Gut microbiota alterations are associated with phenotype and genotype in familial Mediterranean fever.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease associated with MEFV mutations. Disease phenotype and response to treatment vary from one patient to another despite similar genotype suggesting the role of environmental factors. We analyze the gut microbiota of a large cohort of FMF patients in relation to disease characteristics. The gut microbiota of 119 FMF patients and 61 healthy controls was analyzed using 16 s rRNA gene sequencing. Associations between bacterial taxa, clinical characteristics and genotypes were evaluated using multivariable association with linear models (MaAslin2) adjusting on age, sex, genotype, presence of AA amyloidosis (n = 17), hepatopathy (n = 5), colchicine intake, colchicine resistance (n = 27), use of biotherapy (n = 10), CRP levels, and number of daily feces. Bacterial network structures were also analysed. The gut microbiota of FMF patients differs from controls, with an increase in pro-inflammatory bacteria, such as Enterobacter, Klebsiella and Ruminococcus gnavus group. Disease characteristics and resistance to colchicine correlated with homozygous mutations and were associated with specific microbiota alteration. Colchicine treatment was associated with the expansion of anti-inflammatory taxa such as Faecalibacterium and Roseburia, while FMF severity was associated with the expansion of Ruminococcus gnavus group and Paracoccus. Colchicine-resistant patients exhibited an alteration of the bacterial network structure with decreased inter-taxa connectivity. The gut microbiota of FMF patients correlates with disease characteristics and severity, with an increase in pro-inflammatory taxa in the most severe patients. This suggests a specific role for the gut microbiota in shaping FMF outcomes and response to treatment.

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