Duodenal Bacteria From Patients With Celiac Disease and Healthy Subjects Distinctly Affect Gluten Breakdown and Immunogenicity

Caminero, Alberto; Galipeau, Heather J.; McCarville, Justin L.; Johnston, Chad W.; Bernier, Steve P.; Russell, Amy K.; Jury, Jennifer; Herrán, Alexandra R.; Casqueiro, Javier; Tye–Din, Jason A.; Surette, Michael G.; Magarvey, Nathan A.; Schuppan, Detlef; Verdú, Elena F.

doi:10.1053/j.gastro.2016.06.041

Cited by 190 publications

(186 citation statements)

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“…Early on, it was hypothesized that CD is a digestive disorder that is caused by enzyme deficiencies (reviewed in reference 27). Our new findings in saliva, and the previous work on feces (23,24), show enhanced and altered bacterial gluten degradation in CD, suggesting that enzymatic processing may play an auxiliary role in CD pathogenesis. Gluten processing by microorganisms colonizing the oral cavity may be particularly relevant.…”

Section: Discussionsupporting

confidence: 72%

“…Partial digestion may be highly relevant, however, from the perspective of how gluten is being presented further downstream in the gastrointestinal tract. Recently, it was demonstrated in a CD mouse model that gluten was partly digested by Pseudomonas aeruginosa, which liberated smaller peptides that were then more easily translocated through the mouse intestinal barrier and fueled disease activity (24). Analogously, oral microbial enzyme activities may likewise contribute to liberating more immunogenic gluten peptides.…”

Section: Discussionmentioning

confidence: 99%

“…Gluten metabolisms in patients with CD, and the role of the endogenous microbiome in this process, have received renewed attention since the discovery of elevated fecal protease activities in CD (23). More recently, an in vivo study in mice populated with human intestinal bacteria showed that the microbiome of CD patients processes gluten differently compared to the microbiome of healthy subjects (24). Oral gluten digestion occurs prior to the gluten metabolites reaching the CDaffected duodenum, and therefore, in the present study, we quantified the endogenous gluten-degrading protease activities in saliva from healthy subjects and CD and RCD patients.…”

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confidence: 99%

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Salivary Gluten Degradation and Oral Microbial Profiles in Healthy Individuals and Celiac Disease Patients

Tian

Faller²,

Leffler

et al. 2017

Appl Environ Microbiol

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Celiac disease (CD) is a chronic immune-mediated enteropathy induced by dietary gluten in genetically predisposed individuals. Saliva harbors the second highest bacterial load of the gastrointestinal (GI) tract after the colon. We hypothesized that enzymes produced by oral bacteria may be involved in gluten processing in the intestine and susceptibility to celiac disease. The aim of this study was to investigate salivary enzymatic activities and oral microbial profiles in healthy subjects versus patients with classical and refractory CD. Stimulated whole saliva was collected from patients with CD in remission (n ϭ 21) and refractory CD (RCD; n ϭ 8) and was compared to healthy controls (HC; n ϭ 20) and subjects with functional GI complaints (n ϭ 12). Salivary gluten-degrading activities were monitored with the tripeptide substrate Z-Tyr-Pro-Gln-pNA and the ␣-gliadin-derived immunogenic 33-mer peptide. The oral microbiome was profiled by 16S rRNA-based MiSeq analysis. Salivary glutenase activities were higher in CD patients compared to controls, both before and after normalization for protein concentration or bacterial load. The oral microbiomes of CD and RCD patients showed significant differences from that of healthy subjects, e.g., higher salivary levels of lactobacilli (P Ͻ 0.05), which may partly explain the observed higher gluten-degrading activities. While the pathophysiological link between the oral and gut microbiomes in CD needs further exploration, the presented data suggest that oral microbe-derived enzyme activities are elevated in subjects with CD, which may impact gluten processing and the presentation of immunogenic gluten epitopes to the immune system in the small intestine.IMPORTANCE Ingested gluten proteins are the triggers of intestinal inflammation in celiac disease (CD). Certain immunogenic gluten domains are resistant to intestinal proteases but can be hydrolyzed by oral microbial enzymes. Very little is known about the endogenous proteolytic processing of gluten proteins in the oral cavity. Given that this occurs prior to gluten reaching the small intestine, such enzymes are likely to contribute to the composition of the gluten digest that ultimately reaches the small intestine and causes CD. We demonstrated that endogenous salivary protease activities are incomplete, likely liberating peptides from larger gluten proteins. The potentially responsible microbes were identified. The study included refractory CD patients, who have been studied less with regard to CD pathogenesis.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Salivary Gluten Degradation and Oral Microbial Profiles in Healthy Individuals and Celiac Disease Patients

Tian

Faller²,

Leffler

et al. 2017

Appl Environ Microbiol

Self Cite

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“…We have previously shown that the severity of gluten immunopathology in NOD/DQ8 mice is influenced by the microbiota with which these mice are colonized and that administration of recombinant L. lactis expressing elafin can attenuate the inflammatory response of the host to gluten (12,23,24). Serpins are produced by a wide range of organisms and play a key role in maintaining immune homeostasis (25,26).…”

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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“…Clearly, Lactobacillus spp. have the capacity to degrade gluten resulting in decreased immunotoxicity of its major immunogens such as the 33-mer of alpha-gliadin [76]. At the same time, however, the full pathogenic potential of dysbiotic bacterial taxa including Lactobacillaceae , Streptococcaceae and others in GS individuals still needs to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Dietary Gluten-Induced Gut Dysbiosis Is Accompanied by Selective Upregulation of microRNAs with Intestinal Tight Junction and Bacteria-Binding Motifs in Rhesus Macaque Model of Celiac Disease

et al. 2016

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The composition of the gut microbiome reflects the overall health status of the host. In this study, stool samples representing the gut microbiomes from 6 gluten-sensitive (GS) captive juvenile rhesus macaques were compared with those from 6 healthy, age- and diet-matched peers. A total of 48 samples representing both groups were studied using V4 16S rRNA gene DNA analysis. Samples from GS macaques were further characterized based on type of diet administered: conventional monkey chow, i.e., wheat gluten-containing diet (GD), gluten-free diet (GFD), barley gluten-derived diet (BOMI) and reduced gluten barley-derived diet (RGB). It was hypothesized that the GD diet would lower the gut microbial diversity in GS macaques. This is the first report illustrating the reduction of gut microbial alpha-diversity (p < 0.05) following the consumption of dietary gluten in GS macaques. Selected bacterial families (e.g., Streptococcaceae and Lactobacillaceae) were enriched in GS macaques while Coriobacteriaceae was enriched in healthy animals. Within several weeks after the replacement of the GD by the GFD diet, the composition (beta-diversity) of gut microbiome in GS macaques started to change (p = 0.011) towards that of a normal macaque. Significance for alpha-diversity however, was not reached by the day 70 when the feeding experiment ended. Several inflammation-associated microRNAs (miR-203, -204, -23a, -23b and -29b) were upregulated (p < 0.05) in jejunum of 4 biopsied GS macaques fed GD with predicted binding sites on 16S ribosomal RNA of Lactobacillus reuteri (accession number: NR_025911), Prevotella stercorea (NR_041364) and Streptococcus luteciae (AJ297218) that were overrepresented in feces. Additionally, claudin-1, a validated tight junction protein target of miR-29b was significantly downregulated in jejunal epithelium of GS macaques. Taken together, we predict that with the introduction of effective treatments in future studies the diversity of gut microbiomes in GS macaques will approach those of healthy individuals. Further studies are needed to elucidate the regulatory pathways of inflammatory miRNAs in intestinal mucosa of GS macaques and to correlate their expression with gut dysbiosis.

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Duodenal Bacteria From Patients With Celiac Disease and Healthy Subjects Distinctly Affect Gluten Breakdown and Immunogenicity

Cited by 190 publications

References 50 publications

Salivary Gluten Degradation and Oral Microbial Profiles in Healthy Individuals and Celiac Disease Patients

Salivary Gluten Degradation and Oral Microbial Profiles in Healthy Individuals and Celiac Disease Patients

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

Dietary Gluten-Induced Gut Dysbiosis Is Accompanied by Selective Upregulation of microRNAs with Intestinal Tight Junction and Bacteria-Binding Motifs in Rhesus Macaque Model of Celiac Disease

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