Background/Purpose:   Intestinal microbiome studies in IBD and AS have shown significant bacterial dysbiosis (i.e., a substantial alteration of the individual species) in similar populations, as compared to healthy controls. However, the mechanistic linkage between the microbiota, changes in mucosal immunology, and the subsequent pathogenic targeting of the spine has not been defined. Intraepithelial lymphocytes (IELs) are a unique population of antigen-experienced T cells which are anatomically associated with intestinal epithelial cells and function to protect the host from microbial invasion and maintain epithelial homeostasis. Our ongoing studies have revealed that dysbiosis in patients with IBD and mouse models alters the function of IELs. We hypothesize that resident bacteria educate IELs, which in turn, traffic systemically and cause arthritis under dysbiotic conditions.

Methods:  Dysbiosis is modeled by administration of broad-spectrum antibiotics (ampicillin, neomycin, metronidazole, and vancomycin) in the drinking water for one week; recolonization of mice is done by cohousing with unmanipulated littermates for one week. KikGR mice contain a transgene for a photoconvertible green-to-red fluorescent protein. Endoscopy-guided violet light allowed photoconversion of distal colonic IELs in vivo. TNF^ΔARE/+ mice contain a mutation in the AU-rich element of the TNF-α gene resulting in increased mRNA stability and systemically elevated TNF-α. As a result, these mice develop ileitis and arthritis beginning around 8 weeks of age. Microbial analysis was performed on fecal pellets via high-throughput 16S rRNA gene sequencing. Trafficking of photoconverted lymphocytes was determined by flow cytometry of tissues.

Results:   One week following photoconversion of the distal colon lymphocytes in KikGR mice, labeled intestinal lymphocytes were detected systemically in tissues including the spleen, liver, lungs, and Achilles entheses; few lymphocytes remained in the colon. Treatment of mice with antibiotics following photoconversion resulted in substantially reduced trafficking to distal tissues as well as a depletion of the colonic population. After recolonization, labeled colonic lymphocytes substantially increased in the colon while few remained in distal tissues. Our analysis of TNF^ΔARE/+ mice demonstrates significant dysbiosis occurs as mice age and develop disease compared to TNF^+/+ littermates.

Conclusion:   Manipulation of intestinal bacteria through antibiotic use alters intestinal lymphocyte trafficking to extra-intestinal tissues. We have generated TNF^ΔARE/+ X KikGR mice, and our future studies will link dysbiosis, lymphocyte trafficking, and disease. Our goal is to identify triggers for systemic IEL trafficking from the intestine during health and IBD-related SpA and define the role of trafficked IELs in the target tissue. Through understanding these mechanisms we hope to identify biomarkers of gut-joint trafficking to diagnose patients earlier and/or treatment strategies to improve disease outcomes for SpA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/intestinal-dysbiosis-influences-gut-joint-lymphocyte-trafficking/