Intestinal Microbiota and Atherosclerosis Risk in Chronic Kidney Disease
Description: Patients with chronic kidney disease (CKD) demonstrate a disproportionate burden of atherosclerosis compared with individuals possessing normal kidney function. Furthermore, a higher prevalence of traditional risk factors for the development of atherosclerosis, such as diabetes and hyperlipidemia, does not fully account for the accelerated atherosclerosis observed in CKD patients, suggesting that unique risk factors must be present in this population. Accumulating evidence suggests that alterations to the intestinal microbiome may play an active role in the development of several comorbidities commonly observed in CKD, including atherosclerosis. As such, several byproducts of intestinal bacteria have been observed to potentiate atherosclerosis formation in animals and associate with atherosclerosis-related clinical outcomes in humans. Among these compounds are lipopolysaccharide (LPS), a bacterial endotoxin produced by Gram-negative bacteria that populate the intestinal lumen, and trimethylamine-N-oxide (TMAO), an organic compound derived from the metabolism of dietary L-carnitine and choline by intestinal bacteria. Interestingly, recent evidence by our group and others suggests that circulating concentrations of both bacterial endotoxin and TMAO increase in early CKD and become substantially elevated in more advanced stages of disease, potentially supporting a role of these compounds to promote the inflammatory phenotype and accelerated atherosclerosis formation that accompanies CKD progression. We hypothesize that byproducts of the intestinal microbiome contribute to accelerated atherosclerosis formation in patients with CKD. In the proposed studies we plan to: (i) define the association between serum LPS and TMAO with atherosclerosis-related endpoints in a large end-stage renal disease (ESRD) cohort (Aim 1); and (ii) determine if short-term oral antibiotic therapy targeting intestinal microbes can lower serum LPS and TMAO concentrations, and reduce pro-inflammatory cytokine levels in CKD patients (Aim 2).
Funder: American Heart Association
Amount: $143,000
Funding type: research
Funder scheme: Grant-in-Aid
Start date: 2015-07-01
End date: 2017-06-30
Investigators: Jason Stubbs, Jason Stubbs
Institution: University of Kansas Medical Center Research Institute, Inc.
Funded outputs count: 1
Funder award ID: 15GRNT25700231
OpenAlex ID: G5044570876