Microbe-derived uremic solutes enhance thrombosis potential in the host

0580216 - FGÚ 2024 RIV US eng J - Journal Article
Nemet, I. - Funabashi, M. - Li, X. S. - Dwidar, M. - Sangwan, N. - Skye, S. M. - Romano, K. A. - Čajka, Tomáš - Needham, B. D. - Mazmanian, S. K. - Hajjar, A. M. - Rey, F. E. - Fiehn, O. - Tang, W.H.W. - Fischbach, M. A. - Hazen, S.L.
Microbe-derived uremic solutes enhance thrombosis potential in the host.
mBio. Roč. 14, č. 6 (2023), č. článku e0133123. ISSN 2161-2129. E-ISSN 2150-7511
Institutional support: RVO:67985823
Keywords : gut microbes * uremic toxins * p-cresol sulfate * indoxyl sulfate * cardiovascular disease * mortality
OECD category: Cardiac and Cardiovascular systems
Impact factor: 6.4, year: 2022
Method of publishing: Open access
https://doi.org/10.1128/mbio.01331-23

p-Cresol sulfate (pCS) and indoxyl sulfate (IS), gut microbiome-derived metabolites, are traditionally associated with cardiovascular disease (CVD) risks in the setting of impaired kidney function. While pharmacologic provision of pCS or IS can promote pro-thrombotic phenotypes, neither the microbial enzymes involved nor direct gut microbial production have been linked to CVD. Untargeted metabolomics was performed on a discovery cohort (n = 1,149) with relatively preserved kidney function, followed by stable isotope-dilution mass spectrometry quantification of pCS and IS in an independent validation cohort (n = 3,954). Genetic engineering of human commensals to produce p-cresol and indole gain-of-function and loss-of-function mutants, followed by colonization of germ-free mice, and studies on host thrombosis were performed. Systemic pCS and IS levels were independently associated with all-cause mortality. Both in vitro and within colonized germ-free mice p-cresol productions were recapitulated by collaboration of two organisms: a Bacteroides strain that converts tyrosine to 4-hydroxyphenylacetate, and a Clostridium strain that decarboxylates 4-hydroxyphenylacetate to p-cresol. We then engineered a single organism, Bacteroides thetaiotaomicron, to produce p-cresol, indole, or both metabolites. Colonizing germ-free mice with engineered strains, we show the gut microbial genes for p-cresol (hpdBCA) and indole (tryptophanase) are sufficient to confer a pro-thrombotic phenotype in vivo. Moreover, human fecal metagenomics analyses show that abundances of hpdBCA and tryptophanase are associated with CVD. These studies show that pCS and IS, two abundant microbiome-derived metabolites, play a broader potential role in CVD than was previously known. They also suggest that therapeutic targeting of gut microbial p-cresol- and indole-producing pathways represent rational targets for CVD.
Permanent Link: https://hdl.handle.net/11104/0348968