Histamine Signaling Is Essential for Tissue Macrophage Differentiation and Suppression of Bacterial Overgrowth in the Stomach

Role of histamine-mediated macrophage differentiation in clearance of metastatic bacterial infection

“…The stomach is in a highly acidic condition due to the secretion of gastric acid by parietal cells ( 30 ). Our previous study suggested that histamine signal deficiency results in chronic inflammation of the stomach and hypertrophic gastropathy, and these effects were largely attributed to the consequent loss of the phagocytic activity of stomach-specific macrophages ( 31 ). Therefore, we hypothesized that histamine signal deficiency alters the function and phenotype of the PM population.…”

Beyond Regulation of Acid Secretion: A Novel Role for Histamine in Gastric Macrophage Differentiation and Function

“…Development of hypertrophic gastropathy in the HDC-KO model was thought to be caused by histamine regulating both parietal cell acid secretion and gastric epithelial cell growth and lineage differentiation. 3 However, in an interesting new study published in this edition of Cellular and Molecular Gastroenterology and Hepatology , Kim et al 5 demonstrate that vastly more complex pathways and feedback loops involving the bone marrow, peripheral immune mechanisms, the gastric microbiome, and gastric epithelial cells lead to hypertrophic gastropathy upon histamine deficiency.…”

“…Kim et al 5 observed that, in addition to the morphologic and functional changes to the gastric epithelium, HDC-KO mice developed severe gastric bacterial overgrowth and inflammatory changes to the gastric mucosa with a significant long-term increase in gastric macrophages. Importantly, hyperplastic gastropathy did not occur in germ-free HDC-KO mice, indicating a central role for the gastric microbiota in the regulation of epithelial cell growth and differentiation.…”

“…In functional experiments, gastric macrophages from the HDC-KO mice showed significantly decreased phagocytosis, associated with a reduced expression of complement receptors (CD21/35). Kim et al 5 then used a highly creative experimental approach to differentiate between the role of parietal cells versus macrophages in gastric dysbiosis. In the HDC-KO mice, all bacteria were eliminated using antibiotics, the stomach was acidified through drinking water, and then the HDC-KO mice were gavaged with bacteria from wild-type mice.…”

“…Notably, a previous H pylori infection study found milder cytokine responses and reduced gastric pathology in HDC-KO mice compared with wild-type mice infected at 6 to 8 weeks of age. 10 However, most changes in the study by Kim et al 5 required 12 months to develop. Future research also is needed to determine whether hyperplastic gastropathy in human Ménétrier disease involves histamine deficiency, macrophage dysfunction, or gastric dysbiosis.…”