Interplay between gut microbiota, bone health and vascular calcification in chronic kidney disease

Abstract

Deregulations in gut microbiota may play a role in vascular and bone disease in chronic kidney disease (CKD). As glomerular filtration rate declines, the colon becomes more important as a site of excretion of urea and uric acid, and an increased bacterial proteolytic fermentation alters the gut microbial balance. A diet with limited amounts of fibre, as well as certain medications (eg phosphate binders, iron supplementation, antibiotics) further contribute to changes in gut microbiota composition among CKD patients. At the same time, both vascular calcification and bone disease are common in patients with advanced kidney disease. This narrative review describes emerging evidence on gut dysbiosis, vascular calcification, bone demineralization and their interrelationship termed the 'gut-bone-vascular axis' in progressive CKD. The role of diet, gut microbial metabolites (ie indoxyl sulphate, p-cresyl sulphate, trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFA)), vitamin K deficiency, inflammatory cytokines and their impact on both bone health and vascular calcification are discussed. This framework may open up novel preventive and therapeutic approaches targeting the microbiome in an attempt to improve cardiovascular and bone health in CKD.

Keywords: bone; chronic kidney disease; gut microbiota; vascular calcification.

FIGURE 1

The uraemic milieu is one of the main contributors for gut dysbiosis in CKD. As renal function declines, the colon replaces the kidney as the primary site of excretion of urea and uric acid, which become alternative substrates for the gut bacteria, instead of indigestible complex carbohydrates. Besides, renal diet (limited intake of fibre‐rich foods, eg fruits and vegetables) and polypharmacy (ie phosphate binders, antibiotics, iron supplementation, PPI, immunosuppressants) may account for altered gut dysbiosis in CKD setting. The hypothesis upon gut‐vascular‐bone axis in CKD revolves around the augmented exposure of the referred tissues to uremic toxins, such as indoxyl sulphate (IS) and p‐cresyl sulphate (P‐CS), TMAO (Trimethylamine‐N‐oxide) and pro‐inflammatory cytokines given the presence of a disrupted intestinal barrier. In addition, the reduced production of SCFA (short‐chain fatty acids) and the deficiency of vitamin K might also exacerbate this mechanism