TLR7 activation impairs gut barrier in lupus-prone mice in association with an expansion of Ruminococcus gnavus, a pathobiont that exacerbates lupus pathology

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Presentation Time: 02:15 PM - 03:30 PM
Poster Board Number: B112
Abstract ID: 5165

Presenting Author:
Natalie Six , Graduate Research Assistant at UT Hlth. San Antonio

Abstract:

Gut microbial dysbiosis and loss of intestinal barrier integrity (“leaky gut”) are two common manifestations of lupus in humans and mouse models. TLR7 activation, which occurs in lupus, has been associated with leaky gut in lupus mice. However, the mechanism by which this process occurs is currently unknown. We have shown that lupus-prone B6.Sle1.Sle2.Sle3 triple congenic (TC) mice treated with R848, a TLR7 agonist, developed leaky gut and a marked increase in plasma cells relative to untreated controls. However, neither non-autoimmune B6 nor TC.Rag2^-/- mice treated with R848 developed leaky gut, indicating that both lupus susceptibility genes and lymphocytes are required. The frequency of Ruminococcus gnavus (Rg), a gut pathobiont associated with disease flares in lupus patients, was increased by R848 in TC mice with a strong correlation to loss of barrier integrity. We monocolonized B6 mice treated with R848 as well as B6.Sle1 and Sle1.Yaa (a TLR7 transgenic model) mice with Rg. While both the B6.Sle1 and Sle1.Yaa cohorts were successfully monocolonized, only the Sle1.Yaa mice sustained a high level of Rg over time, suggesting that TLR7 signaling in combination with the Sle1 susceptibility locus can promote Rg overgrowth and associated leaky gut. Our results demonstrate that TLR7 signaling in lupus-prone mice can alter the gut microbial composition, which may directly, or in combination, with the induced changes in the adaptive immune response alter gut barrier integrity.