Gut-Derived Protein-Bound Uremic Toxins

Abstract

Chronic kidney disease (CKD) afflicts more than 500 million people worldwide and is one of the fastest growing global causes of mortality. When glomerular filtration rate begins to fall, uremic toxins accumulate in the serum and significantly increase the risk of death from cardiovascular disease and other causes. Several of the most harmful uremic toxins are produced by the gut microbiota. Furthermore, many such toxins are protein-bound and are therefore recalcitrant to removal by dialysis. We review the derivation and pathological mechanisms of gut-derived, protein-bound uremic toxins (PBUTs). We further outline the emerging relationship between kidney disease and gut dysbiosis, including the bacterial taxa altered, the regulation of microbial uremic toxin-producing genes, and their downstream physiological and neurological consequences. Finally, we discuss gut-targeted therapeutic strategies employed to reduce PBUTs. We conclude that targeting the gut microbiota is a promising approach for the treatment of CKD by blocking the serum accumulation of PBUTs that cannot be eliminated by dialysis.

Keywords: gut-kidney axis; intestinal microbiota; protein-bound uremic toxins.

Figure 1

Gut-Derived Protein-Bound Uremic Toxins. Blue text: human enzymes, red text: microbial enzymes, purple text: both human and microbial enzymes. AGE, advanced glycation end product; CYP450, cytochrome P450; FAT, phenylalanine dehydrogenase or transaminase; feaB, phenylacetaldehyde dehydrogenase; GUS, beta-glucuronidase; IaaH, indole-3-acetamide hydrolase; IaaM, tryptophan 2-monooxygenase; MAT, methionine adenosyltransferase; PPDC, phenylpyruvate decarboxylase; SAHH, s-adenosylhomocysteine hydrolase; SULT, sulfotransferase; ThiH, tyrosine lyase; TPase, tryptophanase; TPL, tyrosine phenol-lyase; UGT, UDP-glucuronosyltransferase.

Figure 2

The gut–kidney axis. Impaired kidney function and other CKD-related causes lead to uremic toxin accumulation and gut dysbiosis, which then furthers gut-derived uremic toxin accumulation and subsequent systemic damage.