Abstract
Gut commensal microorganisms have been linked with chronic inflammation at the extra-intestinal niche of the body. The object of the study was to investigate on the chronic effects of a gut commensal Escherichia coli on extra-intestinal glands. The presence of autoimmune response was diagnosed by autoantibody levels and histological methods. Repeated injection of E. coli induced mononuclear cell inflammation in the Harderian and submandibular salivary glands of female C57BL/6 mice. Inflammation was reproduced by adoptive transfer of splenocytes to immune-deficient Rag2 knockout mice and CD4+ T cells to mature T cell-deficient TCRβ-TCRδ knockout mice. MALDI TOF mass spectrometry of the protein to which sera of E. coli-treated mice reacted was determined as the outer membrane protein A (OmpA) of E. coli. Multiple genera of the Enterobacteriaceae possessed OmpA with high amino-acid sequence similarities. Repeated injection of recombinant OmpA reproduced mononuclear cell inflammation of the Harderian and salivary glands in mice and elevation of autoantibodies against Sjögren’s-syndrome-related antigens SSA/Ro and SSB/La. The results indicated the possibility of chronic stimuli from commensal bacteria-originated components as a pathogenic factor to elicit extra-intestinal autoimmunity.
Highlights
The structure of the human gut microbiota is established early in life, and thereafter maintains a symbiotic relationship with their host in an anaerobic environment for decades [1,2]
Early colonization of E. coli is indispensable for the development of oral tolerance [7], Enterobacteriaceae constitute only a small fraction of less than 1% of the gut microbiota in healthy adults [8] due to restricted carbohydrate sources that they need for growth, for which they compete with the obligate anaerobe counterparts [9]
To examine whether chronic exposure of bacteria or bacterial cell wall components could induce autoimmunity in mice by systemic immunization, six weeks old mice were treated with E. coli, peptidoglycan (PGN), muramyl dipeptide (MDP), lipoteichoic acid (LTA), lipopolysaccharide (LPS) or phosphate buffered saline (PBS), by intraperitoneal injection once a week for a total of eight weeks
Summary
The structure of the human gut microbiota is established early in life, and thereafter maintains a symbiotic relationship with their host in an anaerobic environment for decades [1,2]. Early colonization of E. coli is indispensable for the development of oral tolerance [7], Enterobacteriaceae constitute only a small fraction of less than 1% of the gut microbiota in healthy adults [8] due to restricted carbohydrate sources that they need for growth, for which they compete with the obligate anaerobe counterparts [9]. OmpA is one of the most abundant proteins expressed at high levels up to 100,000 copies per cell on the outer membrane of Enterobacteriaceae [19] to maintain cell integrity under osmotic stress [20]. The structure of OmpA from E. coli is composed of 325 amino acids consisting of N-terminal 171 residues, which adopt β-barrel domain composed of eight membrane-spanning β-strands [21]. The findings of the present study indicate that chronic stimuli from the outer membrane protein of commensal E. coli may act to trigger inflammatory cell infiltration in the extra-intestinal glands and production of autoantibodies
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