Affiliation:
1. Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Program Oklahoma City
2. Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Program and University of Oklahoma Health Sciences Center Oklahoma City
3. Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Program, University of Oklahoma Health Sciences Center, and Oklahoma City VA Medical Center
Abstract
ObjectiveFemales have reduced osteoarthritis (OA) in surgical models. The objective of the current study was to evaluate a sex‐linked gut microbiome in the pathogenesis of OA.MethodsWe induced OA via destabilization of the medial meniscus surgery in adult male and female C57BL6/J mice with and without opposite‐sex microbiome transplantation. Eight weeks later, animals were euthanized, and OA severity, synovitis, and osteophyte scores were determined. Serum lipopolysaccharide was measured chromogenically, and serum cytokines were quantified via multiplex immunoassay. Cecal microbiome profiles were generated using 16S deep sequencing.ResultsMales had worse OA histology (3.5x, P = 6 × 10−7), synovitis (2.4x, P = 5 × 10−4), and osteophyte scores (3.7x, P = 3 × 10−4) than females. Male‐into‐female transplantation worsened all outcomes (histology 1.8x, P = 0.02; synovitis 2.0x, P = 3 × 10−5; osteophyte 2.1x, P = 0.01) compared to females, whereas female‐into‐male transplantation improved all outcomes except for synovitis (histology 0.53x, P = 2 × 10−4; osteophyte 0.28x, P = 5 × 10−4) compared to males. In the gut microbiome analysis, 44 clades were different in at least one group comparison; 5 clades were correlated with the Osteoarthritis Research Society International score (Lactobacillus R = −0.40, Aldercreutzia R = −0.40, rc4_4 R = −0.55, Sutterella R = −0.37, and Clostridiales R = 0.36). In the cytokine analysis, 10 analytes were different in at least one group comparison; 3 were different in two groups (female and female‐into‐male transplants vs male comparisons, all reduced in female and female‐into‐male transplants), including interleukin‐12 (0.66x, P = 0.02; 0.66x, P = 0.02, respectively), eotaxin (0.74x, P = 5 × 10−6; 0.57x, P = 0.03), and tumor necrosis factor ⍺ (0.49x, P = 0.03; 0.52x, P = 0.009).ConclusionSex‐linked differences in the mouse gut microbiome are associated with OA outcomes, are reversible by opposite‐sex microbiome transplantation, and are associated with serum cytokine changes.image
Funder
Congressionally Directed Medical Research Programs
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Subject
Immunology,Rheumatology,Immunology and Allergy