The organic anion transporter-1 (OAT1), located at the basal side of kidney proximal tubule cells, plays a crucial role in metabolic waste excretion. In chronic kidney disease (CKD), the progressive decline in renal function leads to the accumulation of endogenous metabolites in the bloodstream, exacerbating comorbidities. CKD also leads to gut dysbiosis, increasing the production of uremic metabolites and reducing the production of nephroprotective short chain fatty acids (SCFAs), such as acetate, propionate and butyrate, thereby contributing to disease progression. This study investigates the potential of SCFAs to enhance kidney function by modulating OAT1 activity and facilitating the secretion of uremic toxins. Our findings demonstrate that propionate and butyrate significantly enhance OAT1 activity by upregulating SLC22A6/OAT1 gene and protein expression. Butyrate exposure, in particular, enhances the secretion of the uremic toxin indoxyl sulfate (IS) to the luminal compartment in our kidney-on-chip (KoC) system. Notably, SCFAs exert their effect independently of G-protein coupled receptor (GPCR) activation, instead inhibiting gene expression of class II histone deacetylases (HDACs). Transcriptome analysis suggests that this inhibition modulates cyclic adenosine monophosphate (cAMP) signaling pathway, activating CREB1 and PI3K gene expression, both implicated in cell metabolism and resilience against stress, thereby enhancing cellular fitness. These findings highlight the therapeutic potential of SCFAs in enhancing proximal tubule secretory activity, emphasizing their value as nutritional interventions in CKD management.