N-acetylglucosamine-6-O-sulfation on intestinal mucins prevents obesity and intestinal inflammation by regulating gut microbiota
Hirohito Abo, Aoi Muraki, Akihito Harusato, Tetsuya Imura, Maki Suzuki, Kohta Takahashi, Timothy L. Denning, Hiroto Kawashima
Hirohito Abo, Aoi Muraki, Akihito Harusato, Tetsuya Imura, Maki Suzuki, Kohta Takahashi, Timothy L. Denning, Hiroto Kawashima
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Research Article Gastroenterology Inflammation

N-acetylglucosamine-6-O-sulfation on intestinal mucins prevents obesity and intestinal inflammation by regulating gut microbiota

Abstract

Intestinal mucins play an essential role in the defense against bacterial invasion and the maintenance of gut microbiota, which is instrumental in the regulation of host immune systems; hence, its dysregulation is a hallmark of metabolic disease and intestinal inflammation. However, the mechanism by which intestinal mucins control the gut microbiota as well as disease phenotypes remains nebulous. Herein, we report that N-acetylglucosamine (GlcNAc)-6-O-sulfation of O-glycans on intestinal mucins performs a protective role against obesity and intestinal inflammation. Chst4–/– mice, lacking GlcNAc-6-O-sulfation of the mucin O-glycans, showed significant weight gain and increased susceptibility to dextran sodium sulfate–induced colitis as well as colitis-associated cancer accompanied by significantly reduced immunoglobulin A (IgA) production caused by an impaired T follicular helper cell–mediated IgA response. Interestingly, the protective effects of GlcNAc-6-O-sulfation against obesity and intestinal inflammation depend on the gut microbiota, evidenced by the modulation of the gut microbiota by cohousing or microbiota transplantation reversing disease phenotypes and IgA production. Collectively, our findings provide insight into the significance of host glycosylation, more specifically GlcNAc-6-O-sulfation on intestinal mucins, in protecting against obesity and intestinal inflammation via regulation of the gut microbiota.

Authors

Hirohito Abo, Aoi Muraki, Akihito Harusato, Tetsuya Imura, Maki Suzuki, Kohta Takahashi, Timothy L. Denning, Hiroto Kawashima

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Figure 2

Chst4–/– mice exhibit low-grade inflammation and increased susceptibility to DSS-induced colitis.

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Chst4–/– mice exhibit low-grade inflammation and increased susceptibili...
(A) Analysis of mucus thickness in the colon of 7-week-old healthy WT and Chst4–/– mice by Carnoy’s fixation (WT n = 7, Chst4–/– n = 6). (B) Immunofluorescent staining of Carnoy’s-fixed colonic tissues for MUC2, MALII, and EUB (n = 15). (C) Expression of Lcn2 and Mpo in the colonic tissue of 7-week-old mice (n = 5). (D and E) Weight change and DAI score of mice administered DSS for 5 days, followed by drinking water for 4 days. (F) Picture of colons from WT and Chst4–/– mice. (G) Colon lengths of mice shown in F. (H) Representative H&E-stained colon section and (I) histology scores (WT n = 10, Chst4–/– n = 8). (J) Expression of inflammatory cytokines (Tnfa, Il1b, Il6, Ifng, Il17a) analyzed using qPCR (n = 5). (K) Representative pictures of colonoids derived from WT and Chst4–/– mice. (L–N) Organoid efficiency, frequency of budding organoids, and surface area of WT and Chst4–/– mice (n = 5). Scale bars: 200 μm (A and H), 50 μm (B), and 100 μm (K). Data are representative of 2 independent experiments, and presented as the mean ± SD. NS, not significant, *P < 0.05, **P < 0.01, ***P < 0.001 via unpaired, 2-tailed t test (A–C, I, J, and L–N) or 2-way ANOVA followed by Tukey’s multiple-comparison test (D and E).