title: 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.
abstract: 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.,StreptococcaceaeandLactobacillaceae) were enriched in GS macaques whileCoriobacteriaceaewas 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 ofLactobacillus reuteri(accession number: NR_025911),Prevotella stercorea(NR_041364) andStreptococcus 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.
authors: Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433, USA. mmohan@tulane.edu.
authors: Mahesh
authors: M
authors: Mohan
authors: Second Genome Inc., San Francisco, CA 94080, USA. cheryl@secondgenome.com.
authors: Cheryl-Emiliane T
authors: CT
authors: Chow
authors: Second Genome Inc., San Francisco, CA 94080, USA. caitlin@secondgenome.com.
authors: Caitlin N
authors: CN
authors: Ryan
authors: Second Genome Inc., San Francisco, CA 94080, USA. luisa@secondgenome.com.
authors: Luisa S
authors: LS
authors: Chan
authors: Division of Veterinary Resources, Tulane National Primate Research Center, Covington, LA 70433, USA. jdufour@tulane.edu.
authors: Jason
authors: J
authors: Dufour
authors: Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433, USA. paye@tulane.edu.|Division of Veterinary Resources, Tulane National Primate Research Center, Covington, LA 70433, USA. paye@tulane.edu.
authors: Pyone P
authors: PP
authors: Aye
authors: Division of Veterinary Resources, Tulane National Primate Research Center, Covington, LA 70433, USA. jblanch1@tulane.edu.
authors: James
authors: J
authors: Blanchard
authors: Arcadia Biosciences Inc., Seattle, WA 98119, USA. max.moehs@arcadiabio.com.
authors: Charles P
authors: CP
authors: Moehs
authors: Division of Microbiology, Tulane National Primate Research Center, Covington, LA 70433, USA. ksestak@tulane.edu.|PreCliniTria LLC, Mandeville, LA 70471, USA. ksestak@tulane.edu.
authors: Karol
authors: K
authors: Sestak
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002446:Celiac Disease / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D062445:Claudin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D064806:Dysbiosis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D005243:Feces / Q000737:chemistry / Q000382:microbiology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000276:immunology; D005786:Gene Expression Regulation; D005983:Glutens / Q000009:adverse effects*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D007583:Jejunum / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008253:Macaca mulatta; D008297:Male; D035683:MicroRNAs / Q000737:chemistry / Q000378:metabolism*; D059372:Nucleotide Motifs; D014674:Plant Proteins, Dietary / Q000009:adverse effects*; D012329:RNA, Bacterial / Q000378:metabolism; D012336:RNA, Ribosomal, 16S / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D019108:Tight Junctions / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; D062445:Claudin-1; D035683:MicroRNAs; D014674:Plant Proteins, Dietary; D012329:RNA, Bacterial; D012336:RNA, Ribosomal, 16S; D005983:Glutens
keywords: 16S rRNA; celiac; chronic inflammation; dysbiosis; gluten; gut; macaque; metagenomics; miRNA; microbiome; microbiota; rhesus