Supplementation of Reduced Gluten Barley Diet with Oral Prolyl Endopeptidase Effectively Abrogates Enteropathy-Associated Changes in Gluten-Sensitive Macaques

Sestak, Karol; Thwin, Hazel; Dufour, Jason; Zlobec, Inti; Álvarez, Xavier; Laine, David; Clarke, Adam W.; Doyle, Anthony; Aye, Pyone P.; Blanchard, James; Moehs, Charles P.

doi:10.3390/nu8070401

Cited by 11 publications

(21 citation statements)

References 26 publications

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“…in the feed given to gluten-sensitive rhesus macaques (Sestak et al, 2015). Furthermore, symptoms due to prolamin consumption in these animals were not observed when this low-hordein barley feed was supplemented with a prolamin-degrading enzyme (Sestak et al, 2016). Future research using decreased-gluten wheat will be necessary to expand on these findings.…”

Section: Discussionmentioning

confidence: 92%

Development of Decreased-Gluten Wheat Enabled by Determination of the Genetic Basis of lys3a Barley

et al. 2019

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Celiac disease is the most common food-induced enteropathy in humans, with a prevalence of approximately 1% worldwide. It is induced by digestion-resistant, proline-and glutamine-rich seed storage proteins, collectively referred to as gluten, found in wheat (Triticum aestivum). Related prolamins are present in barley (Hordeum vulgare) and rye (Secale cereale). The incidence of both celiac disease and a related condition called nonceliac gluten sensitivity is increasing. This has prompted efforts to identify methods of lowering gluten in wheat, one of the most important cereal crops. Here, we used bulked segregant RNA sequencing and map-based cloning to identify the genetic lesion underlying a recessive, low-prolamin mutation (lys3a) in diploid barley. We confirmed the mutant identity by complementing the lys3a mutant with a transgenic copy of the wild-type barley gene and then used targeting-induced local lesions in genomes to identify induced single-nucleotide polymorphisms in the three homeologs of the corresponding wheat gene. Combining inactivating mutations in the three subgenomes of hexaploid bread wheat in a single wheat line lowered gliadin and low-molecular-weight glutenin accumulation by 50% to 60% and increased free and proteinbound lysine by 33%.

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Section: Discussionmentioning

confidence: 92%

Development of Decreased-Gluten Wheat Enabled by Determination of the Genetic Basis of lys3a Barley

et al. 2019

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“…Tuberculin skin tests were negative for each individual. The 6 GS macaques had previously been reported with celiac-like GS, i.e., an equivalent of human CD [45]. Approximately 0.5 g of stool were obtained from at least 3 representative macaques at each time point when fed gluten-modified diets: conventional monkey chow, i.e., wheat gluten-containing diet (GD), gluten-free diet (GFD), conventional barley gluten-derived diet (BOMI) and reduced gluten barley-derived diet (RGB) (Supplementary Materials Table S1).…”

Section: Methodsmentioning

confidence: 99%

“…Proximal jejunum biopsy tissues from 4 GS and 6 healthy control macaques fed GD for at least one year (long-term GD) were collected and processed as described [45]. Half of the collected biopsies were preserved in 5 mL of RNA-later solution (Qiagen Inc., Valencia, CA, USA) while second half was embedded in paraffin and 7 μm sections were used for immunofluorescent staining, i.e., confocal microscopy.…”

Section: Methodsmentioning

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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“…We showed that the lys3a barley mutant reduces prolamin-related symptoms when it replaces conventional barley in the feed given to gluten sensitive rhesus macaques [76]. Furthermore, symptoms due to prolamin consumption in these animals were not observed when this low hordein barley feed was supplemented with a prolamin-degrading enzyme [77]. Future research using reduced gluten wheat will be necessary to expand on these findings.…”

Section: Discussionmentioning

confidence: 79%

Development of reduced gluten wheat enabled by determination of the genetic basis of thelys3alow hordein barley mutant

Moehs

Austill

Holm

et al. 2018

Preprint

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Celiac disease is the most common food-induced enteropathy in humans with a prevalence of approximately 1% world-wide [1]. It is induced by digestion-resistant, proline-and glutamine-rich seed storage proteins, collectively referred to as "gluten," found in wheat. Related prolamins are present in barley and rye. Both celiac disease and a related condition called non-celiac gluten sensitivity (NCGS) are increasing in incidence [2] [3]. This has prompted efforts to identify methods of lowering gluten in wheat, one of the most important cereal crops. Here we used BSR-seq (Bulked Segregant RNA-seq) and map-based cloning to identify the genetic lesion underlying a recessive, low prolamin mutation (lys3a) in diploid barley. We confirmed the mutant identity by complementing the lys3a mutant with a transgenic copy of the wild type barley gene and then used TILLING (Targeting Induced Local Lesions in Genomes)[4] to identify induced SNPs (Single Nucleotide Polymorphisms) in the three homoeologs of the corresponding wheat gene. Combining inactivating mutations in the three sub-genomes of hexaploid bread wheat in a single wheat line lowered gliadin and low molecular weight glutenin accumulation by 50-60% and increased free and protein-bound lysine by 33%. This is the first report of the combination of mutations in homoeologs of a single gene that reduces gluten in wheat.Gluten is the common name for a complex mixture of approximately 100 proline-and glutamine-rich seed storage proteins found in wheat endosperm. In hexaploid bread wheat, in particular, gluten is responsible for the unique viscoelastic properties of dough used for making leavened bread. Related prolamins known as hordeins in barley and secalins in rye, but lacking the viscoelastic properties of wheat gluten, are found in the endosperms of these related cereals. Among gluten proteins, the most important for the elasticity and strength of bread dough are the polymeric high molecular weight glutenins [5]; monomeric gluten proteins, primarily gliadins, which are classified based on size, charge and repetitive amino acid sequences into α, β, γ and ω types, contribute to the viscosity of gluten [6] [7].Gluten is the causative factor of celiac disease, the most common food-induced autoimmune enteropathy in humans [1]. Celiac disease is found primarily in individuals expressing human leukocyte antigen (HLA) alleles DQ2 and/or DQ8. Immunodominant peptide epitopes have been found in α gliadins [8] and in ω gliadins of wheat and in C hordeins of barley [9]. Additional epitopes are also found in LMW and HMW-glutenins, gamma-gliadins from wheat and B and gamma hordeins from barley [10] [9]. Celiac disease patients exhibit a range of intestinal and extra-intestinal symptoms of which the most common is flattening of the villi of the small intestine, which can lead to poor absorption of nutrients and other pathological consequences. The only current treatment is a life-long avoidance of all gluten in the diet,which can be challenging given the prevalent use of gluten in diver...

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Supplementation of Reduced Gluten Barley Diet with Oral Prolyl Endopeptidase Effectively Abrogates Enteropathy-Associated Changes in Gluten-Sensitive Macaques

Cited by 11 publications

References 26 publications

Development of Decreased-Gluten Wheat Enabled by Determination of the Genetic Basis of lys3a Barley

Development of Decreased-Gluten Wheat Enabled by Determination of the Genetic Basis of lys3a Barley

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

Development of reduced gluten wheat enabled by determination of the genetic basis of thelys3alow hordein barley mutant

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