Niaoduqing particles ameliorated tubulointerstitial fibrosis by suppressing IκB/NF-κB signalling pathway via inhibiting host- and gut microbiota-mediated tryptophan co-metabolism.

Tubulointerstitial fibrosis (TIF) is an inevitable outcome of progressive chronic kidney disease (CKD). Niaoduqing particles (NDQ) were developed for the treatment of CKD. However, the molecular mechanisms underlying the effect of NDQ on TIF remain unclear. Fecal gut microbiota (GM) and serum metabolites were analyzed using metagenomics and metabolomics in unilateral ureteral obstruction (UUO)-induced TIF rats. NDQ treatment attenuated UUO-induced TIF in rats in a dose- and time-dependent manner. The increased abundance of eight pathogenic bacteria, including Bacillus wiedmannii, Enterococcus mundtii and Fusobacterium varium, showed strong positive correlations with TID scores, whereas the reduced abundance of two probiotic bacteria, Ruminococcus flavefaciens and Clostridium celatum, showed strong negative correlations with tubulointerstitial damage (TID) scores. NDQ treatment reversed these aberrant microbial alterations, indicating its capacity to remodel GM dysbiosis. TID scores were strongly correlated with host- and GM-mediated tryptophan co-metabolites, including indoxyl sulfate, tryptamine and indole-3-acetic acid, in both TIF- and NDQ-treated TIF rats, and NDQ intervention normalized these metabolic disturbances. Notably, Fusobacterium varium and Enterococcus faecium exhibited strong linear correlations with indoxyl sulfate, indole-3-acetic acid, and indole-3-aldehyde in the TIF rat model. Furthermore, NDQ suppressed IκB/NF-κB signaling pathway in both TIF rats and TGF-β1-induced NRK-52E cells. These inhibitory effects were partially reversed by NF-κB p65 knockdown. This study is the first to demonstrate that NDQ alleviates TIF by reshaping microbial dysbiosis and modulating host- and GM-mediated tryptophan metabolism. These findings support that NDQ mitigates TIF by suppressing IκB/NF-κB signaling pathway through regulation of host-microbiota-derived tryptophan metabolism.