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 to 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.