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
View: Text | PDF
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

×

Figure 6

Altered microbiota accelerates weight gain in Chst4–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Altered microbiota accelerates weight gain in Chst4–/– mice. (A) Weight ...
(A) Weight gain of WT and Chst4–/– mice treated with antibiotics (Abx) measured for 6 weeks. (B) Total weight of WT and Chst4–/– mice fed an HFD with antibiotics. (C) Adipose tissue weight in WT and Chst4–/– mice (WT n = 7, WT + Abx n = 6, Chst4–/– n = 7, Chst4–/– + Abx n = 7). (D) Representative H&E and Oil Red O staining of liver and adipose tissue from WT and Chst4–/– mice treated with antibiotics. (E) PCoA analysis of ileal bacteria using unweighted UniFrac distance, after 3 weeks of cohousing. (F) PCoA analysis of fecal bacteria using unweighted UniFrac distance, after 3 weeks of cohousing (n = 4). (G) Representative images of 6-week-old WT and Chst4–/– mice fed an HFD in the cohousing experiment. (H) Weight gain measured over 6 weeks of HFD feeding with cohousing. (I) Total weight of WT and Chst4–/– mice. (J) Adipose tissue weight (WT n = 10, WT/cohoused n = 8, Chst4–/– n = 8, Chst4–/–/cohoused n = 8). (K) Representative images of Oil Red O– and H&E-stained liver tissues from WT and Chst4–/– mice after 6 weeks of HFD feeding with cohousing. Scale bars: 200 μm. 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 and H) or 1-way ANOVA (B, C, I, and J). eWAT, epididymal white adipose tissue.