Gut dysbiosis and brain microhemorrhages in young vs. aged mice with chronic kidney disease

Intestinal dysbiosis and gut-derived toxins in chronic kidney diseases (CKD) are associated with vascular injury. This study examined the relationship between gut dysbiosis and cerebral microhemorrhages (CMH) in young and aged CKD mice (3 vs. 16 months of age) in both sexes. CKD was induced in C57BL/6J mice using a nephrotoxic adenine diet. Serum creatinine, trimethylamine N-oxide (TMAO), indoxyl sulfate (IS) and p-cresyl sulfate (pCS) were measured. CMH was quantified via brain histology, and gut microbial sequencing was analyzed from fecal pellets. Creatinine and uremic toxins were elevated in both young and aged CKD mice compared with controls, and microbial populations were altered by age, sex and CKD status. Age was the most significant factor in microbial variance, with higher levels of IS and pCS in aged CKD mice. Aged male mice had significantly higher creatinine, TMAO and IS than aged females. Males had higher CMH counts than females, and aged CKD males had the highest CMH burden. Age modified the relationship between uremic toxins and CMH burden, with creatinine, TMAO and IS correlating with increased CMH in aged animals. In conclusion, gut dysbiosis in CKD is modulated by sex and age, and gut-derived uremic toxins including TMAO and IS may contribute to vascular injury and CMH development.