Gut microbiota_Low protein diet_CKD_Mice and human

Low-protein diets (LPD) are recommended in chronic kidney disease (CKD) to reduce disease progression. However, their clinical efficacy and safety is 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 non-diabetic CKD patients was investigated, focusing on glucose homeostasis, 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. 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 robust hepatic induction of fibroblast growth factor 21 (FGF21), an endocrine regulator of amino acid deficiency. 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 (LpWJL), a probiotic previously found to enhance growth under nutritional stress in CKD mice. LpWJL restored circulating amino acid levels, suppressed FGF21 induction and stress-related biosynthetic responses, and preserved body weight 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.