Short-Chain Fatty Acids as Potential Mediators of NSAIDs' Effects on Arthritis Pain Relief

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the preeminent choice for treating osteoarthritis (OA) and have demonstrated the ability to regulate the gut microbiome. This study aims to explore the possibility that pharmacologically modified microbiome plays a role in improvement of arthritis.

Rats with the right knee joint subjected to anterior cruciate ligament transection (ACLT) surgery were randomly allocated to eight groups. Four weeks after the procedure, the rats were given an intervention with saline (NS), celecoxib (CE), diclofenac (DF), and tramadol (TM). The rats were executed after 6 weeks of intervention, serum was used to evaluate the levels of inflammation and pain-related factors (IL-1β, IL-6, TNF-α, LPS, CGRP, and NGF), rat joints were used to assess local inflammation in the joints (MyD88) and the effect of the drug on the cartilage (Micro CT, Safranin O-Fast Green stain), Von Frey fibrous filaments were used to assess the sensation of pain in rats, and the differences in feces for the gut microbiome and short-chain fatty acids (SCFAs) were compared by 16S rRNA sequencing and gas chromatographic analyses.

Rats treated with CE, DF, and TM experienced significant relief from joint pain, but the analgesic effect of CE and DF was significantly weakened after the combined application of antibiotics, while the effect of TM on pain remained after the application of antibiotics. The expression of MyD88 in the articular cartilage was somewhat reduced by CE and DF. Additionally, the gas analysis showed a significant increase in the SCFA content in the feces of the drug-intervention group.

NSAID-induced changes in gut microbiota structure and the subsequent increase in SCFA production may contribute to their pain-alleviating effects in rats. Although to a lesser extent, NSAIDs can also slightly reduce localized inflammation in the joints.