Eggerthella lenta augments preclinical autoantibody production and metabolic shift mimicking senescence in arthritis

Abstract

Although the etiology of rheumatoid arthritis (RA) is unknown, a strong genetic predisposition and the presence of preclinical antibodies before the onset of symptoms is documented. An expansion of Eggerthella lenta is associated with severe disease in RA. Here, using a humanized mouse model of collagen-induced arthritis, we determined the impact of E. lenta abundance on RA severity. Naïve mice gavaged with E. lenta produce preclinical rheumatoid factor and, when induced for arthritis, develop severe disease. The augmented antibody response was much higher in female mice, and among patients with RA, women had higher average load of E. lenta . Expansion of E. lenta increased CXCL5 and CD4 T cells, and both interleukin-17– and interferon-γ–producing B cells. Further, E. lenta gavage caused gut dysbiosis and decline in amino acids and nicotinamide adenine dinucleotide with an increase in microbe-dependent bile acids and succinyl carnitine causing systemic senescent-like inflammation.

Causal impact of human blood metabolites and metabolic pathways on serum uric acid and gout: a mendelian randomization study

“…Within the tricarboxylic acid cycle, succinyl coenzyme A undergoes conversion into succinyl carnitine, actively participating in various metabolic pathways. Recent studies have unveiled a correlation between succinyl carnitine levels and systemic inflammatory response as well as heart failure ( 59 , 60 ). Our MR study unequivocally demonstrates a significant causal relationship between succinyl carnitine and elevated SU levels.…”