Celiac disease (CD) is an autoimmune disorder that affects approximately three million people in the United States. The only effective treatment of CD 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, during the past 10 years, our group established and characterized a non-human primate model of CD-like gluten-sensitive enteropathy, i.e., GSE macaques. The macaque celiac model is characterized by:
- Intestinal tissue transglutaminase and anti-gliadin serum antibodies.
- Intestinal inflammatory cytokines, i.e., IFN-gamma and IL-15.
- Small intestinal enteropathy, villous atrophy and increased enterocytic apoptosis.
- Small intestinal intra-epithelial lymphocytosis.
- Gut microbiome dysbiosis.
- Upregulation of specific miRNAs with dysbiotic bacteria-binding motifs.
- Decreased metabolism of xenobiotics, cancer predisposition.
- MHC II (Mamu II) genetic predisposition.
- Validated new celiac therapy based on novel breeds of cereal grains.
Genetic Component of Celiac Disease
Celiac disease is a polygenetic disease disorder associated with multitude of genetic and environmental triggers. Although not all of the individuals that carry human major histocompatibility class II alleles DQ2 or DQ8 develop celiac disease, these two molecules in conjuction with several others play prominent role in recognizing the CD4+ T cell-mediated immune responses that lead to mild or severe forms of dietary gluten-induced enteropathy. Situation in rhesus macaques is similar, with two analogous Mamu II alleles (DQA1*01:05:01/DQB1*06:02 haplotype) identified as "celiac-like" due to their association with TG2+ autoantibodies. Most likely, there are additional, not yet identified alleles playing the role in celiac- and non-celiac-like gluten sensitivities in rhesus macaques.
Celiac Gut Microbiome and Host Luminal Shedding of Fecal microRNAs
Given the unprecedented rise of food allergies and autoimmune disorders in urban populations during recent decades, several studies have indicated that a potential causative association exists between some of these disorders and composition of the host's gut microbiome. It has been reported that bacteria involved in gluten metabolism predominantly belong to phylum Firmicutes, in particular, those from the genus Lactobacillus, followed by Streptococcus, Staphylococcus, and Clostridia. Our group demonstrated that Streptococcaceae and Lactobacillaceae families are enriched in celiac macaques, while Coriobacteriaceae predominate in healthy animals. We recently demonstrated upregulation of several inflammation-associated microRNAs in small intestines of celiac macaques with predicted binding sites on 16S ribosomal RNA of dysbiotic bacterial species. Further studies are needed to elucidate the regulatory pathways of these microRNAs in celiac intestine.
Treatment
- The only efficacious treatment requires exclusion of wheat and other grains such as rye and barley from the diet. Patients on gluten-free diet (GFD) respond well in most cases with resolution of clinical symptoms, however, histological changes take longer to resolve. Some do not respond to GFD and require anti-inflammatory drugs. Strict adherence to GFD is difficult to accomplish due to ubiquity of gluten in foods. Thus, alternative treatment approaches are urgently needed.
- We recently reported that oral prolyl endopeptidase (glutenase) supplementation of reduced gluten barley (novel variety)-based diet induces complete immunological, histopathological and clinical remission of gluten-sensitive enteropathy, comparable with GFD effects. We plan to investigate if such result can be duplicated with another and more desirable cereal grain variety (wheat)-based diet in combination with oral glutenase, anti-inflammatory antibody, or both.
Contact
For more information about our Celiac Disease research programs, contact Dr. Karol Sestak.
