Suppression of Inflammatory Arthritis by Human Gut‐DerivedPrevotella histicolain Humanized Mice

Abstract

Objective The gut microbiome regulates host immune homeostasis. Rheumatoid arthritis (RA) is associated with intestinal dysbiosis. In this study we used a human gut-derived commensal to modulate immune response and treat arthritis in a humanized mouse model. Methods We have isolated a commensal bacterium, Prevotella histicola, native to the human gut that 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 the gut epithelial proteins and immune response as well as systemic cellular and humoral immune responses were studied in treated mice. Results DQ8 mice when treated with P. histicola in prophylactic or therapeutic protocols exhibited significantly decreased incidence and severity of arthritis as compared to controls. The microbial mucosal modulation of arthritis was dependent on the regulation by CD103+ dendritic cells and myeloid suppressors, CD11b+Gr-1, and by generation of T regulatory cells, CD4+CD25+FoxP3+, in the gut, resulting in suppression of antigen-specific Th17 response and increased transcription of IL-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, Zo-1 and Occludin. However, the innate immune response via TLR4 and TLR9 were not affected in treated mice. Discussion 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 low/no side effects.

Significant and conflicting correlation of IL-9 withPrevotellaandBacteroidesin human colorectal cancer

“…Prevotella histicola was used to modulate immune response and treat arthritis in a humanized mouse 520 model, Marietta et al reported that treated mice showed significantly lower levels of IL-17, in 521 agreement with our data. The authors reported also decreased level of IL-9 as compared to placebo 522 treated mice, in contrasting with our results 144 . Finally, Campisciano 145 detected an increase of the 523 relative vaginal abundance of Prevotella timonensis in women infected with HPV, which showed a 524 decreased concentration of the IL-15, IL-7, and IL-9, that however they associated with the virus 525 infections.…”

Opportunistic Sampling of Roadkill as an Entry Point to Accessing Natural Products Assembled by Bacteria Associated with Non-anthropoidal Mammalian Microbiomes

“…The first tactic involves the introduction or elimination of selected microbial taxa from the host. 6−8 This approach was successfully tested in animal models of inflammatory bowel disease, 9−11 arthritis, 12 colon cancer, 13 cystic fibrosis, 14 and depression, 15 resulting in the restoration of disease-free phenotypes. This method was also effectively used in humans to restore resilience against Clostridium difficile colonization.…”

Modulation of Inflammatory Arthritis in Mice by Gut Microbiota Through Mucosal Inflammation and Autoantibody Generation

“…However, using a known oral pathogen, Sandal et al demonstrated that oral infection with Porphyromonas gingivalis could transiently expand Th17 cells in the draining cervical lymph nodes and circulation and exacerbated disease in HLA–DRB1–transgenic mice with CIA, even in those that had previously resisted development of disease . Another study showed that treatment by oral gavage with Prevotella histicola attenuates CIA in HLA–DQ8–transgenic mice by increasing IL‐10–producing Treg cells and reducing Th17 cells in the gut . These provocative findings along with those in the K/BxN model and ours presented herein suggest that specific bacteria that stimulate mucosal Th17 cells drive disease development.…”