Gut microbiota remodeling in HBB-mutant cynomolgus monkeys reveals blood-gut axis disruption associated with β-thalassemia-related gastrointestinal dysfunction

Gastrointestinal symptoms frequently accompany anemia caused by HBB mutations, such as β-thalassemia; however, the mechanisms linking disordered hemoglobin biology to intestinal dysfunction remain incompletely understood. In this study, HBB-mutant cynomolgus monkeys were generated and analyzed together with wild-type (WT) controls through integrated metabolomic and metagenomic profiling. HBB mutation was associated with a marked shift in gut microbial ecology, characterized by reduced microbial diversity and altered abundances of Lactobacillus and Bacteroides. Metabolic profiling revealed broad perturbation of amino acid, lipid, energy, and immune-related metabolic pathways, with 3-oxooctadecanoic acid (HMDB0254633) emerging as a discriminative metabolite between WT and HBB-mutant animals. Multiomics integration indicated that HBB mutation reshaped microbiota-metabolite interactions and may thereby affect host metabolism and immune responses. To examine the functional relevance of this metabolite, 3-oxooctadecanoic acid was administered to C57BL/6 mice with castor oil-induced diarrhea. High-dose treatment alleviated diarrhea severity, improved stool parameters, limited body weight loss, and partially restored gut microbial composition. These findings provide non-human primate evidence that β-thalassemia-associated HBB mutation disrupts intestinal microbiota homeostasis and metabolic output, identifying 3-oxooctadecanoic acid as a candidate biomarker and potential regulator of gastrointestinal dysfunction. This study provides a valuable framework for understanding how host genetic variation contributes to gut microbiome remodeling and gastrointestinal manifestations in β-thalassemia.