title: Suppression of Inflammatory Arthritis by Human Gut-Derived Prevotella histicola in Humanized Mice.
abstract: The gut microbiome regulates host immune homeostasis. Rheumatoid arthritis (RA) is associated with intestinal dysbiosis. This study was undertaken to test the ability of a human gut-derived commensal to modulate immune response and treat arthritis in a humanized mouse model.
  
  
  
  We isolated a commensal bacterium, Prevotella histicola, that is native to the human gut and has systemic immune effects when administered enterally. Arthritis-susceptible HLA-DQ8 mice were immunized with type II collagen and treated with P histicola. Disease incidence, onset, and severity were monitored. Changes in gut epithelial proteins and immune response as well as systemic cellular and humoral immune responses were studied in treated mice.
  
  
  
  When treated with P histicola in prophylactic or therapeutic protocols, DQ8 mice exhibited significantly decreased incidence and severity of arthritis compared to controls. The microbial mucosal modulation of arthritis was dependent on regulation by CD103+ dendritic cells and myeloid suppressors (CD11b+Gr-1+ cells) and by generation of Treg cells (CD4+CD25+FoxP3+) in the gut, resulting in suppression of antigen-specific Th17 responses and increased transcription of interleukin-10. Treatment with P histicola led to reduced intestinal permeability by increasing expression of enzymes that produce antimicrobial peptides as well as tight junction proteins (zonula occludens 1 and occludin). However, the innate immune response via Toll-like receptor 4 (TLR-4) and TLR-9 was not affected in treated mice.
  
  
  
  Our results demonstrate that enteral exposure to P histicola suppresses arthritis via mucosal regulation. P histicola is a unique commensal that can be explored as a novel therapy for RA and may have few or no side effects.
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Eric V
authors.initials: EV
authors.lastname: Marietta
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Murray
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: David H
authors.initials: DH
authors.lastname: Luckey
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Patricio R
authors.initials: PR
authors.lastname: Jeraldo
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Lamba
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Robin
authors.initials: R
authors.lastname: Patel
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Harvinder S
authors.initials: HS
authors.lastname: Luthra
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Mangalam
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Veena
authors.initials: V
authors.lastname: Taneja
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D007422:Intestines / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008822:Mice, Transgenic; D062793:Occludin / Q000378:metabolism; D010539:Permeability; D018720:Prevotella / Q000276:immunology*; D001443:Prevotella melaninogenica / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; C556062:IL10 protein, mouse; D062793:Occludin; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D062826:Zonula Occludens-1 Protein; D016753:Interleukin-10