Commercial rodent diets differentially regulate autoimmune glomerulonephritis, epigenetics and microbiota in MRL/lpr mice

Abstract

The course and severity of lupus in spontaneous murine lupus models varies among laboratories, which may be due to variations in diet, housing and/or local environmental conditions. In this study, we investigated the influence of common rodent diets while keeping other factors constant. Female lupus-prone MRL/lpr (MRL/MpJ-Faslpr/J) mice were subjected to the same housing conditions and given one of the three diets: Teklad 7013 containing isoflavone-rich soy and alfalfa, Harlan 2018 isoflavone-rich soy-based diet or Research Diets Inc. D11112226 (RD) purified-ingredients diet containing casein and no phytoestrogens. While the total caloric intake was similar among all three treatment groups, mice fed on the 2018 diet developed higher levels of proteinuria and mice fed on either 7013 or 2018 developed higher levels of glomerular immune complex deposition. Remarkably, mice fed the RD diet had markedly decreased proteinuria with diminished C3, total IgG, IgG1 and IgG3 immune complex deposition, along with reduced CD11b+ cellular infiltration into the glomeruli. The type of diet intake also influenced cytokine production, fecal microbiota (increased Lachnospiraceae in mice fed on 2018), altered microRNAs (miRNAs; higher levels of lupus-associated miR-148a and miR-183 in mice fed on 7013 and/or 2018) and altered DNA methylation. This is the first study to comprehensively compare the cellular, molecular and epigenetic effects of these commercial diets in murine lupus.

Gut microbiota differently contributes to intestinal immune phenotype and systemic autoimmune progression in female and male lupus-prone mice

“…It has been suggested that maternal microbiota acquired at young ages could be influenced by the host factors such as hormones and environmental factors and eventually change/mature. In a disease-prone background, these changes could profoundly influence the disease outcome [10,14,15,23,50]. The disease susceptibility and changes/differences in the abundances of microbial communities, including increase in Bacteroidetes abundance and diminished diversity close to disease onset, in lupus-prone males and females are in agreement with previous reports [26,32,51].…”

“…Recent studies that used human samples and rodent models have shown that gut microbiota composition influences the rate of disease progression and the overall disease outcome [9][10][11][12][13]. In addition to direct effects on the systemic and gut immune cell functions, dietary factors can change the composition of gut microbiota and affect autoimmune outcomes [10,14,15]. Recent reports from our laboratory demonstrated that minor dietary deviations such as changes in the pH of drinking water alter the composition of gut microbiota and incidence of SLE as well as type 1 diabetes (T1D) in mouse models [13,16].…”

Low-dose 17α-ethinyl estradiol (EE) exposure exacerbates lupus renal disease and modulates immune responses to TLR7/9 agonists in genetically autoimmune-prone mice

“…In our previous study, the estrogen-free diet formulation used in this study reduced histopathologic changes in kidneys of MRL/lpr mice 49 . It is possible that by using this dietary formulation the severe renal disease in MRL/ lpr mice will be delayed.…”

“…In this study, we developed a relevant model of oral EE exposure that involves the use of a grain-free purified-ingredients diet supplemented with 6.8 ppb of EE, a dose corresponding to a daily human exposure dose of 30 µg of EE. This eliminates unintended exposure to phytoestrogens and other common EEDC contaminants found in grain-based diet formulations 49 . This model also reduces mouse handling and the risks associated with daily oral gavage of chemicals of interest, while retaining the exposure of oral mucosa and microbiota to the EEDC of interest.…”

Abundance and nuclear antigen reactivity of intestinal and fecal Immunoglobulin A in lupus-prone mice at younger ages correlate with the onset of eventual systemic autoimmunity

“…Disproportionate functioning of genes as well as sex hormones, estrogen in particular, contribute to the onset and development of disease activities in SLE 2,[5][6][7][8] . Recent studies that used human samples and rodent models have shown that gut microbiota composition influences the rate of disease progression and the overall disease outcome [9][10][11][12][13][14][15] . We have demonstrated that minor dietary deviations alter the composition of gut microbiota and SLE in a mouse model 13 .…”