Sterile triggers drive joint inflammation in TNF‐ and IL‐1β‐dependent mouse arthritis models

Arthritis is the most common extra‐intestinal complication in inflammatory bowel disease (IBD). Conversely, arthritis patients are at risk for developing IBD and often display subclinical gut inflammation. These observations suggest a shared disease etiology, commonly termed “the gut‐joint‐axis.” The clinical association between gut and joint inflammation is further supported by the success of common therapeutic strategies and microbiota dysbiosis in both conditions. Most data, however, support a correlative relationship between gut and joint inflammation, while causative evidence is lacking. Using two independent transgenic mouse arthritis models, either TNF‐ or IL‐1β dependent, we demonstrate that arthritis develops independently of the microbiota and intestinal inflammation, since both lines develop full‐blown articular inflammation under germ‐free conditions. In contrast, TNF‐driven gut inflammation is fully rescued in germ‐free conditions, indicating that the microbiota is driving TNF‐induced gut inflammation. Together, our study demonstrates that although common inflammatory pathways may drive both gut and joint inflammation, the molecular triggers initiating such pathways are distinct in these tissues.