Marked intestinal trans-differentiation by autoimmune gastritis along with ectopic pancreatic and pulmonary trans-differentiation

Chihiro Takeuchi, Junichi Sato, Nobutake Yamamichi, Natsuko Kageyama-Yahara, Akiko Sasaki, Takemi Akahane, Rika Aoki, Shigemi Nakajima, Masayoshi Ito, Mitsue Yamamichi, Yu Yu Liu, Nobuyuki Sakuma, Yu Takahashi, Yoshiki Sakaguchi, Yosuke Tsuji, Kouhei Sakurai, Shuta Tomida, Keiko Niimi, Toshikazu Ushijima, Mitsuhiro Fujishiro

Research output: Contribution to journalArticlepeer-review


Background: Autoimmune gastritis (AIG) is a prevalent chronic inflammatory disease with oncogenic potential that causes destruction of parietal cells and severe mucosal atrophy. We aimed to explore the distinctive gene expression profiles, activated signaling pathways, and their underlying mechanisms. Methods: A comprehensive gene expression analysis was conducted using biopsy specimens from AIG, Helicobacter pylori-associated gastritis (HPG), and non-inflammatory normal stomachs. Gastric cancer cell lines were cultured under acidic (pH 6.5) conditions to evaluate changes in gene expression. Results: Gastric mucosa with AIG had a unique gene expression profile compared with that with HPG and normal mucosa, such as extensively low expression of ATP4A and high expression of GAST and PAPPA2, which are involved in neuroendocrine tumorigenesis. Additionally, the mucosa with AIG and HPG showed the downregulation of stomach-specific genes and upregulation of small intestine-specific genes; however, intestinal trans-differentiation was much more prominent in AIG samples, likely in a CDX-dependent manner. Furthermore, AIG induced ectopic expression of pancreatic digestion-related genes, PNLIP, CEL, CTRB1, and CTRC; and a master regulator gene of the lung, NKX2-1/TTF1 with alveolar fluid secretion-related genes, SFTPB and SFTPC. Mechanistically, acidic conditions led to the downregulation of master regulator and stemness control genes of small intestine, suggesting that increased environmental pH may cause abnormal intestinal differentiation in the stomach. Conclusions: AIG induces diverse trans-differentiation in the gastric mucosa, characterized by the transactivation of genes specific to the small intestine, pancreas, and lung. Increased environmental pH owing to AIG may cause abnormal differentiation of the gastric mucosa.

Original languageEnglish
Pages (from-to)95-108
Number of pages14
JournalJournal of Gastroenterology
Issue number2
Publication statusPublished - 02-2024

All Science Journal Classification (ASJC) codes

  • Gastroenterology


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