Aberrant Gut Microbiome Contributes to Intestinal Oxidative Stress, Barrier Dysfunction, Inflammation and Systemic Autoimmune Responses in MRL/lpr Mice

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.

Biomarkers and Utility of the Antioxidant Potential of Probiotic Lactobacilli and Bifidobacteria as Representatives of the Human Gut Microbiota

“…OS contributes significantly to dysbiosis by reducing the microbial diversity of the gut microbiota [47,48]. The gut microbiota can regulate redox signaling and redox homeostasis in the host [49].…”

Gut Microbiota Dysbiosis in Systemic Lupus Erythematosus: Novel Insights into Mechanisms and Promising Therapeutic Strategies

“…Most notably, leaky gut promotes the production of anti-dsDNA autoantibodies and immune complex deposition, ultimately leading to lupus exacerbation. Recently, another study indicated that impaired intestinal barrier function is associated with intestinal oxidative stress in MRL/lpr lupus mice ( 44 ). This result further complements the mechanism involved in the development of the leaky gut in lupus mice.…”

Medicinal Plant Extracts and Natural Compounds for the Treatment of Cutaneous Lupus Erythematosus: A Systematic Review

“…Studies show that microbiome composition and function have effects on the pathogenesis of autoimmune diseases (ADs). Wang et al examined the role of the gut microbiome and host responses in SLE pathogenesis using female C57BL/6, MRL +/+ , and MRL/lpr mouse models with varying levels of disease progression ( Wang H. et al, 2021 ). The researchers found that N-acetylcysteine treatment decreased the Rikenellaceae population; increased the population of Akkeransiaceae, Erysipelotrichaceae, and Muribaculaceae; and improved Turibaculaceae attenuation.…”

“…The researchers found that N-acetylcysteine treatment decreased the Rikenellaceae population; increased the population of Akkeransiaceae, Erysipelotrichaceae, and Muribaculaceae; and improved Turibaculaceae attenuation. This increase in gut microbiota dysbiosis was linked to an increase in the oxidative stress of the gut, barrier dysfunction, inflammatory responses, and systemic autoimmunity ( Wang H. et al, 2021 ). The skin microbiota is not well-studied, though one study has reported increased Staphylococcus aureus in CLE lesions ( Sirobhushanam et al, 2019 ).…”