Enhanced lupus progression in alcohol‐administered Fc gamma receptor‐IIb–deficiency lupus mice, partly through leaky gut‐induced inflammation

Abstract

Alcohol can induce a leaky gut, with translocation of microbial molecules from the gut into the blood circulation. Although the contribution of inflammation to organ‐mediated damage in lupus has been previously demonstrated, the mechanistic roles of alcohol consumption in lupus activation are not known. Herein, we tested the effects of 10‐week lasting alcohol administration on organ damages and immune responses in 8‐week‐old lupus‐prone Fc gamma receptor IIb–deficient (FcγRIIb−/−) mice. Our study endpoints were evaluation of systemic inflammation and assessment of fecal dysbiosis along with endotoxemia. In comparison with alcohol‐administered wild‐type mice, FcγRIIb−/− mice demonstrated more prominent liver damage (enzyme, histological score, apoptosis, malondialdehyde oxidant) and serum interleukin(IL)‐6 levels, despite a similarity in leaky gut (fluorescein isothiocyanate–dextran assay, endotoxemia and gut occludin‐1 immunofluorescence), fecal dysbiosis (microbiome analysis) and endotoxemia. All alcohol‐administered FcγRIIb−/− mice developed lupus‐like characteristics (serum anti‐dsDNA, proteinuria, serum creatinine and kidney injury score) with spleen apoptosis, whereas control FcγRIIb−/− mice showed only a subtle anti‐dsDNA. Both alcohol and lipopolysaccharide (LPS) similarly impaired enterocyte integrity (transepithelial electrical resistance), and only LPS, but not alcohol, upregulated the IL‐8 gene in Caco‐2 cells. In macrophages, alcohol mildly activated supernatant cytokines (tumor necrosis factor‐α and IL‐6), but not M1 polarization–associated genes (IL‐1β and iNOS), whereas LPS prominently induced both parameters (more prominent in FcγRIIb−/− macrophages than wild type). There was no synergy in LPS plus alcohol compared with LPS alone in both enterocytes and macrophages. In conclusion, alcohol might exacerbate lupus‐like activity partly through a profound inflammation from the leaky gut in FcγRIIb−/− mice.

Alterations of the gut microbiota in the lupus nephritis: a systematic review

“…At the phylum level, six (6/15) clinical studies [ 29–32 , 34 , 36 ] found a lower Firmicutes/Bacteroidetes (F/B) ratio in LN patients than in the HCs ( Figure 2 ). Four (4/14) clinical studies [ 32 , 33 , 36 , 37 ] and one (1/7) animal study [ 43 ] found a higher abundance of Proteobacteria in LN patients than in HCs. At the genus level, three (3/14) clinical studies [27, 35 , 39 ] found a higher abundance of Streptococcus in LN patients than in the HCs.…”

“…was found to be higher in the LN group than in the control group in one (1/14) clinical study [ 28 ] and two (2/5) animal studies [ 28 , 41 ], but one (1/7) animal study [ 44 ] found a lower abundance. The genus Lactobacillus and species Lactobacillus reuteri ( L. reuteri ) were mentioned as having changes in abundance in two (2/14) clinical studies [ 32 , 38 ] and three (3/7) animal studies [ 38 , 42 , 43 ]. The results with consistent variation in bacterial abundance were extracted to draw a phylogenetic diagram ( Figure S1 ).…”

“…Two (2/14) clinical studies [ 25 , 34 ] and five (5/7) animal studies [ 38 , 40 , 41 , 43 , 44 ] reported changes in inflammatory markers and intestinal barrier dysfunction markers. In both clinical and animal studies [ 25 , 36 , 44 ], the inflammatory indicator interleukin (IL)-6 was found to be increased in patients with LN but decreased after Lactobacillus treatment [ 40 ].…”