Abstract
Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide and a key-model to illustrate dysregulation of innate immunity, etiologically determined by pathogenic variants in the MEFV gene, encoding pyrin, leading to uncontrolled interleukin-1β and interleukin-18 release. Despite its genetic basis, FMF shows marked clinical heterogeneity in all-aged patients, mostly in children, suggesting a role of potential environmental modifiers which are far to be exactly unraveled. Recent medical literature has increasingly illuminated the importance of gut microbiota in maintaining overall health and immune functions, and its contribution has been claimed also to explain both FMF inflammatory activity and heterogeneous disease expression. This narrative review summarizes current evidence on the interaction between gut microbiota and FMF, with a specific focus on differences between children and adults. Pediatric studies dedicated to FMF have reported intestinal dysbiosis in terms of reduced microbial diversity and depletion of short-chain fatty acid-producing bacteria, with subsequent enrichment of pro-inflammatory taxa: such alteration could modulate pyrin-inflammasome activation and contribute to systemic inflammation, disease phenotype, and response to colchicine or to other drugs specifically used in colchicine-resistant FMF. Geographic and lifestyle factors may shape intestinal microbiota composition early in life, reinforcing the relevance of gut flora and confirming its activity as a crucial tessera to determine FMF sceneries, mostly in children, and a potential target for future add-on therapeutic strategies. In addition, colchicine therapy appears to partially remodel the gut microbiome, empowering a local beneficial anti-inflammatory microbial profile.