New thoughts on the gut-immune axis of arthritis

Arthritis is associated with varying degrees of intestinal inflammation and microbiota dysbiosis, leading to the 'gut-joint axis hypothesis' in which intestinal and joint inflammation are suggested to be interconnected through immune-microbiota interactions. While clinical observations support this, causality remains uncertain. Rodent models have provided insights into potential mechanisms by uncovering microbial influences and immune pathways that either connect or uncouple gut and joint inflammation. Based on recent findings, we propose the 'immune hypersensitivity hypothesis' whereby central immune hyper-reactivity can independently drive joint inflammation via local sterile triggers, and gut inflammation via microbial triggers. We argue that this suggests a more nuanced role of the microbiota in arthritis pathogenesis that varies according to the predominant immune mechanisms in disease subtypes. We explore gut-immune interactions in arthritis, highlight ongoing challenges, and propose future research directions.