Lactiplantibacillus plantarum WJL ameliorates chronic kidney disease by inhibiting fibroblast growth factor 21 adaptive stress response via low protein diet.

Low-protein diets (LPD) are recommended in chronic kidney disease (CKD) to reduce disease progression. However, their clinical efficacy and safety are debated due to the risk of protein-energy wasting. A deeper mechanistic understanding is therefore required. Herein, the metabolic effects of LPD in both murine models and a randomized controlled trial in nondiabetic CKD patients were investigated, focusing on glucose homeostasis, plasmatic uremic toxin (UTs) levels, gut microbiota remodeling, and endocrine adaptations. In both experimental and clinical settings, LPD improved glucose tolerance and significantly decreased circulating levels of gut-derived UTs while reducing body weight (-33% weight gain in mice and a decrease in body mass index of ~-0.5 kg/m2 in humans). These metabolic improvements were associated with alterations in gut microbiota composition and function, including the downregulation of microbial pathways involved in aromatic amino acid biosynthesis. In both mice and patients, LPD triggered a significant hepatic induction of fibroblast growth factor 21 (FGF21), an endocrine regulator of amino acid deficiency (+2.9-fold in human and 28-fold in mice) FGF21 levels correlated negatively with lean mass and positively with fat mass and glycemic control, supporting a dual role in metabolic adaptation and catabolic signaling. To mitigate the adverse nutritional effects of LPD, we administered Lactiplantibacillus plantarum WJL (LpWJL), a probiotic previously found to enhance growth of under nutritional stress in CKD mice. LpWJL restored circulating amino acid levels, suppressed FGF21 induction (-26%) and stress-related biosynthetic responses, and preserved body weight (+247% weight gain) and composition, without impairing the benefits of LPD on kidney and metabolic parameters. The present findings identify UTs and FGF21 as crucial factors of the metabolic response to LPD, and support microbiota-targeted strategies, such as LpWJL supplementation, to enhance LPD efficacy. Clinical trials are, however, required to confirm their relevance in CKD management.