Current Understanding of CHIP’s Immunobiological Footprint with A Focus on Gastrointestinal Disorders: A Review of the Literature

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the age-associated expansion of hematopoietic stem and progenitor cells (HSPCs) bearing somatic mutations in genes such as DNMT3A, TET2, ASXL1, and JAK2, without overt cytopenias or hematologic malignancy. CHIP is increasingly understood as a systemic inflammatory condition that influences extra-hematopoietic organs. Recent findings highlight its role in gastrointestinal (GI) pathology through immune dysregulation, chronic inflammation, and fibrogenic remodeling.

In the liver, CHIP, particularly TET2 and DNMT3A mutations, enhances IL-6 and NLRP3 inflammasome signaling in Kupffer cells, promoting hepatic inflammation, fibrosis, and heightened risk for cirrhosis and hepatocellular carcinoma. In inflammatory bowel disease (IBD), persistent cytokine exposure may select for pro-inflammatory clones, with TET2-mutant CHIP linked to severe disease phenotypes. In colorectal cancer, mutant macrophage and monocyte populations derived from CHIP alter tumor immune microenvironments, affecting tumor progression and therapeutic responsiveness, including checkpoint blockade efficacy.

Together, these findings suggest that hematopoietic clones harboring specific mutations may act as upstream regulators of chronic inflammation and carcinogenesis within the GI tract. This review consolidates gene-specific mechanisms, interactions with the gut-liver immune axis, and implications for targeted interventions linking CHIP with gastrointestinal inflammation, fibrosis, and malignancy.