Discovery of a Novel and Rich Source of Gluten-Degrading Microbial Enzymes in the Oral Cavity

Helmerhorst, Eva J.; Zamakhchari, Maram; Schuppan, Detlef; Oppenheim, Frank G.

doi:10.1371/journal.pone.0013264

Cited by 85 publications

(75 citation statements)

References 35 publications

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“…While several studies have shown that the levels of Lactobacillus were lower in the duodenal and fecal samples in CD patients compared to healthy controls (31-33), reports on Lactobacillus levels in the oral cavity are inconsistent (34)(35)(36). Regardless of the microbial source, the modest increase in salivary enzyme activity is likely to be derived from bacteria given that dental plaque is a rich source of glutendegrading activity (21).…”

Section: Discussionmentioning

confidence: 97%

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: Discussionmentioning

confidence: 97%

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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“…Due to the increasing awareness of an abnormal duodenal microflora in celiac disease [12][13][14][15]26] it was considered of interest to investigate the expression of the natural antibacterial enzyme lysozyme in duodenal biopsies from patients with celiac disease.…”

Section: Introductionmentioning

confidence: 99%

Lysozyme-rich mucus metaplasia in duodenal crypts supersedes Paneth cells in celiac disease

Rubio

2011

Virchows Arch

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Lysozyme is as an innate enzyme with potent antibacterial properties found in Paneth cells in normal duodenal crypts. Since celiac disease concurs with an abnormal duodenal microbiota we explored the expression of lysozyme in this disease. Fifty-three duodenal biopsies were stained with anti-lysozyme: 15 had normal duodenal mucosa (NDM), 7 chronic active duodenitis (CAD), 3 borderline (BL), 17 subtotal villous atrophy (SVA) and 11 total villous atrophy (TVA). NDM showed lysozyme-positive Paneth cells arranged in "Indian file" in 93.3%. In contrast, lysozyme-positive mucus metaplasia in crypts (LPMMC) replacing Paneth cells was found in 71.5% in CAD, in 96.4% in SVA/TVA, and in 2 cases with B. In 19.3% cases with BL/SVA/TVA, LPMMC replaced all Paneth cells in all crypts in entire sections. In crypts and villi, lysozyme-positive goblet cells (LPGC) were found in 92.8%. Changes were more frequent in the duodenal bulb than in pars descendens. In normal duodenal mucosa, absorptive enterocytes and goblet cells migrate from stem cells upwards, while Paneth cells migrate downwards, towards the base of the crypts. In celiac disease stem cells seem to have been re-programmed, as the normal production of Paneth cells in the crypts was replaced by lysozyme-producing mucus cells. LPMMC and LPGC in celiac disease might mirror an antimicrobial adaptation of stem cells to signals generated by pathogenic duodenal bacteria. The molecular mechanism(s) behind the abrogation of Paneth cells in duodenal crypts and its substitution by LPMMC in celiac disease remains to be elucidated.

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“…[67][68][69] It has also been shown that bacteria present in the gut may hydrolyze dietary gluten. 70 Thus, it can be speculated that a defective/altered microbiome may cause loss of immunotolerance and the onset, in genetically susceptible individuals, of both CD and T1DM. Ciacci and Zingone Finally, viral infections have been suggested to play a role in triggering many autoimmune conditions, including CD and T1DM.…”

Section: Environmentmentioning

confidence: 99%

Dietary gluten and the development of celiac disease and type 1 diabetes

Ciacci¹,

Zingone²

2016

NDS

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Abstract:The objective of this study was to perform a review of the present knowledge on the epidemiology and pathogenesis of the association between celiac disease (CD) and type 1 diabetes mellitus (T1DM). Results from this review show that the estimated prevalence rate of CD in T1DM ranges from 4% to 11.5%, which seems higher in children than in adults, while there is no sex predominance in the prevalence of CD in T1DM. On the basis of the previous literature, screening for CD should be considered at diabetes diagnosis in all subjects and again within 2 and 5 years after diagnosis, even in the absence of symptoms. The anti-islet antibodies detection test, instead, is not recommended in CD, just as in the general population, except for CD patients having a relative with T1DM. Both genes and environmental factors seem to play a role in this association. HLADQ2 has been found to be the most frequent allele in the patients with both CD and T1DM, while gluten may be considered the trigger that induces the production of autoantibodies and the development, in genetically predisposed individuals, of both diseases.

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Discovery of a Novel and Rich Source of Gluten-Degrading Microbial Enzymes in the Oral Cavity

Cited by 85 publications

References 35 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

Lysozyme-rich mucus metaplasia in duodenal crypts supersedes Paneth cells in celiac disease

Dietary gluten and the development of celiac disease and type 1 diabetes

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