A4gnt, encoding α1,4-N-acetylglucosaminyl transferase, is responsible for the biosynthesis of α1,4-linked N-acetylglucosamine residues at the terminus of O-glycans attached to a core protein of gastric gland mucin [3,6]. These O-glycans play roles in various biological processes, potentially related to the establishment and homeostasis of the gastric microbiome and preventing gastric diseases [3]. Gene knockout mouse models have been crucial in studying A4gnt's functions.

A4gnt knockout (KO) mice spontaneously develop gastric adenocarcinoma [1,2,3,4,5,6,7]. A4gnt/Chst4 double-knockout (DKO) mice, lacking gastric sulfomucins, experience severe gastric erosion as early as 3 weeks old, followed by gastritis cystica profunda (GCP) with aging. This shows that sulfomucins, related to A4gnt, prevent severe gastric erosion and GCP by transiently regulating inflammation-related genes like Cxcl1, Cxcl5, Ccl2, and Cxcr2 at 5 weeks of age [1]. In A4gnt KO mice, the gastric microbiome is altered, with increased relative abundance of mutagenic Desulfovibrio and proinflammatory Prevotellamassilia, especially 4 weeks after birth, and decreased functions associated with polysaccharide metabolism and transportation [3].

In conclusion, A4gnt is essential for the biosynthesis of specific O-glycans in gastric gland mucin. Studies using A4gnt KO and DKO mouse models have revealed its role in preventing gastric diseases such as severe gastric erosion, GCP, and potentially gastric cancer, likely through its impact on the gastric microbiome and regulation of inflammation-related genes [1,3].

References:

1. Kawakubo, Masatomo, Komura, Hitomi, Goso, Yukinobu, Fukuda, Minoru, Nakayama, Jun. 2019. Analysis of A4gnt Knockout Mice Reveals an Essential Role for Gastric Sulfomucins in Preventing Gastritis Cystica Profunda. In The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society, 67, 759-770. doi:10.1369/0022155419860134. https://pubmed.ncbi.nlm.nih.gov/31246144/

2. Arai, Junya, Hayakawa, Yoku, Tateno, Hiroaki, Wang, Timothy C, Fujishiro, Mitsuhiro. 2024. Impaired Glycosylation of Gastric Mucins Drives Gastric Tumorigenesis and Serves as a Novel Therapeutic Target. In Gastroenterology, 167, 505-521.e19. doi:10.1053/j.gastro.2024.03.037. https://pubmed.ncbi.nlm.nih.gov/38583723/

3. Gong, Dawei, Gao, Yuqiang, Shi, Rui, Wang, Lili, Dong, Quanjiang. 2025. The gastric microbiome altered by A4GNT deficiency in mice. In Frontiers in microbiology, 16, 1541800. doi:10.3389/fmicb.2025.1541800. https://pubmed.ncbi.nlm.nih.gov/40012782/

4. Iida, Masataka, Desamero, Mark Joseph, Yasuda, Kosuke, Kakuta, Shigeru, Hirayama, Kazuhiro. 2021. Effects of orally administered Euglena gracilis and its reserve polysaccharide, paramylon, on gastric dysplasia in A4gnt knockout mice. In Scientific reports, 11, 13640. doi:10.1038/s41598-021-92013-5. https://pubmed.ncbi.nlm.nih.gov/34210998/

5. Desamero, Mark Joseph, Kakuta, Shigeru, Chambers, James Kenn, Nakayama, Hiroyuki, Kyuwa, Shigeru. 2018. Orally administered brown seaweed-derived β-glucan effectively restrained development of gastric dysplasia in A4gnt KO mice that spontaneously develop gastric adenocarcinoma. In International immunopharmacology, 60, 211-220. doi:10.1016/j.intimp.2018.05.002. https://pubmed.ncbi.nlm.nih.gov/29763881/

6. Karasawa, Fumitoshi, Shiota, Akira, Goso, Yukinobu, Ishihara, Kazuhiko, Nakayama, Jun. 2012. Essential role of gastric gland mucin in preventing gastric cancer in mice. In The Journal of clinical investigation, 122, 923-34. doi:10.1172/JCI59087. https://pubmed.ncbi.nlm.nih.gov/22307328/

7. Yamanoi, Kazuhiro, Nakayama, Jun. 2018. Reduced αGlcNAc glycosylation on gastric gland mucin is a biomarker of malignant potential for gastric cancer, Barrett's adenocarcinoma, and pancreatic cancer. In Histochemistry and cell biology, 149, 569-575. doi:10.1007/s00418-018-1667-8. https://pubmed.ncbi.nlm.nih.gov/29658052/