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 3

Loss of GlcNAc-6-O-sulfation on mucins exacerbates colitis-associated cancer.

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Loss of GlcNAc-6-O-sulfation on mucins exacerbates colitis-associated ca...
(A) Weight change of WT and Chst4–/– mice treated with AOM/DSS. (B) Representative pictures of mouse colons. (C) Number of tumors in WT and Chst4–/– mice. (D–F) Tumor surface area (n = 8). (G) Representative pictures of H&E-stained colonic tissue from AOM/DSS–treated WT and Chst4–/– mice. (H) Immunofluorescent staining for Ki-67. (I) Expression of chemokines related to MDSC infiltration (n = 6–8). (J) Representative FACS plot of monocyte-derived MDSCs among lamina propria cells isolated from colonic tissue. (K) Frequency and cell number shown in J. (L) Representative FACS plot of granulocyte-derived MDSCs among lamina propria cells isolated from colonic tissue. (M) Frequency and cell number shown in L (n = 4). (N) Immunofluorescent staining of colonic tissues with anti–Gr-1 antibody. (O) The mRNA expression of Arg1, Nos2, and Cybb in colonic tumor and normal tissue (n = 6–8). (P) Representative images of human colonic tissue stained with Alcian blue on the left and tissue stained for MUC2 on the right. The square area is shown at higher magnification. (Q) Alcian blue intensity normalized to MUC2 staining (healthy n = 9, UC n = 10, adenoma n = 7). Scale bars: 200 μm (G, H, and N), 100 μm (P, left and middle columns), and 50 μm (P, right column). Data are representative of 2 independent experiments, and presented as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 via 2-way ANOVA followed by Tukey’s multiple-comparison test (A), unpaired, 2-tailed t test (C–F, K, and M), or 1-way ANOVA (I, O, and Q).