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Gut dysbiosis and brain microhemorrhages in young vs. aged mice with chronic kidney disease
Yitong Zhao1, Tiffany Tran1, Chuo Fang2
1Department of Medicine, Division of Nephrology, University of California, Irvine, CA, USA.
Abstract:
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.
Insights
Gut dysbiosis in chronic kidney disease (CKD) is linked to vascular injury. This study found that gut toxins, influenced by age and sex, contribute to cerebral microhemorrhages in CKD mice.
Area of Science:
- Nephrology
- Neurology
- Microbiology
Background:
- Intestinal dysbiosis and gut-derived toxins are implicated in vascular injury in chronic kidney disease (CKD).
- The impact of age and sex on these factors and their relation to cerebral microhemorrhages (CMH) in CKD requires further investigation.
Purpose of the Study:
- To examine the relationship between gut dysbiosis, uremic toxins, and CMH in young and aged male and female CKD mice.
- To determine the influence of age and sex on gut microbial alterations and their association with vascular damage in CKD.
Main Methods:
- CKD was induced in young (3 months) and aged (16 months) male and female C57BL/6J mice using a nephrotoxic adenine diet.
- Measurements included serum creatinine, trimethylamine N-oxide (TMAO), indoxyl sulfate (IS), and p-cresyl sulfate (pCS).
- Cerebral microhemorrhages (CMH) were quantified via brain histology, and gut microbiota were analyzed using fecal sequencing.
Main Results:
- CKD mice exhibited elevated creatinine and uremic toxins, with microbial populations altered by age, sex, and CKD status.
- Age significantly impacted microbial variance, with aged CKD mice showing higher IS and pCS levels.
- Aged male CKD mice had the highest burden of CMH, with creatinine, TMAO, and IS correlating with increased CMH in aged animals.
Conclusions:
- Gut dysbiosis in CKD is modulated by age and sex.
- Gut-derived uremic toxins, specifically TMAO and IS, may contribute to vascular injury and CMH development in CKD.
- Age and sex are critical factors influencing the gut-kidney-brain axis in CKD pathophysiology.
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