gastrointestinal symptoms in the absence of celiac disease (Figure).

In vitro studies have demonstrated that digests of gliadin increase the expression of co-stimulatory molecules and the production of proinflammatory cytokines in monocytes and dendritic cells (40,57,58). Certain “toxic” (that only stimulates the innate immune response) gliadin-derived peptides such as the 31-43mer, may evoke epithelial cell dysfunction, increased IL-15 production and enterocyte apoptosis (59). Recent studies have demonstrated increased expression of TLR-2 in the intestinal mucosa of non-celiac compared to celiac patients, suggesting a role of the innate immune system in the pathogenesis of non-celiac reactions to gluten or other wheat components (49). Other studies have shown that monocytes from HLA-DQ2+ non-celiac individuals spontaneously release 2-3 fold more IL-8 than monocytes from HLA-DQ2 negative patients. This suggests that patients without celiac disease (no enteropathy and negative specific serology), but with positive HLA-DQ2 status, may represent a subpopulation reacting mildly to gluten (60). In terms of gut dysfunction, gluten sensitization in mice has been shown to induce acetylcholine release, one of the main excitatory neurotransmitters in the gut, from the myenteric plexus (57).
This correlates with increased smooth muscle contractility and a hypersecretory status with increased ion transport and water movements (57). These functional effects induced by gluten were not accompanied by mucosal atrophy, and were not observed after sensitization with non-gluten proteins. Interestingly gluten-induced gut dysfunction was particularly notable in mice transgenic for the human celiac gene HLA-DQ8 (57).
ATIs, a group of wheat proteins that confer resistance of the grain to pests, are strong inducers of innate immune responses via TLR4 and via the myeloid differentiation factor 88-dependent and -independent pathway (40). This activation occurs both in vitro and in vivo after oral ingestion of purified ATIs or gluten, while gluten-free cereals display no or minimal activities (61). The role of ATIs in IBS is not yet known, however there is clear description of a mechanism that could be involved in the generation of gut dysfunction and symptoms. These mechanisms are different from those proposed for gluten and thus it is conceivable that they could co-exist in given patients or have a synergistic effect.

Genotipi di grano contenenti sequenze di glutine a bassa tossicità

by luciano

“Precedenti studi hanno documentato che le varietà locali e le varietà di grano più vecchie contengono più combinazioni genetiche diverse per le prolamine (proteine del grano) rispetto alle varietà moderne (10, 11). La letteratura riporta variazioni per specifiche sequenze geniche principalmente nelle regioni epitopiche di Glia-α9, Glia-α2, Glia-α20 e Glia-α nelle vecchie landraces (9). Nell’ultimo decennio nel contesto del CD, l’immunogenicità degli epitopi specifici delle cellule T è stata acquisita in prima linea (9, 12). Il potenziale immunogenico tra le diverse varietà di grano esaploide è variabile; quindi è possibile che vi siano differenze indotte dalla tecnica dell’incrocio dei grani in relazione alla presenza e tipologia di epitopi stimolatori delle cellule T nelle moderne varietà di grano (13, 14). Ciò solleva la questione se vi sia una varietà specifica di grano che è meno immunogenica e può essere utilizzata nei programmi di riproduzione per lo sviluppo di un genotipo di grano completamente sicuro per il consumo da parte dei pazienti affetti da CD ”.

Punti salienti:
• L’identificazione di specie di grano meno / non immunogeniche è una pietra miliare importante che potrebbe aiutare i pazienti o addirittura prevenire la CD.
• Con l’uso di cellule T e PBMC specifici per glutine, è possibile selezionare genotipi di grano contenenti sequenze di glutine a bassa tossicità.

Assenza della gliadina ω-5 nel grano monococcum (Einkorn)

by luciano

Le omega gliadine, soprattutto la omega-5 gliadina termostabile, sono responsabili dell’anafilassi grano-dipendente indotta dall’esercizio fisico (wheat-dependent exercise-induced anaphylaxis, WDEIA) diffusa principalmente tra gli adulti.
“Wheat [Triticum aestivum (T.a.)] ingestion can cause a specific allergic reaction, which is called wheat-dependent exercise-induced anaphylaxis (WDEIA). The major allergen involved is ω-5 gliadin, a gluten protein coded by genes located on the B genome. Our aim was to study the immunoreactivity of proteins in Triticum monococcum (einkorn, T.m.), a diploid ancestral wheat lacking B chromosomes, for possible use in the production of hypoallergenic foods. A total of 14 patients with a clear history of WDEIA and specific immunoglobulin E (IgE) to ω-5 gliadin were enrolled. Skin prick test (SPT) with a commercial wheat extract and an in-house T.a. gluten diagnostic solution tested positive for 43 and 100% of the cases, respectively. No reactivity in patients tested with solutions prepared from four T.m. accessions was observed. The immunoblotting of T.m. gluten proteins performed with the sera of patients showed different IgE-binding profiles with respect to T.a., confirming the absence of ω-5 gliadin. A general lower immunoreactivity of T.m. gluten proteins with scarce cross-reactivity to ω-5 gliadin epitopes was assessed by an enzyme-linked immunosorbent assay (ELISA). Given the absence of reactivity by SPT and the limited cross-reactivity with ω-5 gliadin, T.m. might represent a potential candidate in the production of hypoallergenic bakery products for patients sensitized to ω-5 gliadin. Further analyses need to be carried out regarding its safety”. Study on the Immunoreactivity of Triticum monococcum (Einkorn) Wheat in Patients with Wheat-Dependent Exercise-Induced Anaphylaxis for the Production of Hypoallergenic Foods. Lombardo Cet altri J Agric Food Chem. 2015

Varietà di grano a basso contenuto di frazioni tossiche: un’opportunità per i prodotti dedicati ai bambini.

by luciano

LC/MS ANALYSIS OF GLUTEN PEPTIDES DERIVED FROM SIMULATED GASTROINTESTINAL DIGESTION OF DIFFERENT WHEAT VARIETIES: QUALITY AND SAFETY IMPLICATIONS. Sforza, Stefano & Prandi, Barbara & Bencivenni, Mariangela & Tedeschi, Tullia & Dossena, Arnaldo & Marchelli, Rosangela & Galaverna, Gianni. (2011):

Riassunto

“Il contenuto di glutine nel grano è molto variabile, dipendendo dalla varietà genetica e delle condizioni di coltivazione. La digestione gastrointestinale del glutine produce, oltre ai peptidi corti, anche lunghi, che, l’alto contenuto di prole di gliadine (16-26%) e glutenine (11-13%), rende molto resistenti alla degradazione delle proteasi digestive. Nel presente lavoro, un metodo per l’estrazione della frazione prolamine è stato applicato a diverse varietà di grano, seguite da una digestione gastrointestinale simulata della gliadina estratta. Le miscele peptidiche generate erano caratterizzate da LC / MS e i peptidi più abbondanti sono stati identificati mediante tecniche MS a stadio multiplo a bassa e alta risoluzione e attraverso la sintesi di standard autentici. Questi peptidi erano anche semiquantificati nei diversi campioni rispetto a un adeguato standard interno. Le miscele peptidiche sono risultate molto variabili, a seconda del diverso contenuto e tipo di gliadine presenti nelle varietà di grano, con forti differenze tra le varietà testate, sia qualitativamente (le sequenze dei peptidi generate) sia quantitativamente (la loro quantità).

La differenza più grande è stata trovata tra le varietà di grano duro e quelle comuni. I peptidi presenti solo nelle varietà precedenti sono stati identificati e utilizzati come marcatori molecolari per identificare e quantificare la presenza di grano tenero quando aggiunti a campioni di grano duro. La maggior parte dei peptidi identificati erano già noti per essere patogeni per le persone affette da celiachia, un’enteropatia autoimmune innescata dalle proteine ​​del glutine, che si sviluppa in alcuni soggetti geneticamente suscettibili dopo il consumo di glutine. Alcuni campioni appartenenti a varietà definite hanno mostrato una minore quantità di peptidi patogeni legati alla celiachia durante la digestione, a causa di un contenuto inferiore di gliadina. Sebbene non sia sicuro per i pazienti celiaci, l’uso di queste varietà nelle formulazioni di alimenti per l’infanzia potrebbe essere di grande aiuto per ridurre la diffusione della malattia, poiché la prevalenza della celiachia sembra essere favorita da un’esposizione precoce a una grande quantità di peptidi di glutine”.

 

Diversità genetica del grano

by luciano

A-B-D Genomes

Wheat occurs in a range of diploid, tetraploid and hexaploid forms (summarised in Table 1). The earliest cultivated forms were the A genome diploid einkorn (T. monococcum var monococcum) and tetraploid emmer (T. turgidum var. dicoccum) with the A and B genomes. These are closely related to wild forms: diploid T. monococcum var. monococcum and T. ururtu and tetraploid T. turgidum var. dicoccoides, respectively. Modern tetraploid durum (pasta) wheat (T. turgidum var. durum) probably arose from mutations in cultivated emmer.
Hexaploid wheat (Triticum aestivum) (genomes ABD)
Hexaploid wheat (Triticum aestivum) (genomes ABD) has never existed as a wild species and no wild hexaploid wheats are known. It probably arose by hybridization of cultivated emmer with the related wild grass T. tauschii (goat grass, also called Aegilops tauschii and Ae. squarossa). This hybridization probably occurred in south-eastern Turkey about 9000 years ago (Feldman, 1995, Dubcovsky and Dvorak, 2007) and contributed the D genome. All cultivated hexaploid wheats, including spelt, are forms of T. aestivum.
A major difference between “ancient” cultivated wheats (einkorn, emmer, spelt) and their wild relatives and modern durum and bread wheats is whether the grain are hulled or free threshing. In hulled wheats the glumes and palea adhere to the grain and the threshed material consists of intact spikelets.
α-gliadins
As the most coeliac-active T-cell epitopes are present on the α-gliadins, emphasis has been placed on exploring differences in the amounts and sequences of proteins of this class. Kasarda 
et al. (1976)
33mer fragment of α-gliadin
The studies of van Herpen et al. (2006) showed that T-cell stimulatory epitopes were more abundant in α-gliadins encoded by the D genome, and Molberg et al. (2005) who demonstrated that the immunodominant 33mer fragment of α-gliadin was encoded by chromosome 6D (and hence absent from diploid einkorn and tetraploid wheats).
The absence of the D genome from durum wheat
The absence of the D genome from durum wheat could result in lower coeliac activity due to the absence of the T-cell stimulatory epitopes at the Gli-D2 locus. van den Broeck et al. (2010a) therefore screened 103 accessions of tetraploid wheat by immunoblotting of gluten protein extracts with monoclonal antibodies against the Glia-α9 and Glia-α20 epitopes. This identified three accessions with significantly reduced levels of both epitopes. Further analysis of 61 durum wheat accessions by high throughput transcript sequencing similarly identified some accessions with lower abundances of transcripts containing coeliac disease epitopes (Salentjin et al., 2013).
Other gluten proteins
Although impressive progress has been made with identifying variation in the abundances of coeliac disease epitopes in α-gliadins, it must be borne in mind that other groups of gluten protein also contain coeliac active sequences. This was demonstrated in the survey of gluten protein sequences in the Uniprot protein sequence database by Spaenij-Dekking et al. (2005) which is referred to above. They showed that T-cell stimulatory epitopes were present in all γ-gliadin sequences (17/17), in 95.5% (21/22) of HMW subunit sequences and in 5% of LMW subunit sequences (3/57), in addition to 66% (19/29) of α-gliadin sequences. (Improving wheat to remove coeliac epitopes but retain functionality. Peter R. Shewry and Arthur S. Tatham 2016).