Abstract
Obesity is a risk factor for osteoarthritis (OA), the greatest cause of disability in the US. The impact of obesity on OA is driven by systemic inflammation, and increased systemic inflammation is now understood to be caused by gut microbiome dysbiosis. Oligofructose, a nondigestible prebiotic fiber, can restore a lean gut microbial community profile in the context of obesity, suggesting a potentially novel approach to treat the OA of obesity. Here, we report that - compared with the lean murine gut - obesity is associated with loss of beneficial Bifidobacteria, while key proinflammatory species gain in abundance. A downstream systemic inflammatory signature culminates with macrophage migration to the synovium and accelerated knee OA. Oligofructose supplementation restores the lean gut microbiome in obese mice, in part, by supporting key commensal microflora, particularly Bifidobacterium pseudolongum. This is associated with reduced inflammation in the colon, circulation, and knee and protection from OA. This observation of a gut microbiome-OA connection sets the stage for discovery of potentially new OA therapeutics involving strategic manipulation of specific microbial species inhabiting the intestinal space.
Highlights
Osteoarthritis (OA), a degenerative disease primarily affecting diarthrodial joints [1], afflicts 31 million people in the US [2], with a global prevalence of disease recently estimated to exceed 250 million [3]
Nonmetric multidimensional scaling (NMDS) revealed that the gut microbiome of obese and lean mice was stably distinct throughout the experiment, with oligofructose permanently shifting diversity of both groups within 2 weeks (Figure 1A)
The growing global prevalence of OA makes the current lack of a disease modifying therapy a critical unmet need
Summary
Osteoarthritis (OA), a degenerative disease primarily affecting diarthrodial joints [1], afflicts 31 million people in the US [2], with a global prevalence of disease recently estimated to exceed 250 million [3]. While it has been generally held that joint overloading is a central cause of accelerated OA in obesity, clinical and animal findings suggest that the association is more likely linked to obesity-related increases in systemic and local inflammation [13]. This is driven by migration of activated macrophages and other inflammatory cells to adipose tissue, which release Tnf and other proinflammatory cytokines into the circulation [14,15,16]. Since global ablation of Tnf protects against progression of joint degeneration in the OA of obesity [17], one potential therapeutic approach is to reduce the systemic inflammation in this disease
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