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

Karol Sestak,Jason Dufour,David Liu,Pyone Aye,Charles Moehs,Adam Clarke,James Blanchard,Anthony Doyle,Hazel Thwin,David Laine,Xavier Alvarez

doi:10.3390/nu8070401

Abstract

Celiac disease (CD) is an autoimmune disorder that affects approximately three million people in the United States. Furthermore, non-celiac gluten sensitivity (NCGS) affects an estimated additional 6% of the population, e.g., 20 million in the U.S. The only effective treatment of CD and NCGS requires complete removal of gluten sources from the diet. While required adherence to a gluten-free diet (GFD) is extremely difficult to accomplish, efforts to develop additional supportive treatments are needed. To facilitate these efforts, we developed a gluten-sensitive (GS) rhesus macaque model to study the effects of novel therapies. Recently reported results from phase one of this project suggest that partial improvement—but not remission—of gluten-induced disease can be accomplished by 100-fold reduction of dietary gluten, i.e., 200 ppm—by replacement of conventional dietary sources of gluten with a mutant, reduced gluten (RG) barley (lys3a)-derived source. The main focus of this (phase two) study was to determine if the inflammatory effects of the residual gluten in lys3a mutant barley grain could be further reduced by oral supplementation with a prolylendopeptidase (PE). Results reveal that PE supplementation of RG barley diet induces more complete immunological, histopathological and clinical remission than RG barley diet alone. The combined effects of RG barley diet and PE supplementation resulted in a further decrease of inflammatory mediators IFN-γ and TNF secretion by peripheral lymphocytes, as well as decreased plasma anti-gliadin and anti-intestinal tissue transglutaminase (TG2) antibodies, diminished active caspase production in small intestinal mucosa, and eliminated clinical diarrhea—all comparable with a gluten-free diet induced remission. In summary, the beneficial results of a combined RG barley and PE administration in GS macaques may warrant the investigation of similar synergistic approaches.

Highlights

Any future alternative to the gluten-free diet (GFD) will need to meet a high threshold of safety and efficacy
During phase one of this project, we showed that novel varieties of cereal grains with low gluten content such as reduced gluten (RG) barley can have beneficial health effects in GS macaques [7]
Elevated anti-gliadin plasma antibodies (AGA) and TG2 antibody responses reflected administration and re-introduction of dietary gluten (GD and Bomi + B diets, respectively) while its removal (GFD) or replacement with RGB diet were followed by lowered levels of both antibodies

Summary

Introduction

Any future alternative to the gluten-free diet (GFD) will need to meet a high threshold of safety and efficacy. None of the glutenases are intended to allow celiac patients to deviate from GFD. These are only intended to degrade low quantities of inadvertently ingested gluten. Low gluten versions of cereals such as barley and wheat are being engineered by transgenic or mutagenic means while most retain sufficient gluten levels to make them incompatible with a GFD [4,5,6]. Several studies have been conducted which focus on the ability of glutenases such as prolylendopeptidase (PE) to help proteolytically degrade those gluten peptides with high content of proline residues that are known to be immunotoxic in celiac and/or gluten-sensitive (GS) patients [1,2,3]

Results

Discussion

Conclusion