Gut Microbiota Was Reshaped in Bate-thalassemia Monkeys via the Blood-Gut Axis and Contributed to Gastrointestinal Symptoms

Patients with anemia caused by hemoglobin Bate (HBB) gene mutations, such as Bate- thalassemia, are often present with gastrointestinal symptoms, the underlying mechanisms remain incompletely understood. In this study, we utilized gene editing to create HBB-mutant cynomolgus monkeys and employed metagenomic and metabolomic analyses to investigate the differences in gut microbiome characteristics between HBB gene-edited cynomolgus monkeys and wild-type (WT) cynomolgus monkeys. Ultra performance liquid chromatography-mass spectrometry (UPLC-MS) analysis revealed significant differences in the metabolite profiles between WT and the HBB mutants, particularly in the amino acid and lipid metabolism pathways. Metagenomic analysis demonstrated significant differences in the abundance of Lactobacillus and Bacteroides genera between the two groups, with the HBB mutants exhibiting a lower microbial diversity. Further functional analysis indicated that gene knockout significantly altered several key metabolic pathways, including amino acid and energy metabolism. These integrated findings suggest that HBB mutants potentially affect host metabolism and immune responses by modulating interactions between the gut microbiota and its metabolites. This study, for the first time, demonstrates in non-human primates that Bate- thalassemia can influence gastrointestinal health by altering the homeostasis of the gut microbiota, and offers valuable references for understanding the potential mechanisms underlying Bate-thalassemia symptoms, highlighting the impact of host genetic variations on gut microbiome regulation.