Mechanisms of innate immune activation by gluten peptide p31-43 in mice

Araya, Romina Elizabeth; Castro, María Florencia Gómez; Carasi, Paula; McCarville, Justin L.; Jury, Jennifer; Mowat, A M; Verdú, Elena F.; Chirdo, Fernando Gabriel

doi:10.1152/ajpgi.00435.2015

Cited by 49 publications

(52 citation statements)

References 35 publications

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“…Thus, our results allow us to conclude that the human digestive tract has the necessary tools for gluten-protein hydrolysis. Nevertheless, different authors have indicated that gluten is not completely degraded by proteolytic gastrointestinal activity and consequently, gliadin-derived peptides such as 33-, 19- and 13-mer can accumulate and trigger inflammatory process associated with CD [8], [27]. Using partially purified extracts (ammonium sulfate-fractioned), we verified this (Figure 2).…”

Section: Discussionsupporting

confidence: 67%

“…The gliadin prolamin (from gluten) and related prolamins (from wheat, barley, and rye) are resistant to complete digestion by human digestive enzymes due to their high glutamine and proline contents. Their digestion results in the production of large peptides (10 to ≥30 amino acids) that cross the small intestinal barrier, some of which (such as 13-, 19-, or 33-mer), are capable of triggering inflammatory processes associated with CD [6], [7], [8].…”

Section: Introductionmentioning

confidence: 99%

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The human digestive tract has proteases capable of gluten hydrolysis

Gutiérrez

Pérez-Andrés

Martı́nez-Blanco

et al. 2017

Molecular Metabolism

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ObjectiveTo identify, purify, and characterize the proteins responsible for glutenase activity in the feces of healthy subjects and patients with celiac disease (CD).MethodsSixteen subjects were included in this study; 8 were healthy with no known food intolerances, and 8 were treated CD patients on a gluten-free diet. Fecal samples were homogenized, and precipitated proteins were purified by chromatography. Glutenase activity was evaluated by bioassays, zymography, and high-performance liquid chromatography with immunogenic 33-mer, 19-mer, and 13-mer gliadin peptides.ResultsThe gastrointestinal elastase 3B (CEL3B), elastase 2A (CEL2A), and carboxypeptidase A1 (CBPA1) enzymes degraded human gluten. These proteins fully hydrolyzed 13-mer and 19-mer gliadin peptides that trigger immune-mediated enteropathy in individuals genetically predisposed to CD and partially digested a 33-mer. Feces from patients with CD showed more glutenase activity than feces from individuals without CD (171–466% higher). Peptidase activity against the gliadin peptides also increased in patients with CD.ConclusionThe digestive tracts of patients with CD and healthy subjects have enzymatic machinery needed for gluten degradation. Patients with CD showed more gluten hydrolysis than did healthy individuals, although, in both cases, a fraction of 33-mer peptide remained intact. Gliadin peptides derived from gastrointestinal digestion, especially the 33-mer, can potentially be used by commensal microbiota from both CD-positive and CD-negative individuals, and differences in bacterial hydrolysis can modify its immunogenic capacity.

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

The human digestive tract has proteases capable of gluten hydrolysis

Gutiérrez

Pérez-Andrés

Martı́nez-Blanco

et al. 2017

Molecular Metabolism

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“…Such induction could explain why only limited differences between the two strains [B. longum srp ϩ and B. longum srp(Con)] were observed in this experiment. The innate immune response is a key component in the development of atrophy in CeD (30,31) and has been proposed to be involved in the pathogenesis of NCG/WS (32,33). The influx and release of neutrophil components are increased in patients with CeD (34), and by inhibiting HNE activity, Srp may specifically target a mechanism that contributes to gluten-related disorders.…”

Section: Discussionmentioning

confidence: 99%

A Commensal Bifidobacterium longum Strain Prevents Gluten-Related Immunopathology in Mice through Expression of a Serine Protease Inhibitor

McCarville

Dong

Caminero

et al. 2017

Appl Environ Microbiol

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Microbiota-modulating strategies, including probiotic administration, have been tested for the treatment of chronic gastrointestinal diseases despite limited information regarding their mechanisms of action. We previously demonstrated that patients with active celiac disease have decreased duodenal expression of elafin, a human serine protease inhibitor, and supplementation of elafin by a recombinant Lactococcus lactis strain prevents gliadin-induced immunopathology in the NOD/DQ8 mouse model of gluten sensitivity. The commensal probiotic strain Bifidobacterium longum NCC2705 produces a serine protease inhibitor (Srp) that exhibits immune-modulating properties. Here, we demonstrate that B. longum NCC2705, but not a srp knockout mutant, attenuates gliadin-induced immunopathology and impacts intestinal microbial composition in NOD/DQ8 mice. Our results highlight the beneficial effects of a serine protease inhibitor produced by commensal B. longum strains.IMPORTANCE Probiotic therapies have been widely used to treat gastrointestinal disorders with variable success and poor mechanistic insight. Delivery of specific antiinflammatory molecules has been limited to the use of genetically modified organisms, which has raised some public and regulatory concerns. By examining a specific microbial product naturally expressed by a commensal bacterial strain, we provide insight into a mechanistic basis for the use of B. longum NCC2705 to help treat gluten-related disorders.KEYWORDS probiotic, microbiota, gluten, serpin, celiac, commensal M icrobiota-modulating therapies have been tested for the treatment of chronic gastrointestinal diseases and disorders with inconsistent findings. Probiotics are live microorganisms which, when administered in adequate amounts, confer a health benefit to the host (57). Specific strains have shown modest efficacy in treatment of irritable bowel syndrome (IBS) (1); of complications of inflammatory bowel disease (IBD), such as pouchitis (2); and of celiac disease (CeD), a chronic enteropathy caused by ingestion of gluten-containing cereals in genetically susceptible individuals (3). In particular, a number of strains belonging to the genus Bifidobacterium have been proposed as beneficial supplements for a wide range of health conditions (4). Depletions in bifidobacteria have been noted in patients with CeD (5), and attempts have been made to supplement some strains as a therapy for CeD (3, 6). However, despite great public interest in the clinical use of specific probiotic strains for intestinal

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“…The colocalisation coefficient represents the weighted colocalisation coefficient of Ch1 (red) with respect to Ch2 (green) for each experiment (Araya et al, 2016;Zimmermann et al, 2014). Magnification of the micrographs was 63× objective, 2× zoom in all.…”

Section: Colocalisation Analysismentioning

confidence: 99%

Celiac disease‐associated Neisseria flavescens decreases mitochondrial respiration in CaCo‐2 epithelial cells: Impact of Lactobacillus paracasei CBA L74 on bacterial‐induced cellular imbalance

Labruna

Nanayakkara

Pagliuca

et al. 2019

Cellular Microbiology

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We previously identified a Neisseria flavescens strain in the duodenum of celiac disease (CD) patients that induced immune inflammation in ex vivo duodenal mucosal explants and in CaCo‐2 cells. We also found that vesicular trafficking was delayed after the CD‐immunogenic P31‐43 gliadin peptide‐entered CaCo‐2 cells and that Lactobacillus paracasei CBA L74 (L. paracasei‐CBA) supernatant reduced peptide entry. In this study, we evaluated if metabolism and trafficking was altered in CD‐N. flavescens‐infected CaCo‐2 cells and if any alteration could be mitigated by pretreating cells with L. paracasei‐CBA supernatant, despite the presence of P31‐43. We measured CaCo‐2 bioenergetics by an extracellular flux analyser, N. flavescens and P31‐43 intracellular trafficking by immunofluorescence, cellular stress by TBARS assay, and ATP by bioluminescence. We found that CD‐N. flavescens colocalised more than control N. flavescens with early endocytic vesicles and more escaped autophagy thereby surviving longer in infected cells. P31‐43 increased colocalisation of N. flavescens with early vesicles. Mitochondrial respiration was lower (P < .05) in CD‐N. flavescens‐infected cells versus not‐treated CaCo‐2 cells, whereas pretreatment with L. paracasei‐CBA reduced CD‐N. flavescens viability and improved cell bioenergetics and trafficking. In conclusion, CD‐N. flavescens induces metabolic imbalance in CaCo‐2 cells, and the L. paracasei‐CBA probiotic could be used to correct CD‐associated dysbiosis.

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Mechanisms of innate immune activation by gluten peptide p31-43 in mice

Cited by 49 publications

References 35 publications

The human digestive tract has proteases capable of gluten hydrolysis

The human digestive tract has proteases capable of gluten hydrolysis

A Commensal Bifidobacterium longum Strain Prevents Gluten-Related Immunopathology in Mice through Expression of a Serine Protease Inhibitor

Celiac disease‐associated Neisseria flavescens decreases mitochondrial respiration in CaCo‐2 epithelial cells: Impact of Lactobacillus paracasei CBA L74 on bacterial‐induced cellular imbalance

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