Dietary choline, via gut microbe- generated trimethylamine-N- oxide, aggravates chronic kidney disease-induced cardiac dysfunction by inhibiting hypoxia-induced factor 1α

Abstract

Chronic kidney disease (CKD) is a global public health problem that shortens lifespan primarily by increasing the risk of cardiovascular diseases. Trimethylamine-N-oxide (TMAO), a gut microbiota-derived toxin produced by metabolizing high-choline or carnitine foods, is associated with cardiovascular events in patients with CKD. Although the deleterious effect of TMAO on CKD-induced cardiac injury has been confirmed by various researches, the mechanisms remain unclear. Here, we tested the hypothesis that TMAO aggravates CKD-induced cardiac injury and explores the potential mechanism. CD1 mice underwent 5/6 nephrectomy to induce CKD, and then fed with a diet supplemented with choline (1.2% total) for 8 weeks. Serum TMAO levels were elevated in CKD mice compared with SHAM group, and higher TMAO levels were found in choline-supplemented CKD mice compared with CKD group. Dietary choline aggravated CKD-induced cardiac dysfunction, and reducing TMAO levels via medicinal charcoal tablets improved cardiac dysfunction. RNA-seq analysis revealed that dietary choline affected cardiac angiogenesis in CKD mice. Reduced cardiac capillary density and expressions of angiogenesis-related genes were observed in choline-treated CKD mice. Furthermore, dietary choline inhibited cardiac Hif-1α protein level in CKD mice, and Hif-1α stabilizer FG-4592 could improve cardiac angiogenesis and dysfunction in CKD mice on a high-choline diet. In conclusion, these data indicate that dietary choline, via gut microbe-generated TMAO, inhibits cardiac angiogenesis by reducing Hif-1α protein level, ultimately aggravates cardiac dysfunction in CKD mice.

From heart failure and kidney dysfunction to cardiorenal syndrome: TMAO may be a bridge

“…In addition, giving CKD mice a choline diet can inhibit the protein levels of Hif-1α in the hearts of CKD mice, and the Hif-1α stabilizer FG-4592 can improve heart vascular development and functional impairment in CKD mice fed a high-choline diet. These data suggest that TMAO inhibits cardiac vascular development by reducing Hif-1α protein levels, ultimately exacerbating heart dysfunction in CKD mice (Xie et al, 2022). TMAO has established connections with both heart and kidney failure through both known and unknown pathways.…”

The Interplay Between Dietary Choline and Cardiometabolic Disorders: A Review of Current Evidence

“…More specifically, they documented that increased choline intake via a decrease in the release of HIF-1α may lead to ischemic cardiac disease in a mouse model of CKD-induced CVD [ 79 ]. In ischemic heart disease, angiogenesis plays a crucial role [ 80 , 81 ]. The generation of new vessels in the heart through the release of compounds, such as HIF-1α, HIF-2α, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and angiopoieitin-2, is cardioprotective [ 82 ].…”

Trimetilamīna N-oksīda regulācija kardiometabolo slimību ārstēšanā. Promocijas darba kopsavilkums

“…Lai arī ir zināms, ka TMAO renālais klīrenss pasliktinās līdz ar nieru funkcijas samazināšanos(Zeisel and Warrier, 2017), pašlaik nav skaidru pierādījumu, kas norādītu uz to, ka TMAO izraisa vai veicina hronisku nieru slimību (HNS). Lielākā daļa preklīnisko pētījumu, kas veikti dzīvnieku modeļos, lai pētītu paaugstinātas TMAO koncentrācijas efektus, izmanto paaugstinātu TMAO prekursoru uzņemšanu, kas prasa obligātu zarnu mikrobioma metabolismu(Tang et al, 2015;Gupta et al, 2020;Xie et al, 2022).Līdz ar to šie pētījumi nevar sniegt skaidrus pierādījumus par tiešu TMAO iesaisti HNS progresēšanā. Turklāt jāuzsver, ka paaugstināti TMAO līmeņi KVS pacientiem var būt saistīti ar sākotnēju nieru funkcijas pasliktināšanos, jo vairāki pētījumi ir identificējuši nieru funkciju kā ietekmējošo faktoru (Tang et al, 2015; Kim et al, 2016).…”