Gut-derived trimethylamine N-oxide promotes CCR2-mediated macrophage infiltration in acute kidney injury

Apr 8, 2024Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

Gut-produced trimethylamine N-oxide may increase immune cell entry into the kidney during acute injury

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Abstract

A choline-rich diet increased TMAO levels and exacerbated renal injury in mice with induced acute kidney injury.

Elevated TMAO levels were linked to increased inflammation and fibrosis following renal ischaemia-reperfusion injury.
A specific subset of CCR2+ macrophages was identified as significant responders to TMAO, enhancing immune cell interactions in the kidney.
Sustained CCR2 expression after renal injury was associated with increased macrophage infiltration.
Targeting CCR2 through deletion or the use of an antagonist improved TMAO-related inflammation and kidney damage.

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BACKGROUND: Inflammation is crucial in the development of acute kidney injury (AKI) and subsequent chronic kidney disease (CKD) following renal ischaemia-reperfusion (IR) injury. Gut microbiota metabolites trigger inflammation and affect IR-induced renal damage. Yet the driving factors and mechanisms are unclear. Trimethylamine N-oxide (TMAO), a gut-derived choline metabolite, is a strong pro-inflammatory factor that increases in patients with AKI and CKD. We hypothesized that TMAO can promote renal injury caused by IR.

METHODS: Mice subjected to unilateral renal IR to induce AKI and CKD were fed a high-choline diet to observe the effects of TMAO on kidney inflammation, fibrosis and macrophage dynamics.

RESULTS: A choline-rich diet altered the gut microbiota and elevated TMAO levels, exacerbating IR-induced AKI and subsequent CKD. Single-cell analysis identified a distinct subset of CCR2+ macrophages derived from monocytes as key responders to TMAO, intensifying immune cell interactions and worsening renal injury. TMAO promoted sustained CCR2 expression after IR, increasing macrophage infiltration. CCR2 deletion and antagonist RS-102895 improved TMAO-induced inflammation and fibrosis and alleviated renal injury induced by IR.

CONCLUSIONS: Our study provides valuable insights into the link between TMAO and IR-induced renal inflammation and fibrosis, emphasizing the critical role of TMAO-mediated macrophage infiltration via CCR2 as a key therapeutic target in the acute and chronic phases after IR.

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Gut-derived trimethylamine N-oxide promotes CCR2-mediated macrophage infiltration in acute kidney injury

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