Abstract
Microbiome composition and function have been implicated as contributing factors in the pathogenesis of autoimmune diseases (ADs), including systemic lupus erythematosus (SLE), rheumatoid arthritis and autoimmune hepatitis (AIH). Furthermore, dysbiosis of gut microbiome is associated with impaired barrier function and mucosal immune dysregulation. However, mechanisms by which gut microbiome contributes to the ADs and whether antioxidant treatment can restore gut homeostasis and ameliorate the disease outcome are not known. This study was, therefore, focused on examining the involvement of gut microbiome and host responses in the pathogenesis of SLE using unique female mouse models (C57BL/6, MRL+/+ and MRL/lpr) of 6 and 18 weeks with varying degrees of disease progression. Fecal microbiome diversity and composition, gut oxidative stress (OS), barrier function and inflammation, as well as systemic autoimmunity were determined. Interestingly, each mouse strain had distinct bacterial community as revealed by β-diversity. A lower Firmicutes/Bacteroidetes ratio in 6-week-old MRL/lpr mice was observed, evidenced by decrease in Peptostreptococcaceae under Firmicutes phylum along with enrichment of Rikenellaceae under Bacteroidetes phylum. Additionally, we observed increases in colonic OS [4-hydroxynonenal (HNE)-adducts and HNE-specific immune complexes], permeability changes (lower tight junction protein ZO-2; increased fecal albumin and IgA levels) and inflammatory responses (increased phos-NF-κB, IL-6 and IgG levels) in 18-week-old MRL/lpr mice. These changes were associated with markedly elevated AD markers (antinuclear and anti-smooth muscle antibodies) along with hepatic portal inflammation and severe glomerulonephritis. Notably, antioxidant N-acetylcysteine treatment influenced the microbial composition (decreased Rikenellaceae; increased Akkeransiaceae, Erysipelotrichaceae and Muribaculaceae) and attenuated the systemic autoimmunity in MRL/lpr mice. Our data thus show that gut microbiome dysbiosis is associated with increased colonic OS, barrier dysfunction, inflammatory responses and systemic autoimmunity markers. These findings apart from delineating a role for gut microbiome dysbiosis, also support the contribution of gut OS, permeability changes and inflammatory responses in the pathogenesis of ADs.
Highlights
Autoimmune diseases (ADs), like various complex systemic inflammatory disorders, are driven by combination of genetic, hormonal and environmental factors
Recent studies suggest association of gut microbiome dysbiosis with ADs, it remains to be established how the microbiotia contribute to systemic lupus erythematosus (SLE)/autoimmune hepatitis (AIH) pathogenesis
Some key perturbations in the gut, including increased oxidative stress (OS), changes in permeability and activation of the mucosal immune system are suggested as few mechanisms that could potentially contribute to the pathogenesis of ADs [2]
Summary
Autoimmune diseases (ADs), like various complex systemic inflammatory disorders, are driven by combination of genetic, hormonal and environmental factors. Emerging evidence suggest that imbalance in the gut microbiome composition (dysbiosis), an important environmental factor, is associated with multiple ADs, including systemic lupus erythematosus (SLE) and autoimmune hepatitis (AIH) [1,2,3,4]. Loss of barrier integrity may promote intestinal inflammation and translocation of bacterial components into the circulatory or lymphatic systems, resulting in systemic immune responses, and leading to SLE/AIH [1, 3]. Mechanisms delineating tight junction regulation of gut permeability and inflammation suggest that posttranslational oxidative modification of proteins could contribute to gut leakiness and eventually disease activity [11,12,13]. Contribution of LDRAs and oxidative modification of proteins in microbiome dysbiosis-mediated mucosal and systemic immune responses remain unclear
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