Lactiplantibacillus plantarum WJL ameliorates CKD by inhibiting FGF21 adaptive stress response during low-protein diet

Patients with Chronic Kidney Disease (CKD) are often prescribed low-protein diets (LPDs) to slow disease progression. However, the long-term efficacy and safety of LPDs are debated due to the significant risk of protein-energy wasting, which can lead to malnutrition and poor outcomes. A deeper mechanistic understanding is crucial to optimize LPD strategies and mitigate these adverse effects. This research explores the metabolic adaptations to LPDs, focusing on uremic toxins (UTs) and the endocrine regulator fibroblast growth factor 21 (FGF21), which is induced by amino acid deficiency.

Researchers investigated the metabolic effects of LPDs in both murine models and a randomized controlled trial in nondiabetic CKD patients. The study focused on glucose homeostasis, plasmatic uremic toxin (UTs) levels, gut microbiota remodeling, and endocrine adaptations. To counteract LPD's adverse nutritional effects, a subgroup received Lactiplantibacillus plantarum WJL (LpWJL) supplementation. Key endpoints included body weight, body composition, FGF21 levels, and kidney parameters. Gut microbiota composition and function were analyzed to understand microbial pathway alterations.

In both murine models and human CKD patients, LPDs significantly improved glucose tolerance and decreased circulating levels of gut-derived UTs. LPD also reduced body weight, with -33% weight gain in mice and a decrease in body mass index of approximately -0.5 kg/m2 in humans. These metabolic improvements correlated with changes in gut microbiota composition and function, including downregulation of microbial pathways for aromatic amino acid biosynthesis. LPD triggered a significant hepatic induction of FGF21, an endocrine regulator of amino acid deficiency, by +2.9-fold in humans and +28-fold in mice. FGF21 levels negatively correlated with lean mass and positively with fat mass and glycemic control. > Lactiplantibacillus plantarum WJL supplementation restored circulating amino acid levels, suppressed FGF21 induction by -26%, and preserved body weight (+247% weight gain in mice) and composition, all without compromising LPD's benefits on kidney and metabolic parameters.